TW202529813A - Dosage of antibody drug conjugate rinatabart sesutecan - Google Patents

Abstract

The present invention relates to a method of treating solid tumor by administering to a human subject an antibody-drug conjugate (ADC) comprising an antibody to FOLR1 conjugated via a hydrophilic linker to exatecan. The ADC is administered at a dosage of between 40 mg/m2 and 200 mg/m2. In one embodiment, the ADC is conjugate rinatabart sesutecan (Rina-S). When administered at specified dosages and schedules, the ADC can reduce tumors size and is effective to treat cancers resistant to standard therapies, such as radiation therapy, chemotherapy or immunotherapy. The ADC may be used in combination with other anti-cancer drugs.

Description

Dosage of the Antibody-Drug Conjugate RINATABART SEQUTECAN

The present invention generally relates to dosing schedules of antibody-drug conjugates (ADCs) for use in human subjects. In particular, the present invention relates to dosing schedules of the ADC rinatabart sesutecan (Rina-S) for use in treating cancer (such as solid tumors) in human subjects. The present invention also relates to the dosing schedules of these ADCs. The present invention also relates to combination therapies in which the ADC is used in combination with another anticancer agent.

Folate receptor 1 (FOLR1), also known as folate receptor-α (FRα) or folate binding protein (FBP), is an N-glycosylated protein expressed on the plasma membrane of cells. FOLR1 is overexpressed in the vast majority of ovarian cancers, as well as many uterine, endometrial, pancreatic, renal, lung, and breast cancers. In normal tissues, FOLR1 expression is restricted to the apical membrane of epithelial cells in the proximal tubules of the kidney, alveolar pneumocytes of the lung, bladder, testis, choroidal plexus, and thyroid (Weitman SD, et al., Cancer Res 52: 3396-3401 (1992); Antony A C, Annu Rev Nutr 16: 501-521 (1996); Kalli K R, et al. Gynecol Oncol 108: 619-626 (2008)). The antibody-drug conjugate (ADC), rinatabart sesutecan (Rina-S; previously known as PRO1184), was developed to target FOLR1 and comprises a FOLR1 antibody and a drug unit, each of which comprises exatecan linked to the antibody via a hydrophilic linker. Rina-S has been shown to induce cytotoxicity in cancer cells in vitro and in vivo and exhibit anti-tumor activity. However, there remains a need for effective methods of administering Rina-S to human subjects. Preferably, such methods comprise optimized dosing and administration schedules that maximize the efficacy and minimize the toxicity of Rina-S in therapeutically useful human subjects. There is also a need for combination therapies for treating FOLR1-positive cancers.

In one aspect, the present invention provides a method for treating a solid tumor, comprising administering to a human subject having the solid tumor an antibody-drug conjugate (ADC) having the characteristics recited herein, wherein the ADC comprises an antibody against FOLR1 conjugated to the anticancer drug exetitecan via a hydrophilic linker. In any of the embodiments described herein, the ADC may be Rina-S.

Provided herein are methods and dosing schedules for administering Rina-S to human subjects undergoing treatment for cancer, such as, but not limited to, solid tumors.

In one aspect, the present invention provides a method for treating a solid tumor that is positive for folate receptor 1 (FOLR1), the method comprising administering to a human subject having the solid tumor an antibody-drug conjugate (ADC), wherein the ADC has the following structure (Structure 1): wherein the Ab is an antibody that binds to FOLR1 and comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH and VL regions have the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8, and wherein the ADC is administered at a dose of between 40 mg/m ² and 200 mg/m ² (e.g., between 60 mg/m ² and 140 mg/m ² ). In certain embodiments, the human subject suffers from ovarian cancer. In certain embodiments, the human subject suffers from endometrial cancer. In one aspect, the present invention provides a method for treating a human subject suffering from cancer, including a FOLR1-positive solid tumor, comprising administering to the subject an ADC having structure 1, wherein the Ab is an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH and VL regions have the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8, and wherein the ADC is administered at a dose of between 40 mg/m ² and 200 mg/m ² (e.g., between 60 mg/m ² and 140 mg/m ² ). In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is endometrial cancer. In certain embodiments, the ADC is administered at a dose of 100 mg/m ^2. In certain embodiments, the ADC is administered at a dose of 120 mg/m ^2. In certain embodiments, the ADC is administered once every three weeks. In certain embodiments, the ADC has the structure of Structure 1, wherein Ab is an antibody comprising a heavy chain (HC) and a light chain (LC), wherein the HC and LC have the amino acid sequences of SEQ ID NO: 6 and SEQ ID NO: 5, respectively, and wherein n is 8. In certain embodiments, the HC and LC have the amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 5, respectively. In certain embodiments, the ADC has the structure of Structure 1, wherein Ab is an antibody comprising two HCs and two LCs, each of the two HCs having the amino acid sequence set forth in SEQ ID NO: 6, each of the two LCs having the amino acid sequence set forth in SEQ ID NO: 5, and wherein n is 8. In certain embodiments, each of the two HCs having the amino acid sequence set forth in SEQ ID NO: 4, and each of the two LCs having the amino acid sequence set forth in SEQ ID NO: 5.

One aspect of the present invention relates to a method for treating a solid tumor, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having the solid tumor, wherein the ADC is administered at a dose of between 40 mg/ ^m2 and 200 mg/ ^m2 , and the solid tumor is folate receptor 1 (FOLR1)-positive.

In some embodiments of the present invention, the solid tumor is selected from the group consisting of ovarian cancer, endometrial cancer, breast cancer, lung cancer, and mesothelioma. In certain embodiments, the solid tumor is ovarian cancer. In certain embodiments, the solid tumor is platinum-resistant ovarian cancer (PROC). In certain embodiments, the solid tumor is platinum-sensitive ovarian cancer (PSOC). In certain embodiments, the solid tumor is epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In certain embodiments, the solid tumor is endometrial cancer. In certain embodiments, the solid tumor is non-small cell lung cancer (NSCLC). In certain embodiments, the solid tumor is breast cancer, including HER2-negative breast cancer. In certain embodiments, the solid tumor is pleural mesothelioma or peritoneal mesothelioma. In certain embodiments, the solid tumor is localized or metastatic.

In some embodiments, another aspect of the invention relates to treatment with the ADC Rina-S, wherein the ADC is administered at a dose of between 60 mg/ ^m2 and 180 mg/ ^m2 . In certain embodiments, the ADC is administered at a dose of 140 mg/ ^m2 . In certain embodiments, the ADC is administered at a dose of between 100 mg/ ^m2 and 140 mg/ ^m2 . In certain embodiments, the ADC is administered at a dose of between 100 mg/ ^m2 and 120 mg/ ^m2 . In certain embodiments, the ADC is administered at a dose of about 100 mg/ ^m2 . In certain embodiments, the ADC is administered at a dose of about 120 mg/ ^m2 .

Another aspect of the present invention relates to a dosing schedule for the ADC Rina-S, wherein the ADC is administered to the human subject once or twice weekly according to a schedule having a cycle selected from the group consisting of: (i) weekly; (ii) every other week; (iii) one week of treatment followed by two, three, or four weeks of rest; (iv) two weeks of treatment followed by one, two, three, or four weeks of rest; (v) three weeks of treatment followed by one, two, three, four, or five weeks of rest; (vi) four weeks of treatment followed by one, two, three, four, or five weeks of rest; (vii) five weeks of treatment followed by one, two, three, four, or five weeks of rest; and (viii) monthly. In certain embodiments, the ADC dose is administered to the human subject once weekly according to a schedule having a cycle selected from the group consisting of: (i) weekly; (ii) every other week; or (iii) one week of treatment followed by two, three, or four weeks of rest. In certain embodiments, the ADC dose is administered to the human subject on day one of a 21-day treatment cycle. In certain embodiments, the ADC dose is administered to the human subject as a 30-minute intravenous (IV) infusion.

In certain embodiments, the ADC is administered to the human subject in a cycle consisting of: (i) once a week, two weeks on, two, three, or four weeks off; (ii) once a week, three weeks on, two, three, or four weeks off; (iii) once a week, four weeks on, two, three, or four weeks off; (iv) once every other week, four weeks on, two, three, or four weeks off; (v) once a week, five weeks on, two, three, or four weeks off.

In some embodiments, the ADC dose is administered to the human subject once every three weeks. In some embodiments, the dose is 120 mg/m ² . In some embodiments, the ADC dose is administered as an intravenous infusion.

In another aspect of the invention, the treatment is repeated for 2, 4, 6, 8, 10, 12, 16, or 20 cycles. In one embodiment, the treatment is continued as needed. In certain embodiments, the treatment is continued, for example, even though the individual demonstrates tumor size reduction or tumor size stabilization (e.g., according to RECIST v1.1 criteria) and/or duration of objective response (DOR), overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and/or overall survival. For example, treatment with the ADC can be continued until disease progression or unacceptable toxicity occurs.

In another aspect of the present invention, the human subject has previously received at least one anticancer therapy. In some embodiments, the human subject has previously received one to four anticancer therapies. In some embodiments, the at least one anticancer therapy comprises treatment with a chemotherapy agent. In some embodiments, the at least one anticancer therapy comprises treatment with at least one anticancer therapy selected from the group consisting of platinum chemotherapy, bevacizumab, a poly ADP-ribose polymerase (PARP) inhibitor, and mirvetuximab soravtansine. In certain embodiments, the human subject failed to respond to the at least one anticancer therapy prior to treatment with the ADC. In some embodiments, the human subject has been previously treated with sutomicin. In some embodiments, the human subject is not suitable for treatment with sutomicin.

In another aspect of the invention, the treatment with the ADC Rina-S results in a reduction in solid tumor size of at least 15%, at least 20%, at least 30%, at least 40%, or at least 50%.

In yet another aspect of the invention, the ADC is administered in combination with one or more therapeutic modalities selected from the group consisting of unconjugated antibodies, radiolabeled antibodies, drug-conjugated antibodies, toxin-conjugated antibodies, gene therapy, chemotherapy, therapeutic peptides, cytokine therapy, oligonucleotides, localized radiation therapy, surgery, and interfering RNA therapy.

In yet another aspect of the present invention, treatment with the ADC Rina-S improves the individual's outcome. In some embodiments, the improved treatment outcome is an objective response selected from stable disease, partial response, or complete response. In certain embodiments, the improved treatment outcome is reduced tumor burden. In certain embodiments, the improved treatment outcome is progression-free survival or disease-free survival. In certain embodiments, the improved treatment outcome is improved overall survival.

It has been demonstrated herein that treatment with the ADC Rina-S provides clinical benefit to patients with tumors across the full spectrum of FOLR1 expression, thereby raising the possibility of treating patients with Rina-S regardless of pre-treatment established FOLR1 expression. Thus, in another aspect, the present invention provides for the use of Rina-S to treat a human subject having a solid tumor in which FOLR1 expression has not been determined. In certain embodiments, the human subject has ovarian cancer. In certain embodiments, the human subject has been pre-treated with other anti-cancer therapies, e.g., with at least one, two, three, four, or more lines of therapy. In certain embodiments, the human subject is treated with Rina-S at a dose level of 100 mg/ ^m² . In some embodiments, the human subject is treated with Rina-S at a dose level of 120 mg/m ^2. In some embodiments, the dose is administered to the human subject approximately once every three weeks (Q3W). In some embodiments, the Rina-S is administered intravenously, for example, by intravenous infusion.

In yet another aspect, the present invention provides combination therapies for individuals with solid tumors, including methods of combination therapy comprising administering to the individual Rina-S in combination with any of the following: a platinum-containing chemotherapy, an anti-angiogenic agent, a PARP inhibitor, or a checkpoint inhibitor. In one embodiment, the combination therapy comprises Rina-S in combination with a platinum-containing chemotherapy (e.g., carboplatin, cisplatin, or oxaliplatin). In one embodiment, the combination therapy comprises Rina-S in combination with an anti-angiogenic agent (e.g., an anti-VEGF antibody, such as bevacizumab). In one embodiment, the combination therapy comprises Rina-S in combination with a PARP inhibitor, such as olaparib or niraparib. In one embodiment, the combination therapy comprises a combination of Rina-S and a checkpoint inhibitor, such as an inhibitor of the PD-1 or PD-L1 immune checkpoint protein, such as an anti-PD1 antibody (e.g., pembrolizumab, nivolumab, cemiplimab, dostarlimab, retinfanlimab, toripalimab, etc.), or an anti-PD-L1 antibody (e.g., atezolizumab, avelumab, durvalumab, etc.). In certain embodiments, the subject is treated with Rina-S at a dose level of 100 mg/m ^2. In certain embodiments, the subject is treated with Rina-S at a dose level of 120 mg/m ^2. In certain embodiments, the dose is administered to the subject approximately once every three weeks (Q3W). In certain embodiments, the Rina-S is administered intravenously. The dosage and administration regimen of another therapy in the combination of the present invention is in accordance with the approved labeling for the other corresponding therapy.

Thus, the present invention provides various methods for treating cancer by administering Rina-S to a subject, optionally in combination with other anticancer drugs, as described in the above and below aspects. In alternative aspects, the present invention also provides Rina-S for use in treating cancer according to the various aspects of the treatment methods of the present invention, optionally in combination with other anticancer drugs. In other alternative aspects, the present invention also provides Rina-S for use in manufacturing a medicament for treating cancer according to the various aspects of the treatment methods of the present invention, optionally in combination with other anticancer drugs. In a further aspect, the present invention further provides a medicament for treating cancer, comprising Rina-S as an active agent, optionally in combination with other anticancer drugs. When a treatment method is disclosed herein, the present invention also provides a corresponding product for use in the method, and the use of the product in the manufacture of a medicament for use in the described method, and vice versa.

In embodiments described herein where two drugs are said to be administered in combination, the drugs can be administered, for example, simultaneously, separately, or sequentially. In one embodiment, administration in combination may mean that both drugs are administered in the provided methods. The drugs can be administered in the same pharmaceutical composition. Alternatively, the drugs can be administered in separate compositions. In the regimens described herein for administering Rina-S, any other drug can be administered at the same time point, but in separate compositions. In other embodiments, Rina-S and the second drug can be administered in the same composition. In further embodiments, Rina-S can be administered in the regimens described herein for Rina-S, but the second drug is administered in a separate regimen for itself.

Additional features will be set forth to a certain extent in the description that follows, and those skilled in the art will perceive these features to a certain extent after careful study of the following disclosure and the accompanying drawings, or may learn these features by making or operating the embodiments. The features of the present invention may be realized and obtained by practicing or using various aspects of the methods, means, and combinations set forth in the detailed embodiments discussed below.

The following description is presented to enable any person skilled in the art to make and use the invention and is provided in the context of a specific application and its requirements. Those skilled in the art will readily appreciate various modifications to the disclosed embodiments, and the general principles defined herein may be applied to other embodiments and applications without departing from the spirit and scope of the invention. Therefore, the invention is not limited to the embodiments shown but is to be accorded the widest scope consistent with the scope of the claimed invention.

The terminology used herein is for describing specific exemplary embodiments only and is not intended to be limiting. Unless the context clearly indicates otherwise, as used herein, the singular forms "a," "an," and "the" may be intended to include the plural forms as well. It should be further understood that when used in this patent specification, the terms "comprises," "include," "includes," and/or "comprising" specifically specify the presence of recited features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

These and other characteristics and features of the present invention, as well as the methods of operation and the functions of the elements of the related structure, and the assembly and manufacturing economies of the parts, will become more apparent upon consideration of the following description with reference to the accompanying drawings, which form a part of this specification. However, it should be expressly understood that the drawings are for illustration and description purposes only and are not intended to limit the scope of the present invention. It should be understood that the drawings are not drawn to scale.

For convenience, certain terms used in the patent specification, examples, and claims are defined herein. Unless otherwise stated or implied from the context, the following terms and expressions have the meanings provided below. These definitions are provided to assist in describing specific embodiments and are not intended to limit the invention of the claims, as the scope of the invention is limited solely by the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, and unless otherwise specified, the terms "a" and "an" are deemed to mean "one," "at least one," or "one or more." Unless otherwise required by context, as used herein, singular terms shall include pluralities and plural terms shall include the singular.

Unless the context clearly requires otherwise, throughout this specification and claims, the words "comprising," "including," and the like should be interpreted as having an inclusive meaning, as opposed to an exclusive or exhaustive meaning; that is, meaning "including, but not limited to." When "comprising," "including," or similar words are used to describe an embodiment, the present invention also provides embodiments that "consist essentially of (the specified subject matter)." The present invention also provides embodiments that "consist of (the specified subject matter)."

The terms "reduced," "reduction," "reduction," "reduction," "reduction," and "inhibit" are generally used herein to refer to a reduction by a statistically significant amount relative to a reference.

As used herein, the terms "increased," "increase," "enhance," or "activate" generally refer to an increase by a statistically significant amount relative to a reference.

For example, the term "approximately" may allow for variations of up to 10% of the specification. In some embodiments, it may allow for variations of up to 5%. In some embodiments, it may allow for variations of up to 2%. In some embodiments, it may allow for variations of up to 1%. In some embodiments, when the term "approximately" is used, embodiments with the correct specification are also provided.

As used herein, the terms "protein" and "polypeptide" are used interchangeably to refer to a series of amino acid residues, each of which is linked to one another by peptide bonds between the α-amine and carboxyl groups of adjacent residues. The terms "protein" and "polypeptide" also refer to polymers of amino acids, including modified amino acids (e.g., phosphorylated, glycated, glycosylated, etc.) and amino acid analogs, regardless of their size or function. "Protein" and "polypeptide" are generally used to refer to relatively large polypeptides, while the term "peptide" is generally used to refer to small polypeptides, but the usage of these terms in this art overlaps. When referring to encoded gene products and fragments thereof, the terms "protein" and "polypeptide" are used interchangeably herein. Thus, exemplary polypeptides or proteins include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments, and equivalents, variants, fragments, and analogs of the foregoing.

FOLR1 (or folate receptor α) is a cell surface protein that binds to folic acid and reduced folate derivatives and mediates the delivery of 5-methyltetrahydrofolate and folate analogs into cells. It is also known as FRα, adult folate binding protein, FBP, folate receptor 1, adult folate receptor, KB cell FBP, and ovarian tumor-associated antigen MOv18. Human FOLR1 polypeptides include, but are not limited to, those having the amino acid sequence represented by UniProt identifier P15328-1; this sequence is incorporated herein by reference.

Antibody-drug conjugates (ADCs) comprise an antibody conjugated to a drug. The antibody and drug can be conjugated via any suitable means. The antibody and drug can be conjugated via a linker. Alternatively, the antibody and drug can be conjugated directly to each other. The ADCs discussed herein comprise an anticancer drug as the drug portion of the ADC. Antibodies and Antibody - Drug Conjugates (ADCs)

In one embodiment, the present invention provides a method for treating a solid tumor, comprising administering to a human subject having the tumor an antibody-drug conjugate (ADC) having the characteristics described herein, wherein the ADC comprises an antibody directed against FOLR1 conjugated to the drug exetitecan via a hydrophilic linker, wherein the ADC is administered at a dose of between 40 mg/ ^m2 and 200 mg/ ^m2 . In certain embodiments, the dose is between 60 mg/ ^m2 and 140 mg/ ^m2 . In certain embodiments, the dose is 100 mg/ ^m2 . In certain embodiments, the dose is 120 mg/ ^m2 . In any of the embodiments described herein, the tumor can be a solid tumor. In any of the embodiments described herein, the ADC employed may be Rina-S as described in detail herein. As used herein, the term "Rina-S" encompasses the embodiments of the ADC described herein, including biosimilars of Rina-S.

As used herein, Rinatabart sesutecan (Rina-S; sometimes also referred to as PRO1184) is an antibody-drug conjugate (ADC) comprising an antibody against FOLR1 and a sesutecan drug unit, each drug unit linked to the antibody via a hydrophilic linker. In certain embodiments, Rina-S has the following structure (Structure 1): , wherein Ab is an antibody that binds to FOLR1 and comprises a heavy chain and a light chain, the heavy chain comprising three CDRs having the amino acid sequence of the three CDRs as set forth in SEQ ID NO: 1 (each CDR is underlined in the sequence shown below), and the light chain comprising three CDRs having the amino acid sequence of SEQ ID NO: 2 (each CDR is underlined in the sequence shown below). In certain embodiments, the Ab is an antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region having the amino acid sequence of SEQ ID NO: 2. In certain embodiments, the Ab is an IgG1 antibody. In certain embodiments, the Ab is an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO:6 (or, optionally, further comprising an additional C-terminal lysine (K), i.e., a heavy chain having the amino acid sequence of SEQ ID NO:4), and a light chain having the amino acid sequence of SEQ ID NO:5. In Structure 1, n is ^pload , which is the average drug loading (e.g., drug to antibody ratio; or DAR). In certain embodiments, n is 8.

In some embodiments, the ADC comprises an antibody component comprising an Fc domain or region having one or more amino acid substitutions that reduce IgG Fc receptor (FcγR) binding (compared to an IgG1 constant region having the amino acid sequence set forth in SEQ ID NO:3), such as substitutions at positions 234 and 235 (EU numbering of residues) of the Fc region. In some embodiments, the substitutions are L234A and L235A (LALA) according to EU numbering according to Kabat. In some substituted forms, the Fc domain may comprise D265A and/or P329G according to EU numbering according to Kabat in an Fc region derived from a human IgG1 Fc region. In certain embodiments, the substitutions are L234A, L235A, and P329G (LALA-PG) according to EU numbering according to Kabat in the Fc region derived from a human IgG1 Fc region. (See, e.g., WO 2012/130831). In certain embodiments, the substitutions are L234A, L235A, and D265A (LALA-DA) according to EU numbering according to Kabat in the Fc region derived from a human IgG1 Fc region. In certain embodiments, the Ab comprises a light chain constant region of the kappa isotype.

In some embodiments, the ADC is a biosimilar to Rina-S. As used herein, the term "biosimilar" (e.g., a biosimilar to an approved reference product/biologic) refers to a biological product that is similar to the reference product based on data from the following studies: (a) analytical studies demonstrating that the biological product and the reference product are highly similar, despite minor differences in clinically inactive components; (b) animal studies (including toxicity assessments); and/or (c) clinical studies (including immunogenicity and pharmacokinetic or pharmacodynamic assessments) that adequately demonstrate the safety, purity, and efficacy of the reference product under one or more appropriate conditions of use for which it is approved and intended for use and for which approval is sought (e.g., there are no clinically significant differences between the biological product and the reference product with respect to the safety, purity, and efficacy of the product). In some embodiments, the biosimilar biological product and the reference product employ the same mechanism of action under the conditions of use specified, recommended, or suggested in the proposed labeling, but only within the scope of the known mechanism of action of the reference product. In some embodiments, the conditions of use specified, recommended, or suggested in the proposed labeling for the biological product have been previously approved for the reference product. In some embodiments, the route of administration, dosage form, and/or potency of the biological product are the same as those of the reference product. A biosimilar can be, for example, a currently known antibody that has the same primary amino acid sequence as a marketed antibody, but which may be prepared in a different cell type or by a different production, purification, or formulation method. Biosimilar ADCs are typically highly similar in structure to the reference product, including the antibody portion, cytotoxic payload, and linker, but may be produced through slightly different manufacturing processes.

SEQ ID NO: 1 F131 VH amino acid sequence (wherein the three CDRs are indicated by underlining): SEQ ID NO: 2 F131 VL amino acid sequence (wherein the three CDRs are indicated by underlining): SEQ ID NO: 3 Human IgG1 heavy chain constant region UniProt P01857-1: SEQ ID NO: 4 F131 heavy chain amino acid sequence (including C-terminal K): SEQ ID NO: 5 F131 light chain amino acid sequence: SEQ ID NO: 6 F131 heavy chain amino acid sequence (without C-terminal K):

In some embodiments, the heavy chain of the Rina-S antibody component described herein does not contain a C-terminal lysine at the C-terminus of the CH3 region (i.e., corresponding to the C-terminal lysine at position 453 of SEQ ID NO: 4 or the C-terminal lysine at position 330 of SEQ ID NO: 3). The heavy chain of SEQ ID NO: 4 without the C-terminal lysine is provided as SEQ ID NO: 6. For example, the C-terminal lysine can be removed by engineering the heavy chain to lack the C-terminal lysine, or by removing the C-terminal lysine (e.g., using a carboxypeptidase, e.g., during antibody production or processing). Thus, in some embodiments, the heavy chain of the Rina-S antibody component has the amino acid sequence of SEQ ID NO: 6. In any aspect and embodiment of the invention, the heavy chain of the antibody component may thus comprise SEQ ID NO: 6 or SEQ ID NO: 4.

In some embodiments, the antibody component of Rina-S is the F131 antibody of PCT application WO/2022/217022. WO/2022/217022 is incorporated by reference in its entirety. Specific incorporation of WO/2022/217022 also relates to the antibodies disclosed therein, particularly F131 and related antibodies.

In some embodiments, the average DAR (drug-to-antibody ratio) of the Rina-S is about 8. In some embodiments, the average DAR of the Rina-S is 8.

In various embodiments, the present invention relates to using the ADCs provided herein to treat cancer. In some embodiments, the ADC comprises an antibody or antibody fragment comprising VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 1 and SEQ ID NO: 2. The ADC comprises a drug unit (exitecan). The ADC comprises a linker that connects the drug unit to the antibody or antibody fragment. In certain embodiments, the linker comprises a polar unit having the following structure (Structure 2):

In some embodiments, the linker is derived from a linker compound having the following structure (Structure 3): wherein the H on the benzyl OH is optionally substituted by a bond to one of the drug units (ixitencan).

In some embodiments, the ADCs of the present invention have an average DAR of about 4, about 6, or about 8. In some embodiments, the ADCs have an average DAR of about 8.

In various embodiments, the present invention relates to the use of Rina-S, or the ADCs noted above, or other ADCs disclosed in PCT applications WO2023280227 and WO2022217022 for the treatment of cancer. Both WO2023280227 and WO2022217022 are incorporated herein by reference in their entirety, particularly with respect to Rina-S and ADCs.

In any of the embodiments presented herein, the preferred ADC is Rina-S or a biosimilar thereof. In a particularly preferred embodiment, Rina-S (or a biosimilar thereof) has the following structure: , wherein Ab is an antibody comprising a heavy chain and a light chain, the heavy chain and the light chain having the amino acid sequences shown in SEQ ID NO: 6 and SEQ ID NO: 5, respectively, and wherein n is 8. In one embodiment, the Ab has two heavy chains of said SEQ ID NO: 6 and two light chains of said SEQ ID NO: 5. In certain embodiments, Rina-S may comprise the heavy chain sequence shown in SEQ ID NO: 4 to replace the heavy chain sequence shown in SEQ ID NO: 6 (i.e., having an additional C-terminal lysine). In certain embodiments, Rina-S (or a biosimilar thereof) is formulated into a pharmaceutical composition that can be administered to an individual according to the present invention, and the pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, excipients and/or diluents. Patients and cancer types

In various embodiments, the present invention relates to methods for treating cancer (such as, but not limited to, solid tumors) comprising administering the ADC Rina-S to a human subject, wherein the ADC is administered at a dose of between 40 mg/m ² and 200 mg/m ^2. Here, "m ² " (square meters) is a measure of the patient's body surface area (BSA).

In some embodiments, the methods of the present invention can be used to treat a solid tumor. In some embodiments, the individual has multiple solid tumors. In some embodiments, the individual has multiple solid tumors because the cancer has metastasized. In some embodiments, the solid tumor is a primary tumor. In some embodiments, the solid tumor is a secondary tumor. In some embodiments, the individual has multiple solid tumors, both primary and secondary. In certain embodiments, the solid tumor is present in a human individual with a cancer selected from the group consisting of ovarian cancer, endometrial cancer, breast cancer, lung cancer, and mesothelioma. In certain embodiments, the solid tumor is ovarian cancer. In certain embodiments, the solid tumor is platinum-resistant ovarian cancer (PROC). In certain embodiments, the solid tumor is platinum-sensitive ovarian cancer (PSOC). In certain embodiments, the solid tumor may be epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In certain embodiments, the solid tumor may be primary peritoneal cancer. In certain embodiments, the solid tumor may be fallopian tube cancer. In certain embodiments, the solid tumor may be endometrial cancer. In certain embodiments, the solid tumor may be lung cancer, such as non-small cell lung cancer (NSCLC). In certain embodiments, the solid tumor may be breast cancer, including HER2-negative breast cancer. In certain embodiments, the solid tumor may be mesothelioma. In certain embodiments, the solid tumor may be pleural mesothelioma or peritoneal mesothelioma. In some embodiments, the methods of the present invention can be used to treat FOLR1-positive cancers (e.g., solid tumors). As used herein, a "FOLR1-positive" tumor means that at least a portion of the tumor cells express FOLR1 protein detectable by standard methods, such as immunohistochemistry (IHC); and a "FOLR1-positive" cell means that the cell expresses FOLR1 protein detectable by standard methods, such as IHC. In certain embodiments, FOLR1 expression in a tumor is determined by administering a regulatory agency-approved test (e.g., the FDA-approved Ventana FOLR1-2.1 RxDx assay or its partial equivalent) to a tumor sample. In some embodiments, at least 10%, 15%, 20%, 25%, 30%, 40%, or 50% of the cells in a sample from a tumor are FOLR1 positive. In certain embodiments, at least 25% of the cancer cells in a sample from a solid tumor in the human individual are FOLR1 positive. In certain embodiments, at least 75% of the cancer cells in a sample from a solid tumor in the human individual are FOLR1 positive. In certain embodiments, less than 75% of the cancer cells in a sample from a solid tumor in the human individual are FOLR1 positive. In certain embodiments, less than 25% of the cancer cells in a sample from a solid tumor in the human individual are FOLR1 positive. In certain embodiments, the tumor in the human subject has high FOLR1 expression, as identified by FRα membrane staining intensity ≥2+ ("PS2+") in ≥75% of tumor cells in an IHC assay (e.g., the Ventana FOLR1 (FOLR1-2.1) RxDx assay). In certain embodiments, the tumor in the human subject has intermediate FOLR1 expression, as identified by FRα membrane staining intensity ≥1+ ("PS1+") in ≥25% of tumor cells and FRα membrane staining intensity PS2+ in <75% of tumor cells in an IHC assay (e.g., the Ventana FOLR1 (FOLR1-2.1) RxDx assay). In certain embodiments, the tumor in the human subject has low FOLR1 expression, identified as PS1+ in <25% of tumor cells in an IHC assay (e.g., the Ventana FOLR1 (FOLR1-2.1) RxDx assay). In certain embodiments, the human subject is treated with Rina-S according to the present invention before the percentage of FOLR1-positive cancer cells in a solid tumor sample from the human subject has been determined; in certain embodiments thereof, the human subject has ovarian cancer.

In some embodiments, the methods of the present invention can be used to treat localized cancer (e.g., a solid tumor). In some embodiments, the methods of the present invention can be used to treat metastatic cancer (e.g., a solid tumor). In some embodiments, the patient has an advanced solid tumor. In some embodiments, the patient has a localized advanced tumor. In some embodiments, the tumor has spread, such that the patient has secondary solid tumors in addition to the primary tumor. In some embodiments, the tumor cannot be removed surgically, i.e., the tumor is unresectable. In some embodiments, the tumor has spread (the cancer is metastatic) and at least one unresectable solid tumor is present.

In some embodiments, the individual may have well-differentiated epithelial ovarian cancer. In some embodiments, the individual may have well-differentiated serous ovarian cancer.

In certain embodiments described herein, the individual may have a platinum-resistant tumor. In some embodiments, the individual may have well-differentiated serous or endometrioid EOC (epithelial ovarian cancer), primary peritoneal carcinoma, or fallopian tube cancer that is resistant to platinum chemotherapy. In a preferred embodiment, the individual may have platinum-resistant ovarian cancer. Alternatively, the individual may have a platinum-sensitive tumor. In some embodiments, the individual may have platinum-sensitive ovarian cancer.

In some embodiments, the individual to be treated has a histologically or cytologically confirmed metastatic or unresectable solid malignancy. In some embodiments, the individual has ovarian cancer and also has epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In some embodiments, the individual has endometrial cancer. In some embodiments, the individual has non-small cell lung cancer (NSCLC). In some embodiments, the individual has NSCLC with an EGFR mutation. In some embodiments, the individual has breast cancer. In some embodiments, the individual has hormone receptor-positive, HER2-negative, or triple-negative breast cancer. In some embodiments, the individual has mesothelioma. In one embodiment, the cancer is selected from histologically or cytologically confirmed metastatic or unresectable solid malignancies, including ovarian cancer (definitely epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer), endometrial cancer, non-small cell lung cancer, NSCLC with epidermal growth factor receptor (EGFR) mutations, breast cancer (hormone receptor positive, HER2 negative, and triple negative), and mesothelioma.

In some embodiments, the subject to be treated is selected from subjects with well-differentiated serous ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (particularly excluding endometrioid, clear cell, mucinous, poorly differentiated, and those with sarcomatous or neuroendocrine elements).

In one embodiment, the patient has had their FRα expression status determined, e.g., using the Ventana FOLR1-2.1 RxDx assay. In one embodiment, the patient has high FRα expression (i.e., FRα expression ≥75% PS2+), e.g., as measured using the Ventana FOLR1-2.1 RxDx assay. In another embodiment, the patient does not have high FRα expression, and in particular, has FRα expression <75% PS2+, e.g., as measured using the Ventana FOLR1-2.1 RxDx assay. In a further embodiment, the patient has FRα expression <25% PS2+, e.g., as measured using the Ventana FOLR1-2.1 RxDx assay. In certain embodiments, the patient has not had their FRα expression status determined. In these embodiments, Rina-S according to the present invention can be used to treat a patient without prior determination of FRα expression status (e.g., in a patient with ovarian cancer).

In some embodiments, the methods of the present invention may include determining whether the tumor expresses FOLR1. In further embodiments, they may include determining the amount of FOLR1 expressed. In other embodiments, they may not include any of these steps. In certain embodiments, the human subject has ovarian cancer. In certain embodiments, the patient has been pretreated with other therapies directed against the tumor, such as at least 1, 2, 3, 4, or more lines of therapy. In certain embodiments, the patient is treated with an ADC, particularly Rina-S, at a dose level of 100 mg/ ^m2 . In certain embodiments, the patient is treated with an ADC, particularly Rina-S, at a dose level of 120 mg/ ^m2 . In some embodiments, the dose is administered to the patient approximately once every three weeks (Q3W). In some embodiments, the ADC, particularly Rina-S, is administered via an intravenous route.

In some embodiments, the presence or absence of FOLR1 expression cannot be determined unless the presence or absence of any FOLR1 expression is determined. In some embodiments, the amount of FOLR1 expression in the solid tumor is not determined at all prior to treatment. For example, because the vast majority of ovarian cancers express FOLR1, individuals with ovarian cancer may be treated according to the present invention without determining the presence or absence or amount of FOLR1 expression, because the tumor will most likely express FOLR1, and because the exact level of FOLR1 is less important for Rina-S than for other cancer drugs.

In one embodiment, a patient suffering from one of the types of cancer listed herein is treated without determining whether the solid tumor exhibits FOLR1 expression. In certain embodiments thereof, the human subject suffers from ovarian cancer. In certain embodiments, the human subject has been pretreated with other therapies directed against the tumor, e.g., with at least one, two, three, four, or more lines of therapy. In certain embodiments, the human subject is treated with an ADC, particularly Rina-S, at a dose level of 100 mg/m ^2. In certain embodiments, the human subject is treated with an ADC, particularly Rina-S, at a dose level of 120 mg/m ^2. In certain embodiments, the dose is administered to the human subject approximately once every three weeks (Q3W). In certain embodiments, the ADC, particularly Rina-S, is administered via the intravenous route. Dosage, Dosing Regimen, Administration Route, and Patient Assessment

In some embodiments, the dosage of an ADC (e.g., Rina-S) for treating cancer (e.g., solid tumors) of the present invention may range from 40 mg/m ² to 200 mg/m ^2. In some embodiments, the dosage may range from 60 mg/m ² to 180 mg/m ^2. In certain embodiments, the dosage is 40 mg/m ² , 60 mg/m ² , 100 mg/m ² , 120 mg/m ² , 140 mg/m ² , or 180 mg/m ^2. In certain embodiments, the dosage may be 60 mg/m ² to 180 mg/m ² , 100 mg/m ² to 140 mg/m ² , or 100 mg/m ² to 120 mg/m ² . In certain embodiments, the ADC is administered at a dose of 140 mg/m ^2. In certain embodiments, the dose is about 60 mg/m ^2. In certain embodiments, the dose is about 100 mg/m ^2. In certain embodiments, the dose is about 120 mg/m ^2. The dose expressed in mg/m ² is based on the patient's body surface area (BSA), which can be calculated using the Mosteller equation (BSA in m ² is √(height (cm)*weight (kg)/3600)).

In some embodiments, the ADC (e.g., Rina-S) can be administered weekly, twice weekly, or every other week. The dosing schedule may include a treatment cycle of two consecutive weeks of treatment followed by one, two, three, or four weeks of rest, or alternating weeks of treatment and rest, or one week of treatment followed by two, three, or four weeks of rest, or three weeks of treatment followed by one, two, three, or four weeks of rest, or four weeks of treatment followed by one, two, three, or four weeks of rest, or five weeks of treatment followed by one, two, three, four, or five weeks of rest, or administration once every two weeks, once every three weeks, or once a month. Treatment can be extended for any number of cycles, such as at least 2, at least 4, at least 6, at least 8, at least 10, at least 12, at least 16, or at least 20 cycles (e.g., 2 to 20 cycles, 2 to 16 cycles, 2 to 10 cycles, 2 to 4 cycles, 4 to 20 cycles, 4 to 16 cycles, 4 to 10 cycles, 6 to 20 cycles, 6 to 16 cycles, 6 to 10 cycles, 8 to In some embodiments, the ADC is administered to the human subject on day 1 of a 21-day treatment cycle. In some embodiments, the ADC is administered once every 2 to 4 weeks. In some embodiments, the ADC is administered approximately once every 3 weeks. In some embodiments, the ADC is administered once every 3 weeks. Dosing every 3 weeks may also be referred to as Q3W.

In some embodiments, the ADC dose is administered to the human subject as an intravenous (IV) infusion over 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, or 60 minutes. In some embodiments, the ADC dose is administered to the human subject as an intravenous (IV) infusion over 30 minutes.

In some embodiments, treatment with the ADC results in a reduction in size of the solid tumor of at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, or at least 50%. In certain embodiments, treatment with the ADC results in a reduction in size of the solid tumor of at least 15%. In certain embodiments, treatment with the ADC results in a reduction in size of the solid tumor of at least 20%. In certain embodiments, treatment with the ADC results in a reduction in size of the solid tumor of at least 25%. In certain embodiments, treatment with the ADC results in a reduction in size of the solid tumor of at least 15-90%, e.g., 15-75%, 15-50%, 15-40%, 15-30%, 30%-90%, 30%-75%, 30-50%, 30-40%, 40-90%, 40-75%, 40-50%, 50-90%, or 50-75%. One of ordinary skill will recognize that various factors can be considered in selecting the optimal dose of an ADC, such as age, overall health, specific organ function or body weight, and the effects of previous treatments on specific organ systems, and that the dose and/or frequency of administration may be increased or decreased during treatment.

In some embodiments, the treatment of the present invention results in an improved treatment outcome for the individual. This is particularly the case when the human individual has failed a previous treatment. In certain embodiments, the improved treatment outcome is an objective response selected from stable disease, partial response, or complete response. In certain embodiments, the improved treatment outcome is stable disease, indicating that the worsening of the solid tumor has stopped. In certain embodiments, the improved treatment outcome is a partial response. In certain embodiments, the partial response indicates that the size of the solid tumor has been reduced by at least 20%, at least 25%, at least 30%, at least 40%, or at least 50%. In certain embodiments, the partial response indicates that the size of the solid tumor has been reduced by at least 30%. As discussed further below, tumor size can be assessed using RECIST version 1.1 criteria, and in one embodiment, a partial response indicates that the size of the solid tumor has decreased by at least 20%, at least 25%, at least 30%, at least 40%, or at least 50% according to these criteria. In one embodiment, the size of the solid tumor has decreased by at least 30% according to these criteria. In certain embodiments, the improved treatment outcome is a complete response. In certain embodiments, the complete response indicates the absence of detectable cancer. In certain embodiments, the improved treatment outcome is a reduction in tumor burden. In certain embodiments, a reduction in tumor burden means that the size of the solid tumor has decreased by at least 20%, at least 25%, at least 30%, at least 40%, or at least 50%. In some embodiments, the improved treatment outcome is progression-free survival or disease-free survival. In some embodiments, progression-free survival or disease-free survival is assessed after 1, 2, 3, 4, 5, or 10 years.

Any appropriate method can be used to assess tumors and treatment. In some embodiments, the treatment is assessed by RECIST v1.1. In embodiments where the cancer is pleural mesothelioma, mRECIST v1.1 can be used to assess treatment. The RECIST version 1.1 criteria were published by Eisenhauer et al. in the European Journal of Cancer (2009) 228-247 and can be used to define the degree of response. The full text of Eisenhauer et al. has been incorporated herein, particularly with respect to the content related to the RECIST version 1.1 criteria. In some embodiments, the best overall response (BOR) can be assessed. In some embodiments, the overall response rate (ORR) can be assessed. In some embodiments, the disease control rate (DCR) can be assessed. In some embodiments, progression-free survival (PFS) can be assessed. In some embodiments, overall survival can be assessed. In some embodiments, duration of objective response (DOR) can be assessed.

The optimal doses and administration schedules disclosed herein demonstrate unexpectedly superior efficacy and reduced toxicity in human subjects that could not be predicted from animal model studies. This superior efficacy may allow for the treatment of tumors previously found to be resistant to one or more standard anticancer therapies.

Generally, the dosage of an ADC (e.g., Rina-S) administered to a human subject may vary depending on factors such as the patient's age, weight, height, sex, general medical condition, and past medical history. As discussed above, the dosage of Rina-S may range from 40 mg/m ² to 200 mg/m ² , 60 mg/m ² to 180 mg/m ² , 100 mg/m ² to 140 mg/m ² , 100 mg to 120 mg/m ² , or about 60 mg/m ² , about 100 mg/m ² , or about 120 mg/m ² . In certain embodiments, Rina-S is administered IV on day 1 of a 21-day cycle and may be continued until disease progression, unacceptable toxicity, or other reasons for treatment discontinuation. Dose-limiting toxicities were observed at doses of 140 mg/ ^m2 and 180 mg/ ^m2 , both of which were hematologic cytopenias. The administration schedule may include administration once or twice weekly over a cycle selected from the group consisting of: (i) weekly; (ii) every other week; (iii) one week of treatment followed by two, three, or four weeks off; (iv) two weeks of treatment followed by one, two, three, or four weeks off; (v) three weeks of treatment followed by one, two, three, four, or five weeks off; (vi) four weeks of treatment followed by one, two, three, four, or five weeks off; (vii) five weeks of treatment followed by one, two, three, four, or five weeks off; and (viii) monthly. The cycle may be repeated 2, 4, 6, 8, 10, 12, 16, or 20 times. Treatment with the ADC results in a reduction in size of the solid tumor of at least 15%, at least 20%, at least 30%, at least 40%, or at least 50%.

In some embodiments, the subject treated with the ADC Rina-S according to the present invention has previously been treated with other lines of therapy, such as 1, 2, 3, 4, 5, 6, or 7 prior other cancer therapies. In certain embodiments, the subject with ovarian cancer treated with the ADC Rina-S according to the present invention has previously been treated with one or more of bevacizumab, a PARP inhibitor, a platinum-based chemotherapy (e.g., cisplatin, carboplatin, oxaliplatin), and/or sometuximab. In certain embodiments, the subject with endometrial cancer treated with the ADC Rina-S according to the present invention has previously been treated with a PD-1 inhibitor (e.g., pembrolizumab).

In one embodiment, the present invention provides a method for treating a solid tumor, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having the solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every three weeks (Q3W) to approximately every six weeks (Q6W), and the solid tumor is folate receptor 1 (FOLR1)-positive.

In one embodiment of the methods, the dose is administered once every 3 weeks (Q3W). In another embodiment, the dose is administered once every 4 weeks (Q4W). In another embodiment, the dose is administered once every 5 weeks (Q5W). In another embodiment, the dose is administered once every 6 weeks (Q6W).

In one embodiment, the present invention provides a method for treating a solid tumor, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having the solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² approximately every three weeks (Q3W) to approximately every six weeks (Q6W), and the solid tumor is folate receptor 1 (FOLR1)-positive.

In a further embodiment, the present invention provides a method for treating a solid tumor, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having the solid tumor, wherein the ADC is administered at a dose of 120 mg/m ² once every three weeks (Q3W) to every six weeks (Q6W), and the solid tumor is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating a solid tumor, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having the solid tumor, wherein the ADC is administered at a dose of approximately 100 mg/m ² every three weeks (Q3W) and the solid tumor is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating a solid tumor, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having the solid tumor, wherein the ADC is administered at a dose of approximately 120 mg/m ² every three weeks (Q3W) and the solid tumor is folate receptor 1 (FOLR1) positive.

In particular, these regimens can be administered to human subjects with ovarian cancer. In one embodiment, these regimens can be administered to human subjects with platinum-resistant ovarian cancer. In an alternative embodiment, these regimens can be administered to human subjects with platinum-sensitive ovarian cancer. In a further embodiment, these regimens can be administered to human subjects with endometrial cancer.

In one embodiment, the present invention provides a method for treating ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every three weeks (Q3W) to every six weeks (Q6W), and the ovarian cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating ovarian cancer comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of approximately 100 mg/m ² every three weeks (Q3W) and the ovarian cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of approximately 120 mg/m ² every three weeks (Q3W), and the ovarian cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of approximately 100 mg/m ² every three weeks (Q3W) and the ovarian cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of approximately 120 mg/m ² every three weeks (Q3W) and the ovarian cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating platinum-sensitive ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of approximately 100 mg/m ² every three weeks (Q3W) and the ovarian cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating platinum-sensitive ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of approximately 120 mg/m ² every three weeks (Q3W) and the ovarian cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of approximately 100 mg/m ² every three weeks (Q3W), and the endometrial cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of approximately 120 mg/m ² every three weeks (Q3W), and the endometrial cancer is folate receptor 1 (FOLR1) positive.

In other embodiments, the drug is administered approximately every 3 weeks (Q3W) for the treatment of breast cancer. Therefore, further embodiments related to breast cancer using Q3W are described below.

In one embodiment, the present invention provides a method for treating breast cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² about every three weeks (Q3W) to about every six weeks (Q6W), and the breast cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating breast cancer comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² approximately every three weeks (Q3W) and the breast cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating breast cancer comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of approximately 120 mg/m ² every three weeks (Q3W) and the ovarian cancer is folate receptor 1 (FOLR1) positive.

In other embodiments, the drug is administered approximately every 3 weeks (Q3W) to treat non-small cell lung cancer (NSCLC). Therefore, further embodiments of Q3W dosing for the treatment of NSCLC are described below.

In one embodiment, the present invention provides a method for treating NSCLC, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every three weeks (Q3W) to approximately every six weeks (Q6W), and the NSCLC cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating NSCLC cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of approximately 100 mg/m ² every three weeks (Q3W) and the NSCLC cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating NSCLC cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of approximately 120 mg/m ² every three weeks (Q3W) and the NSCLC cancer is folate receptor 1 (FOLR1) positive.

In other embodiments, mesothelioma is treated with a dosing regimen of approximately once every 3 weeks (Q3W). Therefore, further embodiments of treating mesothelioma with a Q3W regimen are described below.

In one embodiment, the present invention provides a method for treating mesothelioma, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every three weeks (Q3W) to approximately every six weeks (Q6W), and the mesothelioma is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating mesothelioma, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of approximately 100 mg/m ² every three weeks (Q3W) and the mesothelioma is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating mesothelioma comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of approximately 120 mg/m ² every three weeks (Q3W) and the mesothelioma is folate receptor 1 (FOLR1) positive. Combination therapy

In some embodiments of the methods of the present invention, the ADC can be used alone or in combination therapy with one or more therapeutic modalities selected from the group consisting of unconjugated antibodies, radiolabeled antibodies, drug-conjugated antibodies, toxin-conjugated antibodies, gene therapy, chemotherapy, therapeutic peptides, cytokine therapy, oligonucleotides, localized radiation therapy, surgery, and interfering RNA therapy.

In one embodiment, when an ADC is used in combination with another drug, the ADC and the other drug can be administered simultaneously. The ADC and the other drug can be administered simultaneously, separately, or sequentially. In one embodiment, the ADC and the other drug can be administered in the same pharmaceutical composition. In an alternative embodiment, the ADC and the other drug can be administered in separate compositions. In one embodiment, while the ADC and the other drug can be administered separately, they can be packaged together, for example, in the form of a kit containing both. In one embodiment, an ADC is provided for use in the methods described herein. In an alternative embodiment, the present invention provides another drug for use in the methods described herein, wherein the ADC is also administered. Various regimens for administering the ADCs described herein are described herein, and the present invention provides such regimens in which a second drug is administered as part of the regimen. For example, the second drug can be administered simultaneously with the ADC. Alternatively, the second drug can be administered according to a standard regimen for the drug. The present invention also provides regimens in which the ADC and the second drug are administered alternately.

In some embodiments, the ADC can be used in combination with a platinum-based chemotherapy drug. Examples of such drugs include cis-platinum, carboplatin, and oxaliplatin. In some embodiments, the ADC can be used in combination with carboplatin.

In some embodiments, the ADC can be used in combination with a drug that acts as a VEGF inhibitor. In some embodiments, the ADC is used in combination with bevacizumab.

In some embodiments, the ADC can be used in combination with an immuno-oncology therapy. In some embodiments, the ADC can be used in combination with a drug that inhibits PD-1. Non-limiting examples of drugs that inhibit PD-1 include pembrolizumab, nivolumab, nofazinlimab, and cemiplizumab. In some embodiments, the ADC can be used in combination with pembrolizumab. In some embodiments, the ADC can be used in combination with nofazinlimab. In some embodiments, the ADC can be used in combination with pembrolizumab. In some embodiments, the ADC can be used in combination with pembrolizumab. In some embodiments, the ADC can be used in combination with a drug that inhibits PD-L1. Non-limiting examples of drugs that inhibit PD-L1 include atezolizumab, avelumab, and durvalumab.

In some embodiments, the ADC can be used in combination with a drug that is a PARP inhibitor. In some embodiments, the ADC can be used in combination with olaparib.

In preferred embodiments, ADCs can be used to treat cancers that are refractory to standard therapies, such as ovarian cancer, endometrial cancer, breast cancer, lung cancer, and mesothelioma. More preferably, the combination of the ADC and other treatments is more effective than the efficacy of any individual treatment alone or the sum of the effects of the individual treatments. In one embodiment, the combination is synergistic.

In one embodiment, an ADC as described herein may be used in combination with olaparib. In one embodiment, the ADC is Rina-S. In certain embodiments, the human subject has endometrial adenocarcinoma. In certain embodiments, the human subject has been pretreated with other therapies directed against the tumor, such as at least one, two, three, four, or more lines of therapy. In certain embodiments, the human subject is treated with Rina-S at a dose level of 100 mg/m ^2. In certain embodiments, the human subject is treated with Rina-S at a dose level of 120 mg/m ^2. In certain embodiments, the dose is administered to the human subject approximately once every three weeks (Q3W). In some embodiments, the Rina-S is administered via an intravenous route.

In one embodiment, an ADC as described herein may be used in combination with carboplatin. In one embodiment, the ADC is Rina-S. In certain embodiments, the human subject has endometrial adenocarcinoma. In certain embodiments, the human subject has been pretreated with other therapies directed against the tumor, such as at least one, two, three, four, or more lines of therapy. In certain embodiments, the human subject is treated with Rina-S at a dose level of 100 mg/m ^2. In certain embodiments, the human subject is treated with Rina-S at a dose level of 120 mg/m ^2. In certain embodiments, the dose is administered to the human subject approximately once every three weeks (Q3W). In some embodiments, the Rina-S is administered via an intravenous route.

In one embodiment, an ADC as described herein may be used in combination with carboplatin to treat ovarian cancer. In one embodiment, the ADC is Rina-S. In certain embodiments, the human subject has endometrial adenocarcinoma. In certain embodiments, the human subject has been previously treated with other therapies directed against the tumor, such as at least one, two, three, four, or more lines of therapy. In certain embodiments, the human subject is treated with Rina-S at a dose level of 100 mg/ ^m² . In certain embodiments, the human subject is treated with Rina-S at a dose level of 120 mg/ ^m² . In some embodiments, the dose is administered to the human subject approximately once every three weeks (Q3W). In some embodiments, the Rina-S is administered via an intravenous route.

In one embodiment, an ADC as described herein can be used in combination with bevacizumab. In one embodiment, the ADC is Rina-S. In certain embodiments, the human subject has endometrial adenocarcinoma. In certain embodiments, the human subject has been pretreated with other therapies directed against the tumor, such as at least 1, 2, 3, 4, or more lines of therapy. In certain embodiments, the human subject is treated with Rina-S at a dose level of 100 mg/m ^2. In certain embodiments, the human subject is treated with Rina-S at a dose level of 120 mg/m ^2. In certain embodiments, the dose is administered to the human subject approximately once every three weeks (Q3W). In some embodiments, the Rina-S is administered via an intravenous route.

In one embodiment, an ADC as described herein can be used in combination with bevacizumab to treat ovarian cancer. In one embodiment, the ADC is Rina-S. In certain embodiments, the human subject has endometrial adenocarcinoma. In certain embodiments, the human subject has been previously treated with other therapies directed against the tumor, e.g., at least 1, 2, 3, 4, or more lines of therapy. In certain embodiments, the human subject is treated with Rina-S at a dose level of 100 mg/m ^2. In certain embodiments, the human subject is treated with Rina-S at a dose level of 120 mg/m ^2. In certain embodiments, the dose is administered to the human subject approximately once every three weeks (Q3W). In some embodiments, the Rina-S is administered via an intravenous route.

In one embodiment, an ADC as described herein may be used in combination with an immunotherapy. In one embodiment, the ADC is Rina-S. In certain embodiments, the human subject has endometrial adenocarcinoma. In certain embodiments, the human subject has been pretreated with other therapies directed against the tumor, such as at least 1, 2, 3, 4, or more lines of therapy. In certain embodiments, the human subject is treated with Rina-S at a dose level of 100 mg/m ^2. In certain embodiments, the human subject is treated with Rina-S at a dose level of 120 mg/m ^2. In certain embodiments, the dose is administered to the human subject approximately once every three weeks (Q3W). In some embodiments, the Rina-S is administered via an intravenous route.

In one embodiment, an ADC as described herein may be used in combination with an immunotherapy. In one embodiment, the ADC is Rina-S. In certain embodiments, the human subject has ovarian cancer. In certain embodiments, the human subject has been pretreated with other therapies directed against the tumor, such as at least 1, 2, 3, 4, or more lines of therapy. In certain embodiments, the human subject is treated with Rina-S at a dose level of 100 mg/m ^2. In certain embodiments, the human subject is treated with Rina-S at a dose level of 120 mg/m ^2. In certain embodiments, the dose is administered to the human subject approximately once every three weeks (Q3W). In some embodiments, the Rina-S is administered via an intravenous route.

In one embodiment, an ADC as described herein can be used in combination with an anti-PD-1 antibody. In one embodiment, the ADC is Rina-S. In certain embodiments, the human subject has endometrial adenocarcinoma. In certain embodiments, the human subject has been pretreated with other therapies directed against the tumor, such as at least 1, 2, 3, 4, or more lines of therapy. In certain embodiments, the human subject is treated with Rina-S at a dose level of 100 mg/m ^2. In certain embodiments, the human subject is treated with Rina-S at a dose level of 120 mg/m ^2. In certain embodiments, the dose is administered to the human subject approximately once every three weeks (Q3W). In some embodiments, the Rina-S is administered via an intravenous route.

In one embodiment, an ADC as described herein can be used in combination with an anti-PD-1 antibody to treat ovarian cancer. In one embodiment, the ADC is Rina-S. In certain embodiments, the human subject has been pretreated with other therapies directed against the tumor, such as at least one, two, three, four, or more lines of therapy. In certain embodiments, the human subject is treated with Rina-S at a dose level of 100 mg/m ^2. In certain embodiments, the human subject is treated with Rina-S at a dose level of 120 mg/m ^2. In certain embodiments, the dose is administered to the human subject approximately once every three weeks (Q3W). In certain embodiments, the Rina-S is administered via intravenous administration. Patient Groups and Medical History

The human subject has previously been treated with at least one anti-cancer therapy. In one embodiment, the subject may have previously been treated with at least one anti-cancer therapy that was ineffective in treating the cancer. In one embodiment, the subject may have previously been treated with at least one anti-cancer therapy that was initially effective but is now less effective or ineffective. In some embodiments, the subject may have become resistant to the previous therapy when administered alone.

In some embodiments, the human subject has previously received one to four anticancer therapies. In some embodiments, the at least one anticancer therapy comprises treatment with a chemotherapy agent. In some embodiments, the at least one anticancer therapy comprises treatment with at least one anticancer therapy selected from the group consisting of platinum chemotherapy, bevacizumab, a poly ADP-ribose polymerase (PARP) inhibitor, and sometuximab. Prior to treatment with the ADC, the human subject had failed to respond to at least one anticancer therapy.

In some embodiments, the subject to be treated is selected from subjects with well-differentiated severe ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (particularly excluding endometrioid, clear cell, mucinous, poorly differentiated, and those with sarcomatous or neuroendocrine elements). In some embodiments, the subject is selected from individuals with the solid tumors, and the subject has received one to three lines of treatment with different anticancer therapies (previous induction plus maintenance is considered one line of treatment, even if some portion of the treatment regimen, induction or maintenance, is interrupted and/or resumed at a later date without disease progression during active treatment—a switch/change in treatment regimen solely due to toxicity or participant preference, rather than disease progression, is not considered a separate line of treatment). In some embodiments, when the cancer is ovarian cancer, it is platinum-resistant/refractory ovarian cancer. In some embodiments, the subject has previously received bevacizumab. In some embodiments, the individual has breast cancer with a known or suspected deleterious germline or somatic BRCA mutation (e.g., as determined by an FDA-approved test) and the individual has been treated with a poly ADP-ribose polymerase (PARP) inhibitor. In some embodiments, the individual may have previously received sulfamethoxazole (MIRV) for FRα status based on an FDA-approved test (e.g., the Ventana FOLR1 RxDx assay). In some embodiments, the individual is FRα positive but is not a suitable candidate for treatment with MIRV, e.g., because FRα expression is too low. In some embodiments, the individual is treated according to the present invention when the amount of FRα expression in the individual's tumor has not been determined by a regulatory agency (e.g., FDA)-approved test. In some embodiments, it is not determined whether the tumor expresses FRα. For example, a high percentage of the cancer may express FRα, and therefore it is not considered necessary to determine the presence of FRα, or at least the amount of FRα expression. In one embodiment, the cancer in these embodiments is ovarian cancer.

In some embodiments, the individual has platinum-sensitive ovarian cancer (PSOC) and has received 1 to 3 prior lines of treatment, particularly when the prior line of treatment was with a platinum-based chemotherapy.

In some embodiments, the individual has a platinum-resistant or platinum-refractory cancer. In some embodiments, the individual has well-differentiated serous or endometrioid EOC, primary peritoneal carcinoma, or fallopian tube cancer that is resistant to platinum chemotherapy. In some embodiments, the individual has a platinum-resistant or platinum-refractory cancer in which the individual has previously received treatment with a platinum-based chemotherapy agent. In some embodiments, the individual has previously received one to two such lines of therapy. In some embodiments, the individual has endometrial cancer, particularly any endometrial cancer subtype other than sarcoma. In some embodiments, the individual will have such endometrial cancer and has previously received platinum-based chemotherapy for recurrent or advanced disease. In some embodiments, with respect to any of the individuals mentioned in this paragraph, they will not have any of the following: (i) another malignancy within 3 years; (ii) active central nervous system (CNS) metastases (treated and stable CNS metastases are allowed); (iii) a Grade 3 or higher infection that is not controlled within 2 weeks of starting treatment; (iv) hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). (v) a positive HIV test; (v) a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis requiring steroids within the past 2 years, current ILD/pneumonitis, or suspected ILD/pneumonitis that could not be ruled out by imaging at the time of screening; (v) use of a strong CYP3A inhibitor (dose escalation only) within 14 days; or (vi) previous treatment with a topoisomerase 1 inhibitor-based antibody-drug conjugate.

In one embodiment, the individual has histologically or cytologically confirmed well-differentiated serous or endometrioid epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. In one embodiment, the individual has previously received 1 to 4 lines of therapy. In a preferred embodiment, the patient will receive at least one of the following: a) Platinum chemotherapy b) Bevacizumab, unless the patient has a documented contraindication c) Poly ADP-ribose polymerase (PARP) inhibitors (for patients with known or suspected deleterious germline or somatic BRCA mutations) d) Suometriumab, if: i. Suometriumab is available in the registration region, and ii. The patient is eligible based on positive FRα expression by an FDA-approved test (or local equivalent), and iii. The patient has no documented medical abnormalities, including chronic corneal conditions, a history of corneal transplantation, or active ocular diseases requiring ongoing treatment/monitoring, such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular lesions, the presence of papilledema, and/or monocular vision.

In one embodiment, individuals who have received only one line of platinum-based therapy will receive at least 4 cycles of platinum therapy and must have responded (complete response [CR] or partial response [PR]) or had non-measurable disease at the start of platinum-based therapy and then worsened between >91 days and ≤183 days after the date of the last platinum dose. In a further embodiment, patients who have received 2 to 4 lines of platinum-based therapy will worsen on or within 183 days after the date of the last platinum dose.

In one embodiment, the individual does not meet one or more of the following exclusion criteria (particularly if the individual is currently receiving PROC): ˙   Prior treatment with an antibody-drug conjugate containing a topoisomerase 1 inhibitor. ˙   Primary platinum-refractory disease, defined as ovarian cancer that has not responded (CR or PR) or has progressed ≤ 91 days after the last dose of a first-line platinum-containing regimen. ˙   History of other malignancies within 3 years prior to the first dose of Rina-S, or evidence of residual disease from any previously diagnosed malignancy. Malignant tumors (including, but not limited to, previously treated cervical carcinoma in situ, non-melanoma skin cancer, ductal carcinoma in situ, or stage I uterine cancer) with a negligible risk of metastasis or death (e.g., 5-year OS ≥ 90%) are excluded. ˙   Known active central nervous system metastases or carcinomatous meningitis. Patients who have previously received treatment for brain metastases may participate, provided they are clinically stable for at least 4 weeks prior to study entry after treatment for brain metastases, have no new or enlarging brain metastases, and have discontinued prescribed corticosteroids and anticonvulsants for symptoms related to brain metastases for at least 7 days prior to the first dose of study drug. Patients suspected of having brain metastases at screening may undergo a computed tomography (CT)/magnetic resonance imaging (MRI) of the brain prior to study entry. ˙   Hospitalization or clinical symptoms for gastrointestinal obstruction within the past 91 days, or radiographic evidence of gastrointestinal obstruction at screening. Patients currently requiring parenteral nutrition must discuss eligibility with the study medical monitor at the time of enrollment. ˙   Ascites requiring frequent paracentesis (approximately every 4 weeks or more frequently) for symptomatic management. Patients with an indwelling peritoneal catheter must discuss eligibility with the study medical monitor at the time of enrollment.

In one embodiment, the subject may have a specific FRα expression level, for example, as measured by the Ventana FOLR1-2.1 RxDx assay. In one embodiment, the subject's tumor does not have high FRα expression as measured by the Ventana FOLR1-2.1 RxDx assay (or a local equivalent test), for example, the patient's FRα expression may be <75% PS2+. In one embodiment, the subject's FRα expression is <25% PS2+. In one embodiment, the subject's tumor does not have high FRα expression as measured by the Ventana FOLR1-2.1 RxDx assay, particularly FRα expression of ≥75% PS2. In one embodiment, the subject has FRα expression ≥75% PS2+ as measured by the Ventana FOLR1-2.1 RxDx assay and has not previously received sutomizukazumab.

In one embodiment, the individual has a tumor that expresses FRα, further defined by whether the individual has been previously treated with sutoximab. In one embodiment, the individual is sutoximab-naive and does not have high FRα expression (i.e., <75% PS2+). In one embodiment, the individual is sutoximab-naive and has high FRα expression (i.e., ≥75% PS2+). In one embodiment, the individual has previously been treated with sutoximab.

In one embodiment, the subject will have received 1 to 4 prior lines of therapy, which must include platinum-based chemotherapy, bevacizumab, and/or sometuximab. Further embodiments

The following sections describe several illustrative implementations.

In one embodiment, the present invention provides a method for treating epithelial ovarian cancer, endometrial cancer, breast cancer, non-small cell lung cancer, and mesothelioma, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 40 mg/m ² to 200 mg/m ² , and the solid tumor is folate receptor 1 (FOLR1)-positive. In one embodiment, the dose is about 100 mg/m ² to about 140 mg/m ^2. In one embodiment, the dose is about 110 mg/m ² to about 130 mg/m ^2. In one embodiment, the dose is about 120 mg/m ² .

In one embodiment, the present invention provides a method for treating a subject with well-differentiated serous or endometrioid EOC, primary peritoneal carcinoma, or fallopian tube carcinoma that is resistant to platinum chemotherapy, the method comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject with a solid tumor, wherein the ADC is administered at a dose of 40 mg/m ² to 200 mg/m ² , and the solid tumor is folate receptor 1 (FOLR1) positive. In one embodiment, the dose is about 100 mg/m ² to about 140 mg/m ^2. In one embodiment, the dose is about 110 mg/m ² to about 130 mg/m ² . In one embodiment, the dose is about 120 mg/m ² .

In one embodiment, the present invention is administered approximately once every four weeks. In one embodiment, administration is performed once every four weeks (Q4W). Therefore, further embodiments utilizing Q4W are described below.

In one embodiment, the present invention further provides a method for treating a solid tumor, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having the solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every four weeks (Q4W), and the solid tumor is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every four weeks (Q4W), and the ovarian cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/ ^m2 approximately every four weeks (Q4W), and the ovarian cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating ovarian cancer comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/ ^m2 approximately every four weeks (Q4W), and the ovarian cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ^ADC is administered at a dose of 100 mg/ ^m2 to 120 mg/m2 approximately every four weeks (Q4W), and the ovarian cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/ ^m2 approximately every four weeks (Q4W), and the ovarian cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating platinum-sensitive ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ^ADC is administered at a dose of 100 mg/ ^m2 to 120 mg/m2 approximately every four weeks (Q4W), and the ovarian cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating platinum-sensitive ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/m ² approximately every four weeks (Q4W), and the ovarian cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every four weeks (Q4W), and the endometrial cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/ ^m2 approximately every four weeks (Q4W), and the endometrial cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/ ^m2 approximately every four weeks (Q4W), and the endometrial cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention employs dosing approximately once every 5 weeks. In one embodiment, dosing is once every 5 weeks (Q5W). Therefore, further embodiments employing Q5W are described below.

In one embodiment, the present invention further provides a method for treating a solid tumor, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having the solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every five weeks (Q5W), and the solid tumor is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every five weeks (Q5W), and the ovarian cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/ ^m2 approximately every five weeks (Q5W), and the ovarian cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating ovarian cancer comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/m ² approximately every five weeks (Q5W), and the ovarian cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ^ADC is administered at a dose of 100 mg/ ^m2 to 120 mg/m2 approximately every five weeks (Q5W), and the ovarian cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/ ^m2 approximately every five weeks (Q5W), and the ovarian cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating platinum-sensitive ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every five weeks (Q5W), and the ovarian cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating platinum-sensitive ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/m ² approximately every five weeks (Q5W), and the ovarian cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every five weeks (Q5W), and the endometrial cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/ ^m2 approximately every five weeks (Q5W), and the endometrial cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/ ^m2 approximately every five weeks (Q5W), and the endometrial cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention employs dosing approximately once every 6 weeks. In one embodiment, dosing is employed once every 6 weeks (Q6W). Therefore, further embodiments employing Q6W are described below.

In one embodiment, the present invention further provides a method for treating a solid tumor, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having the solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every six weeks (Q6W), and the solid tumor is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every six weeks (Q6W), and the ovarian cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² approximately every six weeks (Q6W), and the ovarian cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating ovarian cancer comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/m ² approximately every six weeks (Q6W), and the ovarian cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ^ADC is administered at a dose of 100 mg/ ^m2 to 120 mg/m2 approximately every six weeks (Q6W), and the ovarian cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating platinum-resistant ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/ ^m2 approximately every six weeks (Q6W), and the ovarian cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating platinum-sensitive ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every six weeks (Q6W), and the ovarian cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating platinum-sensitive ovarian cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/ ^m2 approximately every six weeks (Q6W), and the ovarian cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every six weeks (Q6W), and the endometrial cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² approximately every six weeks (Q6W), and the endometrial cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating endometrial cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/ ^m2 approximately every six weeks (Q6W), and the endometrial cancer is folate receptor 1 (FOLR1) positive.

The present invention can also be used to treat breast cancer.

In one embodiment, the present invention utilizes a dosing regimen of approximately every four weeks to treat breast cancer. In one embodiment, a dosing regimen of once every four weeks (Q4W) is utilized to treat breast cancer. Therefore, further embodiments utilizing Q4W dosing in connection with breast cancer are described below.

In one embodiment, the present invention provides a method for treating breast cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every four weeks (Q4W), and the breast cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating breast cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² approximately every four weeks (Q4W), and the breast cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating breast cancer comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/m ² approximately every four weeks (Q4W), and the breast cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention utilizes a dosing regimen approximately every 5 weeks to treat breast cancer. In one embodiment, a dosing regimen of once every 5 weeks (Q5W) is utilized to treat breast cancer. Therefore, further embodiments utilizing Q5W dosing in connection with breast cancer are described below.

In one embodiment, the present invention provides a method for treating breast cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every five weeks (Q5W), and the breast cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating breast cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² approximately every five weeks (Q5W), and the breast cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating breast cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/m ² approximately every five weeks (Q5W), and the breast cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention utilizes a dosing regimen approximately every 6 weeks to treat breast cancer. In one embodiment, a dosing regimen once every 6 weeks (Q6W) is utilized to treat breast cancer. Therefore, further embodiments utilizing Q6W dosing in connection with breast cancer are described below.

In one embodiment, the present invention provides a method for treating breast cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every six weeks (Q6W), and the breast cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating breast cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² approximately every six weeks (Q6W), and the breast cancer is folate receptor 1 (FOLR1)-positive.

In one embodiment, the present invention provides a method for treating breast cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/m ² approximately every six weeks (Q6W), and the breast cancer is folate receptor 1 (FOLR1)-positive.

The present invention can also be used to treat NSCLC cancer.

In one embodiment, the present invention utilizes a dosing regimen approximately every four weeks to treat NSCLC. In one embodiment, a dosing regimen once every four weeks (Q4W) is utilized to treat NSCLC. Therefore, further embodiments utilizing Q4W dosing for NSCLC are described below.

In one embodiment, the present invention provides a method for treating NSCLC cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/ ^m2 to 120 mg/ ^m2 approximately every four weeks (Q4W), and the NSCLC cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating NSCLC cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/ ^m2 approximately every four weeks (Q4W), and the NSCLC cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating NSCLC cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/ ^m2 approximately every four weeks (Q4W), and the NSCLC cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention utilizes a dosing regimen approximately every 5 weeks to treat NSCLC. In one embodiment, a dosing regimen of once every 5 weeks (Q5W) is utilized to treat NSCLC. Therefore, further embodiments utilizing Q5W dosing for NSCLC are described below.

In one embodiment, the present invention provides a method for treating NSCLC cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/ ^m2 to 120 mg/ ^m2 approximately every five weeks (Q5W), and the NSCLC cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating NSCLC cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² approximately every five weeks (Q5W), and the NSCLC cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating NSCLC cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/ ^m2 approximately every five weeks (Q5W), and the NSCLC cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention utilizes a dosing regimen approximately every six weeks to treat NSCLC. In one embodiment, a dosing regimen once every six weeks (Q6W) is utilized to treat NSCLC. Therefore, further embodiments utilizing Q6W dosing for NSCLC are described below.

In one embodiment, the present invention provides a method for treating NSCLC cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/ ^m2 to 120 mg/ ^m2 approximately every six weeks (Q6W), and the NSCLC cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating NSCLC cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/ ^m2 approximately every six weeks (Q6W), and the NSCLC cancer is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating NSCLC cancer, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/ ^m2 approximately every six weeks (Q6W), and the NSCLC cancer is folate receptor 1 (FOLR1) positive.

The present invention can also be used to treat mesothelioma.

In one embodiment, the present invention uses a dosing regimen of approximately once every four weeks to treat mesothelioma. In one embodiment, mesothelioma is treated with a dosing regimen of once every four weeks (Q4W). Therefore, further embodiments related to mesothelioma using Q4W dosing are described below.

In one embodiment, the present invention provides a method for treating mesothelioma, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every four weeks (Q4W), and the mesothelioma is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating mesothelioma, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² approximately every four weeks (Q4W), and the mesothelioma is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating mesothelioma, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/m ² approximately every four weeks (Q4W), and the mesothelioma is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention uses a dosing regimen of approximately once every 5 weeks to treat mesothelioma. In one embodiment, mesothelioma is treated with a dosing regimen of once every 5 weeks (Q5W). Therefore, further embodiments related to mesothelioma using Q5W dosing are described below.

In one embodiment, the present invention provides a method for treating mesothelioma, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every five weeks (Q5W), and the mesothelioma is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating mesothelioma, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² approximately every five weeks (Q5W), and the mesothelioma is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating mesothelioma, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/ ^m2 approximately every five weeks (Q5W), and the mesothelioma is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention uses a dosing regimen of approximately once every 6 weeks to treat mesothelioma. In one embodiment, mesothelioma is treated with a dosing regimen of once every 6 weeks (Q6W). Therefore, further embodiments related to mesothelioma using Q6W dosing are described below.

In one embodiment, the present invention provides a method for treating mesothelioma, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² to 120 mg/m ² approximately every six weeks (Q6W), and the mesothelioma is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating mesothelioma, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 100 mg/m ² approximately every six weeks (Q6W), and the mesothelioma is folate receptor 1 (FOLR1) positive.

In one embodiment, the present invention provides a method for treating mesothelioma, comprising administering the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human subject having a solid tumor, wherein the ADC is administered at a dose of 120 mg/ ^m2 approximately every six weeks (Q6W), and the mesothelioma is folate receptor 1 (FOLR1) positive. Further numbered embodiments The following are numbered embodiments of the present invention: 1. A method for treating a solid tumor, comprising administering an antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) to a human individual having a solid tumor, wherein the ADC is administered at a dose of between 40 mg/m ² and 200 mg/m ² , and the solid tumor is folate receptor 1 (FOLR1) positive. 2. The method of [1], wherein the solid tumor is selected from the group consisting of: ovarian cancer, endometrial cancer, breast cancer, lung cancer, and mesothelioma. 3. The method of [1], wherein the solid tumor is ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer. 4. The method of [1], wherein the solid tumor is endometrial cancer. 5. The method of [1], wherein the solid tumor is non-small cell lung cancer (NSCLC). 6. The method of [1], wherein the solid tumor is breast cancer, including HER2-negative breast cancer. 7. The method of [1], wherein the solid tumor is pleural mesothelioma or peritoneal mesothelioma. 8. The method of [1], wherein the solid tumor is a platinum-resistant tumor. 9. The method of [8], wherein the solid tumor is a well-differentiated serous or endometrioid EOC, primary peritoneal carcinoma, or fallopian tube carcinoma that is resistant to platinum chemotherapy. 10. The method of any one of [1] to [7], wherein the solid tumor is localized or metastatic. 11. The method of any one of [1] to [10], wherein at least one tumor cannot be removed by surgery. 12. The method of any one of [1] to [11], wherein the ADC is administered at a dose of between 60 mg/m ² and 180 mg/m ^2. 13. The method of any one of [1] to [11], wherein the ADC is administered at a dose of between 100 mg/m ² and 140 mg/m ^2. 14. The method of any one of [1] to [11], wherein the ADC is administered at a dose of between 100 mg/m ² and 120 mg/m ^2. 15. The method of any one of [1] to [11], wherein the ADC is administered at a dose of about 120 mg/m ² . 16. The method of any one of [1] to [15], wherein the ADC dose is administered to the human subject once or twice weekly according to a schedule having a cycle selected from the group consisting of: (i) weekly; (ii) every other week; (iii) one week of treatment followed by two, three, or four weeks of rest; (iv) two weeks of treatment followed by one, two, three, or four weeks of rest; (v) three weeks of treatment followed by one, two, three, four, or five weeks of rest; (vi) four weeks of treatment followed by one, two, three, four, or five weeks of rest; (vii) five weeks of treatment followed by one, two, three, four, or five weeks of rest; and (viii) monthly. 17. The method of any one of [1] to [15], wherein the ADC dose is administered to the human subject once weekly according to a schedule having a cycle selected from the group consisting of: (i) weekly; (ii) every other week; (iii) one week of treatment followed by two, three, or four weeks of rest. 18. The method of any one of [16] to [17], wherein the cycle is repeated 2, 4, 6, 8, 10, 12, 16, or 20 times. 19. The method of any one of [1] to [18], wherein the human subject has previously been treated with at least one anticancer therapy. 20. The method of [19], wherein the at least one anticancer therapy comprises treatment with a chemotherapy agent. 21. The method of any one of [19] to [20], wherein the human subject was refractory to the at least one anticancer therapy prior to treatment with the ADC. 22. The method of any one of [1] to [21], wherein the treatment with the ADC results in a reduction in size of the solid tumor of at least 15%, at least 20%, at least 30%, at least 40%, or at least 50%. 23. The method of any one of [1] to [22], wherein the ADC is administered in combination with one or more therapeutic modalities selected from the group consisting of: unconjugated antibodies, radiolabeled antibodies, drug-conjugated antibodies, toxin-conjugated antibodies, gene therapy, chemotherapy, therapeutic peptides, cytokine therapy, oligonucleotides, localized radiation therapy, surgery, and interfering RNA therapy. 24. The method of any one of [1] to [23], wherein the ADC is administered in combination with a platinum-based chemotherapy. 25. The method of [24], wherein the ADC is administered in combination with carboplatin. 26. The method of any one of [1] to [23], wherein the ADC is administered in combination with a VEGF antagonist-based chemotherapy. 27. The method of [26], wherein the ADC is administered in combination with bevacizumab. 28. The method of any one of [1] to [23], wherein the ADC is administered in combination with a PD-1 inhibitor. 29. The method of [28], wherein the ADC is administered in combination with pembrolizumab. 30. The method of any one of [1] to [29], wherein the treatment outcome of the individual is improved. 31. The method of [30], wherein the improved treatment outcome is an objective response selected from the group consisting of stable disease, partial response, and complete response. 32. The method of [31], wherein the improved treatment outcome is a reduction in tumor burden. 33. The method of [31], wherein the improved treatment outcome is progression-free survival or disease-free survival. 34. The method of any one of [1] to [15], wherein the ADC is administered to the human subject once every three weeks. 35. A method for treating a solid tumor, comprising administering to a human subject having a solid tumor the antibody-drug conjugate (ADC) rinatabart sesutecan (Rina-S) and any one of the following: (i) a platinum-based chemotherapy; (ii) an anti-angiogenic agent; (iii) a PARP inhibitor; or (iv) an immune checkpoint inhibitor. 36. The method of [35], comprising administering to the human subject Rina-S and a platinum-based chemotherapy. 37. The method of [36], wherein the platinum-based chemotherapy is selected from carboplatin, cisplatin, and oxaliplatin. 38. The method of [37], wherein the platinum-based chemotherapy is carboplatin. 39. The method of [35], comprising administering to the human subject Rina-S and an anti-angiogenic agent. 40. The method of [39], wherein the anti-angiogenic agent is an anti-VEGF antibody. 41. The method of [40], wherein the anti-VEGF antibody is bevacizumab. 42. The method of [35], comprising administering to the human subject Rina-S and a PARP inhibitor. 43. The method of [42], wherein the PARP inhibitor is olaparib. 44. The method of [35], comprising administering to the human subject Rina-S and an immune checkpoint inhibitor. 45. The method of [44], wherein the immune checkpoint inhibitor is a PD-1 or PD-L1 immune checkpoint inhibitor. 46. The method of [45], wherein the immune checkpoint inhibitor is an anti-PD-1 antibody. 47. The method of [46], wherein the anti-PD-1 antibody is selected from the group consisting of: pembrolizumab, nivolumab, cemiplizumab, dostalimumab, retinoflavam, and toripalimab. 48. The method of [47], wherein the anti-PD-1 antibody is pembrolizumab. 49. The method of [45], wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody. 50. The method of [49], wherein the anti-PD-L1 antibody is selected from the group consisting of: atezolizumab, avelumab, and durvalumab. 51. The method of any one of [35] to [50], wherein the Rina-S is administered at a dose of between 60 mg/m ² and 180 mg/m ^2. 52. The method of any one of [35] to [50], wherein the Rina-S is administered at a dose of between about 100 mg/m ² and 140 mg/m ^2. 53. The method of any one of [35] to [50], wherein the Rina-S is administered at a dose of 100 mg/m ^2. 54. The method of any one of [35] to [50], wherein the Rina-S is administered at a dose of 120 mg/m ^2. 55. The method of any one of [1] to [54], wherein the Rina-S is administered to the subject by intravenous administration. 56. The method of any one of [35] to [55], wherein the Rina-S is administered to the subject once every three weeks (Q3W). 57. The method of any one of [35] to [43] or any one of [51] to [56], wherein the human subject has ovarian cancer. 58. The method of any one of [35] to [56], wherein the human subject has endometrial cancer. 59. The method of any one of [35] or [44] to [56], wherein the human subject has lung cancer. 60. The method of any one of [35] or [44] to [56], wherein the human subject has colorectal cancer. 61. A method for treating a solid tumor, the method comprising administering to a human subject having the solid tumor an antibody-drug conjugate (ADC), wherein the ADC has the following structure (Structure 1): wherein Ab is a folate receptor 1 (FOLR1)-binding antibody comprising a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH and VL regions have the amino acid sequences set forth in SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8, and wherein the ADC is administered at a dose of between about 40 mg/m ² and 200 mg/m ² . 62. A method for treating cancer comprising a solid tumor, the method comprising administering to a human subject having cancer an antibody-drug conjugate (ADC), the ADC having structure 1, wherein Ab is a FOLR1-binding antibody comprising a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region and the VL region have the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8, and wherein the ADC is administered at a dose of between about 40 mg/ ^m2 and 200 mg/ ^m2 . 63. An ADC having structure 1, wherein Ab is a FOLR1-binding antibody comprising a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH and VL regions have the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8, and wherein the ADC is for use in a method of treating a solid tumor, the method comprising administering to a human subject having the solid tumor a dose of the ADC between about ⁴⁰ mg/m2 and 200 mg/ ^m2 . 64. An ADC having structure 1, wherein Ab is a FOLR1-binding antibody comprising a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region and the VL region have the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8, and wherein the ADC is for use in a method of treating cancer comprising a solid tumor, the method comprising administering to a human subject having the cancer a dose of between about 40 mg/m ² and 200 mg/m ² of the ADC. 65. Use of an ADC having structure 1 in the manufacture of a medicament for treating a solid tumor, wherein Ab is a FOLR1-binding antibody comprising a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH and VL regions have the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8, wherein the medicament is administered to a human subject having a solid tumor at an ADC dose of between about 40 mg/ ^m2 and 200 mg/ ^m2 . 66. Use of an ADC having structure 1 in the manufacture of a medicament for treating cancer comprising a solid tumor, wherein the Ab is a FOLR1-binding antibody comprising a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH and VL regions have the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8, wherein the medicament is administered to a human subject having cancer at an ADC dose of between about 40 mg/ ^m2 and 200 mg/ ^m2 . 67. The method, ADC for use in a method, or use of any one of [61] to [66], wherein the solid tumor is folate receptor 1 (FOLR1) positive. 68. The method, ADC for use in a method, or use of [67], wherein the solid tumor is determined to be FOLR1 positive by a test approved by a regulatory agency before the ADC is administered to the human subject. 69. The method, ADC for use in a method, or use of any one of [61] to [66], wherein no step of determining the amount of FOLR1 expression has been performed before the ADC is administered to the human subject. 70. The method, ADC for use in a method, or use of any one of [61] to [69], wherein the ADC is administered at a dose of between 60 mg/ ^m2 and 140 mg/ ^m2 . 71. The method, ADC for use in a method, or use of any one of [61] to [70], wherein the ADC is administered at a dose of 100 mg/ ^m2 . 72. The method, ADC for use in a method, or use of any one of [61] to [70], wherein the ADC is administered at a dose of 120 mg/m ^2. 73. The method, ADC for use in a method, or use of any one of [61] to [72], wherein the human subject has a cancer selected from the group consisting of ovarian cancer, endometrial cancer, breast cancer, lung cancer, and mesothelioma. 74. The method, ADC for use in a method, or use of any one of [61] to [73], wherein the human subject has ovarian cancer. 75. The method, ADC for use in a method, or use of any one of [74], wherein the subject has platinum-resistant ovarian cancer (PROC). 76. The method, ADC for use in a method, or use of any one of [74], wherein the subject has platinum-sensitive ovarian cancer (PSOC). 77. The method, ADC for use in a method, or use of any one of [61] to [73], wherein the human subject has endometrial cancer. 78. The method, ADC for use in a method, or use of any one of [61] to [77], wherein the ADC is administered to the subject once every three weeks (Q3W). 79. The method, ADC for use in a method, or use of any one of [61] to [78], wherein the Ab is an IgG1 antibody comprising an Fc domain having one or more amino acid substitutions that reduce IgG Fc receptor (FcγR) binding compared to an IgG1 constant region having the amino acid sequence set forth in SEQ ID NO: 3. 80. The method, ADC for use in a method, or use of [79], wherein the antibody comprises the substitutions L234A and L235A (LALA) according to EU numbering according to Kabat. 81. The method, ADC for use in a method, or use of any one of [61] to [80], wherein the Ab comprises a heavy chain comprising SEQ ID NO: 6 and a light chain comprising SEQ ID NO: 5. 82. The method, ADC for use in a method, or use of any one of [61] to [80], wherein the Ab comprises a heavy chain comprising SEQ ID NO: 4 and a light chain comprising SEQ ID NO: 5. 83. The method, ADC for use in a method, or use of any one of [61] to [82], wherein the method further comprises administering to the human subject any of the following: (i) a platinum-based chemotherapy, (ii) an anti-angiogenic agent, (iii) a PARP inhibitor, or (iv) a checkpoint inhibitor, or wherein the use is for manufacturing a medicament for administering to the human subject the ADC, and further administering to the human subject any of the following: (i) a platinum-based chemotherapy, (ii) an anti-angiogenic agent, (iii) a PARP inhibitor, or (iv) an immune checkpoint inhibitor. 84. The method, ADC for use in a method, or use of [83], wherein the method further comprises administering to the human subject carboplatin, or wherein the use is for manufacturing a medicament for administering to the human subject the ADC and carboplatin. 85. The method, ADC for use in a method, or use of [83], wherein the method further comprises administering bevacizumab to the human subject, or wherein the use is for manufacturing a medicament for administering the ADC and bevacizumab to the human subject. 86. The method, ADC for use in a method, or use of [83], wherein the method further comprises administering olaparib to the human subject, or wherein the use is for manufacturing a medicament for administering the ADC and olaparib to the human subject. 87. The method, ADC for use in a method, or use of [83], wherein the method further comprises administering an anti-PD-1 antibody or an anti-PD-L1 antibody to the human subject, or wherein the use is for manufacturing a medicament for administering the ADC and an anti-PD-1 antibody or an anti-PD-L1 antibody to the human subject.

Abbreviation

CNS: Central nervous system

HIV: Human immunodeficiency virus

IHC: Immunohistochemistry

EOC: epithelial ovarian cancer

FRα: Folate receptor α (also known as "FOLR1")

HER2: human epidermal growth factor receptor 2

HR: hormone receptor

NSCLC: non-small cell lung cancer

RECIST: Response Evaluation Criteria in Solid Tumors

TRAE: Treatment-related adverse event

ECOG: Eastern Coast Collaborative on Cancer Clinical Research Group Example 1 : Recruiting patients for Study 1

Table 1 shows the individual inclusion and exclusion criteria. Twenty-three patients were treated with Rina-S. Table 2 shows patient trends and demographics.

A total of 23 individuals were enrolled, ranging in age from 43 to 87 years. Of these, 21 were female, 18 were White, 3 were Asian, 1 was Black or African American, and 1 was other. Table 3 shows the baseline characteristics of the patients. Example 2 : Safety, Tolerability, and Maximum Tolerated Dose (MTD) Testing of Rina-S

The objectives of Study 1 were to determine the safety, tolerability, and maximum tolerated dose (MTD) of rinatabart sesutecan (Rina-S; PRO1184).

Figure 1 shows the design of Study 1, which used the PRO1184-001 dosing schedule. Part A (dose escalation) included five tumor types. Part B (dose expansion) included four tumor-specific cohorts and one basket cohort. Five patients with different cancers were administered escalating doses of Rina-S over 21 days, ranging from 60 mg/m ² to a maximum treatment dose of 180 mg/m ² at the end of the study. Study 1 included four tumor-specific cohorts and one basket cohort (ovarian cancer).

Safety assessments included physical examinations, vital signs and measurements, standard clinical laboratory assessments (e.g., hematology, blood chemistry), and monitoring for adverse events and serious adverse events. Table 4 shows a summary of the safety data.

Rina-S was well tolerated at doses up to 120 mg/m ² (140 mg/m ² is under evaluation), with common adverse events including hematologic cytopenias, gastrointestinal adverse events, and fatigue. Most TRAEs were mild or moderate. Eight (34.8%) patients experienced treatment-related adverse events of grade 3 or higher. Three patients experienced serious adverse events (SAEs) related to treatment, all of which were cytopenias. Dose-limiting toxicities were observed at doses of 140 mg/m ² and 180 mg/m ² , all of which were hematologic cytopenias. No interstitial lung disease/pneumonitis, infusion-related reactions, or keratopathy were observed.

The most common treatment-related adverse events (AEs) were nausea (n=5), decreased white blood cell count (n=3), and fatigue, decreased lymphocyte count, and decreased neutrophil count (n=2 each); most events were Grade 1 or 2. ^Two patients receiving 120 mg/m2 reported Grade ≥ 3 hematologic AEs. No treatment-related ocular toxicity or interstitial lung disease was observed. No DLTs were observed. Example 3 : Determination of the Antitumor Activity of Rina-S in Study 1

Fifteen patients underwent at least one post-baseline scan tumor assessment. Ten patients were considered evaluable for response (with a baseline scan and at least one post-baseline tumor assessment). Treatment duration ranged from 0.6 weeks to 31.0 weeks. 17 of 23 patients remain on treatment. Figure 2 shows the best change from baseline in target lesion tumor burden for ovarian and endometrial cancer. Figure 3 shows the percentage change in tumor size over time for ovarian and endometrial cancer. Figure 4 shows the reduction in CA-125 levels.

The overall response rate was 20.0% (95% CI: 2.5, 55.6), with two patients having partial responses (including one confirmed response) and four patients having stable disease (including one confirmed response). Antitumor responses appeared to deepen over time.

In this heavily pretreated patient population, Rina-S demonstrated encouraging anti-tumor activity across the full range of FOLR1 expression, with target lesion reduction in the majority of patients.

Antitumor activity was observed at both dose levels in patients with high, intermediate, and low FOLR1 expression, including a sustained confirmed partial response in one patient with endometrial cancer and a reduction in tumor measurements in another patient. Example 4 : Enrollment of patients in Study 2

Approximately 530 patients with platinum-resistant ovarian cancer (PROC) at approximately 90 sites worldwide were randomly assigned to the study. The inclusion and exclusion criteria for each patient are as follows.

Key Inclusion Criteria ˙ Patients must have histologically or cytologically confirmed well-differentiated serous or endometrioid epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. ˙ Patients must have received 1 to 4 prior lines of therapy. ˙ Patients must have previously received at least one of the following: ○ Platinum chemotherapy ○ Bevacizumab, unless the patient has a documented contraindication ○ Patients with a known or suspected deleterious germline or somatic BRCA mutation must have received treatment with a poly ADP-ribose polymerase (PARP) inhibitor ○ Sometuximab, if: ¡ Sometuximab is available in the registration region, and ¡ Patients who test positive for FRα according to an FDA-approved (or local equivalent) test are eligible, and ¡ Patients do not have documented medical abnormalities, including chronic corneal disease, a history of corneal transplantation, or active ocular diseases requiring ongoing treatment/monitoring, such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, optic disc edema, and/or monocular vision. Note: Diagnostic testing (e.g., for FRα and BRCA) should be performed in a Clinical Laboratory Improvement Amendments (CLIA; or local equivalent)-certified laboratory using tests approved by the relevant regulatory agency (FDA or local equivalent). Patients must have platinum-resistant disease: ○ Patients who received only 1 line of platinum-based therapy must have received at least 4 cycles of platinum therapy and must have had a response (complete response [CR] or partial response [PR]) after the start of platinum-based therapy and then worsened between >91 days and ≤183 days after the date of the last platinum dose. ○ Patients who received 2 to 4 lines of platinum-based therapy must have worsened 183 days or less after the date of the last platinum dose.

Key Inclusion Criteria Prior therapy with an antibody-drug conjugate containing a topoisomerase 1 inhibitor. Ovarian cancer with primary platinum-refractory disease, defined as failure to respond (CR or PR) or progression within 91 days after the last dose of a first-line platinum-containing regimen. A history of other malignancies within 3 years before the first dose of study drug, or evidence of residual disease from any previously diagnosed malignancy. Malignant tumors with negligible risk of metastasis or death (e.g., 5-year OS ≥ 90%) are excluded, including, but not limited to, adequately treated cervical carcinoma in situ, non-melanoma skin cancer, ductal carcinoma in situ, or stage I uterine cancer. Known active central nervous system metastases or carcinomatous meningitis. Patients who have previously received treatment for brain metastases may participate, provided they are clinically stable for at least 4 weeks prior to study entry after treatment for brain metastases, have no new or enlarged brain metastases, and have discontinued prescribed corticosteroids and anticonvulsants for symptoms related to brain metastases for at least 7 days prior to the first dose of study drug. Patients with suspected brain metastases at screening should undergo a brain computed tomography (CT)/magnetic resonance imaging (MRI) prior to study entry. Hospitalization or clinical symptoms for gastrointestinal obstruction within the past 91 days, or radiographic evidence of gastrointestinal obstruction at screening. Patients currently requiring parenteral nutrition must discuss eligibility with the study medical monitor at the time of enrollment. Ascites requiring frequent paracentesis (approximately every 4 weeks or more frequently) for symptomatic management. Patients with an indwelling peritoneal catheter must discuss eligibility with the study medical monitor at the time of enrollment.

The 530 PROC patients were comprised of approximately 420 patients whose tumors did not have high FRα expression (i.e., FRα expression <75% PS2+) according to the Ventana FOLR1-2.1 RxDx assay (or local equivalent), who had previously received sutoxab, and who were not suitable for sutoxab due to health conditions; and approximately 110 patients with high FRα expression (i.e., FRα expression ≥75% PS2+), who had not previously received sutoxab but were registered in regions where sutoxab was not available. Example 5 : Test product, dose, and administration mode for Study 2

Rinatabart Sesutecan (Rina-S): Rina-S will be administered on day one of a 21-day treatment cycle. Rina-S will be administered as a 30-minute intravenous (IV) infusion.

Investigator's Choice (IC) Therapy: Patients will receive one of the following chemotherapy regimens for 4 weeks at the investigator's discretion: Paclitaxel 80 mg/ ^m² administered as a 1-hour intravenous infusion every 4 weeks (Q4W) on days 1, 8, and 15; Topotecan 4 mg/ ^m² administered as a 30-minute intravenous infusion Q4W on days 1, 8, and 15, or Topotecan 1.25 mg/ ^m² administered as a 30-minute intravenous infusion Q3W on days 1 to 5; Pegylated liposomal doxorubicin (PLD) 40 mg/ ^m² administered as a 1-hour intravenous infusion Q4W on day 1; mg/min as an intravenous infusion. After the first cycle, the drug can be administered as a 1-hour infusion; and gemcitabine 1000 mg/ ^m2 or 800 mg/ ^m2, at the investigator's discretion, is administered as a 30-minute intravenous infusion every 4 weeks on days 1, 8, and 15.

The expected duration of treatment is 4 to 6 months (duration of treatment is expected to vary for each patient). Patients will continue to receive study drug until the first occurrence of disease worsening, unacceptable toxicity, investigator decision, withdrawal of consent, pregnancy, death, or early termination of the study by the sponsor. If the investigator believes the patient is clinically stable, patients with ambiguous worsening results may be allowed to continue using study drug with the approval of the medical monitor. If worsening is clearly confirmed at the next response assessment, the study drug will be discontinued. Example 6 : Determination of the anti-tumor activity of Rina-S in Study 2 Primary endpoint of efficacy analysis : PFS as assessed by the investigator

This study was designed to assess PFS in patients with PROC who received either Rina-S or IC, with the hypothesis that Rina-S would be superior to IC in terms of PFS. The study would be considered to have met this objective if Rina-S was superior to IC in terms of PFS using PAS at the final PFS analysis.

PFS was defined as the time from randomization to the first documented progressive disease (PD) according to RECIST v1.1 as assessed by the investigator, or to death from any cause, whichever came first.

The nonparametric Kaplan-Meier method will be used to estimate the PFS curve for each treatment group. The median PFS and its two-sided 95% confidence interval (CI) will be calculated using the complementary log-log transformation (Collett, London: Chapman & Hall, pp. 237-251 (1994)). Treatment differences in PFS will be assessed using a hierarchical log-rank test. The magnitude of the treatment difference (i.e., hazard ratio) between treatment groups will be assessed using a hierarchical Cox proportional hazards model with Efron's method of tie handling. The hazard ratio and its 95% CI from the hierarchical Cox model with Efron's method of tie handling and a single treatment covariate are reported. The same hierarchical factors used for randomization will be applied in the hierarchical log-rank test and hierarchical Cox model.

Because progression is assessed regularly, PD may occur at any time between the last assessment in which PD was not documented and the assessment in which PD was documented. For the primary analysis, for patients with PD, the true date of disease progression will be close to the date of the first assessment in which PD was objectively documented using RECIST v1.1, regardless of whether study drug was discontinued.

PFS is calculated as follows: PFS (days) = (date of first recorded PD or death - date of randomization) + 1

Patients without documented PD or death will be reviewed on the date of the last disease assessment. Patients who receive anticancer therapy other than study drug or are removed from the study before tumor progression is documented will also be reviewed for PFS if they do not have documented PD or death on the date of the last disease assessment. If a patient does not undergo any on-study tumor assessment, PFS will be reviewed on Day 1.

PFS by BICR will be analyzed using the same approach as for the sensitivity analysis. In addition, the agreement between the investigator-assessed and BICR-assessed PD assessments will be assessed. Discrepancies between the investigator-assessed and BICR-assessed review status, time to PD, and time to review will be tabulated, and the discrepant data will be listed. Primary Secondary Endpoint: Overall Survival

OS is defined as the time from randomization to death from any cause. OS is calculated as follows: OS (days) = (date of death - date of randomization + 1).

Surviving patients (without OS events) will be censored at the last known date of survival.

OS curves for each treatment group will be estimated using the nonparametric Kaplan-Meier method. Median OS and its two-sided 95% confidence interval (CI) will be calculated using the complementary log-log transformation (Collett, London: Chapman & Hall, pp. 237-251 (1994)). Treatment differences in OS will be assessed using a stratified log-rank test. The magnitude of the treatment difference (i.e., hazard ratio) between treatment groups will be assessed using a stratified Cox hazard ratio model with Efron's treatment method. Hazard ratios and their 95% CIs from this stratified Cox model with Efron's parallel value treatment method and a single treatment covariate are reported. The same stratification factors used for randomization were applied in the hierarchical log-rank test and the hierarchical Cox model. Kaplan-Meier estimates of 12-month OS rates were compared between the Rina-S group and the IC group, and the hazard ratios were investigated over time.

ORR was defined as the percentage of patients with a best response of confirmed CR or PR using RECIST v1.1. The primary analysis of ORR was the investigator-assessed response, while the response based on BICR (including CA-125 status normalized to CR) was included as a sensitivity analysis.

If the primary analysis was positive for both PFS and OS as assessed by the investigator, a final analysis of ORR as assessed by the investigator was performed. The following hypothesis was tested at a one-sided alpha level of 0.025: _H0 : ORR _Rina-S = ORR _IC vs _Ha : ORR _Rina-S > ORR _IC , where ORR _Rina-S is the ORR in the Rina-S group and ORR _IC is the ORR in the IC group.

ORR will be analyzed using the Cochran-Mantel-Haenszel (CMH) test (Cochran, Biometrics 10, 417-451 (1954); Mantel and Haenszel, J Natl Cancer Inst 22, 719-748 (1959)), which stratifies by randomized factor to test for differences between the Rina-S and IC groups. P values, odds ratios, and 95% confidence intervals (CIs) will be reported. 95% CIs for ORR by treatment group will also be provided based on the Clopper-Pearson method (Clopper and Pearson, Biometrika 26, 404-413 (1934)). The PAS population will serve as the primary population for ORR, and supportive analyses of ORR will be conducted using patients from the ITT and EE analysis sets.

ORR according to BICR will be analyzed as a sensitivity analysis using the same PAS-based approach. In addition, the concordance between the investigator-assessed and BICR-assessed best overall response (BOR) will be assessed. Discrepancies in BOR and time to BOR between the investigator-assessed and BICR-assessed estimates will be tabulated, and discrepant data will be presented.

The primary endpoint of this study was investigator-assessed PFS, with investigator-assessed OS and ORR as key secondary endpoints.

The primary analysis will be conducted on the primary analysis set (PAS). This analysis set excludes patients with high FRα expression who were candidates for sutomicin but did not receive prior treatment because they were registered in regions where sutomicin is not available. Approximately 80% of the study population is expected to be included in the PAS.

The sample size calculation for the final PFS analysis (primary PFS analysis) was focused on demonstrating superior PFS in the Rina-S group compared to the IC group and was based on the following assumptions: PFS follows an exponential distribution, with a median of 4 months in the IC group The hazard ratio between the Rina-S group and the IC group was 0.67 (corresponding to a median PFS of 6 months in the Rina-S group) The enrollment period for the approximately 530 patients was 21 months, resulting in approximately 420 patients in the primary cohort.

The annual review rate for PFS was 10%. The PFS hazard ratio for hypothesis testing proposed in this study was 0.67, corresponding to an approximately 2-month increase in median PFS assuming an exponential distribution, which is considered clinically significant. Among patients with PROC, increased PFS was associated with reduced tumor-related symptoms, improved patient-reported outcomes, and increased overall survival.

With 262 PFS events, the study had 90% power to demonstrate superiority of the Rina-S arm over the IC arm at a one-sided α = 0.025, with a true hazard ratio of 0.67. To ensure adequate follow-up of treated patients, the primary PFS analysis will be conducted when at least 262 PFS events have occurred and patients in the PAS have had the opportunity to be followed for at least 3 months after randomization (or if PD, death, or study withdrawal is documented within 3 months of randomization).

If the primary endpoint of PFS is statistically significant at a one-sided alpha level of 0.025, a hierarchical testing procedure will be used to test two key secondary endpoints in the following order at a one-sided alpha level of 0.025 to control for the overall study type I error rate. ˙   OS ˙   ORR as assessed by the investigator according to RECIST v1.1.

The key secondary endpoint of OS will be tested only after PFS is declared positive. An interim analysis of OS will be performed at that time (approximately 131 OS events [53%] are expected), and a final analysis of OS will be conducted when at least 248 OS events have occurred or at the end of the study, when all treated patients have had the opportunity to be followed for at least 3 years after randomization, have died, or have withdrawn from the study, whichever comes first. The O’Brien-Fleming spending function will be applied to these two OS analysis time points at a one-sided alpha level of 0.025. The exact alpha allocation at the interim analysis of OS depends on the number of OS events that have accumulated at that time. With 248 OS events, the study had 80% power to show superiority of the Rina-S arm over the IC arm at a one-sided α of 0.025, with a true hazard ratio of 0.70. Furthermore, the sample size calculation for the OS analysis assumed a median OS of 13 months for the IC arm, an annualized review rate of 2%, and the same enrollment schedule as specified in the sample size calculation for the PFS analysis.

The investigator-based ORR will be tested after the efficacy threshold for OS has been crossed. Because all patients will be enrolled at that time, the following hypothesis will be tested at a unilateral 2.5% level, without applying the group ordinal spending function: H ₀ : ORR _Rina-S = ORR _IC vs H _a : ORR _Rina-S > ORR _IC , where ORR _Rina-S is the ORR in the Rina-S group and ORR _IC is the ORR in the IC group.

Assuming a true ORR _Rina-S of 30% and a true ORR _IC of 16%, a sample size of approximately 420 patients (210 patients/group) would provide approximately 93% power to detect a 14% difference in ORR (30% vs 16%) using the method of Farrington and Manning (Farrington and Manning, Stat Med 9, 1447-1454 (1990)), which is used in studies to test for differences between two binomial event rates.

The sample size calculations for PFS, OS, and ORR were performed using the gsDesign package in R. Example 7 : Dose escalation and dose expansion in Study 1

As a continuation of Study 1, 53 patients were treated in Part A (dose escalation), regardless of FRα expression, including 32 patients previously treated for ovarian cancer (OC), 11 patients previously treated for endometrial cancer (EC), and 10 patients with other tumor types (NSCLC, breast cancer, and mesothelioma). The median number of prior therapies for patients with ovarian cancer and endometrial cancer was 5 (1 to 14) and 3 (1 to 14), respectively. 75% of patients with ovarian cancer had previously received bevacizumab, and 91% were platinum-resistant. All patients with endometrial cancer received a PD-1 inhibitor. Rina-S doses ranging from 60 to 180 mg/m ² were evaluated in Part A. The MTD was 140 mg/m ² . Doses of 100 and 120 mg/m ² were selected for evaluation in Part B (dose escalation).

In Part B, 35 patients with ovarian cancer and 13 patients with endometrial cancer were treated. The median number of prior therapies for patients with ovarian cancer and endometrial cancer was 3 (1 to 4) and 3 (1 to 7), respectively.

Planned tumor-specific dose expansion includes OC, EC, and EGFR-mutant NSCLC, regardless of FRα expression (FRα levels were retrospectively assessed). Patients with ovarian cancer in Part B (Arm B1, ovarian cancer dose expansion) were randomized 1:1 to receive either Rina-S 100 mg/ ^m² or Rina-S 120 mg/ ^m² . Inclusion criteria for Arm B1 are shown below. 1) Histologically or cytologically confirmed OC (must be epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer) 2) Prior treatment (PROC using 1 to 3 or 4 lines, regardless of platinum sensitivity status) 3) ECOG PS 0-1 4) Measurable disease according to RECIST v1.1 5) Adequate hematologic, liver, kidney, and cardiac function

Table 5 shows the demographic and disease characteristics of patients in group B1. Example 8 : Overall safety of Rina-S

In continuation of Study 1, in Part A patients (n=35) treated with 100 or 120 mg/ ^m2 , the most common (>20%) treatment-related adverse events (TRAEs) were nausea (n=20.57%), neutropenia (n=18.51%), leukopenia (n=16.46%), anemia (n=15.43%), thrombocytopenia (n=11.31%), and vomiting (n=9.26%); most events were Grade 1/2. The most common (>10%) >Grade 3 TRAEs were neutropenia (n=12.34%), anemia (n=9.26%), leukopenia (n=8.23%), and thrombocytopenia (n=5.14%). Table 6 shows the overall safety profile of the B1 group. With OC dose escalation at 100 and 120 mg/ ^m² , any-grade and Grade 3-4 TEAEs were reported in 100% and 60% to 63.6% of patients, respectively. TEAEs leading to dose reduction occurred in 11.1% to 16.2% of patients; the safety profile was similar between groups. Figure 5 shows the detailed overall safety profile.

As a result, no ocular toxicity, neuropathy or interstitial lung disease was observed. The safety profile of Rina-S presented in Part B was consistent with that in Part A. Example 9 : Determination of the antitumor activity of Rina-S in Study 1

As a continuation of Study 1, the antitumor activity of Rina-S was evaluated in dose escalation and dose expansion.

In Part A (dose escalation), Rina-S demonstrated encouraging antitumor activity in heavily pretreated patients with OC and EC. Table 7 shows the antitumor activity results from Part A. Figure 6 shows the optimal change in target lesions with dose escalation of OC and EC.

In Part B, Rina-S at 120 mg/ ^m² demonstrated encouraging antitumor activity, including complete responses in heavily pretreated OC patients. Table 8 shows the antitumor activity results for the B1 arm of Part B. Treatment duration ranged from 3.0 to 42.0+ weeks. The median follow-up duration in the study was 24 weeks. Figure 7 shows the optimal change in target lesions with OC dose escalation.

As shown in Figure 8, in heavily pretreated patients, most responses with Rina-S 120 mg/m ² were observed early (week 6), and all confirmed responses with 120 mg/m ² were ongoing at the time of data cutoff. As shown in Figure 9, responses in OC patients were observed across the full range of FRα expression levels. Example 9 : In vitro activity of combinations of Rina-S with standard of care treatments

Cells were plated at an appropriate density in 96-well plates (flat-bottom wells) for the cell line (typically 1,000 to 3,000 cells per well in 100 µL of appropriate medium). After overnight incubation, cells were treated with increasing concentrations of Rina-S, carboplatin, or olaparib alone, or in combination with Rina-S and carboplatin (12.5 μM) or olaparib (30 μM) (concentrations selected based on IC50 values). Cell viability was assessed after 4 days. Cell-Titer Glo (Promega, CAT# G7572) was added to the wells, and luciferase readings were collected 5 minutes later and analyzed using a microplate reader. All readings were normalized to the percentage of viable cells in untreated control wells, and _IC50 values were calculated using GraphPad Prism® software.

As shown in Figures 10A and 10B, the combination of Rina-S and platinum did not enhance the cytotoxicity of Rina-S against OVCAR-8, while the combination of Rina-S and olaparib enhanced the cytotoxic effect of Rina-S against HEC-1-A. Example 10 : Characteristics of immunogenic cell death (ICD) induced by exitecan and Rina-S

The characteristics of ICD induced by Rina-S and exitecan were evaluated in FOLRα-positive cells. KB and 3LL-FRα were seeded at 5×10 ³ cells per well in 96-well plates (for ATP and HMGB1 detection) or 4×10 ⁴ cells per well in 24-well plates (for cell surface calcification detection) and incubated overnight at 37°C. The plates used had flat-bottomed wells. To measure extracellular ATP (adenosine triphosphate) and HMGB1 (high mobility group box 1), the cell supernatant was removed and 200 μL of serially diluted Rina-S (10-fold dilution; 1000 to 0.1 nM) or exotecan (10-fold dilution; 800 to 0.8 nM) was added to the wells and incubated for 24 to 72 hours. ATP and HMGB1 released into the supernatant were detected using the CTG kit (Promega; catalog number: G7572) and the Lumit HMGB1 immunoassay kit (Promega; catalog number: W6112), respectively. For cell surface calcification detection, the cell supernatant was removed, and 500 μL of serially diluted Rina-S (10-fold dilution; 100 to 1 nM) or exotecan (10-fold dilution; 80 to 0.8 nM) was added to the wells and incubated for 48 hours. Cell surface calcification was detected by flow cytometry using an anti-calcification monoclonal antibody (Enzolifesciences; Catalog No.: ADI-SPA-601PE-D).

Rina-S and ixitecan upregulated ICD biomarkers in FOLRα-positive cells in a concentration-dependent manner, as shown in Figures 11A to 11F. Example 11 : Anti-tumor activity of the combination of Rina-S and SoC in an in vivo mouse model

Combinations of Rina-S with carboplatin, bevacizumab, olaparib (PARPi), or immunotherapy have demonstrated potent antitumor activity. Rina-S was evaluated in combination with standard-of-care (SOC) agents in preclinical in vivo mouse models of ovarian and endometrial cancer. Approximately 15 and 17 days after tumor inoculation, mice with mean tumor sizes ranging from 100.16 to 180.86 ^mm³ were randomly assigned to four groups (n=5 to 6 per group). On day 0 or 1 after randomization (defined as day 0), mice received the indicated concentrations of the test article or PBS. Details: Female NDG (hyperimmune deficient phenotype) mice bearing established OVCAR-8 ovarian cancer xenografts (n = 6 mice/group) were treated with Rina-S (3 mg/kg, single dose) or bevacizumab (5 mg/kg, single dose) (Figure 12A); Rina-S (3 mg/kg, single dose) or carboplatin (60 mg/kg, QW*4) (Figure 12B), alone or in combination, either IV or IP. Female BALB/c nude mice (n = 5 mice/group) bearing established HEC-1-A endometrial cancer xenografts were treated with Rina-S (5 mg/kg, single dose) or olaparib (50 mg/kg, once daily for 5 days × 4 weeks), alone or in combination, either IV or via oral gavage ( Figure 12C ).

The combination of Rina-S and cancer immunotherapy drugs was evaluated in preclinical models of lung and colorectal cancer. Approximately 6 days after tumor inoculation, mice with a mean tumor size of 65-142 ^mm³ were randomly assigned to 4 or 6 groups (n=6 per group). On day 0 or 1 after randomization (defined as day 0), mice received the indicated concentrations of the test article or PBS. Details: Female C57BL/6 mice bearing established lung cancer (3LL-FRα) xenografts (n = 6 mice/group) were treated with Rina-S (2.5 mg/kg, single dose) or CS1003 (nofazinimab; anti-PD-1) (10 mg/kg, Q3D*4) IV, alone or in combination (Figure 12D). Female C57BL/6 mice bearing established MC38-FRα colorectal cancer xenografts (n = 6 mice/group) were treated with Rina-S (1.5 or 2.5 mg/kg, single dose) or CS1003 (0.5 mg/kg, Q3D*4) IV, alone or in combination (Figure 12E).

Tumor size was measured twice weekly using calipers, and tumor volume was calculated in ^mm³ using the following formula: V = ^0.5axb² , where a and b are the major and minor diameters of the tumor, respectively. The study was terminated when the tumor volume exceeded 2000 ^mm³ . Body weight was measured twice weekly. Monitoring animal weight served as an indirect measure of tolerance.

Combinations of Rina-S with carboplatin, bevacizumab, or olaparib resulted in enhanced antiproliferative effects in the OVCAR-8 and HEC-1-A in vivo models, suggesting that these combinations may have benefits in clinically relevant tumor types, such as ovarian and endometrial cancer. No significant weight loss was observed in any treatment group, and no morbidity or mortality was reported during treatment.

The combination of Rina-S and CS1003 (anti-PD-1) resulted in enhanced anti-tumor effects in 3LL-FRα and MC38-FRα in vivo models, suggesting the clinical benefit of combination therapy with Rina-S and immune checkpoint inhibitors (ICIs).

Having thus described the basic concepts, it will be apparent to those skilled in the art, after reading this detailed disclosure, that the foregoing detailed disclosure is intended to be illustrative only and not limiting. Although not expressly stated herein, various changes, improvements, and modifications may be made and are intended by those skilled in the art. Such changes, improvements, and modifications are intended to be apparent from the present invention and are within the spirit and scope of the exemplary embodiments of the present invention.

Furthermore, certain terms have been used to describe embodiments of the present invention. For example, the terms "one embodiment," "an embodiment," and "some embodiments" mean that a particular characteristic, structure, or feature described in connection with that embodiment is included in at least one embodiment of the present invention. Therefore, it is emphasized and understood that two or more references to "one embodiment," "an embodiment," or "an alternative embodiment" in different sections of this patent specification do not necessarily refer to the same embodiment. Furthermore, particular characteristics, structures, or features may be appropriately combined in one or more embodiments of the present invention.

Furthermore, those skilled in the art will appreciate that many aspects of the present invention may be illustrated and described herein in any of the many patentable classes or contexts, including any new and useful process, machine, manufacture or composition of matter, or any new and useful modification thereof.

Furthermore, the order in which elements or sequences of processes are listed, or the use of numbers, letters, or other designations, is not intended to limit the processes and methods of the claimed invention to any order except as may be specifically specified in the claims. While the foregoing disclosure has been discussed in terms of various examples of what are presently considered to be several useful embodiments of the invention, it should be understood that such details are intended solely for that purpose and that the appended claims are not limited to the disclosed embodiments, but rather are intended to cover modifications and equivalent arrangements within the spirit and scope of the disclosed embodiments.

Similarly, it should be understood that in the foregoing description of the embodiments of the present invention, various features are sometimes grouped together in a single embodiment, its drawings, or description to simplify the invention and aid in understanding one or more of the various embodiments. However, this method of invention should not be interpreted as reflecting an intention that the subject matter of the claimed invention requires more features than those expressly recited in the various claims of the claimed invention. Rather, the subject matter of the claimed invention may include fewer features than all of the features of a single embodiment disclosed above.

The present invention is further described with reference to exemplary embodiments. These exemplary embodiments are described in detail with reference to the accompanying drawings. It should be noted that these drawings are not drawn to scale. These embodiments are non-limiting exemplary embodiments, wherein like reference numerals throughout the several views of the drawings represent similar structures, and wherein:

Figure 1 shows a graphic illustrating the PRO1184-001 dosing schedule for Study 1.

Figure 2 shows a graph illustrating the change in target lesion tumor burden relative to baseline.

Figure 3 shows the percentage change in tumor size over time at each dose level.

Figure 4 shows a graph illustrating the reduction in CA-125 (cancer antigen 125) levels in each individual.

Figure 5 shows a graphical representation of treatment-emergent adverse events (TEAEs) in the Rina-S 100 mg/m ² and Rina-S 120 mg/m ² groups.

Figure 6 shows the graph of the best change in target lesions (best change in sum of tumor diameters from baseline) for patients with ovarian and endometrial cancer.

Figure 7 shows the best change in target lesions (best change in sum of tumor diameters from baseline) in ovarian cancer patients treated with Rina 100 mg/m ² or Rina-S 120 mg/m ² .

Figure 8 shows the treatment response over time in patients with ovarian cancer treated with Rina 100 mg/m ² or Rina-S 120 mg/m ^2. One patient in the 120 mg/m ² group who had previously received sometuximab was not evaluable for response. Reasons for discontinuation included elevated alanine aminotransferase (n=1; unrelated to treatment), decreased neutrophil count (n=1; related to treatment), small intestinal perforation (n=1; unrelated to treatment), and rectal bleeding (n=1; unrelated to treatment). CR: complete response, MIRV: somituximab, OC: ovarian cancer, PD: progressive disease, PR: partial response, Rina-S: rinatabart sesutecan, SD: stable disease, tx: treatment.

Figure 9 shows the best change in target lesions (best change in sum of tumor diameters from baseline) by FRα PS2+ status in ovarian cancer patients treated with Rina-S 100 mg/m ² or Rina-S 120 mg/m ^2. FRα: folate receptor, OC: ovarian cancer, PS: positive staining, SoD: sum of diameters, Rina-S: rinatabart sesutecan.

Figure 10A is a graph showing the cell viability of human ovarian cancer cell line OVCAR-8 treated with Rina-S alone, olaparib alone, or a combination of the two versus drug concentration. Figure 10B is a graph showing the cell viability of human endometrial cancer cell line HEC-1-A treated with Rina-S alone, olaparib alone, or a combination of the two versus drug concentration.

Figure 11 shows graphs of various markers following treatment of KB cells (a substrain of human HeLa cells) or 3LL-FR-α cells (a mouse Lewis lung carcinoma cell line expressing FR-α) with either ixitencan or Rina-S. Figures 11A to 11C show the results of treatment of KB cells with ixitencan or Rina-S, measuring extracellular ATP (Figure 11A), the percentage of cells positive for the calreticulum (Figure 11B), and HMGB1 levels (Figure 11C). Figures 11D to 11F show the corresponding results for 3LL-FR-α cells.

Figure 12 provides graphical representations of tumor volume in mouse tumor models treated with Rina-S alone or in combination with various other cancer therapeutics, namely carboplatin ("+carbo"), bevacizumab ("+Bev"), olaparib ("+PARP"), and CS1003 (an anti-PD-1 antibody, "+IO"). Results for a PBS control group are also included in each figure. The xenograft cancers used in each model were the ovarian cancer cell line OVCAR-8 (Figures 12A and 12B), the human endometrial cancer cell line HEC-1-A (Figure 12C), mouse 3LL-FR-α Lewis lung carcinoma cells (Figure 12D), and the mouse colorectal adenocarcinoma cell line MC-38-FR-α (Figure 12E).

TW202529813A_113136785_SEQL.xml

Claims (32)

A method for treating a folate receptor 1 (FOLR1)-positive solid tumor comprises administering rinatabart sesutecan (Rina-S) at a dose of between 40 mg/ ^m2 and 200 mg/ ^m2 to a human subject having the solid tumor. The method of claim 1, wherein the solid tumor is selected from the group consisting of ovarian cancer, endometrial cancer, breast cancer, lung cancer, and mesothelioma. The method of claim 1 or 2, wherein the solid tumor is epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. The method of claim 1 or 2, wherein the solid tumor is endometrial cancer. The method of claim 1 or 2, wherein the solid tumor is ovarian cancer. The method of claim 1, wherein the solid tumor is: a) non-small cell lung cancer (NSCLC); b) breast cancer, including HER2-negative breast cancer; c) pleural mesothelioma; or d) peritoneal mesothelioma. The method of any of the preceding claims, wherein the solid tumor is a platinum-resistant tumor, optionally a well-differentiated serous or endometrioid EOC, primary peritoneal carcinoma, or fallopian tube carcinoma resistant to platinum chemotherapy. The method of any preceding claim, wherein the solid tumor is platinum-resistant ovarian cancer. The method of any one of claims 1 to 3 or 5, wherein the solid tumor is platinum-sensitive ovarian cancer. The method of any preceding claim, wherein the solid tumor is localized or metastatic; and/or wherein at least one tumor is not surgically resectable. The method of any of the preceding claims, wherein Rina-S is administered in an amount between 60 mg/m ² and 180 mg/m ² . The method of any of the preceding claims, wherein Rina-S is administered in an amount between 100 mg/m ² and 140 mg/m ² . The method of any of the preceding claims, wherein Rina-S is administered in an amount between 100 mg/m ² and 120 mg/m ² . The method of any of the preceding claims, wherein Rina-S is administered at a dose of about 100 mg/m ² . The method of any of the preceding claims, wherein Rina-S is administered at a dose of about 120 mg/m ² . The method of any of the preceding claims, wherein the Rina-S dose is administered to the human subject once or twice weekly according to a schedule having a period selected from the group consisting of: (i) weekly; (ii) every other week; (iii) one week of treatment followed by two, three, or four weeks of rest; (iv) two weeks of treatment followed by one, two, three, or four weeks of rest; (v) three weeks of treatment followed by one, two, three, four, or five weeks of rest; (vi) four weeks of treatment followed by one, two, three, four, or five weeks of rest; (vii) five weeks of treatment followed by one, two, three, four, or five weeks of rest; and (viii) monthly. The method of any one of claims 1 to 15, wherein the Rina-S dose is administered to the human subject once every three weeks (Q3W). The method of any of claims 16 to 17, wherein the cycle is repeated 2, 4, 6, 8, 10, 12, 16 or 20 times. The method of any one of claims 1 to 18, wherein the human subject has previously been treated with at least one anti-cancer therapy, optionally wherein (a) the at least one anti-cancer therapy comprises treatment with a chemotherapy agent, and/or (b) the human subject was unresponsive to the at least one anti-cancer therapy prior to treatment with Rina-S. The method of any of the preceding claims, wherein Rina-S is administered in combination with one or more therapeutic modalities selected from the group consisting of unconjugated antibodies, radiolabeled antibodies, drug-conjugated antibodies, toxin-conjugated antibodies, gene therapy, chemotherapy, therapeutic peptides, cytokine therapy, oligonucleotides, localized radiation therapy, surgery, and interfering RNA therapy. The method of any of the preceding claims, wherein Rina-S is: (a) administered in combination with a platinum-based chemotherapy, optionally in combination with carboplatin; (b) administered in combination with a VEGF antagonist-based chemotherapy, optionally in combination with bevacizumab; or (c) administered in combination with a PD-1 inhibitor, optionally in combination with pembrolizumab. The method of any of the preceding claims, wherein the subject has an improved treatment outcome, optionally wherein: (a) the improved treatment outcome is an objective response selected from: stable disease, partial response, or complete response; (b) the improved treatment outcome is a reduction in tumor burden, and/or (c) the improved treatment outcome is progression-free survival or disease-free survival. A method for treating a solid tumor comprises administering rinatabart sesutecan (Rina-S) and any of the following to a human subject having the solid tumor: (i) a platinum-based chemotherapy, such as carboplatin; (ii) an anti-angiogenic agent, such as an anti-VEGF antibody, such as bevacizumab; (iii) a PARP inhibitor, such as olaparib; or (iv) an immune checkpoint inhibitor, such as an inhibitor of the PD-1 or PD-L1 immune checkpoint proteins, such as an anti-PD-1 antibody, such as pembrolizumab. The method of any of the preceding claims, wherein Rina-S has the following structure (Structure 1): Wherein Ab is a folate receptor 1 (FOLR1)-binding antibody, the FOLR1-binding antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH region and the VL region have the amino acid sequences shown in SEQ ID NO: 1 and SEQ ID NO: 2, respectively, and wherein n is 8. The method of claim 24, wherein Ab is a FOLR1-binding antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:6 or, alternatively, SEQ ID NO:4, and a light chain comprising the amino acid sequence of SEQ ID NO:5. A method according to any of the preceding claims, wherein the Rina-S is administered to the human subject by intravenous administration. A method according to any preceding claim, wherein the amount of FOLR1 expression in the tumor has not been determined prior to administration of Rina-S. A method according to any one of claims 1 to 26, wherein the individual's tumor sample has high FOLR1 expression according to a regulatory agency-approved FOLR1 expression test, optionally the Ventana FOLR1-2.1 RxDx assay. A method according to any one of claims 1 to 26, wherein the individual's tumor sample has intermediate or low FOLR1 expression according to a regulatory agency-approved FOLR1 expression test, optionally the Ventana FOLR1-2.1 RxDx assay. A method according to any one of claims 1 to 26 and 28, wherein the human subject is not suitable for treatment with mirvetuximab soravtansine. A method of treating a solid tumor with rinatabart sesutecan (Rina-S), comprising administering to a human subject having the solid tumor an amount of between 40 mg/ ^m2 and 200 mg/ ^m2 of Rina-S, e.g., between 60 mg/ ^m2 and 140 mg/ ^m2 , e.g., 100 mg/ ^m2 or 120 mg/ ^m2 of Rina-S. A use of rinatabart sesutecan (Rina-S) in the manufacture of a medicament for treating a solid tumor, wherein the medicament is administered to a human subject having the solid tumor at a dose between 40 mg/ ^m2 and 200 mg/ ^m2 , for example, between 60 mg/ ^m2 and 140 mg/ ^m2 , for example, 100 mg/ ^m2 or 120 mg/ ^m2 .