BioLoomics

Enhertu Works Well in Breast Cancer Without Engaging the Target!?  🤔 Interesting-Yes, 😢 Generalizable-No 🙋 Most in pharma know ENHERTU®, the HER2 targeting ADC that is FDA approved for any HER2+ indication (the first drug ever to gain that status from the FDA). Although recent data (in comments section) aims to explain why ENHERTU® has high efficacy in breast cancer even in HER2 null patients, ENHERTU®’s efficacy in all other indications highlights that our best ADCs struggle to deliver enough payload outside of high expressing targets and tumors.  Let’s unpack that a bit… 👇👇👇👇 📈 ENHERTU® surprises us with efficacy: Daichii Sankyo and AstraZeneca made ENHERTU® and it created a splash in the Destiny Breast03 trial by showing 78.5% Overall Response Rate. For context, most other ADCs have 30-56% ORR. The path was clear for ENHERTU® to become the reigning queen of ADCs. ENHERTU® then went into a flurry of clinical studies (Destiny-PantumorXX, DESTINY-CRCXX, more DESTINY-BreastXX, the DAISY trial and more).  AFTER ALL THESE TESTS IN HUMANS, WHAT DID WE LEARN? 👉 ENHERTU® is like other good ADCs in most cases: the ORR maxes out in the mid 50%’s for patients with screaming high HER2 tumors, and ORR goes down variably with mid and low HER2 expressing tumors. Simply put, our best ADC struggles to deliver meaningful efficacy unless a patient's tumor is overexpressing the target (HER2 in this case).  👉 Breast cancer is a special case where ENHERTU shines and efficacy appears largely target independent. ENHERTU® works even in HER2 ultralow or null tumors…and it works well (60% ORR). We learned this in the DESTINY-Breast06 trial. A recent Duke University paper by Tsao et. al. makes the case that extracellular release of payload (DXd) drives this target independent mechanism, but it is still unclear if this mechanism will explain the human data. Lesson: ENHERTU® is great in breast cancer for high expressing HER2+ tumors, but it does not look like we can leverage its power outside of breast cancer. Interestingly, the DAISY trial shows when you give ENHERTU® to slightly sicker patients, it does not do nearly as well to shrink tumors.  SO, WHAT WILL IT TAKE TO BRING ADCs BEYOND 50-60% ORR?  💡 Innovation that delivers more payload without added toxicity: ADCs are a delivery tool and they bind receptor targets 1:1 (or even less given that IgG has two binding sites). This stoichiometry limits the total number of ADC molecules that can deliver payload to the cancer cell, as drug developers cannot change the number of receptors on the surface of tumors. If we want better ADCs, we should design new formats that free ADCs from the 1:1 binding limitation! We will explore this in future posts. #antibodydrugconjugates, #ENHERTU, #ADCs