Nabil Ismaili, Director of Medical Oncology and Radiotherapy Department at Mohammed VI University of Sciences and Health, shared on LinkedIn:
“ESMO 2026: The ADC Sequencing Dilemma – Why Switching Targets Isn’t Enough!
I just attended a fascinating Rapid Oral session on Advanced Breast Cancer presented by Prof. Sherene Loi (Peter MacCallum Cancer Centre). We are facing a massive clinical challenge: What should follow a TOP1-payload ADC (like T-DXd or Sacituzumab govitecan) in metastatic breast cancer?
The data presented today provides a crucial reality check on how we sequence these drugs.
The ‘Switch’ Strategy Fails
The SWITCH trial evaluated 4 novel TOP1 ADCs (targeting HER2, TROP2, HER3, and Nectin-4) in heavily pretreated patients (94% had prior TOP1 ADC).
- The Result: A highly disappointing confirmed ORR of 0–8%.
- The Lesson: Changing the target (the antibody) while keeping the same payload class (TOP1 inhibitor) does NOT work. The tumor has already developed payload resistance.
Switching the Payload Works Modestly
Conversely, the Buluntatug fuvedotin trial (a Nectin-4 ADC with a novel MMAE payload) showed modest but real activity in mTNBC patients (100% prior TOP1 ADC), with an ORR of 30%.
Why does Payload Resistance Dominate?
As Prof. Loi explained, most known resistance mechanisms act downstream of the antigen. This includes:
- Efflux pumps (e.g., ABCG2)
- TOP1 mutations or loss
- Enhanced DNA damage repair (DDR/HR)
Therefore, antigen expression (IHC) is a blunt tool. Responses are seen regardless of target expression levels (e.g., B7-H3 or Nectin-4 negative tumors still responded). What matters more is the bystander effect and the intrinsic sensitivity of the tumor to the specific payload.
The Urgent Call to Action
The era of simply swapping the antibody is over. As Prof. Loi concluded, there is an urgent unmet need to develop new ADCs with entirely new payloads (e.g., TopoII inhibitors, novel tubulin binders, immunomodulators) and better biomarkers (ctDNA, functional assays) rather than just chasing new targets.
For my breast oncology colleagues: How are you currently sequencing ADCs in your practice? Are you seeing clinical responses when switching from T-DXd to Sacituzumab govitecan? And how are we preparing for the next generation of payloads?”
You can also read: 25 Posts Not to Miss from ESMO Congress 2026: Day 5
