The O11 trial (Len-Belzutafan vs. Cabozantinib) presents the first randomized Phase 3 data for a VEGF/HIF inhibitor combination. Its results will be pivotal in determining if this more toxic doublet approach is justified over monotherapy for IO-refractory kidney cancer, weighing the magnitude of benefit against increased side effects.
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The O22 trial's positive result for adjuvant Pembrolizumab plus Belzutafan was unexpected, as experts believed kidney cancer recurrence was primarily immune-driven, not HIF-driven. This outcome forces a re-evaluation of the underlying biology of recurrence and suggests a significant role for HIF inhibition in the adjuvant setting.
An FDA analysis showed the survival curve for kidney cancer patients on IO-IO therapy (ipinevo) is much flatter for those with early tumor growth compared to IO-TKI regimens. This suggests early progression on a dual-mechanism IO-TKI therapy indicates true resistance, while on IO-IO it could be delayed response.
In renal cell carcinoma, Arcus's casdadafin demonstrated a 12.2-month median PFS as a monotherapy. This nearly matches the 13.7-month PFS of Merck's competitor drug, belzutafan, when used in combination. This suggests Arcus's upcoming combination data could be substantially superior.
An expert argues the path to curing metastatic cancer may mirror pediatric ALL's history: combining all highly active drugs upfront. Instead of sequencing treatments after failure, the focus should be on powerful initial regimens that eradicate cancer, even if it means higher initial toxicity.
With highly active agents yielding 30% complete response rates, the immediate goal should be to cure more patients by exploring potent combinations upfront. While sequencing minimizes toxicity, an ambitious combination strategy, such as ADC doublets, offers the best chance to eradicate disease and should be prioritized in clinical trials.
Treating 'non-clear cell' kidney cancer as a single entity is a major research limitation. Experts argue that distinct histologies like papillary and chromophobe are different diseases. Future progress requires dedicated, international trials for each subtype rather than grouping them due to rarity.
Despite strong single-agent trial results, experts believe the field is shifting away from continuous monotherapy. The most significant future impact for pirtobrutinib will likely be as a backbone of fixed-duration combination therapies with drugs like venetoclax, aiming for deeper remissions without indefinite treatment.
The failure of the Checkmate 914 adjuvant trial, which used a six-month duration of nivolumab plus ipilimumab, suggests this shorter treatment window may be inadequate. In contrast to positive trials with one year of therapy, this outcome indicates that treatment duration is a critical variable for achieving a disease-free survival benefit in the adjuvant RCC setting.
A sophisticated concern regarding the HIF-2 inhibitor belzutifan is its potential to diminish kidney cancer's antigenicity by reducing human endogenous retrovirus expression. While providing an early benefit, this could theoretically make tumors less responsive to subsequent immunotherapies, negatively impacting long-term outcomes—a critical consideration for sequencing.
Unlike VEGF TKIs that primarily target the tumor vasculature, the HIF-2 inhibitor belzutifan has a direct anti-tumor cell effect. This mechanism may be uniquely effective against micrometastatic disease, following the logic of traditional chemotherapy. This distinction could explain its surprising success in the adjuvant setting where multiple VEGF TKIs have failed.