ASCO 2025 – Exelixis’s son of Cabometyx improves
In first-line renal cancer, zanzalintinib plus Opdivo has outshone Cabometyx plus Opdivo.
In first-line renal cancer, zanzalintinib plus Opdivo has outshone Cabometyx plus Opdivo.
Earlier this year Exelixis’s next-generation tyrosine kinase inhibitor zanzalintinib disappointed in colorectal cancer, but now it has shown more promise in first-line renal cancer, ASCO heard on Saturday. Notably, on a cross-trial basis the asset looks more efficacious than Exelixis’s approved TKI Cabometyx, with lower toxicity.
Exelixis is searching for something to pick up the slack when Cabometyx comes off patent in 2030; zanzalintinib is designed to reduce adverse events, helped by its short half-life. In the uncontrolled phase 1 Stellar-002 trial’s first-line renal cohort this seemed to hold true with a zanzalintinib/Opdivo combo.
This regimen outperformed historical data with Cabometyx plus Opdivo in that regimen's approved use of first-line renal cancer, based on the Checkmate-9ER study. Zanzalintinib plus Opdivo also looked less toxic, in terms of the rate of grade 3 or 4 adverse events.
Cross-trial comparison of zanzalintinib vs Cabometyx in first-line renal cancer
Checkmate-9ER | Stellar-002 | ||
|---|---|---|---|
| Regimen | Cabometyx + Opdivo | Zanzalintinib + Opdivo | Zanzalintinib + Opdivo + relatlimab |
| ORR | 56% | 63% | 40% |
| mPFS | 16.6 months | 18.5 months | 13.0 months |
| Gr3/4 adverse events | 68% | 33% | 32% |
Source: ASCO & OncologyPipeline.
Exelixis will now have to replicate these results in an ongoing controlled trial, and also hope that this apparent benefit will be enough to convince doctors to switch to the next-generation agent.
Still, zanzalintinib plus Opdivo wasn’t without issues. The most common adverse events with the doublet were hypertension (13% at grade 3/4), diarrhoea (6% at grade 3/4) and liver enzyme elevations (5% grade 3/4 AST and ALT increases). There were two grade 4 adverse events, of subdural haematoma and urine output decrease, and two deaths, although both were deemed unrelated to study drugs.
Meanwhile, results were less impressive with a zanzalintinib/Opdivo/relatlimab triplet, which showed similar toxicity but lower efficacy than with the doublet – albeit with a shorter median follow-up time.
Exelixis’s ongoing first-line renal cancer phase 3, Stellar-304, tests zanzalintinib plus Opdivo, versus Sutent, in first-line renal cancer. Data are due in the second half of 2025.
Two more phase 3 trials of zanzalintinib are set to read out in a similar timeframe: Stellar-303 in third-line colorectal cancer (where zanzalintinib is being combined with Tecentriq, versus Stirvaga) and Stellar-305 in first-line PD-L1-positive head & neck cancer (where a Keytruda combo is going up against Keytruda alone).
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