Backed by ASCO data Arcus guns for phase 3

Fresh from a successful ASCO, during which its shares gained 14%, Arcus is starting a phase 3 trial of its HIF2α inhibitor casdatifan. This concerns PD-(L)1-relapsed kidney cancer as part of a combo with Exelixis/Ipsen's Cabometyx, and represents one setting in which casdatifan seems at last to be pulling clear of Merck & Co's marketed HIF2α inhibitor Welireg.

The phase 3 Peak-1 trial is something Arcus has spoken of several times this year, and now it's official, with a new clinicaltrials.gov listing setting a start date of July 2025. This follows neatly on from Arcus's ASCO data, concerning a Cabometyx combo cohort of the Arc-20 study that underscored the rationale for pursuing this use in phase 3.

Arc-20 had previously yielded data from casdatifan monotherapy cohorts, which showed limited backing for Arcus's claims that its molecule could hit HIF2α “harder than Welireg”. Gilead declined to exercise an option on casdatifan, though it did participate in a $150m funding round that now becomes important, since it should take Arcus through readout of Peak-1.

Second chance

As such, combination with Cabometyx offers casdatifan a second chance. The ASCO data showed a 46% confirmed ORR among 24 evaluable patients who had failed immunotherapy (40% had additionally failed a VEGF tyrosine kinase inhibitor), at a 14 March cutoff.

A cross-trial comparison shows this to be a respectable result. Cohort 2 of Merck's Study-003, where Welireg plus Cabometyx were given to a broadly similar post-IO population, yielded a confirmed ORR of just 31%, according to 2022 data published in Lancet Oncology.

Welireg's label contains warnings of anaemia and hypoxia; in Arc-20's Cabometyx combo cohort the rates of these at grade 3 or higher and deemed related to casdatifan were 31% and 7% respectively. Peak-1 will take the same 100mg casdatifan and 60mg Cabometyx doses that gave the optimal result in Arc-20, and compare them against 60mg Cabometyx, with PFS as primary endpoint.

In study-003 Welireg plus Cabometyx showed median PFS of 16.8 months, so Peak-1 must do meaningfully better than this; however, a baseline comparator for Cabometyx is unavailable, since that drug's second-line renal cancer approval came before the advent of immunotherapy in the front line.

Cross-trial comparison of HIF2α inhibitors in renal cell carcinoma

Source: OncologyPipeline.

It's notable that Merck apparently already considers a Welireg/Cabometyx doublet to be lacking punch, as its own pivotal combo trial in immunotherapy-relapsed patients, Litespark-011, combines Welireg with Cabometyx and Lenvima, a triplet that might well be limited by the kinase inhibitors' notorious toxicity profiles.

There's also the possibility of combining Welireg with Exelixis's Cabometyx follow-on zanzalintinib, but such a phase 3 study has yet to be revealed.

Arcus, which is increasingly relying on casdatifan to pick up the slack once its lead project, the anti-TIGIT MAb domvanalimab, suffers its widely expected phase 3 failure, has played up such advantages in recent investor presentations. 

Another renal cancer setting in which Arcus claims to be doing things better than Merck is the front line. Here Welireg is being combined with Keytruda and Lenvima in Litespark-012, but AstraZeneca recently unveiled the phase 1b/3 Evolve-RCC02 study of its anti-PD-1 x CTLA-4 MAb volrustomig, a trial that will include combo cohorts with casdatifan.

Evolve-RCC02 will thus give patients the possibility of a kinase inhibitor-free regimen, Arcus recently told investors.