Triple meeting 2024 – casdatifan looks like Welireg

After arguing hard that it has the best HIF2α inhibitor in casdatifan, Arcus has had its moment of truth. The first clinical data, presented at a Thursday plenary of the Triple symposium, offered limited backing for the earlier enthusiasm, with a critical reading showing casdatifan in kidney cancer to be not meaningfully different from Merck & Co’s marketed HIF2α inhibitor Welireg.

That’s left Arcus pedalling hard on unconfirmed responses, whose inclusion would make a high casdatifan dose look better than Welireg. Unfortunately, most of these patients are no longer in response so seem unlikely to boost casdatifan’s confirmed ORR number, though several do remain on study in “stable disease”.

That, Arcus told ApexOnco, is important because they continue to contribute to a PFS number, which has yet to reach a median at 9-11 months’ median follow-up. Nevertheless, the bear case is that casdatifan is barely differentiated from Welireg, a drug approved for second/third-line kidney cancer, whose supporting Litespark-005 study failed to show an OS benefit.

Some sellside analysts see casdatifan as an important Arcus asset after the disappointments of its anti-TIGIT MAb domvanalimab; in February the company revealed the first case reports, and claimed to be able to hit HIF2α “harder than Welireg”, with 20mg casdatifan giving dose exposure similar to Welireg’s approved 120mg.

Higher doses

Where this claim now stands is unclear, given that data from the phase 1 kidney cancer trial Arc-20, released at the Triple (EORTC-NCI-AACR) symposium, focused on the much higher doses of 50mg either once or twice daily.

The latter was highlighted as being more efficacious, but is virtually identical to Welireg’s 120mg a day. And, on the like-for-like basis of confirmed responses, it’s yielded a similar ORR number: 25%, versus Welireg’s 22%.

The patient populations are very similar too; Litespark-005 limited patients to three lines of prior therapy, with most being fourth line, while most in Arc-20 were third line, though there were a few who had received four or more prior lines.

Arcus claimed three unconfirmed responses with 50mg twice daily casdatifan, for an unconfirmed ORR of 34%, but only one, recorded after cutoff, seems realistically capable of being confirmed; the other two responding patients went to stable disease or progressive disease after one scan.

More similar than different? Casdatifan vs Welireg cross-trial comparison

Source: Arcus & OncologyPipeline.

There had been some hope that hitting HIF2α as hard as Welireg with a lower dose would show casdatifan to have a cleaner safety profile, but with higher dosing such hopes have failed to materialise.

The 50mg twice-daily dose’s rates of all-grade and severe anaemia and hypoxia – both are warned about on Welireg’s label – were no different in Arc-20 versus those reported in Litespark-005.

Where does that leave casdatifan? Arcus says plans are under way for a phase 1 casdatifan combo with AstraZeneca’s anti-PD-1 x CTLA-4 MAb volrustomig, under a recent clinical trial collaboration. The phase 3 Peak-1 trial, pitting casdatifan plus Cabometyx against Cabometyx alone in post-immunotherapy kidney cancer, begins in the first half of 2025.

In another bullish update Evercore ISI analysis wrote that Arcus had shown a “small but potentially meaningful improvement in ORR versus Merck”, and pointed to fewer patients relapsing with progressive disease in Arc-20 versus Litespark-005. The markets dismissed this as minutiae, and on Thursday sent Arcus shares up a weak 3%.