ASCO-GU – Arcus goes it alone in HIF2α

Following the latest iteration of clinical data on Arcus's HIF2α inhibitor casdatifan, the main question for investors was whether Gilead would opt in to the project: and the answer is no, the company revealed on Tuesday.

Arcus professed to being “thrilled” about the prospect of going it alone with casdatifan, but investors didn’t share this enthusiasm, sending the group’s stock down 16% on Tuesday. During a conference call Arcus execs suggested that the decision was merely strategic, with its chief operating officer, Jennifer Jarrett, noting: “I can’t imagine there’s anything in the data that resulted in their decision.”

Gilead did participate in a $150m funding round, also announced Tuesday, that should take Arcus through readout of its pivotal casdatifan trial, Peak-1.

Arc-20

However, there were some questions about the latest results, which come from the phase 1 Arc-20 trial and were presented on Saturday at ASCO's Genitourinary Cancers symposium. Notably, this is the first time that PFS has been reported from this study.

PFS is an important data point because the earlier response rate results seemed not to differ meaningfully versus the registrational study of Merck & Co's rival marketed HIF2α drug Welireg. The headline median PFS number for casdatifan is now revealed to be around nine months, and while that's higher than Welireg's 5.6 months it won't go unnoticed that Arcus has been dialling up dosing.

If nothing else, this alone could cast further doubt on the company's claim to be able to hit HIF2α “harder than Welireg”, something that will be key to establishing an improved therapeutic window for the Arcus project.

Initially Arcus said 20mg casdatifan gave similar dose exposure to Welireg’s approved 120mg, but then shifted to 50mg casdatifan, either once or twice daily. Now, as part of the Arc-20 update, Arcus has confirmed that it's taking 100mg casdatifan daily into phase 3.

100mg daily will be the dose studied in the earlier announced phase 3 Peak-1 trial, which will test a Cabometyx combo versus Cabometyx alone in post-immunotherapy kidney cancer, which is on track to start by mid-2025.

9.7 months in another cohort

The only median PFS number now available is for 50mg twice daily casdatifan, and is 9.7 months. 50mg daily hasn't reached a median at nine to 14 months' follow-up, and neither has the now key 100mg daily dose, though the follow-up range here is just two to six months.

Welireg's registrational Litespark-005 trial, in a similarly relapsed patient population, yielded mPFS of 5.6 months. Going into ASCO-GU Evercore ISI analysts said a "meaningful delta" over 5.6 months was needed to get them really excited, although the results presented apparently weren't enough to excite Gilead.

Cross-trial comparison in HIF2α inhibition

Source: ASCO-GU & Arcus.

As for casdatifan's confirmed ORRs, ASCO-GU showed updated numbers for the 50mg once and twice-daily doses, now including some previously unconfirmed responses, plus those for 100mg once daily. Across the three the ORR is 25-33%, which is numerically higher than Welireg's 22% in Litespark-005, but from far fewer patients.

A key question, especially in light of Arcus's earlier claim of achieving a similar effect with lower dosing, is whether casdatifan is able to achieve a better safety profile than Welireg, whose label carries warnings of anaemia and hypoxia.

Here, even on a generous read of the latest Arc-20 data, it's hard to see a difference, with an open question as to how the profile of the newly disclosed 100mg daily dose will develop. Unfortunately for Arcus, with all the caveats casdatifan continues to looks pretty similar to Welireg.

This is an updated version of a story originally published on 17 February.