Arvinas and Pfizer turn away from Ibrance

Arvinas has been hinting for a while that Pfizer’s CDK4 inhibitor atirmociclib was the partner of choice for the companies’ SERD vepdegestrant in first-line metastatic breast cancer, and now it’s official. Arvinas said on Friday that an upcoming first-line phase 3 trial would combine vepdegestrant with atirmociclib, rather than with Pfizer’s approved CDK4/6 inhibitor Ibrance.

In a planned second-line combo study things are still unclear, with Arvinas only saying that it would combine vepdegestrant with a CDK4/6 inhibitor. This could be Ibrance, Novartis’s Kisqali or Lilly’s Verzenio – but, in an interview with ApexOnco on Thursday, Arvinas seemed to be edging towards the last option.

Both phase 3 trials are slated to start this year, so second-line plans should become clear soon. The decision also means the end of the phase 3 first-line Veritac-3 trial, of vepdegestrant plus Ibrance, which had only got to the safety lead-in stage.

Regulatory risk?

Arvinas telegraphed its preference for atirmociclib in November at the Jefferies London healthcare conference, describing the project as “the crown jewel” in Pfizer’s portfolio and saying that, in future, it could become the front-line standard of care.

Still, there is a risk in testing two unproven drugs in combination, something acknowledged by Arvinas’s chief medical officer, Noah Berkowitz. “How do you create a novel-novel argument to the FDA?” he told ApexOnco. “We’ll lay out the arguments for how we can discern how much of the benefit and safety findings are coming from atirmociclib and how much from vepdegestrant. We don’t view it so much as a risk but just typical development complexity.”

He added that these data won’t all have to come from the planned phase 3 study, but that the partners could also use results from other trials.

Berkowitz also highlighted Pfizer’s imminent atirmociclib monotherapy phase 3 trial, saying this would read out before the vepdegestrant combo study, thereby reducing some of the risk – but this assumes that this study is positive.

Second-line questions

In the second line Kisqali is the most unlikely choice for a combination as, according to Berkowitz, the Novartis drug is now the most popular front-line CDK4/6 inhibitor, so doctors will want to be able to switch to a different drug.

That leaves Ibrance and Verzenio. While a vepdegestrant/Ibrance combo has produced promising efficacy, with an ORR of 42%, neutropenia rates were a problem, leading Arvinas and Pfizer to test other doses, Berkowitz noted. 

Vepdegestrant plus Verzenio, meanwhile, showed a 27% ORR among 16 patients in the Tactive-U trial at the recent San Antonio Breast Cancer Symposium, but Berkowitz pointed to a “great” safety profile and a 63% clinical benefit rate, the same number seen with the Ibrance combo. “We just didn’t have enough data to make a reasonable measure of mPFS [with vepdegestrant plus Verzenio],” he added.

More data from Tactive-U will be presented this year, although he declined to give details of the potential venue.

But the big near-term readout for Arvinas remains the Veritac-2 second-line vepdegestrant monotherapy phase 3 trial, with data due in the first quarter.