Pfizer touts atirmociclib success

Pfizer’s CDK4 inhibitor atirmociclib has had its ups and downs, but the group had some good news on Tuesday with a win in a randomised phase 2 trial, Fourlight-1.

However, the study is in second-line ER-positive, HER2-negative breast cancer, an indication that Pfizer isn't taking forward, since downgrading Fourlight-1 from phase 3 to phase 2. The focus for atirmociclib is in the front line, where the phase 3 Fourlight-3 study could read out in 2027.

Pfizer also highlighted a phase 2 neoadjuvant trial that completed last year, but hasn’t yet yielded results; data are expected at a future medical meeting.

Meanwhile, in second-line breast cancer the company is pinning hopes on its KAT6 inhibitor prifetrastat. That project’s pivotal Katsis-1 trial, set to complete next year, tests prifetrastat plus Faslodex, versus everolimus and investigator’s choice of endocrine therapy, in patients who have previously received CDK4/6 inhibitors like Pfizer’s Ibrance or Novartis’s Kisqali. 

Let there be Fourlight

A post-CDK4/6 population was also enrolled in Fourlight-1. The trial evaluated atirmociclib plus Faslodex, versus investigator's choice of therapy of either Fulvestrant or everolimus plus exemestane, with a primary endpoint of progression-free survival.

Pfizer said on Tuesday that atirmociclib plus Faslodex reduced the risk of disease progression or death by 40% versus control, with a p value of 0.0007.

The company added that the results were consistent across subgroups, including duration of prior CDK4/6 inhibitor therapy, and the CDK4/6 inhibitor received. More details should be available when Pfizer presents the results at an undisclosed upcoming conference.

Meanwhile overall survival, a secondary endpoint, remains immature, with an event rate of 20%. As for adverse events, Pfizer only said that these were “manageable”, and disclosed a 6% treatment-related discontinuation rate.

Previously neutropenia has been a common side effect with atirmociclib, although this hasn’t looked as troublesome as with Ibrance. It’s hoped that selectively targeting CDK4 could lead to lower rates of neutropenia than with CDK4/6 inhibitors, as the side effect is thought to be driven by CDK6 inhibition.

First-line focus

There was no mention in Pfizer’s press release about a planned filing based on Fourlight-1. Instead, the company said the results supported its “strategy to advance atirmociclib in first-line and early-stage disease, where durable endocrine-based control has the potential to have the greatest impact”.

Fourlight-1 had once been a phase 3 trial, but in December 2024 Pfizer changed it to a phase 2, and reduced its recruitment target from 510 to 333 patients; the study actually enrolled 264 patients, according to the company’s latest release.

Ultimately, the company hopes that atirmociclib will become an improved follow-up to Ibrance, which is losing ground to the likes of Kisqali and Lilly’s Verzenio in an evolving breast cancer landscape. 

Still, last year Pfizer also ditched plans to combine atirmociclib with its Arvinas-partnered SERD vepdegestrant in first-line breast cancer. The companies are now looking for a partner for vepdegestrant, which is awaiting an FDA approval decision by 5 June in second-line ESR1-mutant breast cancer.