Pfizer dials down its atirmociclib ambitions

Pfizer has been touting its CDK4 inhibitor atirmociclib as the next big thing in breast cancer, but it has just quietly downgraded a phase 3 trial to phase 2 and decreased its recruitment target, a clinicaltrials.gov listing shows.

This merely shows a shift in priorities, according to a Pfizer spokesperson: the trial in question is in second-line ER-positive HER2-negative breast cancer, while the focus now is first-line and early metastatic disease; a front-line phase 3 began earlier this year.

Meanwhile, in the second line, Pfizer is prioritising its KAT6 inhibitor, PF-07248144, the spokesperson said. The company previously disclosed plans to start a phase 3 trial of that project, in the post CDK4/6 inhibitor setting, in the second half of 2025. In phase 1, PF-07248144 plus Faslodex produced an ORR of 30% and 45% in second and third-line patients respectively.

There isn’t much competition in KAT6 so far, with Menarini and Olema the only other players in the clinic.

Evolving

As for atirmociclib, Pfizer hopes this project will become an improved follow-up to its established CDK4/6-targeting drug Ibrance; the latter is losing ground to the likes of Lilly’s Verzenio and Novartis’s Kisqali in an evolving breast cancer landscape. 

CDK4/6 inhibitors have been linked with neutropenia, and Pfizer reckons it can get around this by selectively targeting CDK4, as neutropenia is thought to be driven by CDK6 inhibition.

Rivals in CDK4 inhibition include BeiGene, which recently unveiled phase 3 plans with its contender, BGB-43395, in both first and second-line breast cancer; and Jiangsu HengRui, whose HRS-6209 is in phase 2 in China. 

As for the big players, Roche paid $850m up front last September for a portfolio of CDK4 inhibitors originated by the private US biotech Regor Pharmaceuticals; however, the lead project there, RGT-419B, is also said to have activity against CDK2 and CDK6. A selective CDK4 inhibitor, RGT-587, is in preclinical development, but has been described by Roche as "phase 1 ready".

Pfizer is also combining atirmociclib with its CDK2 inhibitor, PF-07104091, in an effort to combat resistance to CDK4/6 drugs.

A higher-profile atirmociclib combo is with Pfizer and Arvinas’s Protac estrogen degrader epdegestrant, with a phase 3 front-line trial planned for the second half of this year. However, vepdegestrant recently disappointed as monotherapy in second-line disease, only showing a benefit in ESR1 mutants – the only population in which SERDs have worked so far. 

Key atirmociclib trials in ER-positive, HER2-negative breast cancer

Source: OncologyPipeline & clinicaltrials.gov.