Pfizer’s oral cyclin-dependent kinase 4 (CDK4) inhibitor, atirmociclib, has met the primary endpoint in a Phase II trial as a second-line breast cancer treatment.
In the open-label, randomised FOURLIGHT-1 trial (NCT06105632), atirmociclib in combination with Faslodex (fulvestrant) improved progression-free survival (PFS). It was compared with Faslodex or everolimus plus exemestane in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (MBC) who had received prior cyclin-dependent kinase (CDK) 4/6 inhibitor-based treatment.
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The PFS results were consistent across all prespecified subgroups, including performance status, menopausal status, presence of visceral disease, duration of treatment with prior CDK4/6 inhibitor (< or > 12 months), and regardless of prior CDK4/6 inhibitor received.
Overall survival (OS), a secondary endpoint, was not mature at the time of the analysis, with approximately 20% of patients having an event.
Jeff Legos, chief oncology officer at Pfizer, said: “These results are especially encouraging given that the FOURLIGHT‑1 study enrolled patients whose disease had progressed soon after prior CDK4/6 inhibitor therapy, a difficult-to-treat population. The strength of these data reinforces our confidence that atirmociclib may meaningfully differentiate from the CDK4/6 inhibitor class, the standard-of-care backbone in HR-positive breast cancer, with the potential for improved efficacy and tolerability.”
In FOURLIGHT-1, atirmociclib demonstrated manageable safety and was well tolerated, with 6.4% of patients discontinuing atirmociclib due to treatment-emergent adverse events (TEAEs).
Pfizer said that this Phase II data support the advancement of atirmociclib in first-line and early-stage disease, where durable endocrine-based control has the potential to have the greatest impact. A Phase III registrational study for atirmociclib in the first-line metastatic setting is ongoing (NCT06760637).
Jack Cuthbertson, senior healthcare analyst at GlobalData Healthcare, said that while the readout is positive, Pfizer will be seeking earlier use.
He said: “The second line (post-CDK4/6) setting is not going to be particularly lucrative as it is a highly competitive segment. Data presented at ESMO 2025 for Celcuity’s gedatolisib, combined with Ibrance and endocrine therapy, was particularly impressive. Additionally, ESR1+ patients have access to SERDs, such as Inluryo or Orserdu, and Pik3CA+ patients have Pi3K inhibitors, including Itovebi or Truqap.
“Pfizer will really want the positive readout in the first-line setting with a direct comparison with CDK4/6 inhibitors. The positive PFS readout here gives some confidence that atirmociclib can deliver a positive PFS readout in the first-line setting; however, the FDA will be keeping an eye on the OS readout as well, as changing the first-line therapy will have significant implications on the sequencing of subsequent therapies.”
Pfizer is also in a race against BeOne after its oral CDK4 inhibitor BGB-43395 succeeded in Phase I trials, with the company set to initiate Phase III trials of the drug soon.
According to a GlobalData report, the standard of care (SoC) for early-stage and first-line metastatic HR+ breast cancer has shifted to CDK4/6 inhibitors, and many targeted agents, such as Pi3K/AKT/mTOR pathway inhibitors, have entered the second-line settings and beyond. Antibody drug conjugates (ADCs) are also playing a major role, with AstraZeneca’s Enhertu (fam-trastuzumab deruxtecan-nxki) established as the SoC in the second-line setting for patients who are HER2 low.
GlobalData is the parent company of Clinical Trials Arena.
