Results from FOURLIGHT-1 were presented at the European Society for Medical Oncology (ESMO) Congress 2026. The study evaluated atirmociclib (PF-07220060) plus fulvestrant against investigator’s choice of standard therapy in patients with HR–positive, HER2-negative, advanced or metastatic breast cancer (BC) who had progressed after CDK4/6 inhibitor treatment.
The combination demonstrated a statistically significant improvement in progression-free survival (PFS) compared with standard therapy, with a median PFS of 9.4 months versus 6.6 months (HR 0.60; 95% CI, 0.440–0.825; 1-sided P=0.0007), respectively. Overall survival (OS) data were not yet mature at the time of the data cutoff.
Key finding
In FOURLIGHT-1, atirmociclib plus fulvestrant reduced the risk of progression or death by 40% compared with investigator’s choice of standard therapy in CDK4/6 inhibitor–pretreated HR+/HER2− advanced BC, though OS data remain immature and longer follow-up is needed to determine a survival benefit.
Study Design
| Trial | FOURLIGHT-1 (NCT06105632); open-label, multicenter, randomized phase 2 |
|---|---|
| Population | Adults with HR+/HER2− advanced or metastatic BC who had progressed on prior adjuvant or first-line CDK4/6 inhibitor therapy; 263 patients enrolled (atirmociclib arm, n=126; investigator’s choice arm, n=137) |
| Treatment | Atirmociclib 300 mg orally twice daily plus fulvestrant vs investigator’s choice of fulvestrant alone (n=79) or everolimus plus exemestane (n=58); (1:1 randomization) |
| Primary endpoint | Investigator-assessed PFS |
| Key secondary endpoints | OS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, and safety |
Patients were stratified at randomization by disease site (visceral vs nonvisceral) and duration of prior CDK4/6 inhibitor therapy (less than 12 months vs 12 months or more). The majority of enrolled patients (94.3%) had received a CDK4/6 inhibitor as their immediate prior first-line therapy, while 3.8% had received one in the adjuvant setting. Median follow-up was 13.6 to 13.7 months.
Results and Safety
Atirmociclib plus fulvestrant achieved a median PFS of 9.4 months (95% CI, 7.3–13.6) compared with 6.6 months (95% CI, 3.8–7.8) for investigator’s choice, representing a hazard ratio of 0.60 (95% CI, 0.440–0.825; 1-sided P=0.0007). A consistent PFS benefit was observed across most prespecified subgroups. Among patients with measurable disease, the confirmed ORR was 19.3% (95% CI, 13.0–27.7) with atirmociclib versus 11.3% (95% CI, 6.7–18.4) with investigator’s choice (odds ratio 1.914; 1-sided P=0.0451). Median DoR was 14.8 months (95% CI, 7.4–not estimable) in the atirmociclib arm versus 9.3 months (95% CI, 5.5–not estimable) in the comparator arm, based on 21 and 13 confirmed responses, respectively. The clinical benefit rate was 61.9% versus 46.0% (odds ratio 1.972; 1-sided P=0.0041) with investigational intervention and investigator’s choice treatment, respectively. Overall survival data were immature at the data cutoff on January 12, 2026, and were not reported.
The most common treatment-related adverse events (TRAEs) in the atirmociclib arm were neutropenia (46.4%) and leukopenia (32.8%), consistent with the known class effects of CDK inhibitors. Discontinuation of atirmociclib due to TRAEs occurred in 4.0% of patients. Detailed safety data for the investigator’s choice arm were not provided in the available source material.
Clinical Context
CDK4/6 inhibitor–based endocrine therapy has been the standard first-line treatment for HR+/HER2− metastatic BC for nearly a decade, yet disease progression on these agents remains a significant clinical challenge with limited subsequent options. Atirmociclib is a next-generation cell cycle inhibitor designed to be highly selective for CDK4, a property that may differentiate it from approved CDK4/6 inhibitors. The investigators characterized FOURLIGHT-1 as the first randomized study to demonstrate a significant PFS improvement with a next-generation CDK inhibitor in the post-CDK4/6 inhibitor setting.
The findings are described as supporting the continued development of atirmociclib in earlier lines of therapy. An ongoing phase 3 study is evaluating atirmociclib versus a CDK4/6 inhibitor, each in combination with letrozole, in first-line HR+/HER2− metastatic BC. Key questions that remain unanswered include whether the PFS benefit will translate into an OS improvement and how atirmociclib will compare with other emerging post-CDK4/6 inhibitor strategies, including PI3K pathway inhibitors and antibody-drug conjugates, in this setting.
Sources
- Giordano A, et al. “Efficacy and safety of atirmociclib (ATI) + fulvestrant (FUL) in patients with HR+/HER2– advanced/metastatic breast cancer who progressed on prior CDK4/6 inhibitor in a randomized phase 2 study (FOURLIGHT-1).” Presented at ESMO 2026 Congress. Abstract 1842O. Data cutoff: January 12, 2026.
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