The combination of atirmociclib (PF-07220060) and fulvestrant (Faslodex) improved investigator-assessed progression-free survival (PFS) vs investigator's choice of therapy (ICT) in patients with
At a median follow-up of 13.7 months in the atirmociclib arm (n = 126) and 13.6 months in the ICT arm (n = 137), the median PFS was 9.4 months (95% CI, 7.3-13.6) with atirmociclib plus fulvestrant compared with 6.6 months (95% CI, 3.8-7.8) with ICT (stratified HR, 0.60; 95% CI, 0.440-0.825; one-sided P = .0007). The 12-month PFS rates were 44.8% and 22.5%, respectively.1
"Atirmociclib, a highly selective and potent CDK4 inhibitor with up to 33-fold greater selectivity than the approved CDK4/6 inhibitors, has the potential to increase anticancer activity with less myelosuppression," lead study author Antonio Giordano, MD, PhD, medical oncologist at Dana-Farber Cancer Institute, said in a presentation of the data.
CDK4/6 inhibitors plus endocrine therapy are the standard of care for HR-positive, HER2-negative metastatic breast cancer; however, resistance ultimately limits durable disease control, leaving a setting of substantial unmet need after progression.1
Recent approvals after progression on endocrine therapy have focused on biomarker-selected populations, such as imlunestrant (Inluriyo) plus abemaciclib (Verzenio) for ER-positive, HER2-negative, ESR1-mutated advanced breast cancer.3 Antitumor activity in estrogen receptor–positive disease is driven primarily by CDK4, whereas neutropenia is linked to CDK6 inhibition.
Atirmociclib is an investigational oral CDK4 inhibitor that blocks the CDK4/cyclin D1 complex and Rb phosphorylation. A March 2026 news release indicated that FOURLIGHT-1 was positive.4
Eligible patients were at least 18 years of age and had HR-positive, HER2-negative advanced or metastatic breast cancer with measurable disease or nonmeasurable bone-only disease per RECIST v1.1 and an ECOG performance status of 2 or lower.1
Patients must have received a prior CDK4/6 inhibitor either as adjuvant therapy, with metastatic recurrence during treatment or within 12 months of completion, or as first-line treatment for advanced disease followed by progression. Up to 2 prior lines of therapy for advanced disease were permitted, including a CDK4/6 inhibitor plus a nonsteroidal aromatase inhibitor and an approved agent targeting ESR1, PIK3CA/AKT1/PTEN, or BRCA alterations.
Patients were randomly assigned 1:1 to atirmociclib at 300 mg orally twice daily continuously in 28-day cycles plus fulvestrant at 500 mg intramuscularly on days 1 and 15 of cycle 1 and day 1 of each subsequent cycle, or to ICT of fulvestrant alone or everolimus (Afinitor) at 10 mg plus exemestane (Aromasin) at 25 mg, each given orally once daily. ICT was declared before randomization; 58% of patients in the ICT arm were assigned to fulvestrant and 42% to everolimus plus exemestane. Randomization was stratified by visceral disease and duration of prior CDK4/6 inhibitor treatment (<12 vs ≥12 months).
The primary end point was investigator-assessed PFS. Secondary end points included overall survival, objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), and safety.
In the atirmociclib and ICT arms, respectively, the median ages were 57 and 58 years, and 52% of patients in each arm were Asian. Visceral metastases were present in 65% and 64% of patients, liver metastases in 44% and 29%, ESR1 alterations in 41% and 35%, and PIK3CA/AKT1/PTEN alterations in 37% and 45%. Prior CDK4/6 inhibitor exposure lasted at least 12 months in 74% and 71% of patients.1
Among patients with measurable disease (n = 109; n = 115), the confirmed ORR was 19.3% (95% CI, 13.0%-27.7%) with atirmociclib vs 11.3% (95% CI, 6.7%-18.4%) with ICT (nominal 2-sided P = .0901), including 1 complete response in each arm.1 The median DOR was 14.8 months (95% CI, 7.4-not estimable [NE]) vs 9.3 months (95% CI, 5.5-NE). The CBR in the full analysis set was 61.9% (95% CI, 53.2%-69.9%) vs 46.0% (95% CI, 37.9%-54.3%; nominal 2-sided P = .0083).
The PFS benefit with atirmociclib was observed in patients with ESR1-altered disease (HR, 0.47; 95% CI, 0.284-0.773), PIK3CA/AKT1/PTEN-altered disease (HR, 0.46; 95% CI, 0.281-0.764), and visceral disease (HR, 0.59; 95% CI, 0.402-0.851). The HR was 0.51 (95% CI, 0.335-0.769) when ICT was fulvestrant and 0.80 (95% CI, 0.504-1.284) when ICT was everolimus plus exemestane. The HR was 1.05 (95% CI, 0.584-1.879) in patients aged 65 years or older and 0.49 (95% CI, 0.337-0.700) in those younger than 65 years.1
In the safety population (n = 125; n = 136), any-grade treatment-emergent adverse events (TEAEs) occurred in 96.8% of patients in the atirmociclib arm vs 88.2% of the ICT arm; grade 3 or 4 TEAEs occurred in 37.6% vs 24.3%, and serious TEAEs in 11.2% vs 19.9%, respectively.1 Grade 5 TEAEs were reported in 3.2% vs 3.7% of patients; 1 death in the atirmociclib arm, due to pneumonitis, was considered treatment related by the investigator.
The most common TEAEs with atirmociclib were neutropenia (47%; grade 3, 22%), leukopenia (34%), diarrhea (28%), and fatigue (21%); stomatitis (30%) was the most common TEAE with ICT. TEAEs led to atirmociclib discontinuation in 6.4% of patients, dose reduction in 13.6%, and dose interruption in 44.0%.
The investigators noted that the findings support development of atirmociclib in earlier lines, including the phase 3 FOURLIGHT-3 trial (NCT06760637) comparing atirmociclib with CDK4/6 inhibitors, each plus letrozole, in the first-line setting; accrual is complete.1
