Atirmociclib Plus Letrozole Demonstrates Preliminary Efficacy and Safety in HR+/HER2-Negative Metastatic Breast Cancer

A preliminary analysis of an ongoing phase 1/2a study (NCT04557449) evaluating the safety, tolerability, and efficacy of atirmociclib (PF-07220060) in combination with letrozole demonstrated preliminary antitumor activity and a favorable safety profile in treatment-naive patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer. Data from the study were presented at the 42nd Annual Miami Breast Cancer Conference.

Findings showed that. in the overall study population (n = 34), all confirmed responses were partial responses (PRs), leading to an overall response rate (ORR) of 58.8% (95% CI, 40.7%-75.4%). The clinical benefit rate (CBR), defined as ORR or stable disease (SD) lasting at least 24 weeks, was 94.1% (95% CI, 80.3%-99.3%). The median time to response was 3.7 months (range, 1.6-15.6), and the median duration of response (DOR) was not reached. Among patients with measurable disease at baseline (n = 33), the confirmed ORR was 60.6%, and the CBR was 93.9%.

At the 300-mg, twice-daily dose, the incidence of grade 3 or higher neutropenia and other treatment-related adverse effects (TRAEs) were low, and there were no reported grade 4 or 5 TRAEs.

“At the recommended phase 3 atirmociclib dose of 300 mg [twice per day], high [>90%] relative dose intensity was achieved in 85% of patients, potentially ensuring higher anti-cancer activity,” lead study author Antonio Giordano, MD, PhD, and colleagues wrote in the poster presentation. Giordano is a senior physician at Dana-Farber Cancer Center and an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts.

Study Design

The phase 1/2a study is an open-label, multicenter trial evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of atirmociclib, a next-generation CDK4/6 inhibitor, as monotherapy and in combination with endocrine therapy (ET) in patients with metastatic or advanced solid tumors. Cohort 2B is specifically investigating atirmociclib in combination with letrozole in patients with HR-positive, HER2-negative metastatic breast cancer who are treatment-naive for advanced disease.

Eligible patients are required to be at least 18 years of age, have measurable disease per RECIST 1.1 criteria, and have an ECOG performance status of 0 or 1. Exclusion criteria include prior treatment with a CDK4/6 inhibitor or disease recurrence within 12 months of prior neoadjuvant or adjuvant treatment with an aromatase inhibitor.

Patients enrolled in cohort 2B are receiving atirmociclib at 300 mg twice daily in combination with letrozole at 2.5 mg once daily.

The primary objective of cohort 2B is to assess the safety and tolerability of atirmociclib plus letrozole. Secondary end points include ORR, DOR, and progression-free survival (PFS). Tumor assessments are performed at baseline and every 8 weeks for the first 6 months, then every 12 weeks for up to 2 years, followed by every 4 months thereafter.

Additionally, genomic alterations in circulating tumor DNA (ctDNA) are analyzed using next-generation sequencing platforms to explore potential biomarkers associated with response.

Patient Demographics

Among the 34 patients enrolled in cohort 2B, the median age at screening was 59 years (range, 32–84). The majority of patients were between 45 and 64 years of age (52.9%); 32.4% were 65 years or older, and 14.7% were aged 18 to 44 years.

All enrolled patients were female. Regarding racial distribution, 67.6% were White, 23.5% were Asian, and 5.9% were American Indian or Alaskan Native. Ethnic background data showed that 64.7% identified as Hispanic or Latino, and 35.3% were not Hispanic or Latino.

ECOG performance status was 1 in 55.9% of patients and 0 in 44.1% of patients. With respect to prior treatment history, 55.9% of patients had undergone prior surgery, and 47.1% had received prior adjuvant or neoadjuvant therapy. Notably, no patients had received prior systemic anticancer therapy in the advanced metastatic setting.

Safety and Subgroup Analysis Observations

With a median follow-up duration of 16.5 months, median PFS had not been reached at the time of data cutoff. At the time of analysis, 25 of 34 patients remained on treatment without disease progression.

Response findings were largely independent of PIK3CA/AKT1/PTEN mutations. In patients with PIK3CA/AKT1/PTEN mutations (n = 13), the ORR was 61.5%; in those without these mutations (n = 15), the ORR was 53.3%. The CBR was 84.6% in mutation-positive patients and 100% in mutation-negative patients.

TRAEs were reported in 82.4% of patients, with grade 3 TRAEs occurring in 41.2% of patients. The most frequently reported any-grade TRAEs included neutropenia (61.8%), leukopenia (41.2%), anemia (23.5%), and lymphopenia (20.6%). Grade 3 TRAEs included neutropenia (23.5%) and lymphopenia (2.9%).

Serious AEs were reported in 2 patients (5.9%), with 1 patient experiencing grade 3 hypokalemia and another developing grade 3 interstitial lung disease (ILD). The ILD event was the only instance of ILD reported during the study.

TRAEs led to dose reductions in 8.8% of patients, dose interruptions in 38.2% of patients, and atirmociclib discontinuation in 2.9% of patients. The median relative dose intensity of atirmociclib was 99.3% (range, 35.4%-100%), with 85.3% of patients maintaining a relative dose intensity greater than 90%.

Reference

Giordano A, Magallanes M, Xu B, et al. The next-generation CDK4-selective inhibitor atirmociclib (PF-07220060) in combination with letrozole as first-line treatment in patients with HR+/HER2– metastatic breast cancer. Presented at: 42nd Annual Miami Breast Cancer Conference. March 6-9, 2025; Miami Beach, FL. Poster 32.