Dalpiciclib a 1L option for HR-positive, HER2-negative advanced breast cancer regardless of menopausal status

Adding dalpiciclib to an aromatase inhibitor (AI) significantly improves progression-free survival (PFS) vs an AI alone in first-line (1L) treatment of hormone receptor (HR)–positive, HER2-negative advanced breast cancer regardless of patients’ menopausal status, a phase III trial in 42 hospitals in China has shown.

Dalpiciclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved in China for use in combination with fulvestrant for treatment of relapsed or progressed HR-positive, HER2-negative advanced breast cancer based on results of the phase III DAWNA-1 trial, which demonstrated significant PFS improvement with the combination vs placebo plus fulvestrant (hazard ratio, 0.42; 95 percent confidence interval [CI], 0.31–0.58; p<0.0001) in patients whose disease progressed after endocrine therapy (ET). [Nat Med 2021;27:1904-1909]

The phase III DAWNA-2 trial evaluated the efficacy and safety of dalpiciclib (150 mg/day orally, 3 weeks on, 1 week off) plus letrozole (2.5 mg/day orally) or anastrozole (1 mg/day orally) vs placebo plus letrozole or anastrozole in patients with previously untreated, HR-positive, HER2-negative advanced breast cancer of any menopausal status who had an Eastern Cooperative Oncology Group performance status of 0–1. A total of 456 patients (median age, 55 years; postmenopausal, 62 percent; visceral metastases, 61 percent; previous ET in neoadjuvant or adjuvant setting, 31 percent) were randomly assigned (2:1) to the dalpiciclib (n=303) or placebo (n=153) group. [Lancet Oncol 2023;24:646-657]

After a median follow-up of 21.6 months (data cut-off, 1 June 2022), the primary endpoint of investigator-assessed PFS showed significant improvement in the dalpiciclib vs placebo group (median, 30.6 months vs 18.2 months; stratified hazard ratio, 0.51; 95 percent CI, 0.38–0.69; p<0.0001), with consistent benefit observed across most prespecified subgroups.

PFS improvement with dalpiciclib vs placebo was observed in both postmenopausal patients (median, 30.6 months vs 19.4 months; unstratified hazard ratio, 0.52; 95 percent CI, 0.36–0.75; p=0.0002) and premenopausal and perimenopausal patients (median, not reached vs 16.6 months; unstratified hazard ratio, 0.53; 95 percent CI, 0.33–0.85; p=0.0039).

Overall survival (OS) data were immature at the time of data cut-off, with similar rates of death reported in the dalpiciclib (12 percent) and placebo (13 percent) groups.

Among patients with measurable disease at baseline, objective response rate was 62 percent vs 51 percent in the dalpiciclib vs placebo group (p=0.015). Complete response was achieved in <1 percent vs none of the patients, while partial response was achieved in 62 percent vs 51 percent. Clinical benefit rate was 86 percent vs 79 percent (p=0.027). Median duration of response was not reached vs 15 months among responders.

Grade 3/4 adverse events (AEs) were reported in 90 percent vs 12 percent of patients in the dalpiciclib vs placebo group, with the most common events being neutropenia (86 percent vs none) and leukopenia (67 percent vs none). Serious AEs occurred in 12 percent vs 7 percent of patients.

Treatment discontinuation due to AEs occurred in 4 percent vs 2 percent of patients in the dalpiciclib vs placebo group, while two treatment-related deaths of unknown causes were reported in the dalpiciclib group.

“Our study, along with previous studies, provides strong evidence for the use of CDK4/6 inhibitors in combination with AIs as standard 1L treatment for patients with HR-positive, HER2-negative advanced breast cancer, regardless of menopausal status,” the investigators noted. “With the expansion of treatment options, physicians and patients now have the flexibility to select a treatment regimen based on efficacy, safety, and accessibility in clinical practice.”