In an interim analysis of a Chinese phase III trial (DAWNA-2) reported in The Lancet Oncology, Zhang et al found that the addition of the CDK4/6 inhibitor dalpiciclib to letrozole or anastrozole improved progression-free survival as first-line treatment in patients with advanced hormone receptor–positive, HER2-negative breast cancer.  

Study Details

In the multicenter double-blind trial, 456 patients were randomly assigned between July 2019 and December 2020 to receive dalpiciclib at 150 mg per day for 3 weeks followed by 1 week off (n = 303) or matching placebo (n = 153) in combination with either letrozole at 2.5 mg or anastrozole at 1 mg once daily continuously. Random assignment stratification factors included visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting, and endocrine therapy partner. In the dalpiciclib group, 55% of patients received letrozole and 45% received anastrozole; in the control group, 54% received letrozole and 46% received anastrozole. Menopause status was postmenopausal in 60% of patients in the dalpiciclib group vs 65% of the control group, and premenopausal or perimenopausal in 40% vs 35%, respectively. The primary endpoint was investigator-assessed progression-free survival.

Progression-Free Survival

At preplanned interim analysis, median progression-free survival was 30.6 months (95% confidence interval [CI] = 30.6 months to not reached) in the dalpiciclib group vs 18.2 months (95% CI = 16.5–22.5 months) in the control group (stratified hazard ratio [HR] = 0.51, 95% CI = 0.38–0.69, P < .0001).

For progression-free survival, hazard ratios were: 0.53 (95% CI = 0.35–0.79) among patients receiving letrozole and 0.51 (95% CI = 0.34–0.78) among those receiving anastrozole; and 0.52 (95% CI = 0.36–0.75) among postmenopausal patients and 0.53 (95% CI = 0.33–0.85) among premenopausal or perimenopausal patients.

On investigator assessment, objective responses (partial responses in all but two patients) were achieved in 57% of the dalpiciclib group vs 48% of the control group. Median duration of response was not reached (95% CI = 26.9 months to not reached) vs 15.0 months (95% CI = 12.9–20.3 months). At time of analysis, death had occurred in 12% of the dalpiciclib group and 13% of the control group.

Adverse Events

Grade 3 or 4 adverse events occurred in 90% of patients in the dalpiciclib group vs 12% of the control group; the most commonly reported events in the dalpiciclib group were neutropenia (86% vs 0% in control group), leukopenia (67% vs 0%), and anemia (7% vs < 1%). Serious adverse events occurred in 12% vs 7% of patients. Dalpiciclib and placebo were discontinued due to adverse events in 4% vs 2% of patients. Two deaths in the dalpiciclib group—both due to unknown cause—were considered possibly related to treatment.

The investigators concluded, “Our findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor–positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape.”

Binghe Xu, MD, of the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences and Jiangsu Hengrui Pharmaceuticals. For full disclosures of the study authors, visit thelancet.com.