Dalpiciclib in advanced breast cancer: introducing CDK4/6 inhibitors as a first-line treatment might not be the best strategy

In the phase 3 trial DAWNA-2, reported by Pin Zhang and colleagues, 1 Zhang P Zhang Q Tong Z et al. Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023; 24: 646-657 Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar the CDK4/6 inhibitor dalpiciclib was investigated at 42 hospitals in China as a first-line treatment in combination with endocrine therapy (letrozole or anastrozole) in patients with hormone receptor-positive, HER2-negative advanced breast cancer. The primary endpoint of progression-free survival was met, with a median PFS of 30·6 months (95% CI 30·6–not reached) in the dalpiciclib group versus 18·2 months (16·5–22·5) in the placebo plus endocrine therapy group (stratified hazard ratio [HR] 0·51 [95% CI 0·38–0·69]; one-sided log-rank p<0·0001). 1 Zhang P Zhang Q Tong Z et al. Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023; 24: 646-657 Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar In a previous trial, DAWNA-1, dalpiciclib showed efficacy in combination with fulvestrant in patients progressing after first-line endocrine therapy (median progression-free survival 15·7 months vs 7·2 months with placebo plus fulvestrant; HR 0·42, p<0·0001). 2 Xu B Zhang Q Zhang P et al. Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial. Nat Med. 2021; 27: 1904-1909 Crossref PubMed Scopus (33) Google Scholar The first-line use of this treatment means a longer exposure to the side-effects of CDK4/6 inhibitors. Notably, grade 3 or 4 neutropenia occurred in 86% of patients in the dalpiciclib group. 1 Zhang P Zhang Q Tong Z et al. Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023; 24: 646-657 Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar High rates of neutropenia also have been shown to occur with palbociclib and ribociclib, and the Asian population has a higher susceptibility to CDK4/6 inhibitors. 3 O'Sullivan CC Clarke R Goetz MP Robertson J Cyclin-dependent kinase 4/6 inhibitors for treatment of hormone receptor-positive, ERBB2-negative breast cancer: a review. JAMA Oncol. 2023; (published online June 29.)https://doi.org/10.1001/jamaoncol.2023.2000 Crossref Google Scholar Additionally, abemaciclib, another CDK4/6 inhibitor, is associated with high rates of gastrointestinal symptoms. 3 O'Sullivan CC Clarke R Goetz MP Robertson J Cyclin-dependent kinase 4/6 inhibitors for treatment of hormone receptor-positive, ERBB2-negative breast cancer: a review. JAMA Oncol. 2023; (published online June 29.)https://doi.org/10.1001/jamaoncol.2023.2000 Crossref Google Scholar Dalpiciclib in advanced breast cancer: introducing CDK4/6 inhibitors as a first-line treatment might not be the best strategy – Author's replyWe appreciate Elif Hindié's interest in the DAWNA-2 study, which focuses on the optimal sequencing of CDK4/6 inhibitors in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. CDK4/6 inhibitors have shown improved outcomes in both first-line and second-line treatments, but comparative evidence supporting their sequencing is absent, despite guidelines recommending their use as a first-line treatment.1 Full-Text PDF