Dalpiciclib added to fulvestrant (Faslodex) was found to significantly prolong progression-free survival compared with fulvestrant monotherapy in patients with hormone receptor–positive, human epidermal growth factor receptor 2-negative advanced breast cancer.
Adding dalpiciclib (SHR6390) to fulvestrant (Faslodex) was found to significantly prolong progression-free survival (PFS) compared with fulvestrant monotherapy in patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, according to findings from the phase 3 DAWNA-1 trial published in Nature Medicine.1
The study found that the dalpiciclib plus fulvestrant combination produced a significantly prolonged investigator-assessed median PFS of 15.7 months (95% CI, 11.1–not reached [NR]) vs 7.2 months (95% CI, 5.6-9.2) compared with fulvestrant alone (HR, 0.42; 95% CI, 0.31-0.58; P < .0001).
“This phase 3 trial showed that adding dalpiciclib to fulvestrant significantly prolonged PFS, with a manageable safety profile,” Binghe Xu, Department of Medical Oncology and Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, and colleagues, wrote in the study. “These findings support the application of dalpiciclib plus fulvestrant as a new treatment option for patients with HR-positive, HER2-negative advanced breast cancer who relapse or progress on previous endocrine therapy.”
Dalpiciclib is an oral, selective CDK4/6 inhibitor that previously showed preliminary activity and synergic efficacy in a phase 1b trial in patients with advanced breast cancer. In the current study, researchers sought to evaluate the safety and efficacy of the dalpiciclib and fulvestrant combination in patients with HR-positive, HER2-negative advanced breast cancer who relapsed or progressed on previous endocrine therapy.
From June 2019 to September 2020, 361 eligible patients were randomized 2:1 to receive either dalpiciclib plus fulvestrant (n = 241) or placebo plus fulvestrant (n = 120). The primary endpoint was investigator assessed PFS, with secondary end points such as PFS per RECIST v1.1 criteria, overall survival (OS), objective response rate (ORR), duration of response, clinical benefit rate (CBR), and safety.2
At the data cutoff of November 15, 2020, 59.8% of patients in the dalpiciclib cohort and 35.8% of patients in the placebo cohort were still receiving treatment. The median follow-up in the investigative and control cohorts was 10.7 months (range, 0.2-16.7) and 10.6 months (range, 0.8-16.7), respectively.
The median age of patients in the dalpiciclib cohort was 50.7 years of age (range, 45.3-59.3) compared with 52.4 years of age (45.5-60.6) in the placebo cohort. Most patients in each cohort were younger than 65 years of age, at 87.5% in the dalpiciclib cohort and 90.0% in the placebo cohort.
Further, most patients in each cohort had an ECOG performance status of 1 (51.9% and 61.7%, respectively), were postmenopausal (79.7% and 75.8%), and were both estrogen receptor-positive and progesterone receptor-positive (79.7% and 75.8%). Most patients in each cohort had measurable disease (82.2% and 81.7%, respectively), fewer than 4 metastatic lesions (82.6% and 81.7%), and visceral metastases (58.9% and 62.5%).
In the study, 72.6% of patients in the dalpiciclib arm and 72.5% of those in the placebo arm had received 1 line of prior endocrine therapy; 27.4% and 27.5% of patients, respectively, received 2 lines. Additionally, 27.0% of patients in the dalpiciclib cohort and 35.0% of those in the placebo cohort received prior chemotherapy for recurrent or metastatic disease.
At the time of the interim analysis, 35.7% of patients in the dalpiciclib cohort and 63.3% of patients in the placebo cohort experienced disease progression or died. PFS rates at 6 and 12 months in the dalpiciclib and placebo cohorts were 76.4% (95% CI, 70.1%-81.5%) vs 53.2% (95% CI, 43.5%-62.0%) and 51.8% (95% CI, 43.2%-59.8%) vs 29.1% (95% CI, 20.2%-38.5%), respectively.
OS data were not mature at the time of the interim analysis, however, 25 deaths were reported, 15 of which in the dalpiciclib group and 10 in the placebo group. Further, 24.1% of patients in the dalpiciclib cohort and 40.8% of those in the placebo cohort received subsequent chemotherapy or died. The median time to first subsequent chemotherapy or death was NR in the dalpiciclib group compared with 14.2 months (95% CI, 9.7-NR) in the placebo group (HR, 0.47; 95% CI, 0.32-0.69; P < .0001).
ORRs in the dalpiciclib and placebo cohorts were 27.0% (95% CI, 21.5%-33.0%) vs 20.0% (95% CI, 13.3%-28.3%), and the CBR was 61.0% (95% CI, 54.5%-67.2%) vs 45.8% (95% CI, 36.7%-55.2%).
Grade 3/4 adverse effects (AEs) were reported in 88.3% of patients in the dalpiciclib cohort and 13.3% in the placebo cohort. These AEs led to dose reduction of dalpiciclib in 27.9% of patients and of placebo in 1.7% of patients. The percentage of patients who discontinued any treatment component due to AEs in each study arm was 2.5% and 3.3%, respectively.
Serious AEs were reported in 5.8% of patients in the dalpiciclib cohort and 6.7% of patients in the placebo cohort, with fatal AEs reported in 0.8% and 3.3% of patients, respectively.
The most common grade 3 or higher AEs reported in the dalpiciclib cohort were neutropenia (84.2%), leukopenia (62.1%), and thrombocytopenia (5.8%). The most common grade 3 or higher AEs reported in the placebo cohort were anemia (1.7%) and hypertriglyceridemia (1.7%).