Phase 2 Trial Shows Survival Benefit With Frontline Dalpiciclib in HR+/HER2– Advanced Breast Cancer


The CDK4/6 inhibitor dalpiciclib in combination with letrozole or anastrozole improved progression free survival in patients with treatment-naïve advanced breast cancer.

According to data from the phase 2 DAWNA-2 trial (NCT03966898) presented at the 2022 European Society for Medical Oncology Congress (ESMO), the CDK4/6 inhibitor dalpiciclib in combination with letrozole or anastrozole reduced the risk of disease progression by 49% vs chemotherapy alone in patients with treatment-naïve, hormone receptor–positive, HER2-negative advanced breast cancer.1

The median progression-free survival (PFS) with the dalpiciclib combination (n = 303) was 30.6 months (95% CI, 30.6-not reached [NR]) vs 18.2 months (95% CI, 16.5-22.5) with placebo (n = 153) with an HR of 0.51 (95% CI, 0.38-0.69; P < .0001). The median follow-up was 21.7 months and 21.4 months, respectively.

“These findings support dalpiciclib plus letrozole or anastrozole as a new first-line treatment option in patients with hormone receptor–positive, HER2-negative advanced breast cancer,” said Binghe Xu, MD, PhD, professor and director of the Department of Medical Oncology at the Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China.

The PFS benefit with the dalpiciclib was observed regardless of menopausal status. In pre-/perimenopausal women, the median PFS was NR (95% CI, 27.7-NR) with dalpiciclib compared with 16.6 months (95% CI 12.9-27.7) with placebo (HR, 0.53; 95% CI, 0.33-0.85; log-rank 1-sided P = .0039). Among postmenopausal women, the median PFS was 30.6 months (95% CI, 34.9-NR) vs 19.4 months (95% CI, 16.6-24.9), respectively (HR, 0.52; 95% CI, 0.36-0.75; log-rank 1-sided P = .0002).

The overall response rate (ORR) per investigator assessment among all treated patients was 57.4% (95% CI, 51.6%-63.1%) with dalpiciclib vs 47.7% (95% CI, 39.6%-55.9%) with placebo (P = .0233). Two patients in the dalpiciclib arm had a complete response (CR) and partial responses (PR) were reported among 56.8% of patients and 28.7% had stable disease (SD). In the placebo arm, 47.8% of patients had a PR and 38.6% had SD.

The median duration of response (DOR) was NR with the investigative combination vs 15.0 months with placebo. The clinical benefit rates (CBR) were 86.8% (95% CI, 82.5%-90.4%) vs 79.7% (95% CI, 72.5%-85.8%), respectively.

CDK4/6 inhibitors have demonstrated synergistic efficacy in combination with endocrine therapy, which has helped mediate resistance in the second-line setting for patients with hormone receptor–positive disease.2 Findings from the phase 3 DAWNA-1 trial (NCT03927456) demonstrated the success of the oral, selective CDK4/6 inhibitor in combination with fulvestrant for the treatment of patients with disease progression following endocrine therapy.2

DAWNA-2 was initiated to evaluate dalpiciclib in the first-line setting and was conducted in 42 centers in China. To be eligible for enrollment, patients must have been between the ages of 18 and 75 years having received no prior therapy for advanced hormone receptor–positive disease and an ECOG performance status of 0 or 1. Individuals with clinically significant cardiovascular and cerebrovascular disease were not eligible.1

Patients were randomly assigned 2:1 to receive dalpiciclib or matching placebo in combination with either letrozole (2.5 mg daily) or anastrozole (1 mg daily). Dalpiciclib was administered 150 mg orally once daily for 3 weeks, followed by 1 week off on a 4-week cycle. The primary end point was PFS per investigator assessment. Secondary end points included PFS by RECIST 1.1 criteria, overall survival, ORR, DOR, clinical benefit rate, and adverse event (AE) assessment. Patients were stratified by visceral metastases (yes vs no), prior endocrine therapy in the neoadjuvant setting (yes vs no) and endocrine therapy used in the trial (letrozole vs anastrozole).1

Baseline characteristics were well balanced between the dalpiciclib and placebo arms. The median age was 54 and 57 years, respectively, with approximately 20% of patients in each arm aged 65 years or older. Most patients had postmenopausal status (60% vs 64.7%, respectively) and estrogen/progesterone receptor–positive disease (84.8% vs 87.6%). Visceral metastases were identified in 60.7% of patients in the investigative arm and 60.8% of patients in the placebo arm. Prior neoadjuvant endocrine therapy was received by 30.4% and 31.4% of patients, respectively.

Additional data from the secondary end points were also reported. The median PFS per independent review committee (IRC) was NR in the dalpiciclib arm vs 22.5 months in the placebo arm (HR, 0.50; 95% CI, 0.36-0.70; P < .0001). In a subgroup analysis of PFS, the benefit was maintained across all stratification factors except among those with disease-free survival of 24 months or less (HR, 1.55; 95% CI, 0.42-5.79).

Tumor response per IRC were comparable with investigator assessment. The ORR in the dalpiciclib arm was 62.4% (95% CI, 56.7%-67.4%) vs 53.6% (95% CI, 45.4%-61.7%) in the placebo arm. Eight patients in the investigative arm had a complete response, with 59.7% and 16.8% of patients have a PR or SD. In the control arm, 53.6% of patients had a PR and 13.7% had SD.

The CBRs were 86.5% (95% CI, 82.1%-90.1%) and 75.8% (95% CI, 68.2%-82.4%), respectively. The median DOR was NR vs 20.9 months, respectively.

Investigators concluded that the agent was well tolerated in the first-line setting. “The most frequent AEs with dalpiciclib combination therapy were neutropenia and leukopenia, which were generally tolerable and manageable and in agreement with the known class effects of CDK4/6 inhibitors,” Xu said.

Grade 3 or higher neutropenia and leukopenia occurred among 85.5% and 66.6% of patients in the dalpiciclib arm. For patients who experienced neutropenia, the median time to first onset was 28 days (IQR, 27.0-29.0). Eighty-five patients had a dose reduction resulting from neutropenia and 1 patient discontinued treatment.

No patients in the placebo arm experienced these events at grade 3 or 4, and no patients in either arm experienced febrile neutropenia of any grade.

Serious AEs were reported in 11.9% of patients and 6.5% of patients in the investigative and placebo arms, respectively, with 12 patients discontinuing treatment due to AEs, in the dalpiciclib arm and 3 patients discontinuing in the placebo arm. Dose reductions due to toxicity were reported in 98 patients receiving dalpiciclib. Five patients died: 3 in the investigative arm and 2 in the placebo arm.

Other common nonhematologic AEs in the investigative and control arms included AST increase (31.1% vs 37.9%, respectively), ALT increase (27.5% vs 35.3%), urinary tract infection (22.8% vs 22.2%), and hyperglycemia (20.9% vs 16.3%).

Dalpiciclib is now currently under investigation in the United States.3


  • Xu B, Zhang QY, Zhang P, et al. Dalpiciclib plus letrozole or anastrozole as first-line treatment for HR+/HER2- advanced breast cancer (DAWNA-2): a phase III trial. Ann Oncol. 2022;33(suppl 7):LBA16. doi: 10.1016/annonc/annonc1089
  • Xu B, Zhang Q, Zhang P, et al; DAWNA-1 Study Consortium. Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial. Nat Med. 2021;27(11):1904-1909. doi:10.1038/s41591-021-01562-9
  • SHR6390. Accessed September 9, 2022.
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