Dalpiciclib Extends Progression‐Free Survival in HR+/HER2– Advanced Breast Cancer

Short abstract

The phase III DAWNA‐1 trial met its primary endpoint of improved progression‐free survival with dalpiciclib added to fulvestrant in previously treated HR‐positive, HER2‐negative advanced breast cancer, signaling a new option for combination therapy with a CDK4/6 inhibitor and endocrine therapy.

For patients with hormone receptor (HR)‐positive, human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancer that has progressed on prior endocrine therapy, the addition of a cyclin dependent kinase (CDK) 4/6 inhibitor to endocrine therapy has emerged as a new standard of care.

Dalpiciclib (SHR6390) is a novel CDK 4/6 inhibitor that has demonstrated single‐agent antitumor activity in patients with heavily pretreated HR‐positive, HER2‐negative advanced breast cancer [1]. The phase III DAWNA‐1 trial evaluated dalpiciclib plus fulvestrant in patients with HR‐positive, HER2‐negative advanced breast cancer that relapsed or progressed on prior endocrine therapy [2].

Binghe Xu, M.D., Ph.D., of the Chinese Academy of Medical Sciences and Peking Union Medical College, presented results from the DAWNA‐1 trial.

Study Design

The phase III DAWNA‐1 enrolled 361 patients with HR‐positive, HER2‐negative, locally advanced or metastatic breast cancer that relapsed or progressed on prior endocrine therapy. Eligible patients received up to one prior line of chemotherapy for recurrent or metastatic disease. Patients were stratified at study entry by menopausal status and the presence of visceral metastasis.

Patients were randomly assigned 2:1 to treatment with fulvestrant plus dalpiciclib (n = 241) or fulvestrant plus placebo (n = 120). The primary endpoint was investigator‐assessed progression‐free survival (PFS). Key secondary endpoints included PFS assessed by an independent review committee (IRC), overall survival, response, and safety.

Baseline characteristics were similar in both treatment arms (Table 1). Prior chemotherapy exposure was common and spanned the neoadjuvant (15%), adjuvant (84%), and salvage (30%) settings.

Table 1.

Baseline characteristics in patients with HR‐positive, HER2‐negative advanced breast cancer

Characteristic	Dalpiciclib plus fulvestrant (n = 241)	Placebo plus fulvestrant (n = 120)
Median age	51 years	52 years
ECOG PS
0	48.1%	38.3%
1	51.9%	61.7%
Menopausal status
Postmenopausal	56.0%	55.0%
Pre‐ or perimenopausal	44.0%	45.0%
Hormone receptor status
ER‐positive and PR‐positive	79.7%	75.8%
ER‐positive and PR‐negative	19.1%	24.2%
Visceral metastases
Yes	58.9%	62.5%
No	41.%	37.5%
Prior lines of endocrine therapy
1	72.6%	72.5%
2	27.4%	27.5%
Prior chemotherapy
Neoadjuvant	14.9%	15.8%
Adjuvant	83.0%	85.0%
Salvage	27.0%	35.0%

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; PR, progesterone receptor.

Key Findings

Results showed a significant improvement in PFS with dalpiciclib compared with fulvestrant alone. The median investigator‐assessed PFS was 15.7 months in the dalpiciclib group and 7.2 months in the placebo group (HR, 0.42; 95% CI, 0.31–0.58). This represents a 58% reduction in the relative risk of disease progression or death with the addition of dalpiciclib (p < .0001).

Similarly, per IRC assessment, the median PFS was 13.6 months with dalpiciclib/fulvestrant and 7.7 months with placebo/fulvestrant (HR, 0.45; 95% CI, 0.32–0.64; p < .0001). The PFS subgroup analysis favored the addition of dalpiciclib in all groups defined by patient age, ECOG performance status, menopausal status, hormone receptor status, presence of visceral metastases, and prior treatment history.

Response endpoints also favored the addition of dalpiciclib. Per investigator assessment, the overall response rate (ORR) was 27.0% with dalpiciclib plus fulvestrant and 20.0% with fulvestrant alone (p = .0727). The clinical benefit rate (CBR) was 61.0% and 45.8%, respectively (p = .0033). This was consistent with the IRC assessment, which demonstrated a statistically significant improvement with dalpiciclib relative to fulvestrant alone in ORR (30.3% vs. 15.8%; p = .0015) and CBR (60.2% vs. 43.3%; p = .0013).

The addition of dalpiciclib delayed the need for subsequent chemotherapy. After 12 months, 70.8% of patients in the dalpiciclib group remained free from subsequent chemotherapy, compared with 52.4% of those treated with fulvestrant alone (p < .0001). The median time to subsequent chemotherapy was not reached in the dalpiciclib group and 14.2 months with fulvestrant alone (HR, 0.47; 95% CI, 0.32–0.69).

In the safety analysis, 88.3% of patients in the dalpiciclib group experienced any grade 3–4 adverse event (AE), compared with 11.7% of patients in the fulvestrant group. There were no differences between groups in patients having serious AEs (5.8% vs. 6.7%) or AEs leading to treatment discontinuation (2.5% vs. 3.3%).

The most common grade 3–4 AEs in the dalpiciclib group were hematologic toxicities, including neutropenia (84.2%), leukopenia (62.1%), thrombocytopenia (5.8%), lymphopenia (5.0%), and anemia (2.9%). Among those with neutropenia, the median time to first onset was 15 days, and the median duration of grade ≥3 neutropenia was 3 days. There were no cases of febrile neutropenia or neutropenia leading to treatment discontinuation or death.

As options for CDK4/6 inhibition continue to expand, findings from the phase III DAWNA‐1 trial support a potential role for dalpiciclib plus fulvestrant in patients with HR‐positive, HER2‐negative advanced breast cancer that has relapsed or progressed on prior endocrine therapy.