Addition of Dalpiciclib to Fulvestrant Improves PFS in HR+ Advanced Breast Cancer

The addition of dalpiciclib (SHR6390) to fulvestrant (Faslodex) significantly prolonged progression-free survival (PFS) vs fulvestrant alone in patients with hormone receptor (HR)–positive, HER2-negative advanced breast cancer, according to data from an interim analysis of the phase 3 DAWNA-1 trial (NCT03927456) published in Nature Medicine.¹

Results from the trial showed that the combination yielded 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) 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. “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.”

Although endocrine therapy has served as the cornerstone of treatment for those with HR-positive breast cancer, acquired resistance develops in most patients. As such, an urgent unmet need for new therapies that can overcome or delay the onset of endocrine resistance remains. Prior phase 3 clinical trials have examined the addition of CDK4/6 inhibitors to endocrine therapy in this population, and agents like palbociclib (Ibrance), ribociclib (Kisqali), or abemaciclib (Verzenio) combined with fulvestrant have been shown to improve survival outcomes for patients.

Dalpiciclib is a new, orally administered, selective CDK4/6 inhibitor that has demonstrated preliminary activity and synergic efficacy in a phase 1b trial (NCT03481998) in patients advanced breast cancer. Here, investigators sought to examine the safety and efficacy of the combination in those with HR-positive, HER2-negative advanced breast cancer who relapsed or progressed on previous endocrine therapy.

From June 2019 to September 2020, a total of 361 eligible patients were randomized 2:1 to receive either dalpiciclib plus fulvestrant (n = 241) or placebo plus fulvestrant (n = 120). The primary end point of the study was investigator assessed PFS, and secondary end points included PFS per RECIST v1.1 criteria, overall survival (OS), objective response rate (ORR), duration of response, clinical benefit rate (CBR), and safety.²

As of the data cutoff of November 15, 2020, 59.8% of patients in the dalpiciclib arm and 35.8% of those in the placebo arm were still receiving treatment. The median follow-up in the investigative and control arms 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 arm was 50.7 years (range, 45.3-59.3) vs 52.4 years old (45.5-60.6) in the placebo arm, and most of the patients in each arm were younger than 65 years, at 87.5% and 90.0% of patients, respectively. Moreover, most patients in each arm 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%). Furthermore, most patients in each arm had measurable disease (82.2% and 81.7%, respectively), less than 4 metastatic lesions (82.6% and 81.7%), and visceral metastases (58.9% and 62.5%).

In terms of prior endocrine therapy, 72.6% of patients in the dalpiciclib arm and 72.5% of those in the placebo arm had received 1 line of treatment; 27.4% and 27.5% of patients, respectively, received 2 lines. Additionally, 27.0% of patients in the dalpiciclib arm and 35.0% of those in the placebo arm received prior chemotherapy for recurrent or metastatic disease.

At the time of the interim analysis, 35.7% of patients in the dalpiciclib arm and 63.3% of those in the placebo arm had experienced disease progression or died. Additional data showed that the PFS rates at 6 and 12 months in the dalpiciclib and placebo groups 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, but a total of 25 deaths were reported; 15 occurred in the dalpiciclib group, and 10 occurred in the placebo group. Moreover, 24.1% of patients in the dalpiciclib arm and 40.8% of those in the placebo arm received subsequent chemotherapy or died, and the median time to first subsequent chemotherapy or death was NR in the dalpiciclib group vs 14.2 months (95% CI, 9.7-NR) in the placebo group (HR, 0.47; 95% CI, 0.32-0.69; P < .0001).

The ORRs in the dalpiciclib and placebo groups 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%).

The median duration of treatment was 9.4 months (range 4.3-11.4) for dalpiciclib and 9.9 months (range, 4.7-11.9) for fulvestrant in the dalpiciclib plus fulvestrant group, and 5.8 months (range, 3.1-10.4) for placebo and 6.1 months (range, 3.7-11.0) for fulvestrant in the placebo plus fulvestrant group.

Grade 3/4 adverse effects (AEs) were reported in 88.3% of patients in the dalpiciclib group and 13.3% of those in placebo group. These toxicities 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 experienced by 5.8% of patients in the dalpiciclib group and 6.7% of those in the placebo group, and fatal AEs were reported in 0.8% and 3.3% of patients, respectively.

The most common grade 3 or higher AEs reported in the dalpiciclib arm were neutropenia (84.2%), leukopenia (62.1%), and thrombocytopenia (5.8%). The most common grade 3 or higher AEs reported in the placebo group were anemia (1.7%) and hypertriglyceridemia (1.7%).

References

1. 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(11):1904-1909. doi:10.1038/s41591-021-01562-9
2. A study of SHR6390 in combination with fulvestrant in patients with HR positive and HER2 negative advanced breast cancer. ClinicalTrials.gov. Updated June 3, 2021. Accessed February 14,22. https://clinicaltrials.gov/ct2/show/NCT03927456