Dalpiciclib Plus Pyrotinib and Endocrine Therapy Displays Efficacy in ER+, HER2+ Advanced Breast Cancer

The novel CDK4/6 inhibitor dalpiciclib (SHR6390) in combination with pyrotinib and endocrine therapy was safe and effective for the treatment of patients with estrogen receptor (ER)–positive, HER2-positive advanced breast cancer, according to data from the phase 2 PLEASURABLE trial (NCT03772353) published in PLOS Medicine.1

At a median follow-up of 27.3 months (IQR, 24.8-30.5), the investigator-assessed confirmed overall response rate (ORR) among efficacy-evaluable patients who received the combination (n = 47) was 70.2% (95% CI, 55.1%-82.7%), with a complete response rate of 2.1%, and the disease control rate (DCR) was 100% (95% CI, 92.5%-100%). The median progression-free survival (PFS) was 22.0 months (95% CI, 16.4-26.9) and the median duration of response (DOR) was 22.3 months (95% CI, 16.4-26.9).

“The nonintravenous, chemotherapy-sparing combination of dalpiciclib, pyrotinib, and endocrine therapy demonstrated anti-tumor activity with a manageable safety profile in the frontline treatment of ER-positive, HER2-positive advanced breast cancer, supporting its further evaluation as a potential alternative,” Jian Zhang, MD, a professor at Shanghai Cancer Center, Fudan University, in China, and his coauthors wrote in the study.

PLEASURABLE Trial Overview

PLEASURABLE was a prospective, single-arm, multicenter study that enrolled patients with unresectable, locally advanced, recurrent, or metastatic ER-positive, HER2-positive breast cancer at 6 centers in China. Eligible patients needed to be 18 to 75 years old, female, have at least 1 measurable lesion per RECIST 1.1 criteria, have an ECOG performance status of 0 or 1, and adequate organ function. Patients were permitted to have received up to 1 prior systemic regimen for recurrent or metastatic breast cancer.

Patients received dalpiciclib at 125 mg once daily on days 1 through 21 of each 28-day cycle, pyrotinib at 320 mg once daily, and endocrine therapy. Endocrine therapy consisted of letrozole (n = 28) or fulvestrant (n = 20 and was determined by physician’s choice.

The primary end point was ORR. Secondary end points included PFS, DOR, DCR, clinical benefit rates, safety, pharmacokinetics, and biomarker analysis.

At baseline, the median age was 52.5 years (range, 29-74). Most patients underwent prior had prior endocrine therapy (77.1%), had an ECOG performance status of 1 (72.9%), were postmenopausal (72.9%), had metastatic recurrent disease (81.2%), and had less than 3 metastatic sites. Metastatic sites included visceral (77.1%), brain (16.7%), liver (29.2%), lung (56.3%), and non-visceral (22.9%).

The median number of prior systemic regimens at baseline was 1 (range, 0-3). Most patients received prior systemic therapy in the neoadjuvant or adjuvant setting (64.6%), chemotherapy (77.1%), and trastuzumab (Herceptin; 64.6%).

Additional Efficacy and Safety Data

The clinical benefit rate in this trial was 87.2% (95% CI, 74.3%-95.2%). Although overall survival (OS) data were immature at the time of publication, the estimated 48-month OS rate was 82.6% (95% CI, 66.3%-91.5%).

The confirmed ORRs among patients who received first- (n = 29) and second-line (n = 18) HER2-directed therapy were 79.3% (95% CI, 60.3%-90.2%) and 55.6% (95% CI, 30.8%-78.5%), respectively. The median PFS values were 22.3 months (95% CI, 16.6-26.6) and 20.1 months (95% CI, 7.6-44.1), respectively.

In the safety population (n = 48), all patients experienced at least one treatment-related adverse event (TRAE). The most common any-grade TRAEs included neutropenia (97.9%), leukopenia (95.8%), diarrhea (91.7%), anemia (87.5%), oral mucositis (70.8%), and thrombocytopenia (50.0%). Patients experienced grade 3 and 4 TRAEs at respective rates of 68.8% and 12.5%. Common grade 3 TRAEs included neutropenia (60.4%), leukopenia (56.3%), and anemia (10.4%).

Serious treatment-related adverse effects requiring hospitalization occurred in 4 patients. No treatment-related deaths were reported. Three patients discontinued treatment due to TRAEs and 33.3% of patients required a dose adjustment.

“The combination of dalpiciclib and pyrotinib with endocrine therapy demonstrated a manageable safety profile, with no new or unexpected safety signals,” the study authors wrote.

References

Zhang J, Meng Y, Wang B, et al. Dalpiciclib combined with pyrotinib and endocrine therapy in women with ER-positive, HER2-positive advanced breast cancer: a prospective, multicenter, single-arm, phase 2 trial. PLoS Med. 2025;22(7):e1004669. doi:10.1371/journal.pmed.1004669