Dalpiciclib plus pyrotinib, endocrine therapy passes trial for advanced breast cancer

Treatment with dalpiciclib combined with pyrotinib and endocrine therapy exhibits antitumour activity with no new safety signals in estrogen receptor (ER)-positive HER2-positive advanced breast cancer, as shown by the results of a phase II trial.

“The nonintravenous, chemotherapy-sparing combination of dalpiciclib, pyrotinib, and endocrine therapy demonstrated antitumour 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,” the investigators said.

Fifty-one patients underwent screening, of whom 48 were included (median age 52.5 years, 64.6 percent had prior HER2-target therapy, and 77.1 percent had received prior endocrine therapy) in the trial conducted at six centres in China.

Participants received dalpiciclib 125 mg once daily (QD), on days 1–21 of each 28-day cycle, and pyrotinib 320 mg QD plus endocrine therapy determined by the physician’s choice (letrozole or fulvestrant). Thirty (62.5 percent) patients received the combination therapy as first-line treatment and 18 (37.5 percent) as second-line treatment for advanced breast cancer.

The investigators examined treatment efficacy in the modified intention-to-treat population, including patients with at least one postbaseline tumour assessment. They also assessed safety in all participants who received at least a single dose. At data cutoff, six patients were lost to follow-up. The median follow-up was 27.3 months.

The objective response rate (ORR) was 70.2 percent (95 percent confidence interval [CI], 55.1–82.7), while the disease control rate (DCR) was 100 percent (95 percent CI, 92.5–100). The clinical benefit rate was 87.2 percent (95 percent CI, 74.3–95.2). [PLoS Med 2025;22:e1004669]

Participants had a median progression-free survival of 22.0 months (95 percent CI, 16.6–26.6). The median duration of response was 22.3 months (95 percent CI, 16.4–26.9).

Safety profile

The combination treatment demonstrated a manageable safety profile, with no treatment-related deaths occurring. One patient (2.1 percent) had a grade 1 alopecia, and none had interstitial lung disease. Of the participants, 68.8 percent and 12.5 percent developed grade 3 or 4 treatment-related adverse events (AEs; mostly myelosuppression), respectively.

Haematologic toxicities, such as neutropenia and leukopenia, were the most common grade 3 or 4 AEs associated with dalpiciclib. These were resolved through dose modifications and granulocyte colony-stimulating factor support. None of the patients discontinued treatment due to neutropenia.

“Other gastrointestinal adverse event (eg, nausea, vomiting, and constipation) and nervous system toxicities (eg, headache and peripheral neuropathy) were also numerically less frequent than those reported with HER2-targeted therapy combined with chemotherapy,” the investigators said. [Lancet Oncol 2020;21:519-530]

“However, the limited sample size and absence of a direct comparison with chemotherapy-based regimens preclude definitive conclusions,” they added.

In pharmacokinetics analysis, the investigators found no major drug accumulation for dalpiciclib or pyrotinib over the treatment period. Notably, three patients with detected BRCA mutations (n=2) or increased 68Ga-HER2 affibody uptake over the initial two cycles (n=2) showed no objective response.

“These findings outline a prospective path for further research on CDK4/6 inhibitors in the ER-positive, HER2-positive breast cancer,” the investigators said. 

“The findings of this study should be interpreted with caution due to the limited patient cohort and sample size in exploratory analyses,” they added.