Dalpiciclib Plus Pyrotinib and Endocrine Therapy Shows Promising Antitumor Activity in ER-Positive, HER2-Positive Metastatic Breast Cancer

The results of the phase 1b LORDSHIPS study showed promising antitumor activity with the combination of the novel cyclin-dependent kinase 4/6 inhibitor dalpiciclib plus the HER2 tyrosine kinase inhibitor pyrotinib and the nonsteroidal aromatase inhibitor letrozole in patients with HER2-positive, hormone receptor–positive metastatic breast cancer.¹ Based on these encouraging results, the phase 2 dose-expansion PLEASURABLE study is evaluating dalpiciclib combined with pyrotinib and endocrine therapy in women with dual receptor–positive (estrogen receptor [ER]-positive/HER2-positive) metastatic breast cancer. The initial results of this trial were presented at the 2023 ASCO annual meeting.²

The phase 2 study enrolled patients with ER-positive, HER2-positive metastatic breast cancer who are eligible for first- or second-line treatment. Eligible patients received dalpiciclib plus pyrotinib and endocrine therapy (physician’s choice of letrozole or fulvestrant). The primary end point was the objective response rate (ORR). For biomarkers analysis, ⁶⁸Ga-HER2 affibody was assessed by positron emission tomography or computed tomography, and pretreatment tissue-derived DNA and circulating tumor DNA (ctDNA) were assessed by next-generation sequencing (NGS). The data cutoff date was January 19, 2023.

A total of 48 patients were enrolled; of these patients, 17 (35.4%) were treatment naïve and 31 (64.6%) had previously received treatment with trastuzumab. In the overall population, the ORR was 68.1% (32/47), and the disease control rate was 100% (47/47). The ORR was 81.3% (13/16) in the treatment-naïve subgroup and 61.3% (19/31) in the trastuzumab-pretreated subgroup. The progression-free survival and overall survival data were not mature by the cutoff date.

The safety analysis did not find new safety signals. The frequent treatment-related grade ≥3 adverse events were neutropenia (95.8%), leukopenia (91.7%), diarrhea (87.5%), anemia (79.2%), oral mucositis (68.8%), and decreased platelet count (41.7%).

In terms of biomarker analysis, ⁶⁸Ga-HER2 affibody uptake was heterogeneous at baseline (n=16) and after receiving 2 cycles of therapy (n=12); however, the responders had a decline in ⁶⁸Ga-HER2 affibody uptake, whereas nonresponders had an increased uptake in ⁶⁸Ga-HER2 affibody. The NGS on baseline tissue (n=10) and ctDNA (n=10) samples detected BRCA mutations in 2 patients, both of whom had no tumor responses.

Based on these results, the investigators concluded that “the chemotherapy-sparing regimens showed significant antitumor activity for ER-positive, HER2-positive, metastatic breast cancer patients in the front-line setting.”

Sources:

1. Zhang J, Meng Y, Wang B, et al. Dalpiciclib combined with pyrotinib and letrozole in women with HER2-positive, hormone receptor-positive metastatic breast cancer (LORDSHIPS): a phase Ib study. Front Oncol. 2022;12:775081.
2. Zhang J, Meng Y, Wang B, et al. PLEASURABLE: results and biomarkers analysis from the phase II study of dalpiciclib combined with pyrotinib and endocrine therapy (ET) in women with dual-receptor positive (ER+/HER2+) metastatic breast cancer (MBC). Abstract presented at: ASCO Annual Meeting, June 2-6, 2023; Chicago, IL. Abstract 1046.