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.”
- 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.
- 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.