Dalpiciclib Combined With Pyrotinib and Endocrine Therapy in Dual Receptor–Positive (ER-Positive/HER2-Positive) MBC

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 letrozole in patients with HER2-positive/hormone receptor–positive metastatic breast cancer (MBC).1 Based on these encouraging results, a phase 2 dose-expansion study (PLEASURABLE; NCT03772353) is evaluating dalpiciclib combined with pyrotinib and endocrine therapy (ET) in women with dual receptor–positive (estrogen receptor [ER]-positive/HER2-positive) MBC. 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 MBC who are eligible for first- or second-line treatment. Eligible patients received dalpiciclib plus pyrotinib and ET (physician’s choice of letrozole or fulvestrant). The primary end point was objective response rate (ORR). For biomarkers analysis, 68Ga-HER2 affibody was assessed by positron emission tomography/computed tomography, and pretreatment tissue-derived DNA and circulating tumor DNA (ctDNA) were assessed by next-generation sequencing (NGS). Date of data cutoff was January 19, 2023.

A total of 48 patients were enrolled; of these, 17 (35.4%) were treatment naïve, and 31 (64.6%) had received previous 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. Progression-free survival and overall survival data were not mature by the cutoff date.

The safety analysis did not find new safety signals. Common 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, both at baseline (n=16) and after 2 cycles of therapy (n=12); however, responders showed a decline in 68Ga-HER2 affibody uptake, whereas nonresponders showed increased uptake. NGS on baseline tissue (n=10) and ctDNA (n=10) samples detected BRCA mutations in 2 patients; both had no tumor responses.

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


  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.

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