Preliminary analysis of pyrotinib and dalpiciclib-based therapy in HER2-positive advanced breast cancer (ABC)

e13027 Background: The efficacy of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) and HER2 target agents combined with endocrine treatment (ET) has been demonstrated in hormone receptor (HR)-positive and HER2+ ABC, while little was known about the role of CDK4/6i in HR-/HER2+ ABC. In this prospective, multi-center, multi-cohort, phase 2 study (NCT04095390), we assessed the efficacy and safety of pyrotinib (P) and a CDK4/6i, dalpiciclib (D)-based therapy in HER2+ ABC with disparate HR statuses. Methods: HER2+ ABC females with known HR status were eligible if previously treated with trastuzumab (T). No more than one prior systemic regimen in advanced setting was allowed. Cohort A: HR+ pts received P (320 mg QD) and D (125 mg QD, 21 days on and 7 days off) combined with letrozole (2.5 mg QD). Cohort B or C: HR- pts were randomized to receive P and D combined with or without capecitabine (500 mg TID). Pts were treated until progression or unaccepted toxicity. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: As of Jan. 16, 2023, 33 pts were enrolled. We describe pts' distribution and characteristics. 26 pts had at least one efficacy assessment, and 17 (65.4%) achieved confirmed objective responses. ORR was 66.7% (10/15), 80% (4/5), and 50% (3/6) in cohort A, B, and C, respectively. Among the ITT population, the estimated median PFS was 24.9 mo. (24.9 mo., NR, and 20.2 mo. in cohort A, B, and C, respectively). 32 (97.0%) pts experienced treatment-related adverse events (TRAEs). Grade (G) 3-4 TRAEs occurred in 81.8% of pts, and the most frequent (≥ 10%) ones were neutropenia (72.7%), leukopenia (57.6%), diarrhea (21.2%), and mucositis (12.1%). Safety profiles were similar among cohorts, except more G3-4 mucositis, hand-foot syndrome and thrombocytopenia in cohort B. Two in cohort B discontinued due to toxicity (1 rash, and 1 neutropenia). One death was reported after withdrawal and unrelated to the study. Median OS was not reached. Conclusions: Our study shows P and D combined with ET is effective in HR+/HER2+ ABC, providing a chemo-free option to these pts. In HR-/HER2+ ABC, we preliminarily observed that the addition of chemotherapy could improve effectiveness of P and D, but also increase toxicities. Due to the limited sample, the findings need further confirmation. Clinical trial information: NCT04095390 . [Table: see text]