A phase II study of trastuzumab emtansine (T-DM1) combined with ribociclib in patients with HER2-positive metastatic breast cancer (RibHER).

1041 Background: HER2-targeted therapy has significantly improved outcomes for patients with HER2-positive metastatic breast cancer (MBC). Cyclin D and cyclin-dependent kinases 4/6 (CDK4/6) act as downstream effectors of HER2 signaling, providing a rationale for combining CDK4/6 inhibitors with anti-HER2 therapies. However, combining CDK4/6 inhibitors with anti-HER2 antibody–drug conjugates (ADCs) raises the concerns of hematologic toxicities. This prospective, single-center, single-arm, phase II study evaluated the antitumor activity and safety of trastuzumab emtansine (T-DM1) plus ribociclib in patients with HER2-positive MBC previously treated with trastuzumab and a taxane, and with no prior ADC exposure. Methods: Patients received T-DM1 (3.6 mg/kg IV, day 1 of each 21-day cycle) and ribociclib (400 mg orally, days 8-21). Those with ER-positive disease could receive concomitant endocrine therapy (aromatase inhibitor or fulvestrant) per prior treatment; premenopausal patients also received ovarian function suppression. The primary endpoint was overall response rate (ORR). Secondary endpoints included clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Results: From August 2020 to October 2024, 12 patients were enrolled. With the subsequent availability of trastuzumab deruxtecan (T-DXd), the study was terminated prematurely due to difficulties in patient enrollment. As of December 1, 2025, the median follow-up was 22.5 months (range: 8.7-25.2). The overall ORR was 41.7% and the CBR was 58.3%. Median PFS was 5.25 months (95%CI: 3.3-NA). In subgroup analyses, ORR (28.6% vs. 60.0%), CBR (57.1% vs. 60.0%), and median PFS (6.0 months, 95% CI: 3.5-NA vs. 4.5 months, 95% CI: 3.0-NA) differed between ER-positive and ER-negative subgroups, respectively. Median OS was not reached. All patients experienced treatment-related adverse events (TRAEs), most commonly thrombocytopenia (75.0%), neutropenia (66.7%), leukopenia (66.7%), anemia (50.0%), fatigue (50.0%), and elevated aspartate aminotransferase (50.0%). Grade ≥3 TRAEs included neutropenia (33.3%), leukopenia (25.0%), and thrombocytopenia (16.7%). Thrombocytopenia led to dose reduction in 5 patients and discontinuation in 2; one patient required platelet transfusion and another experienced grade 3 intracranial hemorrhage attributed to thrombocytopenia. No treatment-related deaths occurred. Conclusions: In this small preliminary study, T-DM1 plus ribociclib achieved an ORR of 41.7% in HER2-positive MBC. No clear PFS benefit was observed regardless of ER status. Overlapping hematologic toxicities, especially thrombocytopenia, were notable and warrant consideration in future combination strategies. Clinical trial information: NCT06481956 .