Phase IB and II study of ribociclib with trastuzumab plus endocrine therapy in HR+/HER2+ advanced breast cancer patients: Korean Cancer Study Group BR 18-2 MINI trial.

1016 Background: In HER2+ advanced breast cancer (ABC), standard treatment has been anti-HER2 therapy with chemotherapy, regardless of hormone receptor status. While prior studies support the use of CDK4/6 inhibitors with anti-HER2 and endocrine therapy in pretreated HR+/HER2+ ABC, data on their first line use without chemotherapy are limited. This study investigates ribociclib, trastuzumab, and letrozole as a first-line combination in HR+/HER2+ ABC. Methods: This multicenter, single-arm, prospective trial was conducted across 17 academic institutions in South Korea (NCT03913234). Eligible patients were HR+/HER2+ ABC with no prior systemic therapy for metastatic disease. The Phase IB study used a 3+3 design to determine the recommended Phase II dose (RPIID) of ribociclib with fixed doses of letrozole (2.5 mg QD) and trastuzumab (8 mg/kg loading, then 6 mg/kg every 3 weeks). The Phase II trial evaluated efficacy and safety at the RPIID. The primary endpoint was progression-free survival (PFS), targeting an improvement from 8 to 12 months. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety. PAM50 testing assessed correlations between intrinsic subtype and treatment efficacy. Results: Phase IB (n = 13) identified the RPIID as ribociclib 600 mg QD, with one dose-limiting toxicity (Grade 3 ALT elevation) at 400 mg. In Phase II, 77 patients were enrolled, with a median age of 61 years (range 31–85), 18.2% (14/77) premenopausal, 66.2% (51/77) HER2 IHC 3+ and recurrent disease in 64.9% (50/77). 66.2% (51/77) had visceral metastases. At a median follow-up of 15.8 months (95% CI: 12.9-19.1) months, the median PFS was 30.4 months (95% CI: 19.6–NA), meeting the primary endpoint. The median OS was not reached. The ORR was 61.1%, including 3 complete and 41 partial responses, with a DOR of 11.8 months (95% CI: 7.6-13.4). Common adverse events included neutropenia (66.7%), pruritus (24.4%), and nausea (22.2%). There was a death reported due to aortic aneurysm. PAM50 analysis in 75 patients (phase IB/II) showed no significant correlation between intrinsic subtype and efficacy. Conclusions: Ribociclib, trastuzumab, and letrozole as first-line therapy in HR+/HER2+ ABC demonstrated a median PFS of 30.4 months with a manageable safety profile, supporting its potential as a chemotherapy-free option. Clinical trial information: NCT03913234 .