HER2+ Breast Cancer
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First-line therapy with ribociclib (Kisqali), trastuzumab (Herceptin), and the aromatase inhibitor (AI) letrozole (Femara) with or without a GnRH agonist was effective with a manageable safety profile in patients with metastatic hormone receptor–positive, HER2-positive breast cancer, supporting the regimen’s use as a chemotherapy-free option in this population, according to data from the phase 1b/2 MINI trial (NCT03913234), which was conducted in South Korea.1
Findings presented during the2025 ASCO Annual Meeting showed that, at median follow-up of 15.8 months (95% CI, 12.9-19.1), the median PFS in the phase 2 population (n = 77) was 30.4 months (95% CI, 19.6-not applicable [NA]). The median overall survival (OS) in this population was NA (95% CI, NA-NA).
The overall response rate (ORR) in the total study population (n = 90), comprising patients in both the phase 1b (n = 13) and phase 2 portions, was 60.7%. This included a complete response (CR) rate of 3.3% and a partial response (PR) rate of 53.3%. Stable disease (SD) was achieved by 36.7% of patients, no patients experienced disease progression, and 6.7% of patients were not evaluable (NE). The clinical benefit rate (CBR) in the overall population was 84.5%, and the median duration of response (DOR) was 12.2 months (range, 7.6-13.8).
In the phase 1b portion of the study, the ORR was 58.3%; the PR rate was 53.9%, the SD rate was 38.5%, and 7.7% of patients were NE. No patients achieved a CR. The CBR was 83.3%, and the median DOR was 17.5 months (range, 7.3-35.5).
In the phase 2 portion, the ORR was 61.1%, comprising CR, PR, and SD rates of 3.9%, 53.2%, and 36.4%, respectively. In total, 6.5% of patients were NE. The CBR was 84.7%, and the median DOR was 11.8 months (range, 7.6-13.4).
“The MINI trial reinforces the rationale for first-line use of CDK4/6 inhibitors as a chemotherapy-free strategy in HER2-positive, hormone receptor–positive metastatic breast cancer, aligning with the prior findings from [the phase 3] DETECT V [NCT02344472] and [phase 1/2] ASPIRE [NCT03304080] trials,” lead study author Joohyuk Sohn, MD, PhD, stated during an oral presentation of the data. Sohn is a professor in the Division of Medical Oncology in the Department of Internal Medicine at Yonsei Cancer Center, part of Yonsei University College of Medicine in Seoul, South Korea.
MINI Trial: Background, Design, and Baseline Characteristics
This multicenter, single-arm, prospective trial was conducted across 17 academic institutions in South Korea and comprised both a phase 1b and phase 2 portion.1,2
Pre- and post-menopausal patients with hormone receptor–positive, HER2-positive metastatic breast cancer were enrolled onto both parts of the study. Other key eligibility requirements included no prior systemic treatment for metastatic breast cancer, and a baseline left ventricle ejection fraction within normal range. Prior exposure to neoadjuvant/adjuvant trastuzumab or endocrine therapy was not permitted, excepting patients with a disease-free interval of more than 12 months after their last dose of trastuzumab, and those more than 2 years out from their last dose of adjuvant endocrine therapy. Patients with stable central nervous system (CNS) metastases were allowed to enroll.
The phase 1b portion comprised a standard 3+3 design, in which 13 patients were treated with 8 mg/kg of trastuzumab as a loading dose, followed by 6 mg/kg every 3 weeks; 2.5 mg ofletrozole daily; and escalating daily doses of ribociclib (200 mg, 400 mg, and 600 mg) for 3 weeks on/1 week off, with or without a GnRH agonist.
In phase 2, all 77 patients were treated with the recommended phase 2 dose (RP2D) of ribociclib plus trastuzumab and letrozole, with or without a GnRH agonist.
The primary end point in phase 1b was the identification of the RP2D. In phase 2, the primary end point was PFS. Secondary end points included OS, overall response rate, duration of response, and safety. Of note, PAM50 testing was conducted to determine correlations between intrinsic subtype and treatment efficacy in the phase 2 patient population.
The median age of all patients in the study was 60 (range, 31-85).1 Most patients had an ECOG performance status of 0 (60%) vs 1 (40%), were postmenopausal (84.4%), and had immunohistochemistry (IHC) 3+ HER2 expression (66.7%) vs IHC 2+ expression with positive in situ hybridization (33.3%). Almost all patients were also estrogen receptor–positive (96.7%), and 85.6% of patients were progesterone receptor–positive. Over half of patients had recurrent disease (58.9%), whereas 41.1% of patients had de novo stage IV disease. Most patients had 1 metastatic site (41.1%), followed by 2 (32.2%) and 3 or more (26.7%) metastatic sites. Metastatic sites included bone-only (12.2%), lung (48.9%), liver (27.8%), and the CNS (2.2%). Prior exposure to neoadjuvant/adjuvant therapy was reported in 33.3% of patients, with 47.8% of patients having previously received nonsteroidal AIs in the adjuvant setting.
Safety Data and PAM50 Analysis
The overall safety profile of the investigational combination was consistent with previously reported data with ribociclib plus endocrine therapy, Sohn reported. Any-grade adverse effects (AEs) occurred in all patients, 77.8% of which were grade 3 or higher. Serious AEs were reported in 17.8% of patients. Dose reductions were required for 33.3% of patients, and 7.8% of patients experienced AEs leading to permanent treatment discontinuation. One patient died due to an aortic aneurysm.
The most common hematologic toxicity was neutropenia (any-grade, 66.7%; grade ≥ 3, 63.3%), followed by anemia (18.9%; 5.6%). The most frequent nonhematological AEs were pruritus (24.4%; 0.0%), nausea (22.2%; 0.0%), arthralgia (18.9%; 5.6%), rash (16.7%; 1.1%), and elevated alanine transaminase levels (15.6%; 2.2%). AEs of special interest included decreased ejection fraction (2.2%; 0.0%), heart failure (1.1%; 1.1%), and QTc prolongation (1.1%; 0.0%).
PAM50 subtype distribution and survival analysis (n = 77) showed an even distribution among luminal A (31.2%), luminal B (36.4%), and HER2-enriched (31.2%) subtypes; the incidence of basal subtype was low, at 1.3%. No significant correlation between intrinsic subtype and median PFS was observed (P = .8326).
References
- Sohn J, Lim S, Jeong JH et al. 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. J Clin Oncol. 2025, 43(suppl 16):1016.doi:10.1200/JCO.2025.43.16_suppl.1016
- Phase IB and II study of ribociclib with trastuzumab plus letrozole in postmenopausal HR+, HER2+ advanced breast cancer patients. ClinicalTrials.gov. Updated May 10, 2022. Accessed August 19, 2025. https://clinicaltrials.gov/study/NCT03913234