Background: In the Phase III MONALEESA (ML)-2, -3 and -7 trials, a 600 mg dose of ribociclib (RIB) demonstrated significant overall survival benefit in patients (pts) with HR+/HER2− advanced breast cancer (ABC) but was associated with QTcF (>480 ms, 3%-7%) and neutropenia (G3/4, 57%-64%) adverse events (AEs) which were managed by dose reductions. The Phase II AMALEE study was performed as a postmarketing commitment to assess whether reducing the starting dose of RIB from the recommended dose (3 wk on, 1 wk off) of 600 mg/day to 400 mg/day decreases QTcF prolongation without compromising the efficacy of first-line RIB in pts with HR+/HER2− ABC. Here, we present efficacy and safety results from the primary analysis of AMALEE. Methods: AMALEE is a randomized Phase II open-label study including pre- and postmenopausal pts with HR+/HER2− ABC with no prior therapy for ABC. Pts received RIB 400 mg + nonsteroidal aromatase inhibitor (NSAI) or RIB 600 mg + NSAI. The primary endpoint is to determine whether overall response rate (ORR) in the 400 mg arm is noninferior to the 600 mg arm. The key secondary endpoint is QTcF prolongation at cycle 1, day 15 (C1D15) 2 hours post dose. Additional endpoints included safety, progression-free survival (PFS), duration of response (DOR), time to response (TTR), and pharmacokinetics. Results: A total of 376 pts were randomized 1:1 to receive RIB at either 400 mg or 600 mg doses. Baseline (BL) characteristics and prior antineoplastic therapy were balanced across treatment (tx) arms. At the time of the data cutoff (June 11, 2021), median follow-up was 14.9 mo (min, 6.1; max, 23.8), and all pts had been treated for ≥6 months from randomization or had discontinued study tx. ORR for RIB was 41.5% (95% CI, 34.4-48.7) with 400 mg vs 45.3% (95% CI, 38.1-52.6) with 600 mg (ORR ratio for RIB 400 mg vs 600 mg, 0.921 [90% CI, 0.757-1.121]). The lower 90% CI boundary did not meet the prespecified noninferiority (NI) margin of 0.814. Results for ORR by subgroups were consistent with the overall analysis set. RIB plasma exposure was lower at 400 mg than 600 mg; the geometric mean Cmax and AUC0-24h at C1D15 were approximately 28% and 43% lower in the 400 mg than the 600 mg arm (Cmax 1080 vs 1500 ng/mL and AUC0-24h 16400 vs 28600 ng × h/mL). This study met the key secondary endpoint, change in QTcF at C1D15 in the RIB 400 mg group with a 90% CI upper boundary of < 20 ms. Mean change in QTcF from BL to C1D15 2 hours post dose was lower in the 400 mg (12.5 ms, 90% CI, 10.9-14.1) than the 600 mg arm (19.7 ms, 90% CI, 17.4-22.0). QTcF ≥501 ms occurred in 1.6% of pts in the 400 mg arm vs 0.5% in the 600 mg arm. Rates of G3/4 neutropenia were lower in the 400 mg (31.4%) than the 600 mg arm (46.3%). Other safety results were consistent with those previously reported for RIB in the ML trials. Median duration of exposure to RIB was 8.0 mo (min, 0.1; max, 23.7) in the 400 mg arm vs 8.8 mo (min, 0.5; max, 20.8) in the 600 mg arm. Dose reductions of RIB were more frequent in the 600 mg group with 30.5% vs 13.8% of pts requiring 1 dose reduction in the 600 mg and 400 mg groups, respectively. Dose reductions were primarily attributable to AEs, with neutropenia being the most frequently reported AE requiring a dose modification. Rates of discontinuation due to AEs were similar in the 400 mg vs 600 mg arms (8.5% vs 9.6%). PFS, DOR, and TTR data are currently immature. Conclusions: RIB at the 400 mg dose shows a better safety profile vs 600 mg in terms of key AEs that are RIB concentration dependent (neutropenia and QTcF prolongation). ORR was 3.8% lower with 400 mg than 600 mg. The lower 90% CI boundary of the ORR ratio did not meet the NI margin, thus this study was unable to demonstrate statistical NI of the 400 mg vs 600 mg dose of RIB using ORR as the endpoint. Updated results with additional follow-up and the clinically relevant endpoint PFS will be presented at the congress.

Citation Format: Fatima Cardoso, William Jacot, Sherko Küemmel, Sudeep Gupta, Rama Balaraman, Liudmila Lebedeva, Yan Ji, Aparna Lakshmanan, Khalid Amin, Zheng Li, Joseph Sparano. Primary efficacy and safety results from the AMALEE trial evaluating 600 mg vs 400 mg starting doses of first-line ribociclib in patients with HR+/HER2− advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD17-12.