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Clinical Trial
. 2025 Nov 1;11(11):1356-1363.
doi: 10.1001/jamaoncol.2025.3687.

600- vs 400-mg First-Line Ribociclib in Hormone Receptor-Positive/ERBB2-Negative Advanced Breast Cancer: The AMALEE Randomized Clinical Trial

Fatima Cardoso  1 , William Jacot  2 , Sherko Kuemmel  3 , Sudeep Gupta  4 , Felipe Cruz  5 , Rama Balaraman  6 , Ana Ferreira  7 , Tytti Ahola  8 , Yana Chapko  9 , Lyudmila Zhukova  10 , Wendy Chiang  11 , Zheng Li  11 , Yan Ji  11 , Nadia Kaakiou  12 , Natalia Bolotova  12 , Joseph A Sparano  13
Affiliations
Clinical Trial

600- vs 400-mg First-Line Ribociclib in Hormone Receptor-Positive/ERBB2-Negative Advanced Breast Cancer: The AMALEE Randomized Clinical Trial

Fatima Cardoso et al. JAMA Oncol. .

Abstract

Importance: Ribociclib, 600 mg showed substantial survival benefits in patients with hormone receptor-positive (HR+)/ERRB2-negative (ERBB2-; formerly HER2) advanced breast cancer (ABC) in the phase 3 MONALEESA trials but was associated with dose-dependent adverse events (AEs) that were manageable with dose reductions.

Objective: To investigate whether a 400-mg ribociclib starting dose could reduce the incidence of AEs while maintaining efficacy in ABC.

Design, setting, and participants: The AMALEE phase 2, multicenter, randomized, open-label, interventional noninferiority study was conducted between June 18, 2019, and December 8, 2020, and included pre- and postmenopausal women with newly diagnosed HR+/ERBB2- ABC. The study was conducted across 107 sites in 23 countries (across Europe and Australia, Latin America, North America, and Asia). The data were analyzed at the final data cutoff (August 30, 2024).

Interventions: Randomization 1:1 to ribociclib, 400 mg + a nonsteroidal aromatase inhibitor or ribociclib, 600 mg + a nonsteroidal aromatase inhibitor (premenopausal patients also received goserelin).

Main outcomes and measures: Overall response rate (ORR; primary end point); ΔFridericia-corrected QT interval (QTcF) from baseline to cycle 1 day 15, 2 hours postdose (ΔQTcF; secondary end point); duration of response (DOR); time to response (TTR); progression-free survival (PFS); pharmacokinetics; and safety. Final analysis results are reported.

Results: Baseline characteristics and prior anticancer therapy were balanced among the 376 patients (median [range] age, 58.0 [27-96] years). Median (range) follow-up from randomization was 53.5 (36.0-64.0) months (final data cutoff: August 30, 2024). The absolute ORR difference between ribociclib, 400 mg and ribociclib, 600 mg was -7.2% (ORR ratio, 0.87; 90% CI, 0.74-1.03). With ribociclib, 400 mg vs ribociclib, 600 mg, median PFS (26.9 vs 25.1 months) and DOR (26.5 vs 28.8 months) were similar; TTR was longer (13.1 vs 9.0 months). The maximal plasma concentration after dose and the 24-hour area under the curve (measured at the primary data cutoff) were 28.0% and 42.7% lower, respectively, with ribociclib, 400 mg than ribociclib, 600 mg. Ribociclib, 400 mg had a shorter ΔQTcF (12.5 vs 19.7 milliseconds at cycle 1 day 15, 2 hours postdose), lower grade 3 or4 neutropenia rate (41.0% vs 58.5%), and fewer patients who required dose reduction due to AEs (29 patients [15.4%] vs 69 patients [36.9%]). Liver-related AEs, kidney toxic effects, interstitial lung disease or pneumonitis, and AE-prompted discontinuation rates were similar between arms.

Conclusions and relevance: The AMALEE randomized clinical trial did not demonstrate ORR noninferiority of ribociclib, 400 mg vs ribociclib, 600 mg, with comparable DOR and PFS between doses. Ribociclib, 400 mg had longer TTR, lower pharmacokinetic exposure, and lower rates of QTcF prolongation and neutropenia. The final results confirmed the standard ribociclib, 600 mg starting dose in HR+/ERBB2- ABC while supporting dose reduction to manage dose-dependent AEs.

Trial registration: ClinicalTrials.gov Identifier: NCT03822468.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cardoso reported personal fees from Novartis, Pfizer, Lilly Advisory role during the conduct of the study as well as personal fees from Amgen, Astellas/Medivation, AstraZeneca, Bayer, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, Gilead, GlaxoSmithKline, Iqvia, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva, and Touchime outside the submitted work. Dr Jacot reported grants from Daiichi Sankyo and AstraZeneca; personal fees from Daiichi Sankyo, AstraZeneca, BMS, Novartis, Roche, Eisai, Lilly France, MSD, Gilead, Pfizer, and Seagen; nonfinancial support from AstraZeneca, Chugai Pharma, Eisai, GSK, Lilly France, Pfizer, Novartis, Pierre Fabre, Roche, and Sanofi Aventis outside the submitted work. Dr Kuemmel reported personal fees from Amgen, Lilly, Pfizer, Novartis, Gilead, AstraZeneca, Daiichi Sankyo, Stemline, Hologic, PINK, Agendia, Exact Science, Roche, and MSD during the conduct of the study as well as personal fees from Novartis, Roche, Daiichi Sankyo, Stemline, and WSG. Dr Gupta reported grants from Novartis during the conduct of the study. Dr Melo Cruz reported lecture fees from Astellas, MSD, and Johnson & Johnson outside the submitted work. Dr Li reported being a Novartis employee during the conduct of the study. Dr Ji reported being an employee of and owning stock in Novartis outside the submitted work. Dr Bolotova reported being an employee of and holding company shares in Novartis outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
Patients were screened and randomized to either receive ribociclib, 400 mg + a nonsteroidal aromatase inhibitor (NSAI) or ribociclib, 600 mg + NSAI.
Figure 2.
Figure 2.. Kaplan-Meier Plots of Duration of Response (DOR), Time to Response (TTR), and Progression-Free Survival (PFS) Between the Ribociclib, 400 mg (RIB400), and Ribociclib, 600 mg (RIB600) Arms
Patients in the RIB400 arm received RIB400 + a nonsteroidal aromatase inhibitor (NSAI), while those in the RIB600 arm received RIB600 + NSAI. The events per number for RIB400 and RIB600 were 46 of 90 and 48 of 103 (A), 90 of 188 and 103 of 188 (B), and 103 of 188 and 97 of 188 (C), respectively. The median DOR of RIB400 and RIB600 was 26.5 and 28.8 months, respectively, the median TTR of RIB400 and RIB600 was 13.1 and 8.0 months, respectively, and the median PFS of RIB400 and RIB600 was 26.9 and 25.1, respectively. B, The probability of a response to treatment over time for the 2 treatment arms.
See this image and copyright information in PMC

Comment on

References

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