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

Fatima Cardoso; William Jacot; Sherko Kuemmel; Sudeep Gupta; Felipe Cruz; Rama Balaraman; Ana Ferreira; Tytti Ahola; Yana Chapko; Lyudmila Zhukova; Wendy Chiang; Zheng Li; Yan Ji; Nadia Kaakiou; Natalia Bolotova; Joseph A Sparano

doi:10.1001/jamaoncol.2025.3687

. 2025 Sep 25;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

¹Breast Unit, Champalimaud Clinical Center/Champalimaud Foundation and ABC Global Alliance, Lisbon, Portugal

²Institut du Cancer de Montpellier Val d’Aurelle, Montpellier University, INSERM U1194, Montpellier, France

³Breast Unit, Kliniken Essen-Mitte, Essen, Germany and Department of Gynecology with Breast Unit, Charité Hospital Berlin, Berlin, Germany

⁴Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India

⁵Nucleo Pesquisa da Rede Sao Camilo, Sao Paulo, Brazil

⁶Florida Cancer Affiliates, Ocala

⁷Instituto Português Oncologia Porto, Porto, Portugal

⁸HUS Comprehensive Cancer Center, Helsinki, Finland

⁹Arkhangelsk Regional Clinical Oncology Dispensary, Arkhangelsk, Russian Federation

¹⁰Loginov Moscow Clinical Scientific Center, Moscow, Russian Federation

¹¹Novartis Pharmaceuticals Corporation, East Hanover, New Jersey

¹²Novartis Pharma AG, Basel, Switzerland

¹³Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, New York

Accepted for Publication: June 16, 2025.

Published Online: September 25, 2025. doi:10.1001/jamaoncol.2025.3687

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Corresponding Author: Fatima Cardoso, MD, Medical Oncology, ABC Global Alliance, Lisbon, Portugal (fcardoso@abcglobalalliance.org).

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License, which does not permit alteration or commercial use, including those for text and data mining, AI training, and similar technologies. © 2025 Cardoso F et al. JAMA Oncology.

Author Contributions: Drs Li and Chiang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Cardoso, Jacot, Kuemmel, Li, Ji, Sparano.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Jacot, Melo Cruz, Balaraman, Zhukova, Chiang, Li, Ji.

Critical review of the manuscript for important intellectual content: Cardoso, Jacot, Kuemmel, Gupta, Melo Cruz, Balaraman, Ferreira, Ahola, Chapko, Chiang, Li, Ji, Kaakiou, Bolotova, Sparano.

Statistical analysis: Li, Ji.

Administrative, technical, or material support: Cardoso, Kuemmel, Chiang, Sparano.

Supervision: Cardoso, Kuemmel, Melo Cruz, Balaraman, Ferreira, Ahola, Chiang, Bolotova.

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.

Funding/Support: This work was supported by Novartis Pharmaceuticals Corporation.

Role of the Funder/Sponsor: Novartis Pharmaceuticals Corporation was responsible for design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank the patients who participated in the trial and their families and caregivers; the members of the trial steering committee; the staff members who assisted with the trial at each site; and Molly Amador, PhD, Nucleus Global, an Inizio company, for medical editorial assistance with earlier versions of the manuscript. Ribociclib was discovered by the Novartis Institutes for BioMedical Research in collaboration with Astex Pharmaceuticals. Dr Amador was not compensated beyond her salary for her contributions.

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Corresponding author.

PMCID: PMC12464849 PMID: 40996770

Key Points

Question

Does ribociclib, 400 mg, preserve efficacy with reduced toxic effects vs ribociclib, 600 mg, in hormone receptor–positive (HR⁺)/ERRB2–negative (ERBB2⁻) advanced breast cancer?

Findings

In the final analysis of this phase 2 randomized clinical trial of 376 women with HR⁺/ERBB2⁻ advanced breast cancer, ribociclib, 400 mg, did not meet noninferiority criteria vs ribociclib, 600 mg, for overall response rate (48.9% vs 56.1%). The response duration and progression-free survival were similar, while Fridericia-corrected QT interval prolongation and neutropenia rates were lower with ribociclib, 400 mg.

Meaning

The trial results suggest that the ribociclib starting dose for HR⁺/ERBB2⁻ advanced breast cancer should remain 600 mg, but dose reduction can help manage certain adverse events.

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

This randomized clinical trial examines whether a 400-mg ribociclib starting dose can reduce the incidence of adverse events while maintaining efficacy in advanced breast cancer.

Introduction

The current standard of care for hormone receptor–positive (HR⁺)/ERRB2–negative (ERBB2⁻; formerly HER2) advanced breast cancer (ABC) is endocrine therapy (ET) plus a cyclin-dependent kinase (CDK) 4/6 inhibitor (4/6i).¹ Ribociclib at 600 mg per day with ET showed substantial progression-free survival (PFS) and overall survival (OS) benefits in patients with HR⁺/ERBB2⁻ ABC in the phase 3 MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials.^{2,3,4,5,6,7,8} Adverse events of special interest (AESIs) with ribociclib, 600 mg include neutropenia, QT prolongation, and liver-related adverse events (AEs).^6,7,8 Grade 3 or 4 neutropenia (grouped term) occurred for 53% to 64% of participants in the MONALEESA trials,^{2,3,4,5,6,7,9} and a Fridericia-corrected QT interval (QTcF) of more than 480 milliseconds for 4% to 7%.^3,4,5 These AEs were dose dependent and manageable with dose adjustments, resulting in low discontinuation rates.^3,4,5,10,11 All-grade alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level elevations occurred for 11.9% to 15.6% of patients (grade ≥3, 3.6%-9.3%) receiving ribociclib, 600 mg^2,3,4,12 and 16.2% to 19.5% of patients receiving ribociclib, 400 mg, daily in the early breast cancer setting (NATALEE trial) and were generally manageable with dose modifications.^12,13

Given the concentration dependency of QTcF prolongation with ribociclib,¹¹ the phase 2, postmarketing AMALEE trial (NCT03822468) was requested by the US Food and Drug Administration (FDA) to determine whether reducing the starting dose to ribociclib, 400 mg would decrease the incidence of QTcF prolongation with similar efficacy as ribociclib, 600 mg in the first-line setting in HR⁺/ERBB2⁻ ABC. The study also assessed AESIs and additional efficacy end points. Ribociclib, 400 mg was selected based on pharmacokinetic (PK)/pharmacodynamic (PD) modeling and an exposure-response analysis that suggested this dose would result in a lower mean change in QTcF (ΔQTcF), a smaller reduction in absolute neutrophil cell counts, and a lower incidence of neutropenia than ribociclib, 600 mg.^10,11 The primary results have been presented.¹⁴ We present the final AMALEE efficacy, PK, and safety data of ribociclib, 400 mg vs ribociclib, 600 mg in combination with a nonsteroidal aromatase inhibitor (NSAI) in first-line HR⁺/ERBB2⁻ ABC.

Methods

Study Design

AMALEE was a phase 2, multicenter, randomized, open-label, noninferiority trial conducted among pre- and postmenopausal patients with HR⁺/ERBB2⁻ ABC (Supplement 1 and Supplement 2). The study protocol and the protocol amendment were reviewed by the independent ethics committee or institutional review board of each center. The study was conducted in accordance with the ICH E6 Guideline for Good Clinical Practice that originates from the Declaration of Helsinki. Written informed consent was obtained from each patient before screening for any study specific procedure that was performed. Patients were randomized 1:1 to ribociclib, 400 mg orally (3 weeks on/1 week off) + an NSAI (letrozole [2.5 mg per day, orally] or anastrozole [1 mg per day, orally]) (experimental arm) or ribociclib, 600 mg + NSAI (control arm) between June 18, 2019, and December 8, 2020. Premenopausal patients also received goserelin (3.6 mg subcutaneously every 4 weeks). Patients with breast cancer that was not subject to curative therapy with prior antineoplastic (ANP) therapy for ABC and had measurable disease (≥1 lesion per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1), an Eastern Cooperative Oncology Group status of 1 or less, a QTcF of less than 450 milliseconds at screening, and adequate bone marrow and organ function as assessed by central laboratory were eligible. Prior (neo)adjuvant ET was allowed, but prior aromatase inhibitor–based ET must have been completed 12 months or longer before randomization. Patients were excluded if they had symptomatic visceral disease, previously received systemic treatment for ABC (eg, ET, chemotherapy, and CDK4/6is), or had clinically significant uncontrolled heart disease and/or cardiac repolarization abnormality. Treatment continued until radiologically documented disease progression (RECIST 1.1), unacceptable toxic effects, death, or discontinuation of study treatment for any other reason. Continuation of study treatment beyond initial disease progression (RECIST 1.1) was not allowed. Patients were followed up to 36 months and thereafter when clinically indicated. The end of the study was declared as the earliest of the following: all patients died or discontinued treatment or had been followed up for approximately 3 years postrandomization; patients were still deriving clinical benefit and could continue receiving the study treatment in an alternative setting (investigator assessed); or another clinical study became available that could provide ribociclib, and all patients with ongoing treatment were eligible to transfer to that study. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

The primary objective of AMALEE was to determine whether the overall response rate (ORR) in the experimental arm (ribociclib, 400 mg) was noninferior to that in the control arm (ribociclib, 600 mg), with ORR defined as the proportion of patients with a best overall response of a confirmed complete response (CR) or partial response (PR) based on local tumor assessments (RECIST 1.1). The key secondary objective was to evaluate QTcF prolongation in the experimental arm, with ΔQTcF at cycle 1 day 15 (C1D15) at 2 hours postdose. Other secondary end points included safety and tolerability, PFS, clinical benefit rate, time to response (TTR), and duration of response (DOR) per RECIST, version 1.1, and PK.

Study Assessments

Tumor imaging was performed at screening (≤28 days before randomization), every 8 weeks after randomization for the first 18 months and then every 12 weeks until 36 months, and thereafter as clinically indicated until disease progression, death, withdrawal of consent, loss to follow-up, or participant or guardian decision and at the end of treatment (EOT). Tumor assessment was performed at EOT for patients who discontinued treatment before the first (8-week) assessment after baseline and whose previous tumor assessment, if performed longer than 21 days before the EOT visit, did not demonstrate progression. PR and CR were confirmed based on RECIST 1.1. Patients who discontinued treatment for reasons other than radiological documentation of progression underwent an efficacy assessment at EOT unless imaging was performed for tumor measurement 21 days or less before EOT.

Plasma ribociclib concentrations were measured for all patients to evaluate PK. In each arm, extensive PK blood samples (predose; 2, 4, 6, and 24 hours postdose on C1D15) were collected from approximately 20 patients, and sparse samples (predose; 2 and 4 hours postdose on C1D15) were collected from remaining patients. Plasma ribociclib concentration was measured using a validated liquid chromatography–tandem mass spectrometry assay.¹⁵ Noncompartmental analysis was used to determine PK parameters, including area under the curve (AUC) from 0 to 24 hours, maximal plasma concentration after dose, time to reach the maximal plasma concentration after dose, and apparent clearance.

Safety assessments included monitoring and recording of AEs (including serious AEs [SAEs]) and regular laboratory and standard triplicate 12-lead electrocardiogram (ECG) assessments. AEs were coded according to the Common Terminology Criteria for Adverse Events, version 4.03.

Statistical Analysis

For ORR, noninferiority of ribociclib, 400 mg vs ribociclib, 600 mg was established if the lower limit of the 90% CI of the ORR ratio (ribociclib, 400 mg/ribociclib, 600 mg) was greater than the prespecified noninferiority margin of 0.814, which was calculated based on a 50% retention on the log-scale of the ratio of 43.9% (MONALEESA-2) and 29.1% (MONALEESA-7) per FDA guidelines. The confidence interval was determined with the Mantel–Haenszel method, as stratified by lung/liver metastasis. ORR was assessed in the per-protocol set, which included all patients in the intent-to-treat (ITT) population who did not have major protocol deviations.

For QTcF, the objective of mitigating QT prolongation was met if the upper 90% CI limit of the ΔQTcF at C1D15 (2 hours postdose) with ribociclib, 400 mg was less than 20 milliseconds. This cutoff was based on FDA and European Medicines Agency guidelines that stated that drugs prolonging the QT/QTc interval by longer than 20 milliseconds are substantially more likely to be proarrhythmic.¹⁶ QT/QTc was assessed in the safety set, which included all patients who received 1 or more doses of study treatment.

PFS, TTR, and DOR were analyzed in the ITT population by Kaplan-Meier analysis. Median survival was obtained with 95% CIs that were calculated using the Brookmeyer and Crowley method. PFS was analyzed via local radiological assessments. PFS was censored at the last adequate tumor assessment if a patient did not have an event or if it occurred after 2 or more missing tumor assessments. PFS was also censored at the last adequate tumor assessment before the initiation of a new ANP therapy (if given before protocol-defined progression). Summary statistics were calculated for clinical benefit rate in the ITT population; best overall response was also assessed in the ITT population. Safety end points, such as AE rates and vital signs, were summarized in the safety set. AESIs for ribociclib were grouped with customized standardized Medical Dictionary for Regulatory Activities (MedDRA) queries (MedDRA, version 27.0; International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use). PK end points were analyzed in the PK set, which included all patients who received 1 or more ribociclib doses and had 1 or more evaluable PK concentrations. Statistical analyses were performed using SAS, version 9.4 (SAS Institute). The sample size calculations were proposed to meet the noninferiority margin of 0.814, with 80% power and a 1-sided 5% level of significance.

Results

Baseline Characteristics and Duration of Follow-Up

Overall, 376 patients were randomized, with 188 (50.0%) assigned to each arm (Figure 1). Baseline characteristics were well balanced between arms (Table 1). Similar numbers of patients had received chemotherapy and (neo)adjuvant ET.

Table 1. Baseline and Disease Characteristics.

Characteristic	No. (%)
Characteristic	RIB400 + NSAI (n = 188)	RIB600 + NSAI (n = 188)	All patients (N = 376)
Female	188 (100)	188 (100)	376 (100)
Menopausal status
Premenopausal	48 (25.5)	55 (29.3)	103 (27.4)
Postmenopausal	140 (74.5)	133 (70.7)	273 (72.6)
Median age, y	58.0	58.0	58.0
Disease-free interval^a
De novo	91 (48.4)	84 (44.7)	175 (46.5)
≤12 mo	9 (4.8)	7 (3.7)	16 (4.3)
>12 to ≤24 mo	9 (4.8)	11 (5.9)	20 (5.3)
>24 mo	79 (42.0)	86 (45.7)	165 (43.9)
Prior ET^b
None	120 (63.8)	116 (61.7)	236 (62.8)
Progressed ≤12 mo of end of (neo)adjuvant ET	32 (17.0)	34 (18.1)	66 (17.6)
Progressed >12 mo of end of (neo)adjuvant ET	35 (18.6)	37 (19.7)	72 (19.1)
Missing	1 (0.5)	1 (0.5)	2 (0.5)
Metastatic sites
Bone only	4 (2.1)	2 (1.1)	6 (1.6)
Visceral	123 (65.4)	128 (68.1)	251 (66.8)

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Abbreviations: ET, endocrine therapy; NSAI, nonsteroidal aromatase inhibitor; RIB400, ribociclib, 400 mg; RIB600, ribociclib, 600 mg.

^{^a}

Disease-free interval was defined as the time from initial diagnosis to first recurrence or progression.

^{^b}

Categories may not add up to 100% due to rounding.

At the final data cutoff (August 30, 2024), the median duration of follow-up from randomization to cutoff was 53.5 months (minimum-maximum, 36.0-64.0 months), and all patients had either completed the follow-up or discontinued treatment. Median (range) relative dose intensity was 97.0% (41.3%-131.8%) with ribociclib, 400 mg and 92.0% (30.8%-127.3%) with ribociclib, 600 mg. The median (range) duration of exposure with ribociclib, 400 mg vs ribociclib, 600 mg was 12.5 (0.1-52.3) vs 17.1 (0.5-55.9) months, respectively.

ORR

ORR was 48.9% with ribociclib, 400 mg vs 56.1% with ribociclib, 600 mg, with a ratio (400 mg/600 mg) of 0.87 (90% CI, 0.74-1.03). In the primary analysis,¹⁴ the lower boundary of the 90% CI was less than the prespecified noninferiority margin of 0.814, and the primary end point was not met. The final analysis findings were consistent, indicating that AMALEE cannot demonstrate noninferiority of ribociclib, 400 mg vs ribociclib, 600 mg (Table 2). The ORR for the ITT population was 47.9% with ribociclib, 400 mg vs 54.8% with ribociclib, 600 mg, with a ratio of 0.87 (90% CI, 0.74-1.03), which was consistent with the per-protocol set.

Table 2. Overall Response Rate (ORR), Best Overall Response (BOR), and Clinical Benefit Rate (CBR).

Characteristic	No. (%)						ORR ratio, RIB400/RIB600 (90% CI)
	All patients		Patients with liver/lung metastases at baseline		Patients without liver/lung metastases at baseline
	RIB400 + NSAI	RIB600 + NSAI	RIB400 + NSAI	RIB600 + NSAI	RIB400 + NSAI	RIB600 + NSAI
ORR, per-protocol set
No.	182	180	110	112	72	68	NA
ORR, %	48.9	56.1	52.7	55.4	43.1	57.4	NA
ORR ratio in per-protocol set	NA	NA	NA	NA	NA	NA	0.87 (0.74-1.0f3)
ORR, BOR, and CBR: ITT population
No.	188	188	114	115	74	73	NA
ORR, %	47.9	54.8	50.9	54.8	43.2	54.8	NA
ITT set	NA	NA	NA	NA	NA	NA	0.87 (0.74-1.03)
BOR
Complete response	2 (1.1)	3 (1.6)	0	1 (0.9)	2 (2.7)	2 (2.7)	NA
Partial response	88 (46.8)	100 (53.2)	58 (50.9)	62 (53.9)	30 (40.5)	38 (52.1)
Stable disease	77 (41.0)	53 (28.2)	43 (37.7)	30 (26.1)	34 (45.9)	23 (31.5)
Noncomplete response/nonprogressive disease	0	1 (0.5)	0	0	0	1 (1.4)
Progressive disease	14 (7.4)	17 (9.0)	10 (8.8)	14 (12.2)	4 (5.4)	3 (4.1)
Unknown	7 (3.7)	14 (7.4)	3 (2.6)	8 (7.0)	4 (5.4)	6 (8.2)
CBR^a	142 (75.5)	133 (70.7)	85 (74.6)	78 (67.8)	57 (77.0)	55 (75.3)

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Abbreviations: ITT, intent to treat; NA, not applicable; NSAI, nonsteroidal aromatase inhibitor; RIB400, ribociclib, 400 mg; RIB600, ribociclib, 600 mg.

^{^a}

Includes complete and partial responses as well as stable disease lasting 24 weeks or longer.

DOR and TTR

Median DOR was numerically similar between arms, at 26.5 months (95% CI, 16.8 to not estimable [NE] due to follow-up) with ribociclib, 400 mg and 28.8 months (95% CI, 22.6 to NE) with ribociclib, 600 mg0 (Figure 2A). However, TTR was numerically longer with ribociclib, 400 mg vs ribociclib, 600 mg, with a median TTR of 13.1 months (95% CI, 7.4-NE) and 9.0 months (95% CI, 5.6-16.4) (Figure 2B).

PFS

Median PFS was 26.9 months (95% CI, 20.3-30.4) with ribociclib, 400 mg and 25.1 months (95% CI, 19.4-33.6) with ribociclib, 600 mg (Figure 2C). Eighty-five patients (45.2%) were censored with ribociclib, 400 mg and 91 (48.4%) with ribociclib, 600 mg. The most common reason for censoring across arms was initiation of new ANP therapy (91 patients [48.4%]). Among those patients, 45 (12.0%) did so due to study termination by the sponsor (the FDA postmarketing requirement had been fulfilled); 42 of 45 continued to take ribociclib at the same dose through a posttrial access program or commercial access.

PK

Plasma ribociclib exposure was lower with ribociclib, 400 mg than ribociclib, 600 mg (assessed at the primary data cutoff, June 11, 2021). Specifically, the geometric mean of the ribociclib maximal plasma concentration after dose was 28.0% lower with ribociclib, 400 mg than ribociclib, 600 mg, and the geometric mean of the AUC from 0 to 24 hours was 42.7% lower (eTable 1 and the eFigure in Supplement 3).

Safety and Tolerability

AEs were reported for 180 patients (95.7%) receiving ribociclib, 400 mg and 182 (96.8%) receiving ribociclib, 600 mg. The most common all-grade AEs with ribociclib, 400 mg vs ribociclib, 600 mg were neutropenia (AESI grouped term; 124 [66.0%] vs 144 [76.6%]), leukopenia (40 [21.3%] vs 52 [27.7%]), anemia (31 [16.5%] vs 49 [26.1%]), increased ALT levels (49 [26.1%] vs 47 [25.0%]), and nausea (31 [16.5%] vs 44 [23.4%]) (eTable 2 in Supplement 3). Grade 3 or greater AEs occurred for 123 patients (65.4%) receiving ribociclib, 400 mg vs 149 (79.3%) receiving ribociclib, 600 mg, the most common being neutropenia (AESI grouped term; 77 [41.0%] vs 110 [58.5%]) and increased ALT levels (27 [14.4%] vs 22 [11.7%]) (eTable 2 in Supplement 3). SAEs occurred for 38 patients (20.2%) who were receiving ribociclib, 400 mg and 37 (19.7%) receiving ribociclib, 600 mg. The most common SAE was dyspnea (4 patients), all cases of which occurred with ribociclib, 600 mg. Five patients died while receiving treatment with ribociclib, 400 mg (due to study indication [n = 2], acute respiratory failure [n = 1], COVID-19 [n = 1], and embolism [n = 1]) and 6 while receiving treatment with ribociclib, 600 mg (due to study indication [n = 3], acute respiratory distress syndrome [n = 1], disorientation [n = 1], and pneumonia [n = 1]).

The mean ΔQTcF from baseline to C1D15 at 2 hours postdose was numerically lower with ribociclib, 400 mg than ribociclib, 600 mg (12.5 milliseconds [90% CI, 10.9-14.1 milliseconds] with ribociclib, 400 mg vs 19.7 milliseconds [90% CI, 17.4-22.0 milliseconds] with ribociclib, 600 mg) (eTable 3 in Supplement 3).¹⁴ The upper bound of the 90% CI for ribociclib, 400 mg was less than 20 milliseconds, indicating that the key secondary end point was met. The incidence of notable ECG values was numerically lower with ribociclib, 400 mg than ribociclib, 600 mg; for example, 4 patients (2.1%) receiving ribociclib, 400 mg had an increase in QTcF from baseline of longer than 60 milliseconds vs 7 patients (3.7%) receiving ribociclib, 600 mg (eTable 3 in Supplement 3). Overall incidence of AESI QT interval prolongation was also lower with ribociclib, 400 mg (9.0%) than ribociclib, 600 mg (14.4%) (eTable 2 in Supplement 3). No AE ECG QT prolonged were considered SAEs or led to discontinuation. One patient receiving ribociclib, 400 mg had a new QTcF of longer than 500 milliseconds vs no patients receiving ribociclib, 600 mg (eTable 3 in Supplement 3). This patient had hypertension, diabetes, and asymptomatic atrial fibrillation before entering the study, and the event was a single occurrence observed by local ECG assessment predose on day 71. The event resolved on the same day. After a 6-day interruption, the patient resumed taking the same dose level of ribociclib, and no further QTcF prolongation was recorded.

Neutropenia, leukopenia, anemia, and thrombocytopenia were generally observed less frequently with ribociclib, 400 mg than ribociclib, 600 mg (eTable 2 in Supplement 3). Infections were also less common with ribociclib, 400 mg than ribociclib, 600 mg. Liver-related AEs, kidney toxic effects, and interstitial lung disease/pneumonitis exhibited similar rates between arms.

Fewer patients taking ribociclib, 400 mg than ribociclib, 600 mg required dose reduction (41 [21.8%] vs 90 [48.1%]) or dose interruption (128 [68.1%] vs 142 [75.9%]). Dose reductions and interruptions were primarily due to AEs (ribociclib, 400 mg vs ribociclib, 600 mg: 29 [15.4%] vs 69 [36.9%] and 97 [51.6%] vs 114 [61.0%], respectively), which were most commonly neutropenia (12 [6.4%] vs 32 [17.0%] and 66 [35.1%] vs 91 [48.4%]). Ribociclib discontinuations were most often due to progression (98 [52.1%] with ribociclib, 400 mg vs 94 [50.0%] with ribociclib, 600 mg) and study termination by the sponsor (46 [24.5%] vs 53 [28.2%]). Ribociclib discontinuations due to AEs were similar in both treatment arms (42 [22.3%] with ribociclib, 400 mg vs 37 [19.8%] with ribociclib, 600 mg). Across both arms, 32 patients initiated new ANP therapy due to AEs (18 due to increased ALT/AST levels) and were censored from PFS analysis; 21 of 32 switched to another CDK4/6i, 7 of 32 switched to hormonal monotherapy, 3 of 32 switched to chemotherapy, and 1 of 32 switched to everolimus. AEs required additional therapy (including all nondrug therapy and concomitant medications) for 133 patients (70.7%) receiving ribociclib, 400 mg vs 153 (81.4%) receiving ribociclib, 600 mg, most frequently increased ALT levels (16 [8.5%] vs 10 [5.3%]), increased AST levels (15 [8.0%] vs 8 [4.3%]), urinary tract infection (15 [8.0%] vs 17 [9.0%]), arthralgia (15 [8.0%] vs 12 [6.4%]), back pain (14 [7.4%] vs 16 [8.5%]), nausea (14 [7.4%] vs 28 [14.9%]), and COVID-19 (13 patients [6.9%] at both doses).

Discussion

The AMALEE randomized clinical did not meet its primary end point, as it did not statistically demonstrate the noninferiority of ribociclib, 400 mg vs ribociclib, 600 mg for ORR in patients with HR⁺/ERBB2⁻ ABC who were treated in the first-line setting. However, ribociclib, 400 mg and ribociclib, 600 mg were associated with high ORR, and the median PFS was similar between doses. ORR and TTR were numerically superior with ribociclib, 600 mg vs ribociclib, 400 mg.

These efficacy data were consistent with the results of a previous exposure–response analysis based on the MONALEESA trials that revealed a flat relationship between ribociclib exposure and PFS and showed that patients continued to benefit from ribociclib treatment following dose reduction.¹¹ A time-varying Cox regression analysis in the exposure–response study suggested a trend toward a greater likelihood of an earlier response with increased plasma ribociclib concentration, which was similar to the TTR results in AMALEE.¹¹ The observed AMALEE PFS findings, specifically at 400 mg, were consistent with the PFS findings in the pooled MONALEESA data when the 600 mg dose was reduced for AE management.¹⁷ In the pooled MONALEESA analysis, patients receiving ribociclib, 600 mg that received 71% or less, 72% to 96%, and 97% to 100% (30th, 60th, and 90th percentiles, respectively) dose intensity had median PFS values of 24.8, 24.9, and 29.6 months, respectively.¹⁷ In the AMALEE study, median PFS with ribociclib, 600 mg was 25.1 months and 26.9 months with ribociclib, 400 mg.

The geometric means for the maximal plasma concentration after dose and the AUC from 0 to 24 hours obtained with ribociclib, 600 mg at C1D15 were comparable with steady state values reported by Ji et al¹⁸ for the same dose level. Lower values for maximal plasma concentration after dose and AUC from 0 to 24 hours observed with ribociclib, 400 mg vs ribociclib, 600 mg confirmed that ribociclib, 400 mg resulted in lower exposure.

The median ribociclib exposure duration of 12.47 months with ribociclib, 400 mg and 17.05 months with ribociclib, 600 mg was sufficient for safety assessment and was similar to the MONALEESA trials (14.6 months).¹⁷ The AESIs rates with ribociclib, 600 mg in AMALEE were consistent with the MONALEESA trials at the same initial dose. For example, neutropenia occurred for 66.5% of patients with ribociclib, 600 mg in AMALEE and 69.6% to 76.9% of those taking ribociclib in the MONALEESA trials,^2,3,4,5,7,9 while a postbaseline QTcF of less than 480 milliseconds occurred for 3.2% of those taking ribociclib, 600 mg in AMALEE and 3.6% to 6.9% of those who received ribociclib in the MONALEESA trials.^3,4,5

The lower PK exposure with ribociclib, 400 mg vs ribociclib, 600 mg explained the observed reductions in certain AEs. AMALEE met its key secondary end point, as ribociclib, 400 mg resulted in a smaller mean increase in QTcF from baseline to C1D15 2 hours postdose than ribociclib, 600 mg. The frequency of all-grade QTcF events was low in both arms, and per-protocol monitoring allowed their early detection and adequate management. Previous exposure–response and PK/PD analyses based on pooled data of phase 1 to 3 trials have shown that QTcF prolongation is directly related to ribociclib concentration.^10,11,18 As expected, the incidence of the AESI QT interval prolongation in AMALEE was observed at a lower rate with ribociclib, 400 mg than ribociclib, 600 mg. Neutropenia is another AE known to be related to ribociclib exposure, and absolute neutrophil cell counts are related to ribociclib PK/PD profiles^10,11,18; consistent with this, overall and grade 3 or higher neutropenia incidence was lower with ribociclib, 400 mg than ribociclib, 600 mg in AMALEE. ribociclib, 400 mg in AMALEE was also associated with reduced incidence of AESIs leukopenia, anemia, and thrombocytopenia and infections, including grade 3 or higher events.

AESIs, including liver-related AEs, kidney toxic effects, interstitial lung disease/pneumonitis, and reproductive toxic effects, were observed at comparable rates between arms, and these events were generally reversible and manageable with recommended dose modification guidance. Specifically, the similar incidences of increased ALT and AST levels between the 2 ribociclib doses in this study suggest that AEs were not directly related to ribociclib exposure; rather, their nature was likely multifactorial.

Limitations

This study had limitations. The AMALEE trial was not designed to assess OS or patient-reported outcomes, which were secondary end points in the MONALEESA trials.^2,3,4 Ribociclib, 600 mg, has been shown to improve OS in patients with HR⁺/ERBB2⁻ ABC.^6,7,8 AMALEE was not designed to compare ribociclib, 400 mg + NSAI with NSAI alone. Moreover, the COVID-19 pandemic led to protocol deviations, such as off-site study visits, home delivery of study treatment, and remote monitoring at some sites, that affected efficacy assessments and treatment compliance; however, deviations were balanced between the arms and did not affect the data analysis. Finally, this trial was only powered to assess ORR, the FDA-requested end point, and not PFS as in a phase 3 study; thus, PFS could not be statistically compared between dose levels, and the high rate of censoring in AMALEE due to this study design limited interpretation of PFS data.

Conclusions

The results of the AMALEE randomized clinical trial, specifically the greater ORR and shorter TTR with ribociclib, 600 mg + NSAI vs ribociclib, 400 mg + NSAI, support continued use of 600 mg as the initial dose of ribociclib in first-line treatment for patients with HR⁺/ERBB2⁻ ABC. The findings also support dose reduction to 400 mg as an effective option to manage AEs, such as QTcF prolongation and hematologic events.

Supplement 1.

Trial protocol

jamaoncol-e253687-s001.pdf^{(13.3MB, pdf)}

Supplement 2.

Statistical analysis plan

jamaoncol-e253687-s002.pdf^{(706.2KB, pdf)}

Supplement 3.

eTable 1. Summary of Ribociclib Pharmacokinetic Parameters on C1D15

eTable 2. AEs and AESIs

eTable 3. Notable ECG Values in the Safety Set Throughout the Study and ΔQTcF From Baseline to C1D15 2 Hours Post Dose

eFigure. Geometric and Arithmetic Means (SDs) of Plasma Concentration–Time Profiles for Ribociclib by Treatment Group on C1D15

jamaoncol-e253687-s003.pdf^{(307.4KB, pdf)}

Supplement 4.

Data sharing statement

jamaoncol-e253687-s004.pdf^{(14.4KB, pdf)}

References

1.Cardoso F, Paluch-Shimon S, Schumacher-Wulf E, et al. 6th and 7th International consensus guidelines for the management of advanced breast cancer (ABC guidelines 6 and 7). Breast. 2024;76:103756. doi: 10.1016/j.breast.2024.103756 [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375(18):1738-1748. doi: 10.1056/NEJMoa1609709 [DOI] [PubMed] [Google Scholar]
3.Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465-2472. doi: 10.1200/JCO.2018.78.9909 [DOI] [PubMed] [Google Scholar]
4.Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904-915. doi: 10.1016/S1470-2045(18)30292-4 [DOI] [PubMed] [Google Scholar]
5.Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29(7):1541-1547. doi: 10.1093/annonc/mdy155 [DOI] [PubMed] [Google Scholar]
6.Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med. 2022;386(10):942-950. doi: 10.1056/NEJMoa2114663 [DOI] [PubMed] [Google Scholar]
7.Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382(6):514-524. doi: 10.1056/NEJMoa1911149 [DOI] [PubMed] [Google Scholar]
8.Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316. doi: 10.1056/NEJMoa1903765 [DOI] [PubMed] [Google Scholar]
9.Neven P, Fasching PA, Chia S, et al. Updated overall survival from the MONALEESA-3 trial in postmenopausal women with HR+/HER2− advanced breast cancer receiving first-line ribociclib plus fulvestrant. Breast Cancer Res. 2023;25(1):103. doi: 10.1186/s13058-023-01701-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Lu Y, Yang S, Ho YY, Ji Y. Ribociclib population pharmacokinetics and pharmacokinetic/pharmacodynamic analysis of neutrophils in cancer patients. J Clin Pharmacol. 2021;61(8):1054-1068. doi: 10.1002/jcph.1856 [DOI] [PubMed] [Google Scholar]
11.Ji Y, Darstein C, Yang S, et al. Quantitative assessment of ribociclib exposure-response relationship to justify dose regimen in patients with advanced breast cancer. J Clin Pharmacol. 2023;63(12):1359-1370. doi: 10.1002/jcph.2310 [DOI] [PubMed] [Google Scholar]
12.Harbeck N, Jacot W, Ezquerra MB, et al. Descriptive analysis of hepatic safety in patients with HR+/HER2− breast cancer treated with ribociclib + endocrine therapy. Poster presented at ESMO Breast Cancer 2024; May 15, 2024; Berlin, Germany. Accessed February 1, 2025. https://www.esmoopen.com/article/S2059-7029(24)01103-7/fulltext [Google Scholar]
13.Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus endocrine therapy in early breast cancer. N Engl J Med. 2024;390(12):1080-1091. doi: 10.1056/NEJMoa2305488 [DOI] [PubMed] [Google Scholar]
14.Cardoso F, Jacot W, Kuemmel S, et al. 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. Poster presented at the San Antonio Breast Cancer Symposium; 2022; December 6, 2022; San Antonio, Texas. Accessed February 1, 2025. https://aacrjournals.org/cancerres/article/83/5_Supplement/PD17-12/717285/Abstract-PD17-12-Primary-efficacy-and-safety [Google Scholar]
15.Ji Y, Abdelhady AM, Samant TS, Yang S, Rodriguez Lorenc K. Evaluation of absolute oral bioavailability and bioequivalence of ribociclib, a cyclin-dependent kinase 4/6 inhibitor, in healthy subjects. Clin Pharmacol Drug Dev. 2020;9(7):855-866. doi: 10.1002/cpdd.853 [DOI] [PubMed] [Google Scholar]
16.European Medicines Agency . ICH topic E 14: the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Accessed February 1, 2025. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-14-clinical-evaluation-qtqts-interval-prolongation-and-proarrhythmic-potential-non-antiarrhythmic-drugs-step-5_en.pdf
17.Burris HA, Chan A, Bardia A, et al. Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, −3 and −7 trials in hormone receptor-positive, HER2-negative advanced breast cancer. Br J Cancer. 2021;125(5):679-686. doi: 10.1038/s41416-021-01415-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Ji Y, Schiller H, Yang S, et al. Use of pharmacokinetic and pharmacodynamic data to develop the CDK4/6 inhibitor ribociclib for patients with advanced breast cancer. Clin Pharmacokinet. 2024;63(2):155-170. doi: 10.1007/s40262-023-01338-z [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial protocol

jamaoncol-e253687-s001.pdf^{(13.3MB, pdf)}

Supplement 2.

Statistical analysis plan

jamaoncol-e253687-s002.pdf^{(706.2KB, pdf)}

Supplement 3.

eTable 1. Summary of Ribociclib Pharmacokinetic Parameters on C1D15

eTable 2. AEs and AESIs

eTable 3. Notable ECG Values in the Safety Set Throughout the Study and ΔQTcF From Baseline to C1D15 2 Hours Post Dose

eFigure. Geometric and Arithmetic Means (SDs) of Plasma Concentration–Time Profiles for Ribociclib by Treatment Group on C1D15

jamaoncol-e253687-s003.pdf^{(307.4KB, pdf)}

Supplement 4.

Data sharing statement

jamaoncol-e253687-s004.pdf^{(14.4KB, pdf)}

[coi250057r1] 1.Cardoso F, Paluch-Shimon S, Schumacher-Wulf E, et al. 6th and 7th International consensus guidelines for the management of advanced breast cancer (ABC guidelines 6 and 7). Breast. 2024;76:103756. doi: 10.1016/j.breast.2024.103756 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250057r2] 2.Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375(18):1738-1748. doi: 10.1056/NEJMoa1609709 [DOI] [PubMed] [Google Scholar]

[coi250057r3] 3.Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465-2472. doi: 10.1200/JCO.2018.78.9909 [DOI] [PubMed] [Google Scholar]

[coi250057r4] 4.Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904-915. doi: 10.1016/S1470-2045(18)30292-4 [DOI] [PubMed] [Google Scholar]

[coi250057r5] 5.Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29(7):1541-1547. doi: 10.1093/annonc/mdy155 [DOI] [PubMed] [Google Scholar]

[coi250057r6] 6.Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med. 2022;386(10):942-950. doi: 10.1056/NEJMoa2114663 [DOI] [PubMed] [Google Scholar]

[coi250057r7] 7.Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382(6):514-524. doi: 10.1056/NEJMoa1911149 [DOI] [PubMed] [Google Scholar]

[coi250057r8] 8.Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316. doi: 10.1056/NEJMoa1903765 [DOI] [PubMed] [Google Scholar]

[coi250057r9] 9.Neven P, Fasching PA, Chia S, et al. Updated overall survival from the MONALEESA-3 trial in postmenopausal women with HR+/HER2− advanced breast cancer receiving first-line ribociclib plus fulvestrant. Breast Cancer Res. 2023;25(1):103. doi: 10.1186/s13058-023-01701-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250057r10] 10.Lu Y, Yang S, Ho YY, Ji Y. Ribociclib population pharmacokinetics and pharmacokinetic/pharmacodynamic analysis of neutrophils in cancer patients. J Clin Pharmacol. 2021;61(8):1054-1068. doi: 10.1002/jcph.1856 [DOI] [PubMed] [Google Scholar]

[coi250057r11] 11.Ji Y, Darstein C, Yang S, et al. Quantitative assessment of ribociclib exposure-response relationship to justify dose regimen in patients with advanced breast cancer. J Clin Pharmacol. 2023;63(12):1359-1370. doi: 10.1002/jcph.2310 [DOI] [PubMed] [Google Scholar]

[coi250057r12] 12.Harbeck N, Jacot W, Ezquerra MB, et al. Descriptive analysis of hepatic safety in patients with HR+/HER2− breast cancer treated with ribociclib + endocrine therapy. Poster presented at ESMO Breast Cancer 2024; May 15, 2024; Berlin, Germany. Accessed February 1, 2025. https://www.esmoopen.com/article/S2059-7029(24)01103-7/fulltext [Google Scholar]

[coi250057r13] 13.Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus endocrine therapy in early breast cancer. N Engl J Med. 2024;390(12):1080-1091. doi: 10.1056/NEJMoa2305488 [DOI] [PubMed] [Google Scholar]

[coi250057r14] 14.Cardoso F, Jacot W, Kuemmel S, et al. 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. Poster presented at the San Antonio Breast Cancer Symposium; 2022; December 6, 2022; San Antonio, Texas. Accessed February 1, 2025. https://aacrjournals.org/cancerres/article/83/5_Supplement/PD17-12/717285/Abstract-PD17-12-Primary-efficacy-and-safety [Google Scholar]

[coi250057r15] 15.Ji Y, Abdelhady AM, Samant TS, Yang S, Rodriguez Lorenc K. Evaluation of absolute oral bioavailability and bioequivalence of ribociclib, a cyclin-dependent kinase 4/6 inhibitor, in healthy subjects. Clin Pharmacol Drug Dev. 2020;9(7):855-866. doi: 10.1002/cpdd.853 [DOI] [PubMed] [Google Scholar]

[coi250057r16] 16.European Medicines Agency . ICH topic E 14: the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Accessed February 1, 2025. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-14-clinical-evaluation-qtqts-interval-prolongation-and-proarrhythmic-potential-non-antiarrhythmic-drugs-step-5_en.pdf

[coi250057r17] 17.Burris HA, Chan A, Bardia A, et al. Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, −3 and −7 trials in hormone receptor-positive, HER2-negative advanced breast cancer. Br J Cancer. 2021;125(5):679-686. doi: 10.1038/s41416-021-01415-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250057r18] 18.Ji Y, Schiller H, Yang S, et al. Use of pharmacokinetic and pharmacodynamic data to develop the CDK4/6 inhibitor ribociclib for patients with advanced breast cancer. Clin Pharmacokinet. 2024;63(2):155-170. doi: 10.1007/s40262-023-01338-z [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

600- vs 400-mg First-Line Ribociclib in Hormone Receptor–Positive/ERBB2-Negative Advanced Breast Cancer

Fatima Cardoso, MD

William Jacot, MD

Sherko Kuemmel, MD, PhD

Sudeep Gupta, MD, DM

Felipe Cruz, MD, PhD

Rama Balaraman, MD

Ana Ferreira, MD

Tytti Ahola, MD, PhD

Yana Chapko, MD

Lyudmila Zhukova, MD

Wendy Chiang, MD

Zheng Li, PhD

Yan Ji, PhD

Nadia Kaakiou, PharmD

Natalia Bolotova, MD

Joseph A Sparano, MD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Design

Study Assessments

Statistical Analysis

Results

Baseline Characteristics and Duration of Follow-Up

Figure 1. CONSORT Diagram.

Table 1. Baseline and Disease Characteristics.

ORR

Table 2. Overall Response Rate (ORR), Best Overall Response (BOR), and Clinical Benefit Rate (CBR).

DOR and TTR

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.

PFS

PK

Safety and Tolerability

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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