Dataset Information

Safety and Efficacy of Ribociclib in Combination with Letrozole in Patients with HR+, HER2- Advanced Breast Cancer: Results from the Italian Subpopulation of Phase 3b CompLEEment-1 Study.

ABSTRACT:

Background

Ribociclib plus letrozole demonstrated manageable safety and efficacy profiles in hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) in the Phase 3b CompLEEment-1 trial.

Objective

To evaluate the safety and efficacy of ribociclib plus letrozole in the Italian subpopulation with HR+, HER2- ABC from the CompLEEment-1 trial.

Patients and methods

Patients with HR+, HER2- ABC received ribociclib (600 mg/day, 3 weeks on/1 week off) plus letrozole (2.5 mg/day) while men and premenopausal women additionally received goserelin. Patients were allowed with ≤ 1 line of prior chemotherapy and an Eastern Cooperative Oncology Group performance status of ≤ 2. The primary outcome included safety and tolerability.

Results

Of the 554 Italian patients, 246 (44.4 %) patients completed treatment. The reasons for treatment discontinuation included progressive disease (PD; 36.6 %), adverse events (AEs; 11.9 %), and death (1.6 %). All-grade AEs and grade ≥ 3 AEs occurred in 98.9 % and 77.8 % patients, respectively. The most common treatment-related AEs were neutropenia (73.6 %), followed by leukopenia (32.1 %), and nausea (25.3 %). The overall response rate was 28.2 % (95 % confidence interval [CI], 24.4-32.1); clinical benefit rate was 71.7 % (95 % CI, 67.7-75.4); and median time to progression was 26.7 months (95 % CI, 24.8-non-estimable). Health-related quality of life scores were maintained during treatment.

Conclusion

The safety and efficacy profiles of ribociclib plus letrozole in the Italian subpopulation was found to be consistent with the CompLEEment-1 global population result, MONALEESA-2, and MONALEESA-7 outcomes, which reaffirm ribociclib plus letrozole as the frontline treatment option in patients with HR+, HER2- ABC.

Trial registration number and date of registration

NCT02941926 (30 November 2016).

SUBMITTER: De Laurentiis M

PROVIDER: S-EPMC9684264 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Safety and Efficacy of Ribociclib in Combination with Letrozole in Patients with HR+, HER2- Advanced Breast Cancer: Results from the Italian Subpopulation of Phase 3b CompLEEment-1 Study.

De Laurentiis Michelino M Caputo Roberta R Mazza Manuelita M Mansutti Mauro M Masetti Riccardo R Ballatore Zelmira Z Torrisi Rosalba R Michelotti Andrea A Zambelli Alberto A Ferro Antonella A Generali Daniele D Vici Patrizia P Coltelli Luigi L Fabi Alessandra A Marchetti Paolo P Ballestrero Alberto A Spazzapan Simon S Frassoldati Antonio A Sarobba Maria Giuseppina MG Grasso Donatella D Zamagni Claudio C

Targeted oncology 20220924 6

<h4>Background</h4>Ribociclib plus letrozole demonstrated manageable safety and efficacy profiles in hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) in the Phase 3b CompLEEment-1 trial.<h4>Objective</h4>To evaluate the safety and efficacy of ribociclib plus letrozole in the Italian subpopulation with HR+, HER2- ABC from the CompLEEment-1 trial.<h4>Patients and methods</h4>Patients with HR+, HER2- ABC received ribociclib (600 ...[more]

PMID: 36152144

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Project description:BackgroundThe CDK4/6 inhibitor, ribociclib in combination with endocrine therapy significantly improved progression-free survival in the first line setting in post-menopausal patients with HR+/HER2- advanced breast cancer (ABC) in a pivotal phase 3, placebo-controlled trial (MONALEESA-2) and demonstrated superior overall survival in premenopausal patients with HR+/HER2- ABC (MONALEESA-7). The multinational, phase 3b, CompLEEment-1 trial, which assessed the safety and efficacy of ribociclib plus letrozole in a broader population of patients who have not received prior endocrine therapy for advanced disease, is the largest phase 3 clinical trial to date to evaluate the safety and efficacy of a CDK4/6 inhibitor. We report a subanalysis of data from patients (N = 339) enrolled in the central and south European countries of the SERCE (Southern Europe, RUC, Central Europe) cluster of CompLEEment-1.Patients and methodsMen and women of any menopausal status with HR+/HER2- ABC received once-daily oral ribociclib 600 mg (3-weeks on/1-week-off), plus letrozole 2.5 mg continuously. Men/premenopausal women also received a GnRH-agonist. The primary outcome was the number of patients with adverse events (AEs) over a timeframe of approximately 36 months. Time-to-progression, overall response rate, and clinical benefit rate were also measured.ResultsSafety results in the SERCE subgroup were consistent with those in the pivotal clinical trials of ribociclib in combination with endocrine therapy. Treatment-related AEs leading to dose adjustments/interruption occurred in 63.1% of patients but led to treatment discontinuation in only 10.6%. The most common treatment-related AEs of grade ≥ 3 were neutropenia and transaminase elevations. There were no fatal treatment-related events.ConclusionsThese findings from the SERCE subgroup support the safety and manageable tolerability of ribociclib in a broad range of patients with HR+/HER2- ABC more representative of patients in real-world clinical practice.

Project description:BackgroundCurrent standard-of-care first-line treatment of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) is cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + endocrine therapy. In the MONALEESA-2 trial, first-line ribociclib + letrozole demonstrated statistically significant overall survival (OS) benefit versus placebo + letrozole in postmenopausal patients with HR+/HER2- ABC. In the PALOMA-2 trial, first-line palbociclib + letrozole did not show OS benefit versus placebo + letrozole in a similar patient population. Understanding OS outcomes in the respective trials is critical for treatment decisions; however, there are no head-to-head clinical trial data comparing ribociclib and palbociclib.ObjectivesTo conduct a matching-adjusted indirect comparison (MAIC) to compare progression-free survival (PFS) and OS of first-line ribociclib + letrozole versus palbociclib + letrozole in postmenopausal patients with HR+/HER2- ABC.DesignLetrozole-anchored MAIC using individual patient data from MONALEESA-2 and published summary data from PALOMA-2.MethodsUsing individual data, patients from MONALEESA-2 who matched inclusion criteria from PALOMA-2 were selected, and weighting was conducted to ensure baseline characteristics were similar to those in published aggregated data from PALOMA-2. The Bucher method was used to generate corresponding hazard ratios (HRs).ResultsThe final effective sample size compared n = 150 (ribociclib) and n = 112 (placebo) MONALEESA-2 patients with n = 444 (palbociclib) and n = 222 (placebo) PALOMA-2 patients. After matching and weighting, patient characteristics were well balanced. MAIC analysis showed a numerical PFS benefit [HR, 0.80; 95% confidence interval (CI), 0.58-1.11; p = 0.187] and significant OS benefit (HR, 0.68; 95% CI, 0.48-0.96; p = 0.031) with ribociclib + letrozole versus palbociclib + letrozole.ConclusionResults of this cross-trial MAIC analysis showed a numerical PFS benefit and significantly greater OS benefit with first-line ribociclib + letrozole versus palbociclib + letrozole. These results support letrozole + ribociclib as the preferred first-line CDK4/6i for postmenopausal patients with HR+/HER2- ABC.Trial registrationNCT01958021; https://www.clinicaltrials.gov/study/NCT01958021 (MONALEESA-2) and NCT01740427; https://clinicaltrials.gov/study/NCT01740427 (PALOMA-2).

Project description:BackgroundThe global burden of breast cancer (BC) is high, especially in advanced stages. CDK 4/6 inhibitors represent a paradigm shift in the treatment of advanced BC HR+/HER2-, given the clinically and statistically significant gain in overall survival associated with this new class of medications. Nevertheless, as an innovation, the incorporation of these drugs impacts healthcare budgets, requiring cost-effectiveness analyses for decision-making. The aim of this study was to evaluate the cost-effectiveness of ribociclib plus letrozole compared with palbociclib plus letrozole or letrozole as monotherapy for first-line treatment of postmenopausal women with HR+/HER2- locally advanced or metastatic BC (aBC) from a Brazilian private healthcare system perspective.MethodsA model including progression-free survival (PFS), progressed disease, and death health states was used to simulate lifetime costs and outcomes. PFS and overall survival were derived from the MONALEESA-2 trial (lifetime horizon). Healthcare costs included drug acquisition and monitoring, subsequent therapies, adverse events, and end-of-life costs. Effectiveness was measured in quality-adjusted life-years (QALYs). Deterministic and probabilistic sensitivity analyses were performed.ResultsThe total cost of treatment with ribociclib plus letrozole was USD 72,091.82 versus USD 92,749.64 for palbociclib plus letrozole. Total QALYs were 3.30 and 3.16, respectively. Base-case analysis showed ribociclib as dominant over palbociclib in first-line treatment of women with HR+/HER2- aBC, associated with cost savings and QALY gains. The total cost of treatment with ribociclib plus letrozole was USD 83,058.73 versus USD 29,215.10 for letrozole. Total QALYs were 3.84 and 2.61, respectively. Compared with letrozole, ribociclib plus letrozole was associated with an incremental cost of USD 53,843.64 and an incremental QALY gain of 1.23, with incremental cost-effectiveness ratio of USD 43,826.91 per QALY gained.ConclusionsAs demonstrated by the cost-effectiveness dominance over palbociclib, ribociclib results in savings when used as first-line treatment in postmenopausal women with HR+/HER2- aBC, warranting incorporation in the private healthcare system.

Project description:BackgroundDalpiciclib is a novel cyclin-dependent kinase 4/6 inhibitor which showed tolerability and preliminary efficacy as monotherapy for pretreated advanced breast cancer (BC).ObjectivesTo further assess dalpiciclib with endocrine therapy (ET) in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative BC.DesignA multicenter, open-label, phase Ib trial.MethodsPatients with locally recurrent or metastatic BC were enrolled in five cohorts. Patients without prior treatment for advanced disease (cohorts 1-2) were given dalpiciclib (125 or 150 mg) plus letrozole/anastrozole; patients who progressed after ET (cohorts 3-5) were given dalpiciclib (125, 150, or 175 mg) plus fulvestrant. Dalpiciclib was administered orally once daily in 3-weeks-on/1-week off schedule. The primary endpoint was safety.ResultsA total of 58 patients received dalpiciclib with letrozole/anastrozole and 46 received dalpiciclib with fulvestrant. No maximum tolerated dose of dalpiciclib was reached with letrozole/anastrozole or fulvestrant. Across all cohorts, 86.7%-93.8% of patients had a grade ⩾3 adverse event, with the most common being neutropenia (grade 3, 40.0% for dalpiciclib 175 mg and 61.8%-87.5% for lower doses; grade 4, 46.7% and 4.2%-20.6%, respectively) and leukopenia (grade 3, 80.0% for 175 mg and 33.3%-54.2% for lower doses; grade 4, 0% for all doses). At tested dose levels, steady-state areas under the concentration curve and peak concentration of dalpiciclib increased with dose when combined with letrozole/anastrozole and fulvestrant. Dalpiciclib at 150 mg was associated with a numerically higher objective response rate in both patients untreated for advanced disease (67.6%; 95% confidence interval (CI) 49.5-82.6) and patients progressing after ET (53.3%; 95% CI 26.6-78.7); as of July 30, 2022, the median progression-free survival with dalpiciclib 150 mg was 24.1 months (95% CI 16.9-46.0) with letrozole/anastrozole and 16.7 months (95% CI 1.9-24.1) with fulvestrant.ConclusionDalpiciclib plus letrozole/anastrozole or fulvestrant showed an acceptable safety profile. The recommended phase III dose of dalpiciclib was 150 mg.Trial registrationClinicalTrials.gov identifier: NCT03481998.

Dataset Information

Safety and Efficacy of Ribociclib in Combination with Letrozole in Patients with HR+, HER2- Advanced Breast Cancer: Results from the Italian Subpopulation of Phase 3b CompLEEment-1 Study.

Background

Objective

Patients and methods

Results

Conclusion

Trial registration number and date of registration

Publications

Safety and Efficacy of Ribociclib in Combination with Letrozole in Patients with HR+, HER2- Advanced Breast Cancer: Results from the Italian Subpopulation of Phase 3b CompLEEment-1 Study.

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