Ribociclib 200mg tablets

AimsThis study aimed to evaluate the comprehensive safety profile of CDK4/6 inhibitors in breast cancer treatment by analyzing real-world adverse event (AE) data and systematically reviewing clinical trial findings to provide evidence-based safety guidance.MethodsA disproportionality analysis based on real-world data from the FDA adverse event reporting system (FAERS) was combined with a systematic review to evaluate adverse events (AEs) associated with CDK4/6 inhibitors. A total of 16 studies involving 6,722 patients with advanced breast cancer were included to analyze the toxicity risks of CDK4/6 inhibitor combination therapies. Temporal patterns of AEs were assessed using FAERS data, and signal strengths were determined using the reporting odds ratio (ROR).ResultsCombination therapy with CDK4/6 inhibitors significantly increased the risk of grade 3-5 AEs. FAERS analysis revealed that most AEs occurred within the first month of treatment, with the lowest incidence between the second and sixth months, followed by a significant rise thereafter. All CDK4/6 inhibitors were associated with myelosuppression, gastrointestinal toxicity, interstitial lung disease (ILD), and QT prolongation. Disproportionality analysis for "Torsade de pointes/QT prolongation" identified Ribociclib as the only agent with a strong positive signal (ROR 6.16, 95% CI 5.54-6.84). Additionally, unexpected AEs such as peripheral neuropathy, taste disorders, and epistaxis were detected.ConclusionClinicians should prioritize monitoring for myelosuppression, gastrointestinal toxicity, and QT prolongation (particularly with Ribociclib) during the first month of CDK4/6 inhibitor therapy. Long-term surveillance beyond 6 months is crucial to detect delayed-onset AEs.

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BackgroundBreast cancer is the fourth leading cause of cancer mortality worldwide. New drugs, such as cyclin-dependent kinase 4/6 inhibitors (CDKIs), increase the life expectancy of receptor-positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer patients. This class acts to limit the G1/S transition in tumor cells, inducing tumor cell death. Owing to the basic nature of CDKIs, their solubilities are pH dependent and could be influenced by the concurrent use of acid-reducing agents such as proton pump inhibitors (PPIs). This meta-analysis aims to assess the impact of co-administering PPIs on the pharmacokinetics and clinical efficacy of CDKIs in breast cancer patients.MethodsFour databases with English-language restriction were searched for concomitant CDKIs and PPIs keywords from their inception date to 2024 March 7th. Prospective, retrospective, randomized or nonrandomized clinical studies and observational longitudinal studies with at least one outcome of interest were included. The outcomes included pharmacokinetic variables, progression-free survival (PFS), and overall survival (OS).ResultsWe included three pharmacokinetic studies conducted in patients enrolled in clinical trials and seven clinical studies evaluating survival outcomes. When coadministered with palbociclib, PPIs significantly reduced the serum maximum concentration (Cmax) (MD -35.37 ng/mL; 95%CI from -67.59 to -3.16) and increased the clearance (CL/F) (MD 61.24 L/h; 95%CI from 14.66 to 107.82). Ribociclib Cmax and AUC did not significantly differ among the PPIs users. However, the overall PFS favored PPIs non-users (HR 1.74; 95%CI from 1.28 to 2.37). Consistently, coadministration of PPIs with CDKIs significantly increased the likelihood of reduced OS (HR 1.99; 95%CI from 1.18 to 3.33). The effect was confirmed only for the palbociclib subgroup (HR 2.11; 95%CI from 1.17 to 3.81). No data were available for OS evaluation with ribociclib. A single study on abemaciclib revealed nonsignificant differences (HR 1.30; 95%CI from 0.53 to 3.19), with similar results for OS.ConclusionsPPI use in HR + /HER2- breast cancer patients treated with palociclib should be avoided. When strictly necessary, ribociclib may be preferred to palbociclib, even though closer monitoring is strongly advised.Systematic review registrationPROSPERO identifier number CRD42024506456.

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ImportanceRibociclib plus a nonsteroidal aromatase inhibitor (NSAI) has demonstrated a statistically significant invasive disease-free survival (iDFS) benefit over NSAI alone in patients with hormone receptor-positive/ERBB2 (formerly HER2)-negative early breast cancer. Evaluating the efficacy and safety of adjuvant ribociclib beyond the planned 3-year treatment period is critical for understanding the long-term impact on recurrences.ObjectiveTo evaluate efficacy and safety of adjuvant ribociclib in an exploratory 4-year analysis of the NATALEE (New Adjuvant Trial With Ribociclib [LEE011]) randomized clinical trial, with all patients no longer receiving ribociclib treatment.Design, setting, and participantsThis exploratory analysis of an international, open-label, randomized phase 3 trial analyzed adjuvant treatment for premenopausal and postmenopausal women and men with hormone receptor-positive/ERBB2-negative early breast cancer. Eligible patients had anatomic stage IIA (either N0 with additional risk factors or N1 [1-3 axillary lymph nodes]), IIB, or III disease per the American Joint Committee on Cancer Staging Manual, eighth edition. The data cutoff date was April 29, 2024.InterventionsPatients were randomized 1:1 to receive ribociclib (400 mg once daily, days 1-21 of a 28-day cycle, over 36 months) plus NSAI (letrozole, 2.5 mg, or anastrozole, 1 mg, once daily continuously for 60 months) or NSAI alone. Men and premenopausal women also received goserelin (3.6 mg once every 28 days administered subcutaneously).Main outcomes and measuresThe primary end point was iDFS, and secondary efficacy end points included distant disease-free survival, recurrence-free survival, and overall survival. Survival was evaluated by the Kaplan-Meier method.ResultsAmong 5101 patients included in the analysis (median [range] age, 52 [24-90] years; 5081 [99.6%] female), the median follow-up for iDFS was 44.2 months (range, 0-63 months). Ribociclib plus NSAI continued to show iDFS benefit over NSAI alone (hazard ratio, 0.72; 95% CI, 0.61-0.84), with 3-year iDFS rates of 90.8% vs 88.1% (difference, 2.7 percentage points) and 4-year rates of 88.5% vs 83.6% (difference, 4.9 percentage points). The efficacy benefit was consistent across subgroups and secondary end points. Overall survival data remain immature, although a trend in favor of ribociclib plus NSAI over NSAI alone was observed (hazard ratio, 0.83; 95% CI, 0.64-1.07). The incidence of adverse events has remained stable.Conclusions and relevanceThis exploratory analysis of the NATALEE randomized clinical trial, with a median follow-up beyond the 3-year treatment duration, demonstrated consistent iDFS benefit with ribociclib plus NSAI over NSAI alone.Trial registrationClinicalTrials.gov Identifier: NCT03701334.

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ImportanceRibociclib, 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.ObjectiveTo investigate whether a 400-mg ribociclib starting dose could reduce the incidence of AEs while maintaining efficacy in ABC.Design, setting, and participantsThe 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).InterventionsRandomization 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 measuresOverall 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.ResultsBaseline 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 relevanceThe 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 registrationClinicalTrials.gov Identifier: NCT03822468.

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PurposeCyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus aromatase inhibitor (AI) is the recommended first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (mBC). CDK4/6i head-to-head trials have not been conducted, and randomized controlled trials (RCTs) report inconsistent overall survival (OS) results despite similar effects on the primary endpoint of progression-free survival. Real-world evidence can complement RCTs but selection biases and confounders can challenge interpretation. Target trial emulation applies the principles of RCTs to observational data to overcome such challenges. We emulated a hypothetical target trial to investigate whether causal differences in OS between patients receiving first-line CDK4/6i plus AI exist in the real-world clinical setting.MethodsWe used de-identified data (Flatiron Health mBC Enhanced Data Mart) from patients ≥ 18 years old at primary diagnosis who were treated with first-line palbociclib/ribociclib/abemaciclib plus AI for mBC between 2018 and 2024. Statistical adjustments included stabilized inverse-probability weighting (sIPTW), investigation of missing data mechanisms, and analyses for unmeasured confounders.Results2626 patients were included (palbociclib n = 1686; ribociclib n = 537; abemaciclib n = 403). After sIPTW, baseline characteristics were balanced between groups and there was no observable difference in real-world OS (ribociclib vs palbociclib, adjusted hazard ratio 1.00, 95% CI: 0.81-1.24; abemaciclib v palbociclib: 0.91, 95% CI: 0.74-1.14). Results were consistent after sensitivity analyses.ConclusionUsing target trial emulation, real-world OS is similar with palbociclib/ribociclib/abemaciclib plus AI. These findings may contribute to the development of combination strategies to improve clinical outcomes and to guide clinical decision-making.

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Cancer patients prone to toxicities might benefit from dose reduction over fixed-dose recommendations. We develop a predictive index to identify patients with increased probability of dose reduction, intolerable toxicities, or therapy discontinuation (hereafter: dose reduction) in metastatic breast cancer (MBC) and compare real-world effectiveness of reduced (RSD) versus full starting dose (FSD) using this index. This analysis included 618 patients with HR-positive, HER2-negative MBC from the prospective, observational, multicenter registry OPAL (NCT03417115), receiving first-line palbociclib (n = 386) or ribociclib (n = 232) plus endocrine therapy. A logistic regression model was employed to derive the predictive index. Inverse probability of treatment weighting was used to emulate a head-to-head comparison of RSD and FSD by analyzing progression-free (PFS) and overall survival (OS). Within 6 months, 215 patients (35%) underwent dose reduction, including 109 (51%) with RSD. Predictors for dose reduction were age ≥65 years and Charlson comorbidity index (CCI) ≥1. Among patients with increased probability of dose reduction (index ≥1: ≥65 years and/or CCI ≥ 1), median PFS and OS were 30.1 [21.7, 54.0] and 57.6 [40.0, NA] months with RSD vs. 29.3 [24.9, 32.0] and 43.1 [38.8, 50.3] months with FSD. For low-probability patients (index = 0: <65 years and CCI = 0), median PFS and OS were 17.6 [9.1, 29.8] and 32.9 [23.1, 40.9] months with RSD vs. 24.5 [19.8, 32.0] and 54.2 [48.8, NA] months with FSD. In this real-world MBC setting, patients ≥65 years and/or with CCI ≥ 1 had an increased probability of dose reduction and may benefit from RSD, as this yielded outcomes comparable to FSD. Younger, fitter patients may require full dosing. Future studies, ideally randomized controlled trials, should aim to confirm these findings.

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