Dataset Information

Long-term Pooled Safety Analysis of Palbociclib in Combination With Endocrine Therapy for HR+/HER2- Advanced Breast Cancer.

ABSTRACT: BACKGROUND:Palbociclib administered with endocrine therapy was tolerable when the overall incidence of toxicities was assessed separately for three PALOMA studies. This study analyzed pooled, longer-term PALOMA safety data longitudinally. METHODS:Data were pooled from three randomized phase II and III studies (ClinicalTrials.gov: NCT00721409, NCT01740427, NCT01942135) of hormone receptor-positive/human epidermal growth factor receptor 2?negative advanced breast cancer patients. Front-line patients were randomly assigned to receive letrozole with/without palbociclib (PALOMA-1) or letrozole plus palbociclib/placebo (PALOMA-2). In PALOMA-3, patients with prior endocrine resistance received fulvestrant plus palbociclib/placebo. The cumulative event rates of adverse events (AEs), reporting up to 50 months of treatment, were assessed over time. RESULTS:Patients who received endocrine therapy (n = 1343) were included in this pooled analysis (872 were also treated with palbociclib, and 471 were not). The most common AEs with palbociclib plus endocrine therapy were neutropenia and infections (any grade, 80.6% and 54.7%, respectively), which were higher than in the endocrine monotherapy arm (any grade, 5.3% and 36.9%). The most common hematologic AEs (?15.0% in the palbociclib arm) were more likely to be reported in the initial months of the study, after which time the cumulative event rate did not substantially increase. With palbociclib plus endocrine therapy, any grade AEs leading to permanent discontinuation over three years occurred in only 8.3% of patients. CONCLUSIONS:Based on these long-term safety analyses, there is no evidence of specific cumulative or delayed toxicities with palbociclib plus endocrine therapy, supporting the ongoing investigation of palbociclib plus endocrine therapy in early breast cancer (NCT02513394).

SUBMITTER: Dieras V

PROVIDER: S-EPMC6449170 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Long-term Pooled Safety Analysis of Palbociclib in Combination With Endocrine Therapy for HR+/HER2- Advanced Breast Cancer.

Diéras Véronique V Rugo Hope S HS Schnell Patrick P Gelmon Karen K Cristofanilli Massimo M Loi Sherene S Colleoni Marco M Lu Dongrui R DR Mori Ave A Gauthier Eric E Huang Bartlett Cynthia C Slamon Dennis J DJ Turner Nicholas C NC Finn Richard S RS

Journal of the National Cancer Institute 20190401 4

<h4>Background</h4>Palbociclib administered with endocrine therapy was tolerable when the overall incidence of toxicities was assessed separately for three PALOMA studies. This study analyzed pooled, longer-term PALOMA safety data longitudinally.<h4>Methods</h4>Data were pooled from three randomized phase II and III studies (ClinicalTrials.gov: NCT00721409, NCT01740427, NCT01942135) of hormone receptor-positive/human epidermal growth factor receptor 2‒negative advanced breast cancer patients. Fr ...[more]

PMID: 30032196

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Project description:Breast cancer (BC) is the most common malignancy in women worldwide, with approximately two-thirds having hormone receptor-positive (HR+) tumors. New endocrine therapy (ET) strategies include combining ET agents as well as adding inhibitors targeting growth factors, angiogenesis, the mechanistic target of rapamycin, phosphoinositide 3-kinase (PI3K), or cyclin-dependent kinase 4/6 to ET. Level 1 evidence supports use of fulvestrant plus anastrozole or palbociclib plus letrozole as first-line therapy for HR+/HER- advanced BC with special consideration for the former in ET-naïve patients, as well as everolimus plus exemestane or palbociclib plus fulvestrant as second-line therapy with special consideration in select first-line patients. Although the safety profiles of these combinations are generally predictable and manageable, both everolimus and palbociclib are associated with an increased risk of potentially serious or early-onset toxicities requiring individualized a priori adverse event risk stratification, earlier and more rigorous agent-specific monitoring, and patient education. Although each of these combinations improves progression-free survival, none with the exception of anastrazole plus fulvestrant have demonstrated improved overall survival. PI3K catalytic-? mutations assessed from circulating tumor DNA represent the first potentially viable serum biomarker for the selection of ET combinations, and new data demonstrate the feasibility of this minimally invasive technique as an alternative to traditional tissue analysis. Therapeutic ratios of select ET combinations support their use in first- and second-line settings, but optimal sequencing has yet to be determined.2017;22:12-24 IMPLICATIONS FOR PRACTICE: Emerging data show that new endocrine therapy (ET) combinations can improve progression-free and overall survival outcomes in patients with hormone receptor-positive, HER2-negative (HR+/HER-) advanced breast cancer. Level 1 evidence supports consideration of dual ET regimens, particularly in ET-naïve patients, or palbociclib plus letrozole as first-line therapy, as well as the addition of mTOR or CDK4/6 inhibitors to established ET in the second-line setting and in select first-line patients. Some combinations are associated with increased risk of class-specific toxicities that will require individualized risk stratification, earlier and more rigorous agent-specific monitoring, and patient education. Recent data on a noninvasive biomarker assay that predicts response to a phosphoinositide 3-kinase inhibitor demonstrates the feasibility of this minimally invasive technique as an alternative to traditional tissue analysis.

Project description:BackgroundPrevious studies demonstrated the tolerability of palbociclib plus endocrine therapy (ET). This analysis evaluated safety based on more recent cutoff dates and a longer palbociclib treatment exposure.Patients and methodsData were pooled from three randomized studies of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC), including postmenopausal women who had not received prior systemic treatment for advanced disease (PALOMA-1/-2) and pre- and postmenopausal women who had progressed on prior ET (PALOMA-3).ResultsUpdated cutoff dates were December 21, 2017 (PALOMA-1), May 31, 2017 (PALOMA-2), and April 13, 2018 (PALOMA-3). Total person-years of treatment exposure were 1,421.6 with palbociclib plus ET (n = 872) and 528.4 with ET (n = 471). Any-grade neutropenia and infections were more frequent with palbociclib plus ET (82.1% and 59.2%, respectively) than with ET (5.1% and 39.5%). The hazard ratios were 1.6 (p = .0995) for grade 3/4 infections, 1.8 (p = .4358) for grade 3/4 viral infections, 1.4 (p = .0001) for infections, and 30.8 (p < .0001) for neutropenia. Febrile neutropenia was reported in 1.4% of patients receiving palbociclib plus ET. Cumulative incidence of all-grade hematologic adverse events in both arms peaked during the first year of treatment and plateaued over the 5 subsequent years. Interstitial lung disease was reported in 13 patients receiving palbociclib plus ET and 3 receiving ET.ConclusionThis 5-year, long-term analysis demonstrated that palbociclib plus ET has a consistent and stable safety profile and is a safe treatment for patients with HR+/HER2- ABC.Implications for practiceSeveral treatments for patients with breast cancer are associated with long-term or latent adverse events. This long-term, 5-year analysis demonstrated that palbociclib plus endocrine therapy has a consistent and stable safety profile without cumulative or delayed toxicities. These results further support palbociclib plus endocrine therapy as a safe and manageable treatment in clinical practice for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.

Project description:PurposeThe aim of this study was to evaluate the cost-effectiveness of ribociclib compared to palbociclib, both in combination with letrozole, in the first-line treatment of postmenopausal women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (ABC) from the perspective of the Spanish National Health System (NHS).Patients and methodsDisease progression was simulated with a partitioned survival model developed from the parameterization and extrapolation of survival curves of postmenopausal women with HR+/HER2- ABC from clinical trials with ribociclib or palbociclib, both in combination with letrozole. The model was structured on the basis of three health states (progression-free, progressed disease, and death), with a 1-month cycle length and inclusion of subsequent treatments administered for disease progression, over a time horizon of 15 years. Clinical, economic, and quality of life parameters were drawn from clinical trials and the literature. The use of resources and clinical practice in the Spanish setting was validated by a panel of experts. The Spanish NHS perspective was adopted, taking into account exclusively direct health costs from 2017 expressed in Euros. Drug prices used were the reported ex-factory prices. Uncertainty of the parameters and robustness of the results were evaluated using deterministic and probabilistic sensitivity analyses (2,000 iterations).ResultsThis cost-effectiveness analysis showed a greater benefit (0.437 and 0.285 life-years gained [LYGs] and quality-adjusted life years [QALYs] gained, respectively) and a slightly higher cost (€439.86) for ribociclib+letrozole compared to palbociclib+letrozole. The resulting incremental cost-effectiveness and cost-utility ratios were €1,007.69 per LYG and €1,543.62 per QALY gained, respectively. The results of the multiple sensitivity analyses showed limited dispersion of the outcomes, thus corroborating their robustness.ConclusionFrom the NHS perspective, considering the most commonly established willingness-to-pay thresholds in the Spanish setting, ribociclib+letrozole would represent a cost-effective therapeutic option compared to palbociclib+letrozole in the first-line treatment of HR+/HER2- ABC in postmenopausal women.

Project description:Aim:To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET) versus ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa. Methods:This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150?mg twice daily) or placebo plus: anastrozole (1?mg/day) or letrozole (2.5?mg/day) (cohort A) or fulvestrant (500?mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A. Results:In cohort A, 207 patients were randomly assigned to the abemaciclib arm and 99 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: not reached versus 14.7?months; hazard ratio 0.499; 95% confidence intervals (CI) 0.346-0.719; p?=?0.0001). ORR was 65.9% in the abemaciclib arm and 36.1% in the placebo arm (p?<?0.0001, measurable disease population). In cohort B, 104 patients were randomly assigned to the abemaciclib arm and 53 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: 11.5 versus 5.6?months; hazard ratio 0.376; 95% CI 0.240-0.588; p?<?0.0001). ORR was 50.0% in the abemaciclib arm and 10.5% in the placebo arm (p?<?0.0001, measurable disease population). The most frequent grade ?3 adverse events in the abemaciclib arms were neutropenia, leukopenia, and anemia (both cohorts), and lymphocytopenia (cohort B). Conclusion:The addition of abemaciclib to ET demonstrated significant and clinically meaningful improvement in PFS and ORR, without new safety signals observed in this population.Trial Registration: ClinicalTrials.gov identifier: NCT02763566.

Dataset Information

Long-term Pooled Safety Analysis of Palbociclib in Combination With Endocrine Therapy for HR+/HER2- Advanced Breast Cancer.

Publications

Long-term Pooled Safety Analysis of Palbociclib in Combination With Endocrine Therapy for HR+/HER2- Advanced Breast Cancer.

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