Comparison of palbociclib in combination with letrozole or fulvestrant with endocrine therapies for advanced/metastatic breast cancer: network meta-analysis

Abstract

Background: Palbociclib is the first cyclin-dependent kinase 4/6 inhibitor approved in the United States for HR+/HER2- advanced/metastatic breast cancer, in combination with letrozole as initial endocrine-based therapy in postmenopausal women or with fulvestrant in women with disease progression following endocrine therapy. We compared progression-free survival (PFS) and discontinuations due to adverse events for palbociclib combinations against other endocrine therapies using a mixed-treatment comparison meta-analysis of randomized, controlled trials.

Methods: A systematic literature review identified relevant trials. Separate analyses were conducted for each palbociclib combination using a Bayesian approach. Treatment rankings were established using the surface under the cumulative ranking curve (SUCRA).

Results: Sixty-five unique studies met inclusion criteria. Palbociclib plus letrozole had the highest SUCRA value (99.9%) and was associated with significantly longer PFS than all comparators in treatment-naïve patients (hazard ratios [HRs] ranged from 0.41 to 0.58). Palbociclib plus fulvestrant had the second highest SUCRA value (93.9%) and, in previously treated patients, yielded significantly longer PFS than most comparators (HRs ranged from 0.26 to 0.46); the exception was everolimus plus exemestane, with similar PFS (HR, 1.04; 95% credible interval [CrI], 0.58–1.76). Palbociclib plus fulvestrant was associated with significantly lower odds of discontinuation due to adverse events than everolimus plus exemestane (odds ratio, 0.14; 95% CrI, 0.05–0.39).

Conclusions: The results suggest that the two palbociclib combinations yielded significantly greater PFS than endocrine therapy in treatment-naïve and previously treated patients with advanced/metastatic breast cancer. Palbociclib plus fulvestrant was associated with significantly less toxicity than everolimus plus exemestane.

Keywords:

• Breast cancer
• advanced
• metastasis
• meta-analysis
• mixed-treatment comparison
• endocrine therapy
• progression-free survival
• adverse events
• discontinuation

Transparency

Declaration of funding

This research was performed under a research contract between RTI Health Solutions and Pfizer and was sponsored by Pfizer.

Author contributions: C.C. wrote the statistical analysis plan, performed the analyses, contributed to the writing of the first draft of the manuscript, and provided feedback on the manuscript. A.C. and C.L. conducted the systematic literature review and provided feedback on the manuscript. D.O. reviewed the statistical analysis plan, assisted in the interpretation of the results, and provided feedback on the manuscript. J.A.K. reviewed the statistical analysis plan, assisted in interpretation of the results, contributed to the writing of the first draft of the manuscript, and provided feedback on the manuscript. D.M. and S.I. reviewed the statistical analysis plan, assisted in interpretation of the results, and provided feedback on the manuscript.

Declaration of financial/other relationships

D.M. and S.I. have disclosed that they are employees of Pfizer Inc. C.C., A.C., C.L., D.O., and J.A.K. have disclosed that they are employees of RTI Health Solutions, who were paid contractors to Pfizer in the development of this manuscript.

Peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other relevant financial relationships to disclose.

Acknowledgements

This study was sponsored by Pfizer. Editorial assistance was provided by Adele Monroe, Eleanor Sibal, and Joyce Hicks at RTI Health Solutions, and was funded by Pfizer. Project management support was provided by Mary Levine of RTI Health Solutions.