Matching-adjusted indirect comparison of bosutinib, dasatinib and nilotinib effect on survival and major cytogenetic response in treatment of second-line chronic phase chronic myeloid leukemia

Abstract

Objective: In clinical trials of second-line therapies for chronic phase chronic myeloid leukemia (CP-CML), to date, only single-arm trials have been conducted for the available tyrosine kinase inhibitor treatments (bosutinib, dasatinib and nilotinib). These trials included heterogeneous patient populations in terms of disease and baseline characteristics. These hamper the use of standard network meta-analyses for indirect treatment comparison of relative efficacy. In this situation, a matching-adjusted indirect comparison (MAIC) in second-line CP-CML was performed. The aim was to compare the relative efficacies of bosutinib, dasatinib and nilotinib in second-line CP-CML patients.

Methods: The MAIC was preceded by a systematic literature review that ensured inclusion of the underlying data for the analyses. The outcomes were measured in terms of overall survival (OS), progression-free survival (PFS) and major cytogenetic response (MCyR). The treatments were quantitatively compared based on Cox proportional hazard ratio (HR) regressions, on restricted mean survival (RMST, when the proportionality assumption showed evidence of violation) and on odds ratios (for response measures).

Results: Comparing with dasatinib, bosutinib resulted in HRs for PFS and OS of 0.63 (0.44–0.90, p < .05) and 0.82 (0.54–1.26, p = .37) respectively, and resulted in an OR for MCyR of 0.78 (0.53–1.16). Although the proportionality of hazards assumption was violated for PFS, the RMST analyses confirmed the findings of the Cox regression. When compared with nilotinib, bosutinib showed a significant HR of 0.54 (0.38–0.76, p < .01) in favor of bosutinib for PFS, a non-significant HR of 0.72 (0.46–1.13, p = .16) for OS and a non-significant OR of 0.98 (0.71–1.35) for MCyR.

Conclusions: Bosutinib had a significantly greater PFS than both dasatinib and nilotinib. For OS, the findings were numerically in favor of bosutinib, but not statistically significant. For MCyR, the findings were numerically in favor of dasatinib and nilotinib, but not statistically significant.

Keywords:

• Chronic myeloid leukemia
• chronic-phase
• bosutinib
• dasatinib
• nilotinib

Transparency

Declaration of funding

This study was sponsored by Pfizer. This publication reports the results of a Pfizer-sponsored non-interventional study.

Author contributions

J.E.C., B.D.S., C.G.P.: interpretation of the data, revising the paper critically for intellectual content. B.M., C.M., J.C.C., R.J.C., B.H., Y.S.: conception, design, analysis and interpretation of the data, drafting of the paper and revising it critically for intellectual content. All authors agree to be accountable for all aspects of the work.

Declaration of financial/other relationships

J.E.C. has disclosed that he has received consultant and grant support from BMS, Novartis, Pfizer, and Takeda; been a consultant for Fusion Therapeutics; and received grant support from Sun Pharma. B.D.S. has disclosed that he has received honoraria for consulting from Novartis and Pfizer. C.G.P. has disclosed that he has received a research grant from Pfizer. C.M. and J.C.C. have disclosed that they are employees and shareholders of Pfizer Inc. Y.S. and R.J.C. have disclosed that they were employees of Pfizer Inc. at the time of this research. B.H. and B.M. have disclosed that they are employees of Ingress-Health BV, which provides consulting and other research services to pharmaceutical, medical device and related organizations. In their salaried positions, they work with a variety of companies and organizations, and are precluded from receiving payment or honoraria directly from these organizations for services rendered. B.H. has disclosed that he is also an equity holder of Ingress-Health; this company was paid by Pfizer Inc. to conduct this study and develop this manuscript. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgements

Not applicable.