Systematic review of lapatinib in combination with letrozole compared with other first-line treatments for hormone receptor positive(HR+) and HER2+ advanced or metastatic breast cancer(MBC)

Abstract

Background:

Third-generation aromatase inhibitors (letrozole, anastrozole) have shown superior efficacy in early and advanced breast cancer compared with tamoxifen. For HR+, HER2+ MBC, combination of an AI with an anti-HER2 agent (lapatinib or trastuzumab) has shown clinical benefit.

Methods:

Six databases were searched until January 2009 for randomized controlled clinical trials, assessing the safety and efficacy of first-line treatments for postmenopausal women with HR+ and HER2 (ErbB2) positive MBC, who have not received prior therapy for advanced or metastatic disease. Relevant interventions were lapatinib, aromatase inhibitors, tamoxifen, and trastuzumab. Outcomes included overall survival (OS), progression-free-survival (PFS), time-to-progression (TTP), and objective response rate (ORR).

Results:

Eighteen studies (62 papers) were included. Lapatinib + letrozole was significantly superior to letrozole alone based on a direct head-to-head study in terms of PFS/TTP and ORR. Using a network meta-analysis, compared with lapatinib + letrozole, tamoxifen (HR = 0.45 (95% CI: 0.32, 0.65) and anastrozole (HR = 0.53 (0.36, 0.80)) scored significantly worse in terms of PFS/TTP and ORR (tamoxifen: OR = 0.25 (0.12, 0.53), anastrozole: OR = 0.27 (0.12, 0.58). The combination also seemed significantly superior to exemestane in terms of PFS/TTP (HR = 0.52 (0.34, 0.79)). Lapatinib + letrozole also seemed better, although not significantly, in terms of OS versus tamoxifen: HR = 0.74 (0.49, 1.12), anastrozole: HR = 0.71 (0.45, 1.14) and exemestane: HR = 0.65 (0.39, 1.11). When compared with trastuzumab + anastrozole, lapatinib + letrozole seemed to be better in terms of OS (HR = 0.85 (0.47, 1.54)), PFS/TTP (HR = 0.89 (0.54, 1.47)) and ORR (OR = 0.92 (0.24, 3.48)), although, none of these results were significant.

Discussion:

Lapatinib + letrozole was significantly superior to letrozole in terms of PFS/TTP and ORR based on a direct head-to-head study. Indirect comparisons appeared to favor lapatinib + letrozole versus other first-line treatments used in this patient population in terms of three main outcomes: OS, PFS/TTP and ORR. Indirect comparison results are based on a network analysis for which the basic assumptions of homogeneity, similarity and consistency were not fulfilled. Therefore, despite the fact that these are the best available data, the results need to be interpreted with caution.

Keywords::

• Advanced or metastatic breast cancer
• Aromatase inhibitor
• First line treatment
• HR+, HER2+
• Lapatinib

Transparency

Declaration of financial/other relationships

M.A., K.L. and J.D. have disclosed that they are employed by GlaxoSmithKline. D.R. received honoraria from Pfizer, Novartis and Astra Zeneca and he received research funding to his institution from GlaxoSmithKline, Pfizer, Novartis and Astra Zeneca, and provided consultancy to GlaxoSmithKline, Novartis, Pfizer and Astra Zeneca. R.R, C.F., and J.K. have disclosed that they are employees of Kleijnen Systematic Reviews Ltd., a company that received funding from GlaxoSmithKline to conduct this study. Furthermore, R.R., C.F., and J.K. had ultimate editorial control of the manuscript. CMRO peer reviewers on this manuscript have no relevant financial relationships to declare.

Role of the funding source

The sponsors of this study had no control of the study design, data collection or data analysis of the report; J.K., R.R., and C.F. had full and exclusive editorial control. M.A., K.L., J.D. and D.R. provided clinical and scientific advice, helped to retrieve additional data, and commented on different versions of the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Contributions of authors

R.R. and C.F. (Senior Research Fellows) assessed abstracts and titles for inclusion and exclusion, conducted the systematic review, and contributed to writing and editing the report. M.A., K.L. and J.D. (Scientific Advisors Oncology) advised on clinical matters and the interpretation of the data and contributed to the writing of the protocol and report. D.R. (Clinical Expert) advised on clinical matters and the interpretation of the data and contributed to the writing of the protocol and report. J.K. (Director) provided overall project management, wrote the protocol, assessed abstracts and titles for inclusion and exclusion, conducted the systematic review, and contributed to writing and editing the report.