Evaluating the clinical effectiveness and safety of various HER2-targeted regimens after prior taxane/trastuzumab in patients with previously treated, unresectable, or metastatic HER2-positive breast cancer: a systematic review and network meta-analysis

Abstract

Purpose: In the absence of head-to-head trial data, network meta-analysis (NMA) was used to compare trastuzumab emtansine (T-DM1) with other approved treatments for previously treated patients with unresectable or metastatic HER2-positive breast cancer (BC).

Methods: Systematic reviews were conducted of published controlled trials of treatments for unresectable or metastatic HER2-positive BC with early relapse (≤ 6 months) following adjuvant therapy or progression after trastuzumab (Tras) + taxane published from January 1998 to January 2018. Random-effects NMA was conducted for overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety endpoints.

Results: The NMA included regimens from seven randomized controlled trials: T-DM1 and combinations of Tras, capecitabine (Cap), lapatinib (Lap), neratinib, or pertuzumab (Per; unapproved). OS results favored T-DM1 over approved comparators: hazard ratio (HR) (95% credible interval [95% CrI]) vs Cap 0.68 (0.39, 1.10), LapCap 0.76 (0.51, 1.07), TrasCap 0.78 (0.44, 1.19). PFS trends favored T-DM1 over all other treatments: HR (95% CrI) vs Cap 0.38 (0.19, 0.74), LapCap 0.65 (0.40, 1.10), TrasCap 0.62 (0.34, 1.18); ORR with T-DM1 was more favorable than with all approved treatments. In surface under cumulative ranking curve (SUCRA) analysis T-DM1 ranked highest for all efficacy outcomes. Discontinuation due to adverse events was less likely with T-DM1 than with all comparators except neratinib. In general, gastrointestinal side effects were less likely and elevated liver transaminases and thrombocytopenia more likely with T-DM1 than with comparators.

Conclusions: The efficacy and tolerability profiles of T-DM1 are generally favorable compared with other treatments for unresectable or metastatic HER2-positive BC.

Keywords: Capecitabine; Lapatinib; Locally advanced; Neratinib; Pertuzumab; Trastuzumab emtansine.

Fig. 1

PRISMA diagram of included and excluded studies (^aRespectively, the record numbers shown are those from the initial SR covering 1 January 1998 to 2 July 2013, from the first update of the SR, covering 1 October 2012 to 30 June 2016, and from the second update of the SR, covering 1 January 2016 to 3 January 2018. ^bFor each clinical study only the primary references, and not conference abstracts, are cited in the text). A PRISMA checklist is provided in Online Resource 11. PRISMA Preferred Reporting Items for Systematic Reviews and Meta-analyses, SR systematic review

Fig. 2

Treatment network plots for a OS, adjusted OS, PFS, and b ORR. Cap capecitabine, Lap lapatinib, ORR overall response rate, OS overall survival, Per pertuzumab, PFS progression-free survival, T-DM1 trastuzumab emtansine, Tras trastuzumab

Fig. 3

Comparative effectiveness of T-DM1 on OS, adjusted OS, and PFS. Comparators are shown in order of SUCRA ranking, with treatments ranking highest after T-DM1 at the top of the plot. Cap capecitabine, CrI credible interval, HR hazard ratio, Lap lapatinib, OS overall survival, Per pertuzumab, PFS progression-free survival, SUCRA surface under cumulative ranking curve, T-DM1 trastuzumab emtansine, Tras trastuzumab

Fig. 4

Comparative effectiveness of T-DM1 on ORR. Comparators are shown in order of SUCRA ranking, with treatments ranking highest after T-DM1 at the top of the plot. Cap capecitabine, CrI credible interval, Lap lapatinib, OR odds ratio, ORR overall response rate, Per pertuzumab, SUCRA surface under cumulative ranking curve, T-DM1 trastuzumab emtansine, Tras trastuzumab

Fig. 5

Comparative effectiveness of T-DM1 on AEs: a SAEs and AEs leading to discontinuation; b AEs by preferred term. Comparators are shown in order of SUCRA ranking, with treatments ranking highest at the top of the plot. T-DM1 ranks: discontinuation (grade 3+), SAEs, diarrhea, nausea, fatigue, first; vomiting, second; neutropenia, third; increased ALT, fourth; increased AST, fifth. AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, Cap capecitabine, CrI credible interval, Lap lapatinib, OR odds ratio, Per pertuzumab, SAE serious adverse event, SUCRA surface under cumulative ranking curve, T-DM1 trastuzumab emtansine, Tras trastuzumab