Comparative Efficacy and Tolerability of Neoadjuvant Immunotherapy Regimens for Patients with HER2-Positive Breast Cancer: A Network Meta-Analysis

Abstract

This network meta-analysis addresses the need for evidence-based best-practice treatment regimens for HER2-positive breast cancer. We compared the relative efficacy and tolerability of currently available HER2-positive neoadjuvant immunotherapy regimens based on systematic searches of available randomized controlled trials (RCTs) data. Based on intention-to-treat principle, pathological complete response (pCR), overall serious adverse events (SAEs), and breast-conserving surgery (BCS) rate were analyzed using random-effect, Bayesian network meta-analysis, and standard pairwise meta-analysis. 16 RCTs (3868 patients) were included. Analyzed treatment regimens were as follows: chemotherapy+trastuzumab+pertuzumab (CTP), trastuzumab emtansine+pertuzumab (MP), chemotherapy+trastuzumab (CT), chemotherapy+pertuzumab (CP), trastuzumab+pertuzumab (TP), chemotherapy+trastuzumab+lapatinib (CTL), and chemotherapy+lapatinib (CL), and chemotherapy (C) alone. We found that, for the chance of achieving pCR, CTP was ranked first (SUCRA: 97%), followed by CTL, MP, and CT (SUCRA: 80%, 75%, and 55%, resp.). MP provided the safest regimen (SUCRA: 97%), then TP, C, and TPC (SUCRA: 82%, 76%, and 47%, resp.). CTL proved the most toxic therapy (SUCRA: 7%). No significant difference between neoadjuvant regimens was identified for BCS. Hormone receptor status did not impact ORs for pCR in any regimen. In conclusion, our findings support CTP as the optimum neoadjuvant regimen for HER2-positive breast cancer, with the best pCR and acceptable toxicity compared with CT. MP provides a therapeutic option for patients with poor performance status.

Figure 1

Summary of trial selection for network meta-analysis. HER2 indicates human epidermal growth factor receptor 2.

Figure 2

Network diagrams of available treatment comparisons for each outcome. The size of the nodes is proportional to the number of patients (in parentheses) randomized to each treatment, and the width of the lines is proportional to the number of trials (beside the line) comparing the connected treatments. C indicates chemotherapy; CL, chemotherapy plus lapatinib; CP, chemotherapy plus pertuzumab; CT, chemotherapy plus trastuzumab; CTL, chemotherapy plus trastuzumab plus lapatinib; CTP, chemotherapy plus trastuzumab plus pertuzumab; MP, trastuzumab emtansine plus pertuzumab; TP, trastuzumab plus pertuzumab.

Figure 3

Pooled estimates for all possible treatment effects for each outcome (treatments were ordered by ranking). Effect estimates reflect comparison of the treatment in the row heading being compared to the column heading. Effect estimates of all outcomes are expressed as odds ratios (ORs) with 95% credible intervals. ORs with Bayesian p value less than 0.05 are in green. C indicates chemotherapy; CL, chemotherapy plus lapatinib; CP, chemotherapy plus pertuzumab; CT, chemotherapy plus trastuzumab; CTL, chemotherapy plus trastuzumab plus lapatinib; CTP, chemotherapy plus trastuzumab plus pertuzumab; MP, trastuzumab emtansine plus pertuzumab; TP, trastuzumab plus pertuzumab.

Figure 4

Ranking for pathological complete response and serious adverse events. C indicates chemotherapy; CL, chemotherapy plus lapatinib; CP, chemotherapy plus pertuzumab; CT, chemotherapy plus trastuzumab; CTL, chemotherapy plus trastuzumab plus lapatinib; CTP, chemotherapy plus trastuzumab plus pertuzumab; MP, trastuzumab emtansine plus pertuzumab; TP, trastuzumab plus pertuzumab.

Figure 5

The comparison-adjusted funnel plot for each outcome. The funnel plot is a scatterplot of the treatment effect size vs its standard error. A funnel plot that is asymmetrical with respect to the line of the summary effect (vertical red line) implies that there are differences between the estimates derived from small and large studies. The studies are ordered from best to worst according to treatment effects. Missing (small) studies lying on the right side of the zero line suggest that small studies tend to exaggerate the effectiveness of higher-ranked treatments compared with lower-ranked treatments. Red line represents the null hypothesis that the study-specific effect sizes do not differ from the respective comparison-specific pooled effect estimates.