Dual- versus single-agent HER2 inhibition and incidence of intracranial metastatic disease: a systematic review and meta-analysis

Anders Wilder Erickson,Sunit Das,Christianne Hoey,Steven Habbous,Katarzyna J Jerzak

doi:10.1038/s41523-021-00220-0

Abstract

Observational studies have suggested that HER2 inhibition with trastuzumab may be associated with an increased incidence of intracranial metastatic disease (IMD) due to its ability to prolong survival. We hypothesized that prolonged survival associated with dual-agent HER2 inhibition may be associated with an even higher incidence of IMD. This study pooled estimates of IMD incidence and survival among patients with HER2-positive breast cancer receiving dual- versus single-agent HER2 targeted therapy, as well as trastuzumab versus chemotherapy, observation, or another HER2-targeted agent. We searched PubMed, EMBASE, and CENTRAL from inception to 25 March 2020. We included randomized controlled trials that reported IMD incidence for patients with HER2-positive breast cancer receiving trastuzumab as the experimental or control arm irrespective of disease stage. Among 465 records identified, 19 randomized controlled trials (32,572 patients) were included. Meta-analysis of four studies showed that dual HER2-targeted therapy was associated with improved overall survival (HR 0.76; 95% CI, 0.66–0.87) and progression-free survival (HR 0.77; 95% CI, 0.68–0.87) compared to single HER2-targeted therapy, but the risk of IMD was similar (RR 1.03; 95% CI, 0.83–1.27). Our study challenges the hypothesis that prolonged survival afforded by improved extracranial disease control is associated with increased IMD incidence.

Highlights

Intracranial metastatic disease (IMD) is a common and serious complication of breast cancer[1], with a median survival of 13.8 months[2] and reduced quality of life due to disease symptomatology and treatment toxicity[3]
Using a two-step process, we screened abstracts and full texts of selected records to identify randomized controlled trials (RCTs) that reported the incidence of IMD that compared dual human epidermal growth factor receptor 2 (HER2)-targeted regimens to trastuzumab, trastuzumab to another HER2-targeted therapy, or trastuzumab to standard chemotherapy or observation
We evaluated the incidence of IMD among patients receiving HER2-targeted therapy through two separate comparisons: dual HER2-targeted therapy versus trastuzumab; and trastuzumab versus chemotherapy, observation, or another anti-HER agent

Summary

Introduction

Intracranial metastatic disease (IMD) is a common and serious complication of breast cancer[1], with a median survival of 13.8 months[2] and reduced quality of life due to disease symptomatology and treatment toxicity[3]. The anti-HER2-monoclonal antibody trastuzumab has been shown to improve overall survival (OS) for HER2-positive breast cancer patients and has become standard of care[6,7]. Case series and cohort studies have reported a higher incidence of IMD among HER2-positive patients treated with trastuzumab for metastatic, unresectable, or recurrent breast cancer[8–16]. The effectiveness of HER2 inhibition for HER2-positive breast cancer has motivated the development of novel HER2-targeted agents and trials to determine their efficacy as single agents or in combination with trastuzumab. Ongoing studies for margetuximab[32], pyrotinib[33], trastuzumab deruxtecan[34], ARX78835, and PRS-34336 may expand upon or improve current options for patients with HER2-positive breast cancer, and illuminate the impact of additional HER2-targeted agents on IMD incidence

Results

Discussion

Conclusion