European journal of cancer (Oxford, England : 1990), Volume 171, 15 3 2022, Pages 114-123 Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer. van Berge Henegouwen JM, Jebbink M, Hoes LR, van der Wijngaart H, Zeverijn LJ, van der Velden DL, Roepman P, de Leng WWJ, Jansen AML, van Werkhoven E, van der Noort V, van der Wekken AJ, de Langen AJ, Voest EE, Verheul HMW, Smit EF, Gelderblom H

Introduction

In 1-3% of non-small cell lung cancer (NSCLC) human epidermal growth factor 2 (HER2) mutations are identified as a genomic driver. Nevertheless, no HER2-targeted treatment is approved for NSCLC. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for HER2 exon20 mutation positive (HER2m+) NSCLC'.

Methods

Patients with treatment refractory, advanced HER2m+ NSCLC with measurable disease (RECISTv1.1) were eligible. Treatment with intravenous trastuzumab combined with pertuzumab every 3 weeks was administered. The primary end-point was clinical benefit (CB: either objective response or stable disease ≥ 16 weeks). Patients were enrolled using a Simon-like 2-stage design, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 patient had CB in stage 1. At baseline, a biopsy for biomarker analysis, including whole genome sequencing, was obtained.

Results

Twenty-four evaluable patients were enrolled and treated between May 2017 and August 2020. CB was observed in 9 patients (38%); including an objective response rate of 8.3% (2 patients had a partial response) and 7 patients with stable disease ≥ 16 weeks. The most frequently observed HER2 mutation was p.Y772_A775dup (71%, n = 20). Median follow-up was 13 months, median progression-free survival and overall survival 4 (95% CI 3-6) and 10 months (95% CI 4 - not reached), respectively. Whole genome sequencing data (available for 67% of patients) confirmed the inclusion mutation in all cases. No unexpected toxicity was observed.

Conclusion

Despite the fact that the study did meet its primary end-point, trastuzumab/pertuzumab was only marginally active in a subset of patients with heavily pre-treated HER2m+ NSCLC.

Eur J Cancer. 2022 6;171:114-123