Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung cancer
van Berge Henegouwen, J M; Jebbink, M; Hoes, L R; van der Wijngaart, H; Zeverijn, L J; van der Velden, D L; Roepman, P; de Leng, W W J; Jansen, A M L; van Werkhoven, E; van der Noort, V; van der Wekken, A J; de Langen, A J; Voest, E E; Verheul, H M W; Smit, E F; Gelderblom, H
(2022) European Journal of Cancer, volume 171, pp. 114 - 123
(Article)
Abstract
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
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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.
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Keywords: HER2 mutation, Non-small lung cancer, Precision medicine, Targeted therapies, Whole genome sequencing, Oncology, Cancer Research, Journal Article
ISSN: 0959-8049
Publisher: Elsevier Limited
Note: Funding Information: The DRUP trial is supported by the Barcode for Life Foundation (BFL); the Dutch Cancer Society [grant number 10014]; the Hartwig Medical Foundation (HMF) and all participating pharmaceutical companies: Amgen ; AstraZeneca ; Bayer ; Boehringer Ingelheim ; Bristol-Myers Squibb ; Clovis Oncology ; Eisai ; Janssen; Lilly; MSD; Novartis; Pfizer ; Roche . Funding Information: The DRUP trial is supported by the Barcode for Life Foundation (BFL); the Dutch Cancer Society [grant number 10014]; the Hartwig Medical Foundation (HMF) and all participating pharmaceutical companies: Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Clovis Oncology; Eisai; Janssen; Lilly; MSD; Novartis; Pfizer; Roche.The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AW received grants from Boehringer Ingelheim, Pfizer, AstraZeneca, Roche and Takeda and was involved in advisory boards for Lilly, Boehringer Ingelheim, Pfizer, AstraZeneca, Roche, Takeda and Janssen. All outside the submitted work and all money has been received by the UMCG. The other authors declare no competing interests.The authors thank the Hartwig Medical Foundation for their in-kind support by performing sequencing and biomarker analyses on baseline biopsies; the Independent Data Monitoring Committee for their advice on cohort decisions and monitoring of preliminary safety data; and the authors would like to thank the patients, the investigators and research staff from all participating hospitals. Publisher Copyright: © 2022 The Authors
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