Trastuzumab and pertuzumab combination therapy for advanced pre-treated HER2 exon 20-mutated non-small cell lung
J M van Berge Henegouwen1, M Jebbink2, L R Hoes3
1Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands; Oncode Institute, the Netherlands.
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.
Insights
Trastuzumab and pertuzumab showed marginal activity in a subset of patients with advanced human epidermal growth factor 2 (HER2) mutated non-small cell lung cancer (NSCLC), meeting the primary endpoint but indicating limited efficacy in heavily pre-treated cases.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Human epidermal growth factor 2 (HER2) mutations are rare genomic drivers in non-small cell lung cancer (NSCLC), occurring in 1-3% of cases.
- Currently, no HER2-targeted therapies are approved for NSCLC, despite HER2 mutations being a targetable alteration.
- The Drug Rediscovery Protocol (DRUP) utilizes off-label drug administration based on patient molecular profiles.
Purpose of the Study:
- To evaluate the efficacy and safety of trastuzumab combined with pertuzumab in patients with advanced HER2-mutated NSCLC (HER2m+).
- To assess clinical benefit, defined as objective response or stable disease for at least 16 weeks, as the primary endpoint.
- To explore biomarker data, including whole genome sequencing, in patients treated with HER2-targeted therapy.
Main Methods:
- A cohort of patients with treatment-refractory, advanced HER2m+ NSCLC received intravenous trastuzumab and pertuzumab every 3 weeks.
- A Simon-like 2-stage design was employed for patient enrollment, with a primary endpoint of clinical benefit.
- Baseline biopsies were collected for comprehensive biomarker analysis, including whole genome sequencing.
Main Results:
- Out of 24 evaluable patients, 9 (38%) achieved clinical benefit, including 2 partial responses (8.3%) and 7 cases of stable disease ≥16 weeks.
- The most common HER2 mutation was p.Y772_A775dup (71%).
- Median progression-free survival was 4 months and median overall survival was 10 months, with no unexpected toxicity observed.
Conclusions:
- The combination of trastuzumab and pertuzumab demonstrated marginal activity in a subset of heavily pre-treated HER2m+ NSCLC patients.
- The study met its primary endpoint, but the overall efficacy suggests limited benefit in this patient population.
- Further research may be needed to identify predictive biomarkers and optimize treatment strategies for HER2-mutated NSCLC.
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