Neratinib Efficacy in Patients With EGFR Exon 18-Mutant Non-Small-Cell Lung Cancer: Findings From the SUMMIT Basket Trial

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Background Activating mutations in the epidermal growth factor receptor ( EGFR ) gene occur in 7–23% of patients with non-small-cell lung cancer (NSCLC). A small proportion of these (3−5%) are exon 18 mutations. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), had activity in the phase II SUMMIT basket study. We report efficacy and safety of neratinib in patients with EGFR exon 18-mutant NSCLC in SUMMIT, according to prior EGFR TKI treatment. Patients and Methods Eligible patients had ECOG performance status 0–2. Prior EGFR TKIs, chemotherapy, and checkpoint inhibitors were allowed. Patients received neratinib (240 mg orally daily) and mandatory diarrhea prophylaxis with loperamide. The primary endpoint was objective response rate (ORR) at 8 weeks (ORR 8 ); other endpoints included ORR, progression-free survival (PFS), duration of response, and safety. Results Thirty-one patients were included (24/7 with/without prior TKI). ORR 8 was 19.4% (95% CI 7.5–37.5); ORR was 32.3% (95% CI: 16.7−51.4); median PFS 5.75 months (95% CI: 2.27−9.23). Two of seven patients with baseline central nervous system metastasis had partial responses (median PFS 3.6 months; 95% CI: 1.9–9.1). Six patients with G719A/X/C mutations had partial responses >10 months. Diarrhea was generally controlled (10% grade 3, no grade 4; one patient discontinued treatment because of diarrhea). Conclusion Neratinib had meaningful activity in selected patients with EGFR exon 18-mutant NSCLC, including patients pretreated with ≥1 TKI. Diarrhea was generally low grade. Given the lack of effective treatments after EGFR TKI failure for NSCLC with uncommon mutations, further examination of neratinib is warranted. Micro-Abstract A small proportion of non-small-cell lung cancers (NSCLCs) are associated with rare mutations in the EGFR gene. We studied the effects of neratinib on 31 patients with EGFR exon 18 mutations in the SUMMIT study. Ten patients responded to neratinib, some with responses lasting >10 months. These findings indicate that neratinib should be studied further in patients with NSCLC.

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