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Efficacy of neratinib-based therapy in ERBB2-mutant lung adenocarcinomas: findings from 2 international phase 2 studies
Journal article   Peer reviewed

Efficacy of neratinib-based therapy in ERBB2-mutant lung adenocarcinomas: findings from 2 international phase 2 studies

Bob T. Li, Leena Gandhi, Vignesh Ravichandran, Benjamin Besse, Julien Mazières, Geoffrey I. Shapiro, Valentina Boni, Saiama N. Waqar, Haeseong Park, David I. Quinn, …
Clinical lung cancer, Vol.27(2), pp.214-226.e5
03/2026
DOI: 10.1016/j.cllc.2025.09.009
PMCID: PMC12696912
PMID: 41193346

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Abstract

Background ERBB2 mutations are oncogenic drivers in 2–4% of lung cancers and potentially actionable using HER2 tyrosine kinase inhibitors. Patients and Methods Patients with advanced ERBB2-mutant lung cancer entered 2 phase 2 studies (PUMA-NER-4201 [4201]; PUMA-NER-5201 [SUMMIT]). Patients received neratinib (monotherapy 4201; monotherapy SUMMIT), or neratinib with weekly temsirolimus (combination 4201), or trastuzumab every 3 weeks (combination SUMMIT). Protocol-defined endpoints common to both studies were analyzed. Exploratory genomic analyses were conducted. ClinicalTrials.gov: NCT01827267; NCT01953926. Results 60 patients in 4201 (neratinib, n = 17; neratinib plus temsirolimus, n = 43) and 78 in SUMMIT (neratinib, n = 26; neratinib plus trastuzumab, n = 52) received study treatment. Objective response rates were 0% (95% confidence interval [CI], 0.0–19.5; 4201) and 3.8% (95% CI, 0.1–19.6; SUMMIT) with neratinib, 14.0% (95% CI, 5.3–27.9) with neratinib plus temsirolimus, and 9.6% (95% CI, 3.2–21.0) with neratinib plus trastuzumab. Five patients whose tumors harbored ERBB2 exon 20 insertion, L755P and D769Y missense mutations, and a novel ERBB2-SHC1 fusion had responses ≥1 year (neratinib monotherapy, n = 1; SUMMIT; neratinib plus temsirolimus, n = 2; neratinib plus trastuzumab, n = 2). Grade ≥3 treatment-related adverse events occurred in 23.5% (4201) and 34.6% (SUMMIT) of neratinib-treated patients, 37.2% of patients treated with neratinib plus temsirolimus, and 48.1% of patients treated with neratinib plus trastuzumab. Conclusion Single-agent neratinib has limited activity in ERBB2-mutated lung cancers. Combinations with temsirolimus or trastuzumab did not markedly improve overall outcomes, producing durable responses in a limited subset of patients.

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