Efficacy of Neratinib-Based Therapy in ERBB2-Mutant Lung Adenocarcinomas: Findings From 2 International Phase 2 Studies

Background ERBB2 mutations are oncogenic drivers in 2% to 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 Sixty 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.