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Efficacy of Neratinib-Based Therapy in ERBB2-Mutant Lung Adenocarcinomas: Findings From 2 International Phase 2
Bob T Li1, Leena Gandhi2, Vignesh Ravichandran1
1Memorial Sloan Kettering Cancer Center, New York, NY.
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.
Insights
Single-agent neratinib showed limited effectiveness for ERBB2-mutant lung cancer. Combinations with temsirolimus or trastuzumab offered durable responses in only a few patients.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- ERBB2 mutations are key drivers in 2-4% of lung cancers.
- These mutations represent potential targets for HER2 tyrosine kinase inhibitors.
Purpose of the Study:
- To evaluate the efficacy and safety of neratinib, alone and in combination, for advanced ERBB2-mutant lung cancer.
Main Methods:
- Two Phase 2 studies (PUMA-NER-4201 and PUMA-NER-5201) enrolled patients with advanced ERBB2-mutant lung cancer.
- Treatments included neratinib monotherapy, neratinib with temsirolimus, and neratinib with trastuzumab.
Main Results:
- Objective response rates varied: 0-3.8% for neratinib monotherapy, 14.0% for neratinib plus temsirolimus, and 9.6% for neratinib plus trastuzumab.
- Five patients achieved durable responses (≥1 year) with specific ERBB2 mutations or fusions.
- Grade ≥3 treatment-related adverse events ranged from 23.5% to 48.1% across treatment arms.
Conclusions:
- Single-agent neratinib demonstrates limited activity in ERBB2-mutant lung cancer.
- Combination therapies did not significantly improve overall outcomes but yielded durable responses in a subset of patients.
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