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Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial
Ana Oaknin1, Claire F Friedman2, Lynda D Roman3
1Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Objective:
Somatic HER2 mutations occur in ~5% of cervical cancers and are considered oncogenic and associated with poor prognosis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is active in multiple HER2-mutant cancers. SUMMIT is a phase II basket trial investigating the efficacy and safety of neratinib in solid tumors.
Methods:
Patients with HER2-mutant, persistent, metastatic/recurrent cervical cancer with disease progression after platinum-based treatment for advanced/recurrent disease received oral neratinib 240 mg/day with mandatory loperamide prophylaxis during cycle 1. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included: response duration (DOR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety.
Results:
Sixteen eligible patients were enrolled; 10 (62.5%) had endocervical adenocarcinoma. The most common HER2 mutation was S310F (63% of patients). Three of 12 RECIST-measurable patients had confirmed partial responses (ORR 25%; 95%CI 5.5-57.2%); 3 had stable disease ≥16 weeks (CBR 50%; 95%CI 21.1-78.9%). DOR for responders were 5.6, 5.9, and 12.3 months. Median PFS was 7.0 months (95%CI 0.7-18.3 months); median OS was 16.8 months (95%CI 4.1-NE months). Diarrhea (75%), nausea (44%), and decreased appetite (38%) were the most common adverse events. One patient (6%) reported grade 3 diarrhea. There were no grade 4 events, and no diarrhea-related treatment discontinuations.
Conclusions:
Neratinib monotherapy showed evidence of activity in heavily pretreated patients with HER2-mutant cervical cancer, with no new safety signals. Given the few effective options for cervical cancer after platinum-based therapy failure, neratinib warrants further investigation in this molecularly defined patient population.
Trial Registration Number:
NCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).
Insights
Neratinib showed activity in patients with HER2-mutant cervical cancer, offering a potential new treatment option. This irreversible pan-HER inhibitor demonstrated efficacy with manageable side effects in heavily pretreated individuals.
Area of Science:
- Oncology
- Medical Genetics
Background:
- Somatic HER2 mutations are found in approximately 5% of cervical cancers, correlating with poor prognosis.
- Neratinib, a pan-HER tyrosine kinase inhibitor, has shown efficacy in HER2-mutant cancers.
Purpose of the Study:
- To investigate the efficacy and safety of neratinib in patients with HER2-mutant, persistent, metastatic/recurrent cervical cancer.
- To evaluate neratinib's activity in a heavily pretreated patient population post-platinum-based therapy.
Main Methods:
- A phase II basket trial (SUMMIT) administered oral neratinib (240 mg/day) with loperamide prophylaxis.
- Key endpoints included objective response rate (ORR), response duration (DOR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety.
Main Results:
- The study enrolled 16 patients; 62.5% had endocervical adenocarcinoma with S310F as the most common HER2 mutation (63%).
- Confirmed partial responses were observed in 25% of RECIST-measurable patients, with a 50% clinical benefit rate (stable disease ≥16 weeks).
- Median PFS was 7.0 months and median OS was 16.8 months. Common adverse events included diarrhea (75%) and nausea (44%), with no grade 4 events or treatment discontinuations due to diarrhea.
Conclusions:
- Neratinib monotherapy demonstrated activity in heavily pretreated HER2-mutant cervical cancer patients.
- No new safety concerns were identified, and neratinib warrants further investigation in this specific patient group with limited treatment options.
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