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Targeting HER2-mutant metastatic cervical cancer with neratinib: Final results from the phase 2 SUMMIT basket trial
Claire F Friedman1, Anishka D'Souza2, Diana Bello Roufai3
1Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
Objective:
HER2 mutations are associated with poor prognosis and are detected in 3-6% of cervical cancers. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, had activity in several HER2-mutant cancer types in the phase 2 SUMMIT basket study. We present updated and final results from the cervical cancer cohort of SUMMIT.
Methods:
Eligible patients had HER2-mutant, metastatic or recurrent cervical cancer progressing after platinum-based treatment for advanced/recurrent disease. Patients received neratinib 240 mg/day; loperamide was mandatory during cycle 1. Confirmed objective response rate (ORR) was the primary endpoint. Duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and safety were secondary endpoints.
Results:
Twenty-two patients were enrolled; 18 (81.8%) had endocervical adenocarcinoma; median two prior systemic chemotherapy regimens (range 1-4). The most common HER2 variant was S310F/Y mutation (n = 13; 59.1%). Four patients had confirmed partial responses (ORR 18.2%; 95% CI 5.2-40.3); 6 had stable disease ≥16 weeks (CBR 45.5%; 95% CI 24.4-67.8). Median DoR was 7.6 months (95% CI 5.6-12.3). Median PFS was 5.1 months (95% CI 1.7-7.2). All-grade diarrhea (90.9%), nausea (54.5%), and constipation (54.5%) were the most common adverse events. Five patients (22.7%) reported grade 3 diarrhea. There were no grade 4 adverse events, no diarrhea-related treatment discontinuations, and two grade 5 adverse events, unrelated to neratinib: dyspnea (n = 1) and embolism (n = 1).
Conclusions:
Neratinib resulted in durable responses and disease control in patients with HER2-mutant metastatic/recurrent cervical cancer in SUMMIT. These findings support next-generation sequencing and tailored therapy for select patients with advanced cervical cancer. All responses occurred in patients with endocervical adenocarcinoma. Further assessment of neratinib in this setting is warranted.
Trial Registration Number:
NCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).
Insights
Neratinib showed activity in HER2-mutant cervical cancer, providing durable responses and disease control. This supports targeted therapy for advanced cervical cancer patients with specific HER2 mutations.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- HER2 mutations are linked to poor prognosis in 3-6% of cervical cancers.
- Neratinib, a pan-HER tyrosine kinase inhibitor, demonstrated prior activity in HER2-mutant cancers.
Purpose of the Study:
- To present updated results from the cervical cancer cohort of the phase 2 SUMMIT basket study.
- To evaluate the efficacy and safety of neratinib in patients with HER2-mutant metastatic or recurrent cervical cancer.
Main Methods:
- Patients with HER2-mutant, advanced cervical cancer progressing on platinum-based therapy received neratinib 240 mg/day.
- Objective response rate (ORR) was the primary endpoint; duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and safety were secondary endpoints.
- Loperamide was mandatory during cycle 1 to manage potential side effects.
Main Results:
- Of 22 enrolled patients, 18 had endocervical adenocarcinoma; 13 had the common S310F/Y HER2 mutation.
- Confirmed ORR was 18.2% (4 partial responses), with a CBR of 45.5% (6 patients with stable disease ≥16 weeks).
- Median DoR was 7.6 months, median PFS was 5.1 months. Most common adverse events included diarrhea (90.9%), nausea (54.5%), and constipation (54.5%).
Conclusions:
- Neratinib demonstrated durable responses and disease control in HER2-mutant cervical cancer.
- Findings support the use of next-generation sequencing for identifying patients who may benefit from tailored therapy.
- Further investigation of neratinib in this patient population is warranted, particularly in endocervical adenocarcinoma.
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