Targeting HER2-mutant metastatic cervical cancer with neratinib: Final results from the phase 2 SUMMIT basket trial Journal Article

   

Authors:	Friedman, C. F.; D'Souza, A.; Bello Roufai, D.; Tinker, A. V.; de Miguel, M.; Gambardella, V.; Goldman, J.; Loi, S.; Melisko, M. E.; Oaknin, A.; Spanggaard, I.; Shapiro, G. I.; ElNaggar, A. C.; Panni, S.; Ravichandran, V.; Frazier, A. L.; DiPrimeo, D.; Eli, L. D.; Solit, D. B.
Article Title:	Targeting HER2-mutant metastatic cervical cancer with neratinib: Final results from the phase 2 SUMMIT basket trial
Abstract:	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). © 2023 Elsevier Inc.
Keywords:	adult; cancer chemotherapy; clinical article; controlled study; human tissue; treatment response; aged; gene mutation; clinical trial; constipation; bevacizumab; advanced cancer; diarrhea; drug efficacy; drug safety; systemic therapy; treatment duration; progression free survival; phase 2 clinical trial; nausea; epidermal growth factor receptor 2; cohort analysis; histology; multicenter study; prophylaxis; recurrent disease; open study; loperamide; tyrosine kinase inhibitor; protein msh6; disease exacerbation; thoracoscopy; nonsense mutation; uterine cervix carcinoma; cervical cancer; neratinib; notch4 receptor; wedge resection; dna barcoding; cervical metastasis; oncological parameters; response evaluation criteria in solid tumors; high throughput sequencing; clinical benefit rate; uterine cervix adenocarcinoma; objective response rate; phosphatidylinositol 4,5 bisphosphate 3 kinase; human; female; article; her2 mutation; circulating tumor dna; pembrolizumab; patient history of radiotherapy; patient history of surgery; mediastinum lymphadenopathy; ecog performance status; cervical squamous cell carcinoma; treatment response time
Journal Title:	Gynecologic Oncology
Volume:	181
ISSN:	0090-8258
Publisher:	Elsevier Inc.
Date Published:	2024-02-01
Start Page:	162
End Page:	169
Language:	English
DOI:	10.1016/j.ygyno.2023.12.004
PUBMED:	38211393
PROVIDER:	scopus
PMCID:	PMC10922668
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85182012591&doi=10.1016%2fj.ygyno.2023.12.004&partnerID=40&md5=e9cc7b9729d065a0ea9e58f21d1c2336
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Claire F. Friedman -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/213126