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

Claire F Friedman; Anishka D'Souza; Diana Bello Roufai; Anna V Tinker; Maria de Miguel; Valentina Gambardella; Jonathan Goldman; Sherene Loi; Michelle E Melisko; Ana Oaknin; Iben Spanggaard; Geoffrey I Shapiro; Adam C ElNaggar; Stefano Panni; Vignesh Ravichandran; Aimee L Frazier; Daniel DiPrimeo; Lisa D Eli; David B Solit

doi:10.1016/j.ygyno.2023.12.004

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

Claire F Friedman^*, Anishka D'Souza, Diana Bello Roufai, Anna V Tinker, Maria de Miguel, Valentina Gambardella, Jonathan Goldman, Sherene Loi, Michelle E Melisko, Ana Oaknin, Iben Spanggaard, Geoffrey I Shapiro, Adam C ElNaggar, Stefano Panni, Vignesh Ravichandran, Aimee L Frazier, Daniel DiPrimeo, Lisa D Eli, David B Solit

^*Corresponding author for this work

Department of Oncology

2 Citations (Scopus)

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).

Original language	English
Journal	Gynecologic Oncology
Volume	181
Pages (from-to)	162-169
Number of pages	8
ISSN	0090-8258
DOIs	https://doi.org/10.1016/j.ygyno.2023.12.004
Publication status	Published - Feb 2024

Keywords

Cervical cancer
Clinical trial
HER2 mutation
Neratinib
Tyrosine kinase inhibitor

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10.1016/j.ygyno.2023.12.004

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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. (2024). Targeting HER2-mutant metastatic cervical cancer with neratinib: Final results from the phase 2 SUMMIT basket trial. Gynecologic Oncology, 181, 162-169. https://doi.org/10.1016/j.ygyno.2023.12.004

Friedman, CF, D'Souza, A, Bello Roufai, D, Tinker, AV, de Miguel, M, Gambardella, V, Goldman, J, Loi, S, Melisko, ME, Oaknin, A, Spanggaard, I, Shapiro, GI, ElNaggar, AC, Panni, S, Ravichandran, V, Frazier, AL, DiPrimeo, D, Eli, LD & Solit, DB 2024, 'Targeting HER2-mutant metastatic cervical cancer with neratinib: Final results from the phase 2 SUMMIT basket trial', Gynecologic Oncology, vol. 181, pp. 162-169. https://doi.org/10.1016/j.ygyno.2023.12.004

@article{48878b584f894319abc03539cc62c1a5,

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).",

keywords = "Cervical cancer, Clinical trial, HER2 mutation, Neratinib, Tyrosine kinase inhibitor",

author = "Friedman, {Claire F} and Anishka D'Souza and {Bello Roufai}, Diana and Tinker, {Anna V} and {de Miguel}, Maria and Valentina Gambardella and Jonathan Goldman and Sherene Loi and Melisko, {Michelle E} and Ana Oaknin and Iben Spanggaard and Shapiro, {Geoffrey I} and ElNaggar, {Adam C} and Stefano Panni and Vignesh Ravichandran and Frazier, {Aimee L} and Daniel DiPrimeo and Eli, {Lisa D} and Solit, {David B}",

year = "2024",

month = feb,

doi = "10.1016/j.ygyno.2023.12.004",

language = "English",

volume = "181",

pages = "162--169",

journal = "Gynecologic Oncology",

issn = "0090-8258",

publisher = "Academic Press",

}

TY - JOUR

T1 - Targeting HER2-mutant metastatic cervical cancer with neratinib

T2 - Final results from the phase 2 SUMMIT basket trial

AU - Friedman, Claire F

AU - D'Souza, Anishka

AU - Bello Roufai, Diana

AU - Tinker, Anna V

AU - de Miguel, Maria

AU - Gambardella, Valentina

AU - Goldman, Jonathan

AU - Loi, Sherene

AU - Melisko, Michelle E

AU - Oaknin, Ana

AU - Spanggaard, Iben

AU - Shapiro, Geoffrey I

AU - ElNaggar, Adam C

AU - Panni, Stefano

AU - Ravichandran, Vignesh

AU - Frazier, Aimee L

AU - DiPrimeo, Daniel

AU - Eli, Lisa D

AU - Solit, David B

PY - 2024/2

Y1 - 2024/2

N2 - 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).

AB - 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).

KW - Cervical cancer

KW - Clinical trial

KW - HER2 mutation

KW - Neratinib

KW - Tyrosine kinase inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85182012591&partnerID=8YFLogxK

U2 - 10.1016/j.ygyno.2023.12.004

DO - 10.1016/j.ygyno.2023.12.004

M3 - Journal article

C2 - 38211393

SN - 0090-8258

VL - 181

SP - 162

EP - 169

JO - Gynecologic Oncology

JF - Gynecologic Oncology

ER -

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

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