Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2024 Feb:181:162-169.
doi: 10.1016/j.ygyno.2023.12.004. Epub 2024 Jan 11.

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

Claire F Friedman  1 , Anishka D'Souza  2 , Diana Bello Roufai  3 , Anna V Tinker  4 , Maria de Miguel  5 , Valentina Gambardella  6 , Jonathan Goldman  7 , Sherene Loi  8 , Michelle E Melisko  9 , Ana Oaknin  10 , Iben Spanggaard  11 , Geoffrey I Shapiro  12 , Adam C ElNaggar  13 , Stefano Panni  14 , Vignesh Ravichandran  15 , Aimee L Frazier  16 , Daniel DiPrimeo  16 , Lisa D Eli  16 , David B Solit  15
Affiliations
Clinical Trial

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

Claire F Friedman et al. Gynecol Oncol. 2024 Feb.

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.

PubMed Disclaimer

Conflict of interest statement

Declaration of Competing Interest C.F. Friedman: grants, non-financial support and other from Bristol Myers Squibb, grants and other from Merck, grants from AstraZeneca, grants and other from Genentech, grants from Daiichi, grants from Hotspot Therapeutics, grants from Mersana, personal fees from Aadi Biosciences/GOG Partners outside the submitted work. D. Bello Roufai: consulting or advisory role from Lilly and Rain Oncology; support for travel and meeting attendance from GlaxoSmithKline, Rain Oncology, and AstraZeneca. A. Tinker: honoraria (paid to the author) from GlaxoSmithKline, Eisai, Merck, and AstraZeneca; travel costs from GlaxoSmithKline. M. de Miguel: consulting fees from Syneoshealth; honoraria or speakers fees from MDS, Janssen, and Roche. V. Gambardella: advisory Board: Boehringer; research funding: Bayer, Boehringer, Roche Institutional Funding: Genentech, Merck Serono, Roche, BeiGene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas, Fibrogen, Amcure, Natera, Sierra Oncology, AstraZeneca, Medimmune, BMS, and MSD. J. Goldman: institutional research funding from Puma Biotechnology Inc. Consultant for Puma Biotechnology, Inc. S. Loi: research funding to institution from Novartis, Bristol Meyers Squibb, MSD, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, and Seattle Genetics. She has received consulting fees (paid to institution) from Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, Puma Biotechnology, Inc., Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi Sankyo, MSD, Amunix, Tallac Therapeutics, Eli Lilly, and Bristol Meyers Squibb; payment for expert testimony (to institution) from Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, Astra Zeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi Sankyo, MSD, Amunix, Tallac Therapeutics, Eli Lilly and Bristol Myers Squibb; uncompensated consultant to Seattle Genetics, Novartis, Bristol Myers Squibb, MSD, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics, and Roche-Genentech. M. E. Melisko: research funding (to institution) from OBI Pharma, KCRN Research, and Novartis; expert lecture honoraria from Puma Biotechnology, Inc. A. Oaknin: grants to institution from AbbVie Deutschland, Advaxis, Aeterna Zenraris, Amgen, Aprea Therapeutics AB, Bristol Myers Squibb, Clovis Oncology Inc., Eisai Ltd, F. Hoffmann –La Roche, Immunogen Inc., MDS, Millennium Pharmaceuticals Inc, PharmaMar SA, Regeneron Pharmaceuticals, and Tesaro Inc; consulting fees from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, EMD Serono, F. Hoffmann-La Roche, Genmab, GlaxoSmithKline, ImmunoGen, Itheos, MSD, Mersana Therapeutics, Novocure, OneXerna Therapeutics, Inc., PharmaMar, Regeneron, Sattucklabs, Seagen, and Sutro Biopharma; payments or honoraria from AstraZeneca, Clovis Oncology Inc., Eisai Ltd, F. Hoffmann –La Roche, Genmab, GlaxoSmithKline, ImmunoGen, MSD, and Seagen; support for attending meetings and/or travel from AstraZeneca, PharmaMar, and Roche; payment for advisory board participation from Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, EMD Serono, F. Hoffmann-La Roche, Genmab, GlaxoSmithKline, ImmunoGen, Itheos, MSD, Mersana Therapeutics, Novocure, OneXerna Therapeutics, Inc., PharmaMar, Regeneron, Sattucklabs, Seagen, and Sutro Biopharma; leadership or fiduciary role in other board, society, committee or advocacy group (all unpaid): ESMO (member, Officer, Co-Chair of the ESMO Gynaecological Cancers Congress 2023-2025, chair of the Gynaecological Track ESMO 2019, scientific track member Gynaecological Cancers ESMO 2018, ESMO 2020, ESMO 2022, member of the Gynaecological Cancers Faculty, subject editor for the Gynaecological Clinical Practice Guidelines), GCIG (member and Cervix Cancer Chair on behalf of GEICO). I. Spanggaard: institutional Research Funding: Roche/Genentech, Puma Biotechnology, Inc., MSD, Merck, AstraZeneca, Incyte, Orion, Genmab, Bristol Myers Squibb, Bayer/Loxo Oncology, Lilly Pharmaceuticals/Loxo Oncology, Novartis, Pfizer, Amgen, Repare Therapeutics; honoraria: AstraZeneca; support for travel and meeting attendance: Roche, Novartis, Merck/Pfizer, Incyte, and AstraZeneca. G. I. Shapiro: grants or contracts from Merck KGaA/EMD Serono, Tango Therapeutics, Bristol Myers Squibb, Merck & Co., Pfizer, and Eli Lilly; consulting fees from Merck KGaA/EMD Serono, Bicycle Therapeutics, Bayer, Concarlo Holdings, Janssen, Syros, Zentaris, Blueprint Medicines, Kymera Therapeutics, and XinThera; and patents Dosage Regimen For Sapacitabine And Seliciclib (with Cyclacel Pharmaceuticals) and Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition (with Liam Cornell). A. ElNaggar: employee and shareholder of Natera, Inc. S. Panni: payments or honoraria from Bristol Myers Squibb, MSD, and AstraZeneca. A. L. Frazier: employed by and holds stocks and options in Puma Biotechnology, Inc. D. DiPrimeo: employed by and holds stocks and options in Puma Biotechnology, Inc. L.D. Eli: employed by and shareholder of Puma Biotechnology, Inc. D.B. Solit: has acted in a consulting/advisory role for and received personal fees from Function Oncology, Pfizer, Vividion Therapeutics, Scorpion Therapeutics, Rain Therapeutics, Elsie Biotechnologies, Inc., FORE Therapeutics, Fog Pharma, PaigeAi, and BridgeBio; participated in a data safety monitoring board or advisory board for Rain Therapeutics; and holds stock or stock options in Scorpion Therapeutics, Function Oncology, FORE Therapeutics, and Elsie Biotechnologies, Inc. V. Ravichandrana and A. D’Souza declared no interests other than support for the present study from Puma Biotechnology, Inc.

Figures

Fig 1.
Fig 1.
Spectrum of HER2 mutations. aa: amino acids; furin-like: furin-like cysteine-rich region; GF_recept-IV: growth factor receptor domain IV; Pkinase_Tyr: protein tyrosine kinase domain; recep_L: receptor L domain.
Fig. 2.
Fig. 2.
(A) Best change in tumor size and tumor characteristics in RECIST efficacy-evaluable patients (n=20); 2 other patients not shown in part A were PERCIST evaluable only. (B) Duration of treatment and best response in all patients (n=22). *Note: extreme responder had surgical resection at week 95 and was not evaluable. Cut-off date: January 4, 2023. Co-mutation data based on central NGS when tumor tissue was provided, or by enrollment assay genomic report when not provided. ^Patient developed new lesion (progressive disease) and had no post-baseline target lesion measurement. PERCIST: Positron-Emission Tomography Response Criteria in Solid Tumors; RECIST: Response Evaluation Criteria in Solid Tumors; SD: stable disease.
Fig. 2.
Fig. 2.
(A) Best change in tumor size and tumor characteristics in RECIST efficacy-evaluable patients (n=20); 2 other patients not shown in part A were PERCIST evaluable only. (B) Duration of treatment and best response in all patients (n=22). *Note: extreme responder had surgical resection at week 95 and was not evaluable. Cut-off date: January 4, 2023. Co-mutation data based on central NGS when tumor tissue was provided, or by enrollment assay genomic report when not provided. ^Patient developed new lesion (progressive disease) and had no post-baseline target lesion measurement. PERCIST: Positron-Emission Tomography Response Criteria in Solid Tumors; RECIST: Response Evaluation Criteria in Solid Tumors; SD: stable disease.
Fig. 3.
Fig. 3.
(A) Scans demonstrating response to neratinib in a patient with endocervical adenocarcinoma harboring a HER2 S310F mutation, (B) DNA alterations detected from tissue biopsies taken at diagnosis, on treatment, at end of treatment, and during follow-up, and (C) longitudinal circulating tumor DNA variant allele frequencies observed throughout the course of treatment. ACCESS, Memorial Sloan Kettering Analysis of Circulating cfDNA to Examine Somatic Status; EOT: end of treatment; Tx: treatment.
See this image and copyright information in PMC

References

    1. Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, et al., Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer, New England Journal of Medicine. 385 (2021) 1856–1867. doi: 10.1056/NEJMoa2112435. - DOI - PubMed
    1. Coleman RL, Lorusso D, Gennigens C, González-Martín A, Randall L, Cibula D, et al., Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study, The Lancet Oncology. 22 (2021) 609–619. doi: 10.1016/S1470-2045(21)00056-5. - DOI - PubMed
    1. Tewari KS, Monk BJ, Vergote I, Miller A, de Melo AC, Kim H-S, et al., Survival with Cemiplimab in Recurrent Cervical Cancer, New England Journal of Medicine. 386 (2022) 544–555. doi: 10.1056/NEJMoa2112187. - DOI - PubMed
    1. Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, et al., HER kinase inhibition in patients with HER2- and HER3-mutant cancers, Nature. 554 (2018) 189–194. doi: 10.1038/nature25475. - DOI - PMC - PubMed
    1. Connell CM, Doherty GJ, Activating HER2 mutations as emerging targets in multiple solid cancers, ESMO Open. 2 (2017) e000279. doi: 10.1136/esmoopen-2017-000279. - DOI - PMC - PubMed

Publication types

MeSH terms

Associated data