Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial

Ana Oaknin, Claire F Friedman, Lynda D Roman, Anishka D'Souza, Irene Brana, François-Clement Bidard, Jonathan Goldman, Edwin A Alvarez, Valentina Boni, Adam C ElNaggar, Rodolfo Passalacqua, Khanh T M Do, Alessandro D Santin, Kiana Keyvanjah, Feng Xu, Lisa D Eli, Alshad S Lalani, Richard P Bryce, David M Hyman, Funda Meric-Bernstam, David B Solit, Bradley J Monk, Ana Oaknin, Claire F Friedman, Lynda D Roman, Anishka D'Souza, Irene Brana, François-Clement Bidard, Jonathan Goldman, Edwin A Alvarez, Valentina Boni, Adam C ElNaggar, Rodolfo Passalacqua, Khanh T M Do, Alessandro D Santin, Kiana Keyvanjah, Feng Xu, Lisa D Eli, Alshad S Lalani, Richard P Bryce, David M Hyman, Funda Meric-Bernstam, David B Solit, Bradley J Monk

Abstract

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).

Keywords: Cervical cancer; Clinical trial; HER2 mutant; Neratinib; Tyrosine kinase inhibitor.

Conflict of interest statement

Declaration of Competing Interest A. Oaknin: has received advisory board honoraria from Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, Inmunogen, Genmab, and Deciphera and travel/accommodation support from Roche, AstraZeneca, and PharmaMar. C.F. Friedman: has received institutional research funding from Bristol-Myers Squibb, Merck, and Genentech, advisory board honoraria from AstraZeneca, and serves on steering committees for the Genentech MyPathway and the Merck LYNK-002 studies (compensation waived). L.D. Roman: has received advisory board honoraria from Tempus Labs and is a consultant for Quantgene. A. D'Souza: has no competing interests. I. Brana: has received institutional research funding from Puma Biotechnology Inc. F. Clement-Bidard: has received advisory board honoraria from Pfizer, Novartis, Eli Lilly, Amgen, and AstraZeneca. J. Goldman: has received institutional research funding from Puma Biotechnology Inc. E. A. Alvarez: has received advisory board honoraria from Eisai Co. Inc. and ArQule Inc. and has been a medical consultant for Tracon Pharmaceuticals, Inc. V. Boni: has received advisory board honoraria from Loxo Oncology and Ideaya. A.C. ElNaggar: has received institutional research funding from Caris Life Sciences and advisory board honoraria from AstraZeneca, Clovis Oncology, Leap Therapeutics, Tesaro/GSK, and AbbVie Pharmaceuticals. R. Passalacqua: has received advisory board/speaker honoraria from Amgen, Astellas, Bayer, BMS, Ipsen, Janssen, Novartis, Sanofi-Aventis, Roche, MSD, and Pierre-Fabre. K.T.M. Do: has received advisory board honoraria from QED Therapeutics. A.D. Santin: has received advisory board honoraria from Merck and Tesaro and has received institutional research funding from Puma Biotechnology Inc., Immunomedics, Tesaro, Boehringer Ingelheim, and Genentech. K. Keyvanjah: is an employee and shareholder of Puma Biotechnology Inc. F. Xu: is an employee and shareholder of Puma Biotechnology Inc. L.D. Eli: is an employee and shareholder of Puma Biotechnology Inc. A.S. Lalani: is an employee and shareholder of Puma Biotechnology Inc. R.P. Bryce: is an employee and shareholder of Puma Biotechnology Inc. D.M. Hyman: has acted in a consulting/advisory role for Atara Biotherapeutics, Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, and Genentech, and has received institutional research funding from Loxo Oncology, Puma Biotechnology Inc., and AstraZeneca. He is currently employed by Loxo Oncology/Eli Lilly. F. Meric-Bernstam: has received institutional research funding from Novartis, AstraZeneca, Calithera, Aileron, Bayer, Jounce, CytoMx, eFFECTOR, Zymeworks, Puma Biotechnology Inc., Curis, Millennium, Daiichi Sankyo, AbbVie, Guardant Health, Takeda, and GlaxoSmithKline, grants/travel-related fees from Taiho, Genentech, Debiopharm Group, and Pfizer, consultancy fees from Pieris, Dialectica, Sumitomo Dainippon, Samsung Bioepis, Aduro, OrigiMed, Xencor, Jackson Laboratory, Zymeworks, and Parexel International, advisory board fees from Inflection Biosciences, GRAIL, Darwin Health, Clearlight Diagnostics, Spectrum, Mersana, and Seattle Genetics. D.H. Solit: has acted in a consulting/advisory role for Loxo Oncology, Pfizer, Illumina, Vivideon Therapeutics, QED Therapeutics, and Lilly Oncology. B.J. Monk: has received consultancy fees from Puma Biotechnology Inc.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1.
Fig. 1.
Best change in tumor size and characteristics in RECIST efficacy evaluable patients (N = 12). Response based on investigator tumor assessments by RECIST (version 1.1). Only the most common co-mutations, as reported by local testing at time of enrollment, are shown. *Patient developed new lesion (progressive disease) and had no post-baseline target lesion measurement. ECD: extracellular domain; KD: kinase domain; RECIST: Response Evaluation Criteria in Solid Tumors.
Fig. 2.
Fig. 2.
Duration of treatment and best response in all patients per RECIST or PERCIST (N = 16). Response based on investigator assessment. CT: computed tomography; PET: positron-emission tomography; RECIST: Response Evaluation Criteria in Solid Tumors.
Fig. 3.
Fig. 3.
Kaplan–Meier estimates of PFS and OS in safety analysis set (N = 16). NE: not estimable; OS: overall survival; PFS: progression-free survival.

References

    1. Small W Jr., Bacon MA, Bajaj A, et al., Cervical cancer: a global health crisis, Cancer 123 (2017) 2404–2412.
    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin 68 (2018) 394–424.
    1. FIGO World Congress, International Federation of Gynecology and Obstetrics Global Declaration on cervical Cancer elimination, Rev. Bras. Ginecol. Obstet 41 (2019) 102–103.
    1. Siegel RL, Miller KD, Jemal A, Cancer statistics, 2020, CA Cancer J. Clin 70 (2020) 7–30.
    1. Li H, Wu X, Cheng X, Advances in diagnosis and treatment of metastatic cervical cancer, J. Gynecol. Oncol 27 (2016), e43.
    1. Orbegoso C, Murali K, Banerjee S, The current status of immunotherapy for cervical cancer, Rep. Pract. Oncol. Radiother 23 (2018) 580–588.
    1. Tewari KS, Sill MW, Long HJ 3rd, et al., Improved survival with bevacizumab in advanced cervical cancer, N. Engl. J. Med 370 (2014) 734–743.
    1. Tewari KS, Sill MW, Penson RT, et al., Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (gynecologic oncology group 240), Lancet 390 (2017) 1654–1663.
    1. Tewari KS, Monk BJ, Evidence-based treatment paradigms for management of invasive cervical carcinoma, J. Clin. Oncol 37 (2019) 2472–2489.
    1. Moasser MM, The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis, Oncogene 26 (2007) 6469–6487.
    1. Bose R, Kavuri SM, Searleman AC, et al., Activating HER2 mutations in HER2 gene amplification negative breast cancer, Cancer Discov. 3 (2013) 224–237.
    1. Cocco E, Lopez S, Santin AD, Scaltriti M, Prevalence and role of HER2 mutations in cancer, Pharmacol. Ther 199 (2019) 188–196.
    1. Connell CM, Doherty GJ, Activating HER2 mutations as emerging targets in multiple solid cancers, ESMO Open 2 (2017), e000279.
    1. Greulich H, Kaplan B, Mertins P, et al., Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2, Proc. Natl. Acad. Sci. U. S. A 109 (2012) 14476–14481.
    1. Ojesina AI, Lichtenstein L, Freeman SS, et al., Landscape of genomic alterations in cervical carcinomas, Nature 506 (2014) 371–375.
    1. Xiang L, Jiang W, Ye S, et al., ERBB2 mutation: a promising target in non-squamous cervical cancer, Gynecol. Oncol 148 (2018) 311–316.
    1. Zammataro L, Lopez S, Bellone S, et al., Whole exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy, Proc. Natl. Acad. Sci. U. S. A 116 (2019) 22730–22736.
    1. Zhang L Chen L, Yu H, Phase II study of apatinib, a novel tyrosine kinase inhibitor targeting tumor angiogenesis, as second-line treatment for recurrent or advanced cervical cancer patients, Investig. New Drugs (2019. October 21) 10.1007/s10637-019-00858-5 (Epub ahead of print).
    1. Cancer Genome Atlas Research Network, Albert Einstein College of Medicine, Analytical Biological Services, et al., Integrated genomic and molecular characterization of cervical cancer, Nature. 543 (2017) 378–384.
    1. Rabindran SK, Discafani CM, Rosfjord EC, et al., Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase, Cancer Res. 64 (2004) 3958–3965.
    1. Chan A, Delaloge S, Holmes FA, et al., Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial, Lancet Oncol. 17 (2016) 367–377.
    1. Martin M, Holmes FA, Ejlertsen B, et al., Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial, Lancet Oncol. 18 (2017)1688–1700.
    1. Awada A, Colomer L, Inoue K, et al., Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: the NEfERT-T randomized clinical trial, JAMA. Oncol 2 (2016) 1557–1564.
    1. Saura C, Oliveira M, Feng Y-H, et al., Neratinib + capecitabine vs lapatinib + capecitabine in HER2+ metastatic breast cancer previously treated with two or more HER2-directed regimens: phase III NALA trial, J. Clin. Oncol (2020) July 17; doi: 10.1200/JCO.20.00147. Online ahead of print.
    1. Hyman DM, Piha-Paul SA, Won H, et al., HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature 554 (2018) 189–194 (Erratum in: Nature. 566 (2019) E11-E12).
    1. cBioPortal for Cancer Genomics, Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma, TCGA Firehose Legacy; cBioPortal for Cancer Genomics, MSK Clinical Sequencing Cohort, Cervical Cancer, .
    1. McLachlan J, Boussios S, Okines A, et al., The impact of systemic therapy beyond first-line treatment for advanced cervical cancer, Clin. Oncol 29 (2017) 153–160.
    1. Chung HG, Ros W, Delord JP, et al., Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study, J. Clin. Oncol 37 (2019) 1470–1478.
    1. Frenel JS, Le Tourneau C, O’Neil B, et al., Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1-positive cervical cancer: results from the phase Ib KEYNOTE-028 trial, J. Clin. Oncol 35 (2017) 4035–4041.
    1. Yan M, Parker BA, Schwab R, Kurzrock R, HER2 aberrations in cancer: implications for therapy, Cancer Treat. Rev 40 (2014) 770–780.
    1. Cerami E, Gao J, Dogrusoz U, et al., The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data, Cancer Discov. 2 (2012) 401–404.
    1. Zehir A, Benayed R, Shah RH, et al., Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients, Nat. Med 23 (2017) 703–713.
    1. Nayar U, Cohen O, Kapstad C, et al., Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor-directed therapies, Nat. Genet 51 (2019) 207–216.
    1. Razavi P, Chang MT, Xu G, et al., The genomic landscape of endocrine-resistant advanced breast cancers, Cancer Cell 34 (2018) 427–438 (e6).
    1. Minuti G, D’Incecco A, Cappuzzo F, Targeted therapy for NSCLC with driver mutations, Expert. Opin. Biol. Ther 13 (2013) 1401–1412.
    1. Moon JY, Song IC, Ko YB, Lee HJ, The combination of cisplatin and topotecan as a second-line treatment for patients with advanced/recurrent uterine cervix cancer, Medicine 97 (2018), e0340.
    1. Guo Q, Sun Y, Kong E, et al., Apatinib combined with chemotherapy or concurrent chemo-brachytherapy in patients with recurrent or advanced cervical cancer: A phase 2, randomized controlled, prospective study, Medicine (Baltimore) 99 (2020) (e19372).
    1. Naumann RW, Hollebecque A, Meyer T, et al., Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: results from the phase I/II CheckMate 358 trial, J. Clin. Oncol 37 (2019) 2825–2834.
    1. Ma CX, Bose R, Gao F, et al., Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer, Clin. Cancer Res 23 (2017) 5687–5695.
    1. Wardley AM, Kilburn L, Kernaghan S, et al., Results from plasmaMATCH trial treatment Cohort B: a phase II trial of neratinib plus fulvestrant in ER positive breast cancer or neratinib alone in ER negative breast cancer in patient with a ERBB2 (HER2) mutation identified via ctDNA screening (CRUK/15/010). Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10–14; San Antonio, TX. Philadelphia (PA): AACR, Cancer Res. 80 (4 Suppl) (2020) (Abstract No. P1-19-07).

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