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Update on the phase II SUMMIT trial: Neratinib + fulvestrant for HER2-mutant, HR-positive, metastatic breast cancer


03 May 2019


Poster lunch


Lillian Smyth


Annals of Oncology (2019) 30 (suppl_3): iii1-iii26. 10.1093/annonc/mdz095


L.M. Smyth1, C. Saura2, S.A. Piha-Paul3, J. Lu4, I.A. Mayer5, A.M. Brufksy6, I. Spanggaard7, M. Arnedos8, R.E. Cutler9, D.M. Hyman10

Author affiliations

  • 1 Medical Oncology, St. Vincent’s University Hospital, D04 T6F4 - Dublin/IE
  • 2 Breast Cancer Unit, Medical Oncology Service, Vall d`Hebron University Hospital, Barcelona/ES
  • 3 Investigational Cancer Therapeutics, MD Anderson Cancer Center, Houston/US
  • 4 Medicine, USC Norris Comprehensive Cancer Center, Los Angeles/US
  • 5 Internal Medicine, Division Of Hematology-oncology, Vanderbilt University Medical Center/ Vanderbilt-Ingram Cancer Center, Nashville/US
  • 6 Hematology / Oncology, UPMC Hillman Cancer Center, Pittsburgh/US
  • 7 Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen/DK
  • 8 Medical Oncology, Gustave Roussy Cancer Campus, Villejuif/FR
  • 9 Clinical Science, Puma Biotechnology Inc, Los Angeles/US
  • 10 Early Drug Development Service, Memorial Sloan Kettering Cancer Center, New York/US



Somatic mutations in HER2 (ERBB2) are oncogenic and may confer resistance to endocrine therapy in hormone receptor-positive (HR+) metastatic breast cancer (MBC). Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has single-agent clinical activity in HER2mutant MBC and is synergistic with fulvestrant in preclinical studies. In SUMMIT (NCT01953926), a phase 2 basket trial of neratinib in HER2-mutant solid tumors, the HR+ MBC cohort had encouraging outcomes with neratinib plus fulvestrant (N+F) [Oct 2018 datacut; Smyth et al. SABCS 2018; #PD3-06]. Updated results from this cohort will be reported, detailing the impact of prior therapies on clinical efficacy of N+F in HER2-mutant HR+ MBC.


HR+ HER2 non-amplified MBC patients with locally detected HER2 mutations received oral neratinib 240 mg once daily and intramuscular fulvestrant (labeled dose). Loperamide prophylaxis was mandatory during cycle 1. Efficacy endpoints were: objective response rate (ORR); clinical benefit rate (CBR); duration of response (DOR); and progression-free survival (PFS). Response was assessed by RECIST 1.1 and/or PET Response Criteria.


A total of 47 patients were enrolled between Jul 2013 and Jan 2019. Most (79%) patients had visceral disease and were heavily pretreated; the median number of prior metastatic therapies was 3 (range 1–11). ORR was 30%, CBR was 47% and median DOR in the 14 patients with a confirmed response was 9.2 months. Median PFS was 5.4 months. Twenty-five patients (53%) had received prior fulvestrant and 20 (43%) had received prior CDK4/6 inhibitor (CDK4/6i) therapy, with ORRs of 16% and 30%, respectively. Diarrhea was the most common adverse event (grade 3, 11%; median duration, 1.5 days) but did not lead to treatment discontinuation.


N+F is clinically active in heavily pretreated HER2-mutant HR+ MBC patients, including in those who had received prior fulvestrant and CDK4/6i therapy, where some durable responses were noted. No new safety signals were identified; the incidence of diarrhea was similar to that seen with single-agent neratinib and was not dose limiting.

Editorial acknowledgement

Lee Miller (Miller Medical Communications Ltd).

Clinical trial identification


Legal entity responsible for the study

Puma Biotechnology Inc.


Puma Biotechnology Inc.


L.M. Smyth: Consulting or advisory role: Roche Genentech, AstraZeneca; Research funding (Inst): Puma Biotechnology, AstraZeneca, Roche Genentech; Travel, accommodations, expenses: Pfizer; Honoraria: Pfizer, AstraZeneca. C. Saura: Consulting fees: Puma Biotechnology Inc. S.A. Piha-Paul: Contracted research: Puma Biotechnology Inc. I.A. Mayer: All (unrelated) financial disclosures below: Institutional research funding: Novartis, Genentech, Pfizer; Ad. board consultant: Novartis, Genentech, Lilly, AstraZeneca, GSK, Immunomedics, Seattle Genetics, Macrogenics. A.M. Brufksy: Consultant: Puma Biotechnology, Roche, Eisai, Celgene, Pfizer, Lilly, Novartis. I. Spanggaard: Research grant: Puma Biotechnology Inc. M. Arnedos: Honoraria: Novartis, AstraZeneca, Pfizer, Seattle Genetics; Research grants: Eli Lilly, Pfizer; Travel expenses: AstraZeneca, Pfizer. R.E. Cutler: Employment: Puma Biotechnology Inc. D.M. Hyman: Consulting, advisory role: Atara Biotherapeutics, Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, Genentech; Research funding: Loxo Oncology, Puma Biotechnology, AstraZeneca. All other authors have declared no conflicts of interest.

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