Abstract P1-19-08: Neratinib + trastuzumab + fulvestrant for HER2-mutant, hormone receptor-positive, metastatic breast cancer: Updated results from the phase 2 SUMMIT ‘basket’ trial
Authors: Wildiers Hans , Boni Valentina , Saura Cristina , Oliveira Mafalda , Jhaveri Komal , Won Helen , Bidard François-Clément , Brufsky Adam M , Burkard Mark E , Cervantes Andrés , Fernández-Martos Carlos , Haley Barbara , Loi Sherene , Spanggaard Iben , Panni Stefano , Lu Janice , Dujka Melanie E , Xu Feng , Macia Sonia , Eli Lisa D , Lalani Alshad S , Piha-Paul Sarina , Meric-Bernstam Funda , Solit David B , Hyman David M 
Published: March 2020

Background: HER2 mutations define a subset of metastatic breast cancers (MBCs) with a unique mechanism of oncogenic addiction to HER2 signaling. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has been shown to have encouraging clinical activity when combined with fulvestrant in HER2-mutant, hormone receptor-positive (HR+) MBC [Smyth et al. SABCS 2018]. Genomic analyses suggest that acquired resistance to neratinib may occur by the acquisition of additional HER2 alterations, which may amplify HER2 pathway signaling [Won et al. AACR 2019]. We therefore explored whether dual HER2-targeted therapy may improve clinical benefit in this setting. Here we describe initial results from a cohort of patients with HER2-mutant, HR+ MBC treated with neratinib + trastuzumab + fulvestrant (N+T+F) from the phase 2 SUMMIT ‘basket’ trial (NCT01953926). Methods: Patients with HR+ MBC and known oncogenic driver HER2 mutations identified by genomic sequencing were eligible to receive combination treatment with oral neratinib 240 mg daily, intravenous trastuzumab 8 mg/kg initially followed by 6 mg/kg every 3 weeks, and intramuscular fulvestrant 500 mg on days 1 and 15 of month 1, then on day 1 every 4 weeks (N+T+F). Loperamide prophylaxis was mandatory during cycle 1. There was no restriction on the number of prior lines of systemic treatment for MBC. Efficacy endpoints included: confirmed objective response rate and clinical benefit rate - all defined according to RECIST v1.1 - as well as duration of response and progression-free survival. Genomic profiling from fresh/archival tumor tissues and/or plasma cfDNA was performed retrospectively by next-generation sequencing (MSK-IMPACT). Results: As of 01-May-2019, 19 patients were enrolled into the N+T+F cohort and received study treatment (safety population). 20 HER2 mutations were identified in the 19 patients: 14 kinase domain missense mutations, 3 extracellular domain missense mutations, and 3 exon-20 insertion mutations. Median number of prior systemic regimens for metastatic disease was 4 (range 0-10) and histologies were evenly split between lobular and ductal carcinomas. While the majority of patients remain on study treatment (n=15), only 13 of the 19 enrolled patients are efficacy evaluable at this time (having had ≥1 post-baseline tumor assessment). Clinical activity is summarized in the Table. Diarrhea was the most commonly reported adverse event (84.2% any grade) with 5 patients reporting Grade 3 diarrhea (there were no Grade 4 diarrhea events). Three patients (15.8%) reduced neratinib dose due to diarrhea but no patient discontinued treatment due to diarrhea. Conclusions: The combination of N+T+F resulted in an encouraging response rate and was a well-tolerated regimen in predominantly heavily pretreated HER2-mutant HR+ breast cancers. Based on a pre-planned interim analysis, the cohort has been expanded to enroll a total of 50 patients. Updated efficacy and safety data will be presented.

Neratinib + trastuzumab + fulvestrant(n=13)Confirmed objective response rate, % (95% CI)39 (13.9-68.4)Complete response0Partial response5 (39)Duration of responses range, months4.2*-10.4*Median progression-free survivala,b, months (95% CI)NA (1.9-NA)*Response ongoing; aKaplan-Meier analysis; bincludes all patients enrolled (n=19); NA, not applicable.

Citation Format: Hans Wildiers, Valentina Boni, Cristina Saura, Mafalda Oliveira, Komal Jhaveri, Helen Won, François-Clément Bidard, Adam M Brufsky, Mark E Burkard, Andrés Cervantes, Carlos Fernández-Martos, Barbara Haley, Sherene Loi, Iben Spanggaard, Stefano Panni, Janice Lu, Melanie E Dujka, Feng Xu, Sonia Macia, Lisa D Eli, Alshad S Lalani, Sarina Piha-Paul, Funda Meric-Bernstam, David B Solit, David M Hyman. Neratinib + trastuzumab + fulvestrant for HER2-mutant, hormone receptor-positive, metastatic breast cancer: Updated results from the phase 2 SUMMIT ‘basket’ trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-08.