Abstract PD2-08: Neratinib + fulvestrant in ERBB2-mutant, HER2–non-amplified, estrogen receptor (ER)-positive, metastatic breast cancer (MBC): Preliminary analysis from the phase II SUMMIT trial
Authors: Hyman D , Piha-Paul S , Saura C , Arteaga C , Mayer I , Shapiro G , Loi S , Lalani A , Xu F , Cutler R , Butturini A , Bryce R , Meric-Bernstam F , Baselga J , Solit D 
Published: March 2017

Abstract
Background: Somatic mutations in ERBB2 are a new class of oncogenic drivers in HER2–non amplified MBC. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits the growth of ERBB2-mutant breast tumors in preclinical models and has encouraging single-agent clinical activity in patients (pts) with ERBB2-mutant, HER2–non amplified MBC. Bi-directional signaling between HER2 and ER may limit the effectiveness of endocrine and HER2 directed therapy, if each is given alone, in ER+ MBC with ERBB2 amplifications/mutations. Preclinical data suggest that dual blockade of ER and HER2 signaling results in enhanced anti-tumor activity in ER+ HER2+ MBC. SUMMIT, a multicenter multi-histology phase II 'basket' trial, is investigating the efficacy of neratinib monotherapy (in ER+ and ER– pts) and neratinib + fulvestrant (ER+ pts only) in ERBB2-mutant MBC.
Methods: MBC pts with ERBB2 mutations documented by local testing were eligible and received oral neratinib 240 mg qd. Pts with ER+ MBC received fulvestrant 500 mg, a selective ER degrader, in addition to neratinib on d1 & 15 of month 1 then on d1 q4w. Patients received high dose loperamide prophylaxis during cycle 1. Primary endpoint is objective response rate (ORR) at 8w, defined using RECIST 1.1 and/or modified PERCIST assessments. Secondary endpoints include ORR, clinical benefit rate (CBR), progression free survival (PFS), and safety. Mutation profiling and central confirmation of ERBB2 mutation(s) from available fresh or archival tumor tissues and plasma DNA were performed retrospectively by next-generation sequencing (MSK-IMPACT). Clinicaltrials.gov: NCT01953926.
Results: As of 23 Sep 2016, 35 efficacy-evaluable ERBB2-mutant MBC pts received neratinib, either as monotherapy (n=24) or in combination with fulvestrant (n=11). Efficacy findings are shown in the table. The overall safety profile of neratinib + fulvestrant was similar to that previously reported with neratinib monotherapy. Grade 3 diarrhea rate was 24% with neratinib monotherapy and 18% with neratinib + fulvestrant.
Neratinib monotherapyNeratinib + fulvestrant(n=24)(n=11)Best Overall Response (confirmed and unconfirmed), n (%)8 (33.3)6 (54.5)[95% CI][15.6–55.3][23.4–83.3]CR3 (12.5)2 (18.2)PR5 (20.8)4 (36.4)aORR at 8 weeks, n (%)8 (33.3)5 (45.5)[95% CI][15.6–55.3][16.7–76.6]CR2 (8.3)2 (18.2)PR6 (25.0)3 (27.3)ORR confirmed, n (%)5 (20.8)2 (18.2)b[95% CI][7.1–42.2][2.3–51.8]CR3 (12.5)1 (9.1)PR2 (8.3)1 (9.1)CBR, n (%)10 (41.7)6 (54.5)[95% CI][22.1–63.4][23.4–83.3]CR, complete response; PR, partial response.aThere was 1 pt with PR at week 16; bAt time of data cut-off 4 pts are still on treatment.
Conclusions: Encouraging clinical activity has been observed with neratinib + fulvestrant in heavily pretreated pts with ERBB2-mutant, ER+ MBC. Clinical efficacy in the ER+ MBC cohort met pre-specified efficacy requirements; a confirmatory trial of neratinib + fulvestrant for targeting ERBB2 mutations in ER+ MBC is warranted. The safety profile of neratinib was acceptable and diarrhea was manageable with loperamide prophylaxis.
Citation Format: Hyman D, Piha-Paul S, Saura C, Arteaga C, Mayer I, Shapiro G, Loi S, Lalani A, Xu F, Cutler R, Butturini A, Bryce R, Meric-Bernstam F, Baselga J, Solit D. Neratinib + fulvestrant in ERBB2-mutant, HER2–non-amplified, estrogen receptor (ER)-positive, metastatic breast cancer (MBC): Preliminary analysis from the phase II SUMMIT trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD2-08.