Abstract GS4-10: Neratinib + fulvestrant + trastuzumab for hormone receptor-positive, HER2-mutant metastatic breast cancer and neratinib + trastuzumab for triple-negative disease: Latest updates from the SUMMIT trial
Authors: Jhaveri Komal , Park Haeseong , Waisman James , Goldman Jonathan W , Guerrero-Zotano Angel , Boni Valentina , Haley Barbara , Mayer Ingrid A , Brufsky Adam , Yang Eddy S , García-Sáenz José A , Bidard François-Clement , Crown John , Zhang Bo , Frazier Aimee , Diala Irmina , Eli Lisa D , Barnett Brian , Wildiers Hans 
Published: March 2022

Abstract
Background: HER2 mutations are oncogenic drivers in a subset of metastatic breast cancers (MBC). Neratinib (N) is an oral, irreversible pan-HER tyrosine kinase inhibitor with preclinical and clinical activity against HER2 mutations. Genomic analyses from paired biopsies following N ± fulvestrant (F) suggest that resistance to N may occur via amplification of the mutant allele or by acquisition of secondary HER2 mutations. Addition of trastuzumab (T) to N+F showed encouraging clinical activity with durable responses in the SUMMIT trial in hormone receptor-positive (HR+), HER2-mutant MBC, including patients (pts) who had previously received cyclin-dependent kinase 4 & 6 inhibitors (CDK4/6i) [Jhaveri et al. SABCS 2020]. On the basis of these findings, and in order to better understand the contribution of N to the activity of the N+F+T combination, SUMMIT has recently been expanded to include a randomized Simon 2-stage comparison of N+F+T vs. F+T vs. F in pts with HR+, HER2-mutated, HER2-negative MBC who were exposed to CDK4/6i. Enrollment for stage 1 is now complete (N+F+T, n=7; F+T, n=7; F, n=7), and results will be forthcoming once the data are mature. Here we report updated findings from the breast cancer cohorts of the SUMMIT trial for which data are currently available. Methods: The phase 2 SUMMIT trial (NCT01953926) enrolled pts with HR+, HER2-negative MBC whose tumors harbored activating HER2 mutation(s) identified by genomic sequencing. Prior to starting the randomized portion of the trial, these patients were enrolled in a non-randomized cohort and received N+F+T (oral N 240 mg/d, i.m. F 500 mg d1&15 of cycle 1 then q4w, i.v. T 8 mg/kg initially then 6 mg/kg q3w). Following initiation of the randomized portion of the trial, these pts received N+F+T, F+T or F (1:1:1 ratio; dose schedules as above). Pts with HER2-mutant triple-negative breast cancer (TNBC) were enrolled in a non-randomized cohort and received N+T (dose schedules as above). Loperamide prophylaxis was mandatory during the first 2 treatment cycles. There was no restriction on the number of prior lines of systemic therapy for MBC. Efficacy endpoints: investigator-assessed objective response rate and clinical benefit rate (RECIST v1.1 or other defined criteria); duration of response; best overall response. Results: Prior to enrolling the randomized cohort, 24 pts with HR+, HER2-mutated MBC who had previously received CDK4/6i were enrolled in the non-randomized cohort and received N+F+T, and 17 pts with HER2-mutant TNBC were enrolled and received N+T, as of 18-Jun-2021. Data for randomized pts are not yet mature. HER2 allelic variants across both cohorts (pts may have &gt;1 mutation): kinase domain hotspots (n=26); exon-20 insertion (n=9); extracellular domain hotspot (n=4); exon-19 deletion (n=1); transmembrane domain missense (n=1); kinase domain non-hotspot (n=2). Efficacy findings are reported in the Table. Diarrhea was the most commonly reported adverse event: N+F+T (non-randomized cohort), 96%; N+T (TNBC cohort), 94%. No grade 4 diarrhea was reported.
Conclusions: N+F+T is a promising combination for pts with HR+, HER2-mutated MBC with prior exposure to CDK4/6 inhibitors. N+T also showed encouraging activity in HER2-mutated TNBC. The first results from the randomized comparison of N+F+T vs. F+T vs. F in pts with HR+, HER2-mutated MBC (Simon stage 1 analysis) will be presented at the meeting.
Table: Efficacy findingsHR+, HER2-mutated, HER2-non-amplified MBCHER2-mutant TNBCN+F+T (n=24)N+T (n=17)Confirmed objective response,a n (%)11 (46)5 (29)CR0 (0)1 (6)PR11 (46)4 (24)ORR, % (95% CI)46 (26–67)29 (10–56)Best overall response, n (%)13 (54)7 (41)CR0 (0)1 (6)PR13 (54)6 (35)Best overall response rate, % (95% CI)54 (33–74)41 (18–67)Medianb DOR, months (95% CI)14.4 (6.4–NR)NRClinical benefit, n (%)14 (58)6 (35)CR or PR11 (46)5 (29)SD ≥24 weeks3 (13)1 (6)CBR,b % (95% CI)58 (37–78)35 (14–62)aORR defined as either a CR or PR confirmed no less than 4 weeks after the response criteria are met; bCBR defined as confirmed CR or PR or SD for ≥24 weeks. Note: Tumor response is based on investigator tumor assessments per RECIST v1.1 for HR+, HER2-mutated cohort, and RECIST v1.1 or modified PERCIST for HER2-mutated TNBC cohort. CBR, clinical benefit rate; CI, confidence interval; CR, complete response; DOR, duration of response; F, fulvestrant; HR+, hormone receptor-positive; MBC, metastatic breast cancer; N, neratinib; NR, not reached; ORR, objective response rate; PERCIST, Positron Emission Tomography Response Criteria in Solid Tumors; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; T, trastuzumab, TNBC, triple-negative breast cancer.
Citation Format: Komal Jhaveri, Haeseong Park, James Waisman, Jonathan W Goldman, Angel Guerrero-Zotano, Valentina Boni, Barbara Haley, Ingrid A Mayer, Adam Brufsky, Eddy S Yang, José A García-Sáenz, François-Clement Bidard, John Crown, Bo Zhang, Aimee Frazier, Irmina Diala, Lisa D Eli, Brian Barnett, Hans Wildiers. Neratinib + fulvestrant + trastuzumab for hormone receptor-positive, HER2-mutant metastatic breast cancer and neratinib + trastuzumab for triple-negative disease: Latest updates from the SUMMIT trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-10.