Background: HER2 mutations define a rare subset of metastatic breast cancer (MBC) with a unique mechanism of oncogenic addiction to HER2 signaling. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated single-agent clinical activity in HER2-mutant MBC. In HER2-mutant, HR+ MBC, neratinib + fulvestrant (N+F) appears synergistic vs single-agent neratinib, possibly due to more complete inhibition of bi-directional signaling between HER2 and estrogen receptors. Here we describe interim efficacy results of the expanded HER2-mutant, HR+ MBC cohort treated with N+F from SUMMIT (NCT01953926). Methods: HR+ MBC patients (pts) with HER2 mutations documented by local testing received oral neratinib 240mg qd and intramuscular fulvestrant (labeled dose). Intensive loperamide prophylaxis was mandatory during cycle 1. Efficacy endpoints include objective response rate at week 8 (ORR8); confirmed objective response rate (ORR); clinical benefit rate (CBR); duration of response (DOR); progression-free survival (PFS); response was assessed by RECIST 1.1 and/or PET Response Criteria. Genomic profiling from fresh/archival tumor tissues and/or plasma cfDNA was performed retrospectively by next-generation sequencing (MSK-IMPACT). Results: As of 18 May 2018, 46 HER2-mutant HR+ MBC pts have been treated with N+F. Most pts were pretreated, with 91% having received prior anti-cancer medication for MBC (range 0–10). ORR was 33% and median DOR in the 15 pts with a confirmed response was 9.2 months (95% CI 3.9–18.5). Twenty-four pts had prior fulvestrant exposure, and 19 had received prior CDK4/6i-based therapy. Clinical activity was observed with ORRs of 17% and 26% in prior fulvestrant-treated and prior CDK4/6i-treated pts, respectively. ORRs by HER2 mutation were: V777L 63% (5/8 pts); S310F/Y 67% (4/6 pts); G778_P780dup 50% (3/6 pts). Diarrhea was the most common adverse event (grade 3, 24%; grade 4, 0%). Median cumulative duration of grade 3 diarrhea was 3 days. There were no treatment discontinuations due to diarrhea.  Neratinib + fulvestrantOutcomeaAll patients (N=46)Prior fulvestrant (N=24)Prior CDK4/6i-based therapy (N=19)ORR8 – n (%)19 (41.3)8 (33.3)7 (36.8)95% CI27.0–56.815.6–55.316.3–61.6ORR – n (%)15 (32.6)4 (16.7)5 (26.3)95% CI19.5–48.04.7–37.49.1–51.2DOR for each responder, months 5.6b; 9.2; 9.6b; 18.55.6b; 5.7b; 9.3; 9.6b; 12.9bCBR – n (%)27 (58.7)11 (45.8)9 (47.4)95% CI43.2–73.025.6–67.224.4–71.1Median (95% CI) time to event,c monthsPFS3.9 (3.6–5.7)3.7 (3.5–12.8)3.9 (1.9–NA)DOR9.2 (3.9–18.5)NANAaFor pts with both RECIST- and PET-evaluable lesions, the best of either RECIST or PET response was used to determine response; the earliest progression by RECIST or PET was used for progression; bPt has not progressed; cKaplan-Meier analysis; NA, not applicable Conclusions: N+F demonstrates encouraging clinical activity with durable responses in heavily pretreated pts with HER2-mutant, HR+ MBC. Of note, responses were observed in pts who had received prior fulvestrant or CDK4/6 inhibitors. No new safety signals were identified; the rate of diarrhea was similar to single-agent neratinib and not dose limiting. Updated data after additional follow-up and genomic data will be presented. Citation Format: Smyth LM, Piha-Paul SA, Saura C, Loi S, Lu J, Shapiro GI, Juric D, Mayer IA, Arteaga C, de la Fuente M, Brufksy AM, Mau-Sørensen M, Arnedos M, Moreno V, Sohn J-H, Schwartzberg L, Gonzàlez-Farré X, Cervantes A, Mann G, Shahin S, Cutler, Jr. RE, Eli LD, Xu F, Bagulho T, Lalani AS, Bryce R, Solit DB, Hyman DM, Meric-Bernstam F, Baselga J. Neratinib + fulvestrant for HER2-mutant, HR-positive, metastatic breast cancer: Updated results from the phase 2 SUMMIT trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-06.