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Background: Triple-negative breast cancer (TNBC) is associated with poor survival outcomes and treatment options are limited. These tumors lack therapeutic targets and become rapidly resistant to chemotherapy. The anti–PD-1 antibody pembrolizumab showed durable antitumor activity and manageable safety in patients with TNBC in the KEYNOTE-012, KEYNOTE-086, and KEYNOTE-119 studies. The combination of lenvatinib, an antiangiogenic multiple receptor tyrosine kinase inhibitor, with pembrolizumab has shown promising clinical outcomes in early-phase clinical trials across several cancer types. LEAP-005 (ClinicalTrials.gov, NCT03797326) is an ongoing study evaluating the efficacy and safety of lenvatinib combined with pembrolizumab in patients with previously treated advanced solid tumors. Here, we report the first results from the TNBC cohort of LEAP-005. Methods: This ongoing, multicohort, open-label, phase 2 study enrolled patients aged ≥18 y with previously treated, histologically or cytologically confirmed advanced TNBC. PD-L1 expression was assessed at a central laboratory using the PD-L1 IHC 22C3 pharmDx assay and measured using the combined positive score (CPS; number of PD-L1–positive tumor cells, lymphocytes, and macrophages divided by total number of tumor cells x 100). Patients received lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg every 3 weeks intravenously for a maximum of 35 pembrolizumab doses, then lenvatinib alone until progressive disease or unacceptable toxicity. Primary endpoints were objective response rate (ORR) by blinded independent central review per RECIST version 1.1 and safety. Key secondary endpoints were disease control rate (DCR; defined as best overall response of complete response [CR], partial response [PR], or stable disease [SD] per RECIST v1.1), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Safety was monitored through 30 days after the last dose of study drug (90 days for serious AEs), with AEs graded using NCI CTCAE v4.0. Results: 31 patients have been enrolled in the TNBC cohort of LEAP-005. Median age was 56 y (range, 37 to 85), 58% had received ≥2 prior lines of therapy, and 26% had CPS ≥10 tumors. As of the April 10, 2020 data cutoff, median follow-up was 7 mo (range, 4 to 13). ORR was 29% (95% CI: 14–48), with 1 CR and 8 PRs. 9 pts had SD, and the DCR (CR + PR + SD) was 58% (95% CI: 39–76). 4 responses (1 CR and 3 PRs) were in patients with CPS ≥10 tumors (n=8) for an ORR of 50% (95% CI: 16–84), and 5 responses (all PRs) were in patients with CPS <10 tumors (n=22) for an ORR of 23% (95% CI: 8–45). Median DOR was not reached (range, 0+ to 8+ mo); 7 (78%) responses were ongoing at data cutoff. Median PFS was 4 mo (95% CI: 2–NR), with a 6-mo rate of 49%. Treatment-related AEs (TRAEs) occurred in 97% of pts; 10% discontinued due to TRAEs. 55% of pts had grade 3-5 TRAEs (1 death due to subarachnoid hemorrhage). Conclusions: Lenvatinib in combination with pembrolizumab showed promising antitumor activity with manageable toxicity in patients with previously treated advanced TNBC. Based on these early data, the cohort will be expanded to include 100 patients. Citation Format: Hyun Cheol Chung, Esma Saada-Bouzid, Federico Longo Muñoz, Eduardo Yanez, Seock-Ah Im, Eduardo Castanon, Donna M. Graham, Javier Garcia-Corbacho, Juanita Lopez, Razi Ghori, Corina Dutcus, Alan Smith, Kevin Norwood, Carlos Gomez-Roca. Lenvatinib plus pembrolizumab for previously treated, advanced triple-negative breast cancer: Early results from the multicohort phase 2 LEAP-005 study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-07.