Abstract Background: Durably effective therapeutic options remain elusive for metastatic triple negative breast cancer (mTNBC) patients. RSK is a novel target kinase for mTNBC, given its integral role in the MAPK/PDK-1 pathways. PMD-026, uniquely developed for TNBC, is a first-in-class, potent, oral RSK inhibitor that constitutes a promising avenue of treatment for mTNBC. PMD-026 demonstrated a favorable safety profile and initial signs of clinical benefit in metastatic breast cancer patients in Phase I. The current expansion is investigating PMD-026 in mTNBC patients whose disease has progressed on standard therapy. Methods: This open-label study evaluates the safety and efficacy of single agent PMD-026 in mTNBC patients. Target accrual for this study is a minimum of 20 mTNBC patients dosed at 200 mg q 12 hours who have measurable disease. A food effect (FE) sub-study is enrolling a total of 12 patients with a two-arm crossover design. Exploratory biomarker analysis of tumor tissue is being assessed for activated RSK2 levels. Exploratory objectives are to understand TNBC heterogeneity, with a view to identify patients who may benefit from PMD-026 optimally. Results: Based on the trial results thus far from 25 patients, PMD-026 continues to be well-tolerated with no G4 treatment-related adverse events. The noted toxicities include low incidence of elevated ALT/AST, rash, colitis or low-grade nausea. There has been no hair loss, myelosuppression or peripheral neuropathy. Given that TNBC is such a heterogeneous disease, we sought to identify subsets of patients with extensive prior therapy (≥ 5 lines) who may benefit from PMD-026 as a monotherapy. Based on ongoing analyses in the Phase I and Ib, patients diagnosed with TNBC at their initial diagnosis (de novo TNBC) stayed on study 3-4 times longer than patients who were initially treated for HR+ or HER2+ breast cancer but lost HR or HER2 expression to become TNBC (secondary TNBC). In addition, de novo TNBC patients treated at the recommended phase II dose (RP2D) of 200 mg BID with an H score for RSK2 ≥ 180 had a median progression free survival (PFS) of 3.3 months (n=3). In contrast, patients with an H score < 180 had a median PFS of 0 months (n=3). Furthermore, the PFS of 3.3 months on PMD-026 is longer than the PFS of 1.7 months in a similar population of TNBC patients on chemotherapy, where the average number of prior treatments was 3a. . Conclusions: Updated safety, clinical activity, PK, and biomarker analyses will be presented. Clinical trial information: NCT04115306.aBardia et al, N Engl J Med 2021; 384:1529-154 Citation Format: Muralidhar Beeram, Judy S. Wang, Lida A. Mina, Pavani Chalasani, Rebecca A. Shatsky, Robert Wesolowski, Sara A. Hurvitz, Meghna S. Trivedi, Hyo S. Han, Amita Patnaik, My-my Huynh, Aarthi Jayanthan, Mary Rose Pambid, Lambert Yue, Gerrit Los, Sandra E. Dunn, Andrew Dorr. First-in-human expansion study of oral PMD-026 in metastatic triple negative breast cancer patients [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 P5-17-12.