Imprime 1 (Nct02981303): A Novel Phase 2 Study In Second-Line Plus , Metastatic Triple Negative Breast Cancer Patients Shows Promising Clinical Benefit For The Combination Of The Immune Checkpoint Inhibitor, Pembrolizumab (Pembro), With The Novel Innate Immune Activator, Imprime Pgg

Background: Immune checkpoint inhibitor (ICI) monotherapy shows limited benefit in metastatic triple negative breast cancer (mTNBC) patients (pts), particularly in the second line + setting (ORR ~5-6%, mOS 9 months). In the recent Keynote-119 phase 3 study in 2 or 3L chemorefractory mTNBC pts, pembro monotherapy showed 9.9 month mOS, 9.6% ORR vs 10.8 month mOS, 10.6% ORR for physician9s choice chemotherapy. Imprime PGG (Imprime) is a novel, systemically-delivered Beta Glucan agonist of the Dectin Receptor that activates the innate immune system to reprogram the immunosuppressive tumor microenvironment, activate antigen presenting cells and stimulate antigen-specific T cell activation. In preclinical models, Imprime significantly enhances the anti-cancer efficacy of ICI therapy. Accordingly, we sought to explore whether Imprime might enhance the clinical benefit of the ICI, pembro, in 2L+ mTNBC pts. Methods: IMPRIME 1 is an open-label, Simon 2 stage study (12 pts Stage 1, 32 pts Stage 2) with primary completion Dec. 2019. Pts received Imprime (4 mg/kg IV days 1, 8, 15 of each 3-week cycle) + pembro 200 mg on D1 of each cycle. CT scans were taken at baseline and q6wks thereafter until progression. Primary endpoints were ORR (RECIST v1.1) and safety. Secondary endpoints included PFS, OS. Biopsies and blood samples were collected to assess immune activation. Mechanistically, Imprime-mediated activation of innate immune cells requires anti-beta glucan antibodies (ABA). Enrollment was limited to patients having sufficient ABA IgG (≥20mcg/ml). Results Response and Disease Control Rates (Imprime 1 [95% CI]) Overall Response: 15.9% (7.9- 29.4) Stable Disease: 38.6% (25.7-53.4) Progressive Disease: 40.9% (27.7-55.6) Disease Control (CR+PR+SD): 54.5% (40.1-68.3) Disease Control (CR+PR+SD ≥24w): 25.0% (14.6- 39.4) Survival Median Overall Survival (months): 16.4 (11.1- 23.9) 12 Month Survival: 57.6% (42.4-72.8) 18 Month Survival: 36.7% (21.3-52.1) Clinical benefit was pronounced in mTNBC pts previously treated with endocrine therapy (originally ER/PR+ pts). Peripheral blood shows innate immune activation (e.g. increased CD86 on circulating monocytes) and CD8 T cell activation (PD1+/Ki67+/HLA-DR+) as early as 3 wks on therapy. These changes were associated with enhanced PFS and OS. Paired tumor biopsies showed robust infiltration of tumor tissue by activated myeloid cells (Imprime+/PD-L1+/CD80+) and activated CD4, CD8 T cells (Ki67+/granzyme B+). The combination was well-tolerated. Related Gr 3/4 AEs evident in 3/44 pts. The most common Infusion-related reactions were Gr1/2. Conclusion: IMPRIME 1 provides clinical and molecular/ cellular proof of concept data for the combination of Imprime and pembro. These promising data support additional clinical studies in mTNBC pts for this novel Immuno-onocology combination. Citation Format: Steven J. O9Day, Virginia F. Borges, Bartosz Chmielowski, Ruta D. Rao, Maysa Abu-Khalaf, Alison Stopeck, Joyce A. O9Shaughnessy, Michael Chisamore, Vassiliki Karantza, Joanna Cox, Paulette Mattson, Michele A. Gargano, Bruno Osterwalder, Mark Uhlik, Nandita Bose, Jeremy Graff. IMPRIME 1 (NCT02981303): A novel phase 2 study in second-line +, metastatic triple negative breast cancer patients shows promising clinical benefit for the combination of the immune checkpoint inhibitor, pembrolizumab (pembro), with the novel innate immune activator, Imprime PGG [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT073.