Abstract CT177: A multi-center phase 2a trial of the CXCR4 inhibitor motixafortide (BL-8040) (M) in combination with pembrolizumab (P) and chemotherapy (C), in patients with metastatic pancreatic adenocarcinoma (mPDAC)
Authors: Hidalgo Manuel , Macarulla Teresa , Semenisty Valerya , Borazanci Erkut , Feliu Jaime , Ponz-Sarvise Mariano , Abad David Gutierrez , Oberstein Paul , Alistar Angela , Muñoz Andres , Geva Ravit , Guillén-Ponce Carmen , Fernandez Mercedes Salgado , Peled Amnon , Chaney Marya , Glicko-Kabir Irit , Shemesh-Darvish Liron , Ickowicz Debby , Sorani Ella , Kadosh Shaul E. , Vainstein-Haras Abi , Bockorny Bruno 
Published: July 2021

Abstract
Background: Improving outcomes of PDAC with checkpoint inhibitors (CPIs) have been ineffective, underscoring the need to co-target alternative pathways. Preclinical data showed that CXCR4-SDF1 axis modulates the tumor microenvironment (TME) in PDAC and that CXCR4 inhibition enhances T cell access to the TME, increasing tumor sensitivity to CPIs. This was confirmed in the COMBAT Cohort 1 (CC1) study showing that the dual combination M+P increases activated CD8+ T cells and decreases myeloid derived suppressor cells (MDSCs) within the TME. Moreover, our pre-clinical studies showed that adding C to M+P resulted in improved efficacy vs C alone. The COMBAT Cohort 2 (CC2) aims to test the safety and efficacy of the triple combination of M+P+C in 2L mPDAC. Methods: Single arm phase 2a study in mPDAC. In cohort 2, patients with stage IV PDAC at diagnose who had progressed to 1L gemcitabine-based C received 5 days M priming, followed by M BIW + P Q3W plus C [Irinotecan liposomal injection/5-FU/LV (OFL)] Q2W. The primary endpoint was RR. Results: A total of 43 patients with stage 4 PDAC, 98% of whom were diagnosed with stage 4 disease, were enrolled. Median age was 68 (40-85) and 74.4% had liver disease. The safety profile was consistent with the individual profiles of each treatment alone. Of note, the incidence of ≥G3 neutropenia (G3Neu) was 7% and ≥G3 infection was 7%, which is lower than expected for C (OFL) alone (20% and 17%, respectively). The levels of T-cells increased during M priming and returned to normal values, which remained stable across the study despite the OFL treatment. For the evaluable patients (N=38) the ORR was 21.1% with a 13.2% confirmed ORR (defined as two consecutive assessments showing PR) and a 63.2% DCR (PR+SD). Median duration of clinical benefit was 5.6 months. Median OS and PFS were 6.5 months and 4.0 months, respectively (6.6 months and 3.8 months, respectively, for the ITT population). Conclusions: The triple combination of M+P+C is tolerable and shows encouraging results with cORR 13.2%, mPFS 4.0 months and mOS 6.5 months (compared to 7.7%, ~3 months and 4.7 months, respectively, on a historical basis for OFL alone in the stage 4 diagnosis subpopulation). SD of 42.1% and DCR of 63.2% were also higher than historical data on SoC chemotherapy used in 2L patients. The incidence of severe neutropenia and infections is lower than the historical data on C. The results from the CC2 suggest that M+P may expand the efficacy and safety benefit of OFL in PDAC, and warrants further investigation in a randomized study.
Citation Format: Manuel Hidalgo, Teresa Macarulla, Valerya Semenisty, Erkut Borazanci, Jaime Feliu, Mariano Ponz-Sarvise, David Gutierrez Abad, Paul Oberstein, Angela Alistar, Andres Muñoz, Ravit Geva, Carmen Guillén-Ponce, Mercedes Salgado Fernandez, Amnon Peled, Marya Chaney, Irit Glicko-Kabir, Liron Shemesh-Darvish, Debby Ickowicz, Ella Sorani, Shaul E. Kadosh, Abi Vainstein-Haras, Bruno Bockorny. A multi-center phase 2a trial of the CXCR4 inhibitor motixafortide (BL-8040) (M) in combination with pembrolizumab (P) and chemotherapy (C), in patients with metastatic pancreatic adenocarcinoma (mPDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT177.