Abstract Background: The CD38 monoclonal antibody Isa is approved for the treatment of multiple myeloma, but there are no data on its efficacy in solid tumors. A mechanism of immune resistance to anti-PD-1/PD-L1 therapy caused by CD38 expression in tumor cells has been described in the preclinical setting, providing a rationale for testing a combination of Isa+Atezo (anti-PD-L1 antibody) in the clinic to prevent therapy resistance and further enhance antitumor efficacy. The present study assessed safety and efficacy of Isa+Atezo in pts with epithelial ovarian cancer (EOC; n = 18), glioblastoma multiforme (GBM; n = 33), hepatocellular carcinoma (HCC; n = 27), or squamous cell carcinoma of the head and neck (SCCHN; n = 29), not amenable to local therapy with curative intent. Methods: Phase 1 (NCT03637764) assessed safety and confirmed the recommended Phase 2 dose (RP2D) of Isa according to a 21-day dose-limiting toxicity (DLT) observation period. Pts received Isa 10 mg/kg intravenously (IV) every week for 3 weeks followed by once every 3 weeks + Atezo 1200 mg IV every 3 weeks. Phase 2 used a Simon's 2-stage design to assess the overall response rate (ORR; EOC, HCC, SCCHN cohorts) or progression-free survival at 6 months (PFS-6; GBM cohort). Interim analysis was performed at 6 months following first treatment of the last enrolled pt in each cohort. Pharmacodynamics (PD), including analysis of CD38, PD-L1 and tumor-infiltrating lymphocytes in the tumor microenvironment (TME), were also evaluated. Results: In Phase 1, Isa+Atezo had acceptable safety and tolerability, with no new safety signals, in pts with EOC, GBM, HCC, or SCCHN. No DLTs were observed and RP2D were confirmed. Overall, 99% of pts experienced TEAEs, with >40% being Grade ≥3. The most frequently reported TEAE of any grade for all cohorts was infusion-related reactions (EOC, 83.3%; GBM, 54.5%; HCC, 63.0%; SCCHN, 31.0%). In the GBM Phase 2 cohort, the PFS-6 was 3.1%; no patients responded in Stage 1. In the EOC, HCC, and SCCHN Phase 2 cohorts, ORR was 5.6%, 7.4%, and 13.8%, respectively; therefore, the study did not continue to Stage 2. Tumor-infiltrating CD38+ immune cells were reduced by ~20% after treatment. Isa+Atezo did not lead to significant modulation of Tregs or PD-L1 in the TME. Conclusions: Isa+Atezo had acceptable safety and tolerability. Clinical PD evaluation suggested the efficient target engagement effect of Isa by demonstrating treatment-mediated reduction of CD38+ immune cells in the TME. However, significant reduction of CD38+ Tregs and restoration of T-cell proliferation was not observed. Based on clinical data, CD38 inhibition does not seem to influence response to anti-PD-L1 agents in these pts. Although no new safety signals were observed, efficacy did not fulfil criteria to expand enrollment despite the evidence of target engagement of Isa. Citation Format: Maria Vieito Villar, Matteo Simonelli, Ferry A.L.M. Eskens, Marta Gil-Martin, Chia-Jui Yen, Radka Obermannova, Yee Chao, Vittorina Zagonel, Bohuslav Melichar, Victor Moreno, Ming-Lung Yu, Alberto Bongiovanni, Emiliano Calvo, Sylvie Rottey, Jean-Pascal Machiels, Antonio González-Martín, Luis Paz-Ares, Chih-Long Chang, Warren Mason, Chia-Chi Lin, David Reardon, Elena Garralda, Armando Santoro, Robin Meng, Giovanni Abbadessa, Fatima Menas, Helen Lee, Qianying Liu, Cécile Combeau, Nils Ternes, Christophe Massard. Isatuximab (Isa) plus atezolizumab (Atezo) in patients (pts) with advanced malignancies: Results from a Phase 1/2 open-label multicenter study [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 CT154.