Abstract CT169: Phase Ib/II open-label, randomized study of atezolizumab + regorafenib + AB928 or atezolizumab + regorafenib vs regorafenib for patients with microsatellite-stable, refractory metastatic colorectal cancer in MORPHEUS-CRC

Abstract Background: A major challenge in metastatic colorectal cancer (mCRC) is the development of immunotherapeutic strategies for patients (pts) with microsatellite-stable (MSS) tumors. High levels of adenosine contribute to the immunosuppressive tumor microenvironment of mCRC. Here, atezolizumab (atezo) was combined with regorafenib (rego; a multi-kinase inhibitor) ± AB928 (an inhibitor of the adenosine pathway) to see if these combinations could improve upon rego alone in mCRC. Methods: Pts with MSS mCRC who had disease progression following ≤2 separate lines of treatment (tx) were enrolled into MORPHEUS-CRC (NCT03555149). Pts received atezo (840 mg IV days [D]1, 15) + rego (120 mg PO D1-21) + AB928 (150 mg PO D1-28) (triplet) or atezo + rego (doublet) or control tx with rego (160 mg PO D1-21; comparator). The primary endpoints were ORR and safety. Secondary endpoints included PFS, OS, DOR, and DCR. Biomarker analyses were exploratory. Results: As of March 1, 2023, 15 pts were randomized into both the triplet and doublet arms and 24 pts into the comparator arm. One response was seen with the triplet and 1 with the doublet (see table for efficacy data). Both responders lacked liver metastases. Tx-related adverse events occurred in 100% (n=15), 93% (n=14) and 95% (n=18) of pts receiving triplet, doublet and comparator tx, respectively. Grade 5 AEs (unrelated to study tx) were seen in 1 doublet pt (tumor hemorrhage) and 2 comparator pts (sepsis). Correlations between PD-L1 levels, immune phenotype, KRAS status and efficacy were examined with no clear associations. Conclusion: Atezo + rego ± AB928 did not have sufficient clinical activity to merit further evaluation in an unselected mCRC population. Consistent with other reports of PD-(L)1-directed immunotherapy in mCRC, durable responses were observed in pts without liver metastases. Citation Format: James M. Cleary, Carlos Gomez-Roca, Francois Ghiringhelli, Joon Oh Park, Tae-You Kim, Brandon Beagle, Janelle Soong, Yibing Yan, Hans-Joachim Helms, Janet Lau, Edward Cha, Michel Ducreux. Phase Ib/II open-label, randomized study of atezolizumab + regorafenib + AB928 or atezolizumab + regorafenib vs regorafenib for patients with microsatellite-stable, refractory metastatic colorectal cancer in MORPHEUS-CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT169.