NRG-GI004/SWOG-S1610: Colorectal cancer metastatic dMMR immuno-therapy (COMMIT) study—A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC).

Caio Max Sao Pedro Rocha Lima Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, NC info_outline Caio Max Sao Pedro Rocha Lima, Greg Yothers, Shannon L. Puhalla, Hanna Kelly Sanoff, Deirdre J. Cohen, Katherine A Guthrie, Norah Lynn Henry, Patricia A. Ganz, Scott Kopetz, Peter C. Lucas, Charles D. Blanke, Samuel A. Jacobs, Theodore S. Hong, Norman Wolmark, Howard S. Hochster, Thomas J. George, Michael J. Overman

Authors Caio Max Sao Pedro Rocha Lima Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, NC info_outline Caio Max Sao Pedro Rocha Lima, Greg Yothers, Shannon L. Puhalla, Hanna Kelly Sanoff, Deirdre J. Cohen, Katherine A Guthrie, Norah Lynn Henry, Patricia A. Ganz, Scott Kopetz, Peter C. Lucas, Charles D. Blanke, Samuel A. Jacobs, Theodore S. Hong, Norman Wolmark, Howard S. Hochster, Thomas J. George, Michael J. Overman Organizations Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, NC, NRG Oncology Statistical and Data Management Center, and Department of Biostatistics at University of Pittsburgh School of Public Health, Pittsburgh, PA, NSABP Foundation, Inc.; and UPMC Hillman Cancer Center, Pittsburgh, PA, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, Icahn School of Medicine at Mount Sinai; and NYU Perlmutter Cancer Center, New York, NY, SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Center, Seattle, WA, University of Michigan Medical School, Ann Arbor, MI, UCLA Jonsson Comprehensive Cancer Center, UCLA Fielding School of Public Health, Los Angeles, CA, The University of Texas MD Anderson Cancer Center, Houston, TX, NSABP Foundation, Inc. Pathology Lab; University of Pittsburgh School of Medicine; and Mayo Clinic, Pittsburgh, PA, OHSU Knight Cancer Institute, Portland, OR, NSABP Foundation, Inc., Pittsburgh, PA, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, NSABP Foundation, Inc.; UPMC Hillman Cancer Center; and University of Pittsburgh School of Medicine, Pittsburgh, PA, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, University of Florida Health Cancer Center, Gainesville, FL Abstract Disclosures Research Funding National Cancer Institute Genentech, Inc. Background: Approximately 45% of dMMR/MSI-H mCRC in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC patients (pts) may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Upon AtezoTRIBE subgroup analysis of the 8 pts with dMMR mCRC treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first pt having progression ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow-up have been reduced; as has measurable disease per RECIST. Primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival, objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). Sample size has been modified with the accrual goal of 120 pts randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues. Current accrual (as of 02-02-2024): 96/120. NCT02997228. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.

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