Professor Caio Max S. Rocha Lima, MD, M. Robert Cooper Professor in Medical Oncology, Co-leader GI Oncology and Co-leader Phase I Program, Division of Hematology and Oncology from Wake Forest School of Medicine. In this video he speaks about the ASCO GI 2022 Abstract – 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 (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC).
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Origins:
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Despite the superiority of inhibition of the programmed cell death-1 (PD-1) pathway in dMMR/MSI-H in terms of progression-free survival (PFS) when compared to chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti-epithelial growth factor receptor (EGFRr) antibodies in mCRC, more patients in the anti-PD1 monotherapy arm had progressive disease as the best response (29.4 percent vs. 12. (N Engl J Med 2020; 383:2207). We believe that treating dMMR/MSI-H mCRC patients with a combination of PD-1 pathway inhibition and mFOLFOX6/bevacizumab (bev) rather than anti-PD-1 treatment (atezo) alone may be more successful. In mouse CRC models, preclinical work showed synergistic benefits of anti-PD-1/anti-VEGF and oxaliplatin/anti-PD-1, and phase II data showed anti-PD-1/anti-VEGF activity in chemotherapy-resistant colon cancer. Anti-PD1 plus anti-VEGFr (i.e., HCC and RCC) and anti-PD1 plus chemotherapy (i.e., gastric and esophageal cancers) combinations are also typical first-line treatments in other solid tumor malignancies.
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Methodologies:
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The modified COMMIT experiment was revived on 1/29/2021 as a two-arm prospective phase III open-label trial comparing atezo monotherapy to mFOLFOX6/bev+atezo combination in mCRC dMMR/MSI-H (211 pts). With alpha 0.025 one-sided, we have 80 percent power to detect a hazard ratio of 0.6 (corresponding to 64.4 percent PFS at 24 months) in our control arm, atezo monotherapy, as assessed by the site investigator. BRAFV600E status, metastatic location, and prior adjuvant CRC therapy are all stratification criteria. OS, objective response rate, safety profile, disease control rate, the durability of response, and centrally-reviewed PFS are all secondary goals. An exploration goal is health-related quality of life. Correlative investigations will be conducted using archived tumor tissue and blood samples. mCRC without prior treatment for advanced cancer; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H determined by local CLIA-certified PCR or NGS panel; and detectable disease per RECIST are the main inclusion criteria. Enrollment is still going strong, with a goal of 211 patients randomized between the two immunotherapy arms by the end of the year. UG1CA189867, U24CA196067; Genentech, Inc. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067; Genentech, Inc. NCT02997228 is the number for the clinical trial.