Monalizumab and MEDI5752 in Patients With MSI and/or dMMR Metastatic Cancer

MSI is a molecular indicator of defective DNA mismatch repair (dMMR). The MSI/dMMR status is observed in all tumor types, representing notably 5% of metastatic colorectal cancers (mCRC), 25% of advanced endometrial cancer and 8% of metastatic gastric cancer. MSI/dMMR cancers are highly immunogenic. MSI/dMMR tumors are characterized by a high tumor mutational burden with highly immunogenic neoantigens. These tumors are associated with an upregulation of immune checkpoints (PD1, PDL1, CTLA4, etc.) that protects MSI cancer cells from their hostile immune micro-environment, characterized by a high infiltration of activated cytotoxic T CD8+ and NK lymphocytes. Consequently, MSI/dMMR cancers are highly sensitive to ICIs, whatever the tumor location. MSI/dMMR status is a predictive biomarker for the efficacy of immunotherapy, regardless of the tumor type. Then, by several phase II and III studies The efficacy of immunotherapy has been demonstrated as front-line treatment for patients with chemotherapy-naive MSI/dMMR mCRC and gastric cancer. The phase III KEYNOTE-177 trial evaluating first-line treatment of pembrolizumab in patients with MSI/dMMR mCRC demonstrated its superiority over first-line chemotherapy, with a significant improvement of health-related quality of life. At final analysis, the median follow-up was 44.5 months. Median PFS was 16.5 versus 8.2 months (HR = 0.59; 95%CI 0.45-0.79). The hazard ratio favored pembrolizumab versus chemotherapy with a trend toward reduction in the risk of death (HR 0.74; 95% CI, 0.53-1.03; P=0.0359), despite a 60% effective crossover rate. Pembrolizumab has been approved by the FDA and the EMA for patients with newly diagnosed MSI/dMMR mCRC and is now the standard of care for this population. Also, the phase III CHECKMATE-649 trial reveal that the Combination of immunotherapy and cytotoxic chemotherapy is the new standard of care for patients with newly diagnosed metastatic oesogastric cancer. Importantly, results of the CHECKMAT