Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Hypermutation Status

Arethusa consists of three different phases - SCREENING Phase, PRIMING phase, and TRIAL Phase. * SCREENING PHASE: MMR-Deficient (MMR-D) patients will proceed directly to TRIAL Phase (cohort D) to be treated with pembrolizumab. RAS mutant MMR-Proficient (MMR-P) patients, instead, are further tested for O6-methylguanine-DNA methyltransferase gene expression (MGMT) status in tissue (MGMT protein IHC and MGMT promoter methylation). MGMT IHC negative and promoter methylated patients will proceed to PRIMING phase. * PRIMING PHASE: MMR-P patients showing negative MGMT protein and high levels of MGMT promoter methylation in tissues will receive TMZ therapy until progression. Two tumor biopsies will be taken prior to starting therapy and at progression to determine the mutational load. Patients with a mutational load \< 20 mutations/megabase will go off-study. Patients with a mutational load \>20 mutations/megabase, will proceed to trial phase no longer than week 5 post TMZ-ML. * TRIAL PHASE: Eligible patients, i.e. MMRD patients (cohort D) and patients with a TMZ-ML \> 20 mutations per megabase at TMZ-ML (cohort P), will be treated with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.