A phase II study of avelumab in MSI-H metastatic colorectal cancer patients - Trial in progress
Authors: D. Proszynski, M. Winiarek, K. Marcisz-Grzanka, J. Krynski, J. Zwolinski, J. Pałucki, A. Cencelewicz-Lesikow, K. Kokoszynska, L. Wyrwicz
Journal: Annals of Oncology (2018)

Introduction: Colorectal cancer is one of the most common malignancies in the Western world. The treatment strategy of metastatic disease (mCRC) includes cytotoxic agents (oxaliplatin, irinotecan and fluoropyrimidines) and targeted agents (anti-VEGF and anti-EGFR). Le et al in their fundamental report presented in 2015, has shown that immunomodulating agents can control the progression and potentially affect overall survival in colorectal cancer patients as well as other gastrointestinal malignancies that harbor mismatch-repair deficiency. This molecular phenomenon is leading to the hypermutated phenotype called microsatellite instability (MSI-H). On the phenotypic level, such tumors harbor hundreds-to-thousands mutations, which can make the tumor immunogenic if immune-reaction is not blocked by PD1-PDL1 axis. Avelumab is anti-PD-L1 antibody which can exhibit the similar efficacy in this rare subtype of mCRC. Methods: This is a phase II, two-step, single-arm, open-label study in the biomarker preselected population (MS100070-066; MazoviaGI-2). The eligibility criteria includes diagnosis of metastatic colorectal cancer, refractory to standard therapy with confirmed microsatellite instability or loss of expression of mismatch repair genes (MLH1, MSH2, PMS) by local standards. Other inclusion criteria are good performance status (ECOG 0-1), sufficient organ function and no contraindications for immunotherapy (like autoimmune disorders). Two-step protocol will include two subsequent cohorts. Cohort 1: The cohort of 10 subjects with metastatic colorectal cancer refractory to standard therapy preselected by biomarker (microsatellite instability or mismatch repair deficient tumors) will receive avelumab at dose 10 mg/kg (1h IV infusion) Q2W. Subjects will receive Avelumab until confirmed progression, unacceptable toxicity, or any criterion for withdrawal from the trial. Subjects who have experienced a confirmed complete response (CR), partial remission (PR) or stable disease (SD) should be treated with avelumab for a maximum of 24 months and a minimum of 6 months after response confirmation, at the discretion of the investigator. Subjects who experienced a CR and have already stopped treatment before they could receive at least 6 months of treatment can resume treatment with avelumab at the same dose and schedule in order to complete a minimum exposure of 6 months. The patients will be observed for response per RECIST 1.1 criteria. If 2 patients of 10 are reported with CR or PR, the second cohort will be initiated. If 2 patients with objective response are observed before recruitment of all 10 patients, the second cohort will be started without delay. Cohort 2: The additional cohort of 30 subjects with the metastatic colorectal cancer refractory to the standard therapy preselected by biomarker (microsatellite instability or mismatch repair deficient tumors) will receive avelumab at dose 10 mg/kg (1h IV infusion) Q2W. The study procedures in the second cohort will be the same as in the first one. Total up to 40 patients are planned to be recruited.