A Comprehensive Biomarker Analysis of Microsatellite Unstable/Mismatch Repair Deficient Colorectal Cancer Cohort Treated with Immunotherapy.

The search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were included. According to whether the progression-free survival with PD-1/PD-L1 inhibitors was longer than 6 months or shorter, patients were clustered into the IT-responder group (n: 9 patients) or IT-resistant group (n: 7 patients), respectively. In order to evaluate determinants of benefit with PD-1/PD-L1 inhibitors, we performed multimodal analysis including genomics (through NGS panel tumour-only with 431 genes) and the immune microenvironment (using CD3, CD8, FOXP3 and PD-L1 antibodies). The following mutations were more frequent in IT-resistant compared with IT-responder groups: B2M (4/7 versus 2/9), CTNNB1 (2/7 versus 0/9), and biallelic PTEN (3/7 versus 1/9). Biallelic ARID1A mutations were found exclusively in the IT-responder group (4/9 patients). Tumour mutational burden did not correlate with immunotherapy benefit, neither the rate of indels in homopolymeric regions. Of note, biallelic ARID1A mutated tumours had the highest immune infiltration and PD-L1 scores, contrary to tumours with CTNNB1 mutation. Immune microenvironment analysis showed higher densities of different T cell subpopulations and PD-L1 expression in IT-responders. Misdiagnosis of MSI-H/dMMR inferred by discordances between immunohistochemistry and polymerase chain reaction was only found in the IT-resistant population (3/7 patients). Biallelic ARID1A mutations and Wnt signalling activation through CTNNB1 mutation were associated with high and low T cell immune infiltrates, respectively, and deserve special attention as determinants of response to PD-1/PD-L1 inhibitors. The non-MSI-H phenotype in dMMR is associated with poor benefit to immunotherapy. Our results suggest that mechanisms of resistance to immunotherapy are multi-factorial.

Impact of circulating tumor DNA mutant allele fraction on prognosis in RAS-mutant metastatic colorectal cancer.

Despite major advances in the treatment of metastatic colorectal cancer (mCRC), the survival rate remains very poor. This study aims at exploring the prognostic value of RAS-mutant allele fraction (MAF) in plasma in mCRC. Forty-seven plasma samples from 37 RAS-mutated patients with nonresectable metastases were tested for RAS in circulating tumor DNA using BEAMing before first- and/or second-line treatment. RAS MAF was correlated with several clinical parameters (number of metastatic sites, hepatic volume, carcinoembryonic antigen, CA19-9 levels, primary site location, and treatment line) and clinical outcome [progression-free survival (PFS) and overall survival (OS)]. An independent cohort of 32 patients from the CAPRI-GOIM trial was assessed for clinical outcome based on plasma baseline MAF. RAS MAF analysis at baseline revealed a significant correlation with longer OS [Hazard ratios (HR) = 3.514; P = 0.00066]. Patients with lower MAF also showed a tendency to longer PFS, although not statistically significant. Multivariate analysis showed RAS MAFs as an independent prognostic factor in both OS (HR = 2.73; P = 0.006) and first-line PFS (HR = 3.74; P = 0.049). Tumor response to treatment in patients with higher MAF was progression disease (P = 0.007). Patients with low MAFs at baseline in the CAPRI-GOIM group also showed better OS [HR = 3.84; 95% confidence intervals (CI) 1.5-9.6; P = 0.004] and better PFS (HR = 2.5; 95% CI: 1.07-5.62; P = 0.033). This minimally invasive test may help in adding an independent factor to better estimate outcomes before initiating treatment. Further prospective studies using MAF as a stratification factor could further validate its utility in clinical practice.

Triple-drug chemotherapy regimens in combination with an anti-EGFR agent in metastatic colorectal cancer - prospects from phase II clinical trials.

INTRODUCTION: The addition of monoclonal antibody (mAb) epidermal growth factor receptor (EGFR) inhibitors to classic chemotherapy doublet backbones has improved survival of metastatic colorectal cancer (mCRC). However, the role of triple-drug chemotherapy regimens in combination with an anti-EGFR mAb inhibitor is not yet clear. AREAS COVERED: The activity of triple-drug chemotherapy regimens when combined with an anti-EGFR mAb in mCRC patients is examined. We describe the overall safety and tolerability profiles based on a literature review of all published phase I and II clinical trials in this setting. Drug exposure, tumor mutational status, and metastases resectability are discussed. A review of PubMed and abstracts of major oncology congresses from 2009 to 2018, with MeSH and full-text search terms for clinical trials of anti-EGFR for 'metastatic' or 'advanced' 'colorectal cancer/adenocarcinoma' was implemented. Only English language publications were included. EXPERT OPINION: Efficacy data from phase II trials are promising, but the safety profiles are not as encouraging; the development of severe diarrhea and acneiform rash limit the drug exposure that is critical for improved outcomes. Phase II studies of these triplet chemotherapy/anti-EGFR mAb combinations have focused on conversion therapy in liver-limited disease or in the first-line setting in advanced disease. The identification of biomarkers of response and toxicity may support the use of personalized medicine and more precise design of phase III trials.

The safety of ramucirumab for the treatment of colorectal cancer.

INTRODUCTION: Ramucirumab, a human monoclonal antibody against vascular endothelial growth factor receptor 2 (VEGFR-2), is an antiangiogenic therapy that has been approved in combination with FOLFIRI in second-line treatment of metastatic colorectal cancer (mCRC), after progression on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. A thorough review of the safety of ramucirumab in this setting and in the context of other antiangiogenic agents is merited. Areas covered: We provide an overview of activity and summarize in detail the overall safety and tolerability profile of ramucirumab in mCRC patients on the basis of a literature review of all published clinical trials in this setting, including both single-agent and combination studies. A focus on adverse events of interest and specific populations is included, as well as a critical comparison with other antiangiogenic therapies. Expert opinion: As an effective agent in pretreated mCRC patients, the toxicity profile of ramucirumab is similar to those of other angiogenesis inhibitors used in the second-line mCRC setting. The next challenge will be to find biomarkers of response and toxicity to antiangiogenic therapies in order to more effectively implement personalized medicine in these patients.