Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression–based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMS) with distinguishing features: CMS1 (MSI Immune, 14%), hypermutated, microsatellite unstable, strong immune activation; CMS2 (Canonical, 37%), epithelial, chromosomally unstable, marked WNT and MYC signaling activation; CMS3 (Metabolic, 13%), epithelial, evident metabolic dysregulation; and CMS4 (Mesenchymal, 23%), prominent transforming growth factor β activation, stromal invasion, and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intra-tumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC – with clear biological interpretability – and the basis for future clinical stratification and subtype–based targeted interventions.

Summary Background Metastatic DNA mismatch repair–deficient/microsatellite instability–high (dMMR/MSI-H) colorectal cancer (mCRC) has a poor prognosis following conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators, all features that correspond with response to programmed cell death receptor-1 (PD-1) blockade in other tumour types. Thus, nivolumab, a PD-1 immune checkpoint inhibitor, was evaluated in this population. Methods In this is ongoing, multicentre, open-label, nonrandomised, phase 2 trial, adult patients (aged ≥18 years) with histologically confirmed recurrent or mCRC locally assessed as dMMR/MSI-H who had progressed on/after or been intolerant of at least one prior line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan, were enrolled. Patients were given nivolumab 3 mg/kg every 2 weeks until disease progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors v1·1. All patients who received at least one dose of study drug were included in the primary and safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02060188. Findings Among the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, most (54·1%) had received ≥3 prior therapies. At a median follow-up of 12·0 months (interquartile range 8·57–18·00 months), 23 of 74 patients (31·1% [95% CI 20·8%–42·9%]) achieved an investigator-assessed objective response; 68·9% (95% CI 57·1%–79·2%) of patients had disease control for ≥12 weeks. Median duration of response was not yet reached; all responders were alive, and 8 (34·8%) had responses of ≥12 months. The most common (≥10% of patients) drug-related adverse events was fatigue (n=16 [21·6%]), diarrhoea (n=15 [20·3%]), pruritus (n=10 [13·5%]) and rash (n=8 [10·8%]). The most common grade 3 or 4 drug-related adverse events were increased lipase (n=6 [8·1%]) and amylase (n=2 [2·7%]) levels. Five patients (6·8%) discontinued treatment because of increased alanine aminotransferase, colitis, duodenal ulcer, acute kidney injury, and stomatitis (n=1 each). Twenty-three patients (31·1%) died during the study; none of these deaths was considered to be treatment related by the investigator. Interpretation Nivolumab provided durable responses and disease control, as well as long-term survival in pre-treated patients with dMMR/MSI-H mCRC, and is a new treatment option for these patients.

Purpose Nivolumab provides clinical benefit (objective response rate [ORR], 31%; 95% CI, 20.8 to 42.9; disease control rate, 69%; 12-month overall survival [OS], 73%) in previously treated patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC); nivolumab plus ipilimumab may improve these outcomes. Efficacy and safety results for the nivolumab plus ipilimumab cohort of CheckMate-142, the largest single-study report of an immunotherapy combination in dMMR/MSI-H mCRC, are reported. Patients and Methods Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks. Primary end point was investigator-assessed ORR. Results Of 119 patients, 76% had received ≥ two prior systemic therapies. At median follow-up of 13.4 months, investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control rate for ≥ 12 weeks was 80%. Median duration of response was not reached; most responses (94%) were ongoing at data cutoff. Progression-free survival rates were 76% (9 months) and 71% (12 months); respective OS rates were 87% and 85%. Statistically significant and clinically meaningful improvements were observed in patient-reported outcomes, including functioning, symptoms, and quality of life. Grade 3 to 4 treatment-related adverse events (AEs) occurred in 32% of patients and were manageable. Patients (13%) who discontinued treatment because of study drug-related AEs had an ORR (63%) consistent with that of the overall population. Conclusion Nivolumab plus ipilimumab demonstrated high response rates, encouraging progression-free survival and OS at 12 months, manageable safety, and meaningful improvements in key patient-reported outcomes. Indirect comparisons suggest combination therapy provides improved efficacy relative to anti-programmed death-1 monotherapy and has a favorable benefit-risk profile. Nivolumab plus ipilimumab provides a promising new treatment option for patients with dMMR/MSI-H mCRC.

The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named ‘Immunoscore’ has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune). © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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