PMID- 28734759 OWN - NLM STAT- MEDLINE DCOM- 20170925 LR - 20231004 IS - 1474-5488 (Electronic) IS - 1470-2045 (Print) IS - 1470-2045 (Linking) VI - 18 IP - 9 DP - 2017 Sep TI - Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. PG - 1182-1191 LID - S1470-2045(17)30422-9 [pii] LID - 10.1016/S1470-2045(17)30422-9 [doi] AB - BACKGROUND: Metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment with conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features are associated with the response to PD-1 blockade in other tumour types. Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in patients with dMMR/MSI-H metastatic colorectal cancer. METHODS: In this ongoing, multicentre, open-label, phase 2 trial, we enrolled adults (aged >/=18 years) with histologically confirmed recurrent or metastatic colorectal cancer locally assessed as dMMR/MSI-H from 31 sites (academic centres and hospitals) in eight countries (Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the USA). Eligible patients had progressed on or after, or been intolerant of, at least one previous line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan. Patients were given 3 mg/kg nivolumab every 2 weeks until disease progression, death, unacceptable toxic effects, or withdrawal from study. The primary endpoint was investigator-assessed objective response as per Response Evaluation Criteria in Solid Tumors (version 1.1). All patients who received at least one dose of study drug were included in all analyses. This trial is registered with ClinicalTrials.gov, number NCT02060188. FINDINGS: Of the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, 40 (54%) had received three or more previous treatments. At a median follow-up of 12.0 months (IQR 8.6-18.0), 23 (31.1%, 95% CI 20.8-42.9) of 74 patients achieved an investigator-assessed objective response and 51 (69%, 57-79) patients had disease control for 12 weeks or longer. Median duration of response was not yet reached; all responders were alive, and eight had responses lasting 12 months or longer (Kaplan-Meier 12-month estimate 86%, 95% CI 62-95). The most common grade 3 or 4 drug-related adverse events were increased concentrations of lipase (six [8%]) and amylase (two [3%]). 23 (31%) patients died during the study; none of these deaths were deemed to be treatment related by the investigator. INTERPRETATION: Nivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H metastatic colorectal cancer, and could be a new treatment option for these patients. FUNDING: Bristol-Myers Squibb. CI - Copyright (c) 2017 Elsevier Ltd. All rights reserved. FAU - Overman, Michael J AU - Overman MJ AD - The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: moverman@mdanderson.org. FAU - McDermott, Ray AU - McDermott R AD - St Vincent's University Hospital and Cancer Trials Ireland, Dublin, Ireland. FAU - Leach, Joseph L AU - Leach JL AD - Allina Health System, Minneapolis, MN, USA. FAU - Lonardi, Sara AU - Lonardi S AD - Istituto Oncologico Veneto IOV-IRCSS, Padova, Italy. FAU - Lenz, Heinz-Josef AU - Lenz HJ AD - USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA. FAU - Morse, Michael A AU - Morse MA AD - Duke University Medical Center, Durham, NC, USA. FAU - Desai, Jayesh AU - Desai J AD - Royal Melbourne Hospital/Peter MacCallum Cancer Centre, Victoria, VIC, Australia. FAU - Hill, Andrew AU - Hill A AD - Tasman Oncology Research Ltd, Southport, Queensland, QLD, Australia. FAU - Axelson, Michael AU - Axelson M AD - Bristol-Myers Squibb, Princeton, NJ, USA. FAU - Moss, Rebecca A AU - Moss RA AD - Bristol-Myers Squibb, Princeton, NJ, USA. FAU - Goldberg, Monica V AU - Goldberg MV AD - Bristol-Myers Squibb, Princeton, NJ, USA. FAU - Cao, Z Alexander AU - Cao ZA AD - Bristol-Myers Squibb, Princeton, NJ, USA. FAU - Ledeine, Jean-Marie AU - Ledeine JM AD - Bristol-Myers Squibb, Braine-L'Alleud, Belgium. FAU - Maglinte, Gregory A AU - Maglinte GA AD - Bristol-Myers Squibb, Princeton, NJ, USA. FAU - Kopetz, Scott AU - Kopetz S AD - The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Andre, Thierry AU - Andre T AD - Hopital Saint Antoine, Assistance Publique Hopitaux de Paris and Sorbonne Universites, UMPC Paris 06, Paris, France. LA - eng SI - ClinicalTrials.gov/NCT02060188 GR - P30 CA016672/CA/NCI NIH HHS/United States GR - UL1 TR000371/TR/NCATS NIH HHS/United States PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial DEP - 20170719 PL - England TA - Lancet Oncol JT - The Lancet. Oncology JID - 100957246 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 31YO63LBSN (Nivolumab) SB - IM CIN - Lancet Oncol. 2017 Sep;18(9):1141-1142. PMID: 28734760 EIN - Lancet Oncol. 2017 Sep;18(9):e510. PMID: 28884691 MH - Adult MH - Antibodies, Monoclonal/*therapeutic use MH - Antineoplastic Agents/*therapeutic use MH - Carcinoma/*drug therapy/genetics/secondary MH - Colorectal Neoplasms/genetics/mortality/*pathology MH - *DNA Mismatch Repair MH - Disease-Free Survival MH - Female MH - Humans MH - Male MH - *Microsatellite Instability MH - Middle Aged MH - Nivolumab MH - Programmed Cell Death 1 Receptor/antagonists & inhibitors MH - Treatment Outcome PMC - PMC6207072 MID - NIHMS975292 EDAT- 2017/07/25 06:00 MHDA- 2017/09/26 06:00 PMCR- 2018/10/30 CRDT- 2017/07/24 06:00 PHST- 2017/03/03 00:00 [received] PHST- 2017/05/12 00:00 [revised] PHST- 2017/05/19 00:00 [accepted] PHST- 2017/07/25 06:00 [pubmed] PHST- 2017/09/26 06:00 [medline] PHST- 2017/07/24 06:00 [entrez] PHST- 2018/10/30 00:00 [pmc-release] AID - S1470-2045(17)30422-9 [pii] AID - 10.1016/S1470-2045(17)30422-9 [doi] PST - ppublish SO - Lancet Oncol. 2017 Sep;18(9):1182-1191. doi: 10.1016/S1470-2045(17)30422-9. Epub 2017 Jul 19.