Immunotherapy with nivolumab (Opdivo?; Bristol-Myers Squibb Company) and low-dose ipilimumab (Yervoy?; Bristol-Myers Squibb Company) could become a new first line treatment in patients with some metastatic colorectal cancers following late-breaking results from the CheckMate-142 trial reported at the annual congress of the European Society for Medical Oncology – ESMO 2018, held in Munich, Germany. 
The results of the CheckMate-142 trial show that the combination of nivolumab and low-dose ipilimumab shrank tumors and had beneficial effects on survival in patients with microsatellite instabiliy (MSI)-high metastatic colorectal cancer.
Around 4% of metastatic colorectal cancers are MSI-high, also called mismatch repair deficient. This means that tumor cells have mutations in the genes that usually repair DNA. Patients with MSI-high tumors have shorter survival (~14?19 months) than those with non-MSI-high tumors (~17?25 months), when treated with chemotherapy in a first-line setting. 
The Phase II CheckMate-142 trial previously showed that in patients with MSI-high metastatic colorectal cancer that is resistant to chemotherapy, immunotherapy with nivolumab and low-dose ipilimumab provided durable clinical benefit and manageable side effects, leading to approval by the US Food and Drug Administration (FDA).
The combination of low-dose ipilimumab and nivolumab has a durable clinical response and is well tolerated as first line treatment in patients with MSI-high metastatic colorectal cancer…
Today researchers report for the first time the CheckMate-142 results in patients who have received no prior treatment for MSI-high metastatic colorectal cancer. The study enrolled 45 patients. The median age was 66 years and 51% were male. Patients were followed-up for a median of 13.8 months for the primary endpoint of objective response rate.
The objective response rate was 60% and 7% of patients had a complete response. Some 84% of patients had tumor shrinkage. It took a median of 2.6 months to respond to treatment. The median duration of response, median progression-free survival, and median overall survival have not yet been reached. The 12-month progression-free survival and overall survival rates were 77% and 83%, respectively.
Other trials have tested high-dose ipilimumab combined with nivolumab, but CheckMate-142 used low-dose ipilimumab with nivolumab, which resulted in less toxicity. Treatment-related grade 3 and 4 toxicities were reported in 16% of patients and 7% discontinued therapy due to treatment-related adverse events.
?The combination of low-dose ipilimumab and nivolumab has a durable clinical response and is well tolerated as first line treatment in patients with MSI-high metastatic colorectal cancer. The data suggest that nivolumab and ipilimumab may be a first line treatment option for these patients,? said study author Heinz-Josef Lenz, MD, Professor of Medicine and co-Leader, Gastrointestinal Cancers Program, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
?Nivolumab plus low-dose ipilimumab is effective in most patients with MSI-high metastatic colorectal cancer. Patients improve dramatically and some return to work. It means healthcare systems can be confident that resources are being targeted effectively. This is in contrast to other metastatic cancers (melanoma, lung or kidney) where it is more difficult to select patients who benefit from immunotherapy,? noted Professor Thierry Andr?, Head of Medical Oncology, H?pital Saint-Antoine, Assistance Publique ? H?pitaux de Paris, France.
Andr? noted that these Phase II results could lead the manufacturer to ask the FDA to approve this immunotherapy combination for the first line treatment of MSI-high metastatic colorectal cancer, but the European Medicines Agency (EMA) will probably require a randomized phase III trial. The ongoing phase III KEYNOTE-177 study in MSI-high metastatic colorectal cancer is comparing first line treatment with pembrolizumab (Keytruda?; Merck | Merck Sharp & Dohme) versus chemotherapy with or without targeted therapy and the first results are expected in 2019.
?Another question is whether the combination of nivolumab and ipilimumab is superior to nivolumab alone for the first line treatment of patients with MSI-high metastatic colorectal cancer. Previous results from CheckMate-142 suggest, with indirect comparisons, improved efficacy with nivolumab plus low-dose ipilimumab relative to nivolumab alone in previously treated patients with MSI-high metastatic colorectal cancer,? Andr? said. 
- An Investigational Immuno-therapy Study of Nivolumab, and Nivolumab in Combination With Other Anti-cancer Drugs, in Colon Cancer That Has Come Back or Has Spread (CheckMate142)
- Study of Pembrolizumab (MK-3475) vs Standard Therapy in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Carcinoma (MK-3475-177/KEYNOTE-177)
 Abstract LBA18_PR ?Durable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC)? will be presented by Heinz-Josef Lenz during Proffered Paper Session on Monday 22 October, 09:15 to 10.50 (CEST) in Hall A2 – Room 18. Annals of Oncology, Volume 29 Supplement 8 October 2018
 Heinemann V, et al. Somatic DNA mutations, tumor mutational burden (TMB), and MSI Status: Association with efficacy in patients (pts) with metastatic colorectal cancer (mCRC) of FIRE-3 (AIO KRK-0306). J Clin Oncol. 2018;36:3591?3591. doi: 10.1200/JCO.2018.36.15_suppl.3591
 Venderbosch S, et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res. 2014;20:5322?5330. doi: 10.1158/1078-0432.CCR-14-0332.
 Overman MJ, et al. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol. 2018;36:773?779. doi: 10.1200/JCO.2017.76.9901.
Last Editorial Review: October 22, 2018
Featured Image: Annual Congress of ESMO 2018. Courtesy: ? 2018 European Society for Medical Oncology. Used with permission. Photo 1.0: Heinz-Josef Lenz, MD, Professor of Medicine and co-Leader, Gastrointestinal Cancers Program, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California. Courtesy: ? 2018 European Society for Medical Oncology. Used with permission.
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