Nivolumab in Advanced DNA Mismatch Repair–Deficient or Microsatellite Instability–High Colorectal Cancer


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Michael J. Overman, MD

Michael J. Overman, MD

Scott Kopetz, MD

Scott Kopetz, MD

Thierry André, MD

Thierry André, MD

THE PHASE II CHECKMATE 142 TRIAL has shown that nivolumab (Opdivo) produces durable responses in previously treated recurrent or metastatic DNA mismatch repair–deficient (dMMR)/ microsatellite instability–high (MSI-H) colorectal cancer. These study findings were reported in The Lancet Oncology by Michael J. Overman, MD, of The University of Texas MD Anderson Cancer Center, and colleagues.1 The study supported the recent approval of nivolumab treatment for patients aged ≥ 12 years with dMMR/MSI-H metastatic colorectal cancer progressing after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Study Details 

IN THIS ONGOING TRIAL, 74 patients with recurrent or metastatic colorectal cancer locally assessed as dMMR/MSI-H from 31 sites in Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the United States were enrolled between March 2014 and March 2016 and received nivolumab at 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Patients had progressed on or after or had been intolerant of at least one previous line of treatment, including a fluoropyrimidine plus oxaliplatin or irinotecan. The primary endpoint was investigator-assessed objective response. 

“Nivolumab provided durable responses and disease control in pretreated patients with dMMR/MSI-H metastatic colorectal cancer and could be a new treatment option for these patients.”
— Michael J. Overman, MD, and colleagues

Patients had a median age of 53 years (77% < 65 years), 59% were male, 88% were white, the disease was stage III in 35% and stage IV in 45%, 84% had received at least 2 and 54% at least 3 previous treatments, and 36% had prior radiotherapy. The mutation status was BRAF and KRAS wild-type in 39%, BRAF-mutant in 16%, and KRAS-mutant in 35%. Tumor programmed cell death ligand 1 (PD-L1) expression was ≥ 1% in 28%, < 1% in 64%, and unknown in 8%). A clinical history of Lynch syndrome was present for 36%. A total of 53 patients (72%) were centrally identified as having MSI-H tumors and 14 (19%) as having non–MSI-H (microsatellite-stable/MSI-low) tumors; 7 patients had no central results due to inadequate tumor tissue or DNA. 

Responses 

AT A MEDIAN FOLLOW-UP of 12 months, investigator-assessed objective response had occurred in 23 of all 74 patients (31.1%, all partial responses), with an additional 28 (37.8%) having stable disease for 12 weeks or longer. At the time of analysis, the median duration of response had not been reached, with all responders remaining alive and 8 having responses of 12 months or longer. Twelve-month progression-free survival was 50%, and 12-month overall survival was 73%. On an independent blinded central review, response occurred in 24 patients (32%), including a complete response in 2, and stable disease occurred in an additional 25 (34%). 

IMMUNOTHERAPY FOR dMMR OR MSI-H COLORECTAL CANCER

  • Response was achieved in 31% of patients, with a disease control rate of 69%.
  • Responses were observed irrespective of tumor PD-L1 expression or KRAS- or BRAF- mutation status.

Among the 53 patients with centrally identified dMMR/MSI-H tumors, investigator-assessed response occurred in 19 (36%, all partial responses), with stable disease in 20 (37%); on a central review, response occurred in 19 (36%), including a complete response in 1, and stable disease occurred in 19 (36%). 

Responses were observed across all subgroups, including patents with (≥ 1%; response in 29%, disease control in 52%) and without (< 1%; response in 28%, disease control in 75%) tumor PD-L1 expression, with (response in 33%, disease control in 70%) and without (response in 29% , disease control in 75%) a clinical history of Lynch syndrome, and with or without KRAS or BRAF mutations; response and disease control rates were 25% and 75% in those with BRAF-mutant tumors, 27% and 62% in those with KRAS-mutant tumors, and 41% and 79% in those with BRAF and KRAS wild-type tumors. 

Adverse Events 

THE MOST COMMON treatment-related adverse events of any grade were fatigue (23%), diarrhea (21%), pruritus (14%), increased lipase (12%), and rash (11%). Grade 3 or 4 adverse events occurred in 54% of patients; drug-related grade 3 or 4 adverse events occurred in 20%, with the most common being increased lipase (8%) and increased amylase (3%). Treatment was discontinued due to drug-related adverse events in 7% of patients, with causes including increased alanine transaminase (ALT), colitis, duodenal ulcer, acute kidney injury, and stomatitis (one patient each). Drug-related serious adverse events occurred in 12% of patients, including grade 3 or 4 adrenal insufficiency, increased ALT, colitis, diarrhea, gastritis, stomatitis, acute kidney injury, pain, and arthritis (one patient each). Four patients (5%) died of adverse events (sudden death, cardiac disorder, and disease progression in two), with none considered related to study treatment. 

The investigators concluded: “Nivolumab provided durable responses and disease control in pretreated patients with dMMR/ MSI-H metastatic colorectal cancer and could be a new treatment option for these patients.” 

Dr. Overman is the corresponding author for The Lancet Oncology article. Scott Kopetz, MD, of The University of Texas MD Anderson Cancer Center, and Thierry André, MD, of Pierre and Marie Curie University Paris VI, are the senior coauthors of the article. ■

DISCLOSURE: The study was funded by Bristol-Myers Squibb. For disclosures of the study authors, visit www.thelancet.com. 

REFERENCE 

1. Overman MJ, McDermott R, Leach JL, et al: Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): An open-label, multicentre, phase 2 study. Lancet Oncol 18:1182-1191, 2017. 


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