As reported in the Journal of Clinical Oncology by Heinz-Josef Lenz, MD, and colleagues, in the phase II CheckMate 142 trial, first-line treatment with nivolumab plus low-dose ipilimumab produced a high rate of durable responses in a cohort of patients who had received no prior treatment for microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) metastatic colorectal cancer.
Heinz-Josef Lenz, MD
Findings in the trial cohort of previously treated patients supported the July 2018 accelerated approval of nivolumab as a single agent or in combination with ipilimumab for MSI-H/dMMR metastatic colorectal cancer that had progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
Study Details
In the international trial, 45 patients were enrolled in the first-line cohort between December 2016 and October 2017 and had received treatment by data cutoff in October 2019. Patients received nivolumab at 3 mg/kg every 2 weeks and ipilimumab at 1 mg/kg once every 6 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate on investigator assessment.
Responses
Median follow-up was 29.0 months (range = 24.2–33.7) months. Objective response was observed in 31 patients (69%, 95% confidence interval [CI] = 53%–82%), with complete response in 6 (13%). An additional seven patients had stable disease, yielding a disease control rate of 84% (95% CI = 70.5%–93.5%). Median duration of response was not reached (range = 1.4+ to 29.0+ months), with 71% of responses lasting ≥ 12 months.
Among 14 patients who discontinued study therapy, did not receive subsequent treatment, and had at least one subsequent tumor assessment, 10 remained progression-free. Among patients with known mutation status, an objective response was observed in 62% of 13 patients with wild-type BRAF and KRAS, 76% of 17 with a BRAF mutation, and 80% of 10 with a KRAS mutation.
Median progression-free survival was not reached, with rates at 12 and 24 months of 76.4% and 73.6%. Median overall survival was not reached, with rates at 12 and 24 months of 84.1% and 79.4%.
Adverse Events
Any-grade treatment-related adverse events occurred in 80% of patients, most commonly pruritus (36%), arthralgia (20%), and hypothyroidism (18%). Grade 3 or 4 treatment-related adverse events occurred in 22% of patients. The most common grade 3 event was colitis, which occurred in two patients (4%); one patient experienced grade 4 events, consisting of respiratory failure and hyponatremia.
Serious treatment-related events occurred in 16% of patients. Treatment-related adverse events led to discontinuation of treatment in 13%. Adverse events led to death in two patients, due to peripheral ischemia and respiratory failure with septic shock and hyponatremia; the deaths were not considered related to treatment.
The investigators concluded, “Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated as a first-line treatment for MSI-H/dMMR metastatic colorectal cancer. Based on these promising data, randomized studies are warranted.”
Dr. Lenz, of USC Norris Comprehensive Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Bristol Myers Squibb. For full disclosures of the study authors, visit ascopubs.org.
