ON JULY 31, 2017, nivolumab (Opdivo) was granted accelerated approval for treatment of patients 12 years and older with DNA mismatch repair–deficient (dMMR) and microsatellite instability– high (MSI-H) metastatic colorectal cancer progressing following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.^1,2 Trials of nivolumab have not been conducted in pediatric patients; efficacy of nivolumab for patients aged ≥ 12 years with MSI-H or dMMR metastatic colorectal cancer is extrapolated from the results in the adult population. 

Supporting Efficacy Data 

THE APPROVAL WAS BASED ON FINDINGS of durable responses in 53 patients with locally determined dMMR or MSI-H metastatic colorectal cancer who had disease progression during or after or were intolerant of prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy in the CheckMate 142 trial.^2,3 This was a subset of 74 patients who received at least 1 prior regimen for treatment of metastatic disease containing a fluoropyrimidine with oxaliplatin or irinotecan. All patients received nivolumab at 3 mg/kg every 2 weeks until radiographic disease progression or unacceptable toxicity. A total of 72% had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 15%, 30%, 30%, and 24% received one, two, three, or > four prior lines of therapy; and 42% had received an anti–epidermal growth factor receptor (EGFR) antibody. 

The objective response rate on Response Evaluation Criteria in Solid Tumors 1.1 according to independent radiographic review was 28% (15 responders, 1 complete response) in the 53 patients who received prior fluoropyrimidine, oxaliplatin, and irinotecan. The median duration of response was not reached (range = 2.8+ to 22.1%), with response persisting for ≥ 6 months in 67% of responders. Among all 74 patients, the overall response rate was 32% (24 responders, 2 complete responses); the median response duration was not reached (range = 1.4+ to 26.5 months). See page 30 for more on the CheckMate 142 trial. 

How It Works 

NIVOLUMAB IS A HUMAN immunoglobulin G4 monoclonal antibody that binds the programmed cell death protein 1 (PD-1) receptor on T cells and prevents its interaction with its ligands (PD-L1/PD-L2), thereby releasing PD-1 pathway–mediated inhibition of immune response, including antitumor immune response. Binding of PD-L1 and PD-L2 to the PD-1 receptor inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway may contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse tumor models, blocking PD-1 activity results in decreased tumor growth. 

Combined inhibition mediated by nivolumab (anti–PD-1) and ipilimumab (Yervoy; anti–cytotoxic T-lymphocyte–associated protein 4 [CTLA-4]) results in enhanced T-cell function that is greater than the effects of either antibody alone and improved antitumor responses in metastatic melanoma. In murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in increased antitumor activity. 

How It Is Used 

THE RECOMMENDED DOSE of nivolumab for this indication is 240 mg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 

Infusion should be interrupted or slowed in patients with mild or moderate infusion reactions. Nivolumab should be discontinued for severe or life-threatening infusion reactions. There are no recommended dose modifications for hypothyroidism or hyperthyroidism. 

In patients receiving single-agent nivolumab, treatment should be withheld for grade 2 pneumonitis, grade 2 or 3 diarrhea or colitis, alanine transaminase (ALT) or aspartate transaminase (AST) levels > 3 to 5 times upper limit of normal (ULN) or total bilirubin > 1.5 to 3 times ULN, serum creatinine levels > 1.5 to 6 times ULN, grade 2 or 3 hypophysitis, grade 2 adrenal insufficiency, grade 3 hyperglycemia, grade 3 rash or suspected Stevens-Johnson syndrome or toxic epidermal necrolysis, new-onset moderate or severe neurologic signs or symptoms (potential immune-related encephalitis), and first occurrence of other grade 3 adverse reactions. 

Nivolumab should be permanently discontinued for grade 4 diarrhea or colitis, grade 3 or 4 pneumonitis, AST or ALT > 5 times ULN or total bilirubin > 3 times ULN, grade 4 hypophysitis, grade 3 or 4 adrenal insufficiency, grade 4 hyperglycemia, serum creatinine > 6 times ULN, grade 4 rash or confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis, immune-mediated encephalitis, recurrence of grade 3 adverse reactions, life-threatening or grade 4 adverse reactions, requirement of ≥ 10 mg/d of prednisone or equivalent for > 12 weeks, and persistent grade 2 or 3 adverse reactions lasting ≥ 12 weeks. 

Safety Profile 

NO SPECIFIC ADVERSE EVENT data in this indication are provided in the product labeling. The most common adverse reactions (≥ 20%) in patients receiving nivolumab as a single agent in other indications include fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, and pyrexia. 

As reported by Overman and colleagues,³ grade 3 or 4 adverse events occurred in 54% of all 74 patients in CheckMate 142; drug-related grade 3 or 4 adverse events occurred in 20%, with the most common being increased levels of lipase and amylase. The most common treatment-related adverse events of any grade were fatigue, diarrhea, pruritus, increased lipase levels, and rash. Treatment was discontinued due to drug-related adverse events in 7% of patients. Drug-related serious adverse events occurred in 12% of patients. 

Nivolumab carries warnings/precautions for immune-mediated adverse reactions including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis. It also carries warnings/precautions for infusion reactions, complications of allogeneic hematopoietic stem cell transplantation after nivolumab treatment, and embryofetal toxicity. Patients should be monitored for changes in liver, thyroid, kidney, and neurologic function, and for hyperglycemia. Breastfeeding women should stop breastfeeding while on nivolumab. ■

REFERENCES 

1. U.S. Food and Drug Administration: FDA grants nivolumab accelerated approval for MSI-H or dMMR colorectal cancer. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm569366.htm. Accessed September 20, 2017. 

2. Opdivo (nivolumab) injection prescribing information, Bristol-Myers Squibb Company, July 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125554s034lbl.pdf. Accessed September 20, 2017. 

3. 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). Lancet Oncol 18:1182-1191, 2017.