On July 10, 2018, ipilimumab (Yervoy) was granted accelerated approval for use in combination with nivolumab (Opdivo) for the treatment of patients at least 12 years of age with microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) metastatic colorectal cancer progressing after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.1-3 Use of this combination has been added to the nivolumab labeling. Nivolumab received accelerated approval for this indication as a single agent on July 31, 2017.
Supporting Efficacy Data
The approvals were based on the finding of durable responses in the multicenter nonrandomized, multiple parallel-cohort, open-label CHECKMATE 142 study, which enrolled 82 patients with dMMR or MSI-H metastatic colorectal cancer with disease progression during or following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.2-4 Patients received ipilimumab at 1 mg/kg and nivolumab at 3 mg/kg every 3 weeks for 4 doses followed by nivolumab at 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity.
Both ipilimumab and nivolumab carry a boxed warning for immune-mediated adverse reactions, including hepatitis, endocrinopathy, and skin adverse reactions.
As assessed by an independent radiographic review committee using Response Evaluation Criteria in Solid Tumors v1.1, the objective response occurred in 38 patients (46%), including a complete response in 3 patients (4%). The response duration was at least 6 months in 89% of responders. In a separate cohort of 58 patients with dMMR/MSI-H metastatic colorectal cancer with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy who received nivolumab at 3 mg/kg alone, the overall response rate was 28%, with 67% of responders having a response duration of at least 6 months. The efficacy of ipilimumab plus nivolumab in adolescent patients (12 years and older) in this setting is extrapolated from the results in the adult population.
How It Is Used
The recommended dosage regimen for this indication is nivolumab at 3 mg/kg given intravenously followed on the same day by ipilimumab at 1 mg/kg every 3 weeks for 4 doses and then nivolumab at 240 mg every 2 weeks. When either drug is withheld, the other drug should also be withheld.
Ipilimumab product labeling provides instructions for dose modification for and management of immune-mediated reactions, including immune-mediated toxicities consisting of endocrinopathies, ophthalmologic toxicity, and all other immune-related adverse reactions. Treatment should be permanently discontinued for symptomatic endocrine reactions lasting 6 weeks or longer or the inability to reduce the corticosteroid dose to 7.5 mg of prednisone or equivalent per day; grade 2 to 4 ophthalmologic reactions not improving to grade 1 within 2 weeks while receiving topical therapy or requiring systemic treatment; and all other immune-mediated adverse reactions—grade 2 reactions lasting 6 weeks or longer, an inability to reduce the corticosteroid dose to 7.5 mg of prednisone or equivalent per day, and any grade 3 or 4 reactions. Ipilimumab infusion should be interrupted or slowed in patients with mild or moderate infusion reactions, and treatment should be discontinued in those with severe or life-threatening infusion reactions.
Nivolumab product labeling provides instructions for dose modification for adverse reactions and management of immune-mediated reactions, including dose modification for: diarrhea or colitis, pneumonitis, hepatitis/nonhepatocellular carcinoma, hepatitis/hepatocellular carcinoma, hypophysitis, adrenal insufficiency, hyperglycemia, serum creatinine increase, rash or suspected Stevens-Johnson syndrome or toxic epidermal necrolysis, new-onset moderate or severe neurologic signs or symptoms (suspected immune-related encephalitis), and first occurrence of other grade 3 adverse reactions. There are no recommended dose modifications for hypothyroidism or hyperthyroidism. Nivolumab infusion should be interrupted or slowed in patients with mild or moderate infusion reactions, and treatment should be discontinued in those with severe or life-threatening infusion reactions.
Nivolumab should be permanently discontinued for grade 3 diarrhea or colitis when administered in combination with ipilimumab and grade 4 diarrhea or colitis; grade 3 or 4 pneumonitis; hepatitis/nonhepatocellular carcinoma—for aspartate transaminase (AST) or alanine transaminase (ALT) > 5 times the upper limit of normal (ULN) or total bilirubin > 3 times ULN; for hepatitis/hepatocellular carcinoma—if AST/ALT increases to > 10 times ULN or total bilirubin increases to > 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; grade 3 myocarditis; requirement of ≥ 10 mg/d of prednisone or equivalent for > 12 weeks; and persistent grade 2 or 3 adverse reactions lasting ≥ 12 weeks.
The most common adverse reactions (≥ 20%) in those receiving ipilimumab and nivolumab are fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, dyspnea, decreased appetite, and vomiting.
Safety data are from 119 patients in the ipilimumab plus nivolumab cohort and 74 patients in the nivolumab cohort in CHECKMATE 142. The most common adverse events of any grade in the combination cohort were fatigue (49% vs 52% in the nivolumab cohort), diarrhea (45% vs 43%), pyrexia (36% vs 24%), musculoskeletal pain (36% vs 28%), and abdominal pain (30% vs 34%). The most common grade 3 or 4 adverse events in the combination cohort included rash (4.2% vs 1.4%), musculoskeletal pain (3.4% vs 1.4%), and diarrhea (3.4% vs 2.7%). Serious adverse events occurred in 47% of patients receiving ipilimumab plus nivolumab, with the most common events occurring in at least 2% consisting of colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. The most common grade 3 or 4 laboratory abnormalities in the combination group were increased AST level, increased ALT level, and increased lipase level (12% each).
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
Ipilimumab carries a boxed warning for immune-mediated adverse reactions, including severe fatal cases. These reactions may involve any organ system; the most common severe reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of reactions began during treatment; a minority occurred weeks to months after discontinuation of ipilimumab. Patients should be routinely assessed for the signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and should undergo evaluation with clinical chemistries, including liver function tests, adrenocorticotropic hormone level, and thyroid function tests, before starting treatment and before each dose.
Ipilimumab also carries warnings/precautions for immune-mediated adverse reactions, including hepatitis, endocrinopathies, pneumonitis, nephritis and renal dysfunction, encephalitis, infusion-related reactions, and embryofetal toxicity. Women should discontinue breastfeeding before treatment with ipilimumab.
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. Women should discontinue breastfeeding before treatment with nivolumab. ■
1. U.S. Food and Drug Administration: FDA grants accelerated approval to ipilimumab for MSI-H or dMMR metastatic colorectal cancer. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm613227.htm. Accessed August 21, 2018.
2. Yervoy (ipilimumab) injection prescribing information, Bristol-Myers Squibb Company, July 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/125377s096lbl.pdf. Accessed August 21, 2018.
3. Opdivo (nivolumab) injection prescribing information, Bristol-Myers Squibb Company, July 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s063lbl.pdf. Accessed August 21, 2018.
4. Overman MJ, Lonardi S, Wong KYM, et al: Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 36:773-779, 2018.