On October 2, 2020, the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) was approved for first-line treatment of adult patients with unresectable malignant pleural mesothelioma.1-3
Supporting Efficacy Data
Approval was based on findings in the open-label phase III CheckMate 743 trial (ClinicalTrials.gov identifier NCT02899299).2,3 In the trial, 605 patients with unresectable malignant pleural mesothelioma and no prior anticancer therapy were randomly assigned to receive nivolumab at 3 mg/kg every 2 weeks and ipilimumab at 1 mg/kg every 6 weeks for up to 2 years (n = 303) or six cycles of platinum doublet chemotherapy (n = 302). Chemotherapy consisted of cisplatin at 75 mg/m2 plus pemetrexed at 500 mg/m2 or carboplatin AUC = 5 plus pemetrexed at 500 mg/m2 every 3 weeks for up to six cycles.
Among all patients, the median age was 69 years (range = 25–89 years; 72% aged ≥ 65 years and 26% ≥ 75 years); 77% were male; 85% were White and 11% were Asian; the baseline Eastern Cooperative Oncology Group performance status was 0 (40%) or 1 (60%) in all patients; 35% had stage III and 51% had stage IV disease; 75% had epithelioid and 25% had nonepithelioid histology; 75% had tumors with PD-L1 expression ≥ 1% and 22% had tumors with PD-L1 expression < 1%.
At a prespecified interim analysis, median overall survival was 18.1 months (95% confidence interval [CI] = 16.8–21.5 months) in the nivolumab/ipilimumab group vs 14.1 months (95% CI = 12.5–16.2 months) in the chemotherapy group (hazard ratio [HR] = 0.74, 95% CI = 0.61–0.89, P = .002).
Median progression-free survival on blinded independent central review was 6.8 months (95% CI = 5.6–7.4 months) in the nivolumab/ipilimumab group vs 7.2 months (95% CI = 6.9–8.1 months) in the chemotherapy group (HR = 1.0, 95% CI = 0.82–1.21). The confirmed overall response rate on blinded independent central review was 40% vs 43%, with a median response duration of 11.0 months vs 6.7 months.
In a prespecified exploratory analysis based on histology, the hazard ratio for overall survival in the subgroup of patients with epithelioid histology was 0.85 (95% CI = 0.68–1.06), with a median duration of 18.7 vs 16.2 months. In the subgroup with nonepithelioid histology, the hazard ratio was 0.46 (95% CI = 0.31–0.70), with a median duration of 16.9 vs 8.8 months.
How It Is Used
The recommended doses for unresectable malignant pleural mesothelioma are nivolumab at 360 mg every 3 weeks via 30-minute intravenous (IV) infusion and ipilimumab at 1 mg/kg every 6 weeks via 30-minute IV infusion until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression.
For management of adverse reactions, if either agent is withheld, the other should also be withheld. For both agents, infusion should be interrupted or slowed in patients with mild or moderate infusion-related reactions and discontinued in patients with severe or life-threatening infusion-related reactions.
Nivolumab prescribing information provides instructions on dose modification, including withholding or discontinuing treatment, for colitis, pneumonitis, hepatitis/nonhepatocellular carcinoma, hepatitis/hepatocellular carcinoma, hypophysitis, adrenal insufficiency, type 1 diabetes, nephritis and renal dysfunction, skin toxicity (including Stevens-Johnson syndrome and toxic epidermal necrolysis), encephalitis, persistent grade 2 or 3 adverse reactions, other grade 3 adverse reactions, life-threatening or grade 4 adverse reactions, grade 3 myocarditis, and requirement for ≥ 10 mg/d of prednisone or its equivalent for more than 12 weeks. There are no recommended dose modifications for hypothyroidism or hyperthyroidism.
Ipilimumab prescribing information provides instructions on dose modification, including withholding or discontinuing treatment, for immune-mediated adverse reactions (including colitis/diarrhea, hepatitis, exfoliative or bullous dermatologic conditions, endocrinopathies, hypophysitis, pneumonitis, nephritis with renal dysfunction), neurologic toxicities, myocarditis, ophthalmologic adverse reactions, and infusion-related reactions. Instructions on dose modification are also provided for persistent grade 2 reactions or grade 3 reactions lasting at least 12 weeks after the last ipilimumab dose (excluding endocrinopathy) and an inability to reduce the corticosteroid dose to ≤ 10 mg of prednisone or its equivalent per day within 12 weeks of initiating steroids.
In CheckMate 743, the median duration of treatment with nivolumab/ipilimumab was 5.6 months (range = 0–26.2 months), with 48% of patients receiving treatment for at least 6 months and 24% for at least 1 year.
The most common adverse events of any grade (incidence ≥ 20%) in patients receiving nivolumab/ipilimumab in CheckMate 743 were fatigue (43% vs 45% in chemotherapy group), musculoskeletal pain (38% vs 17%), rash (34% vs 11%), diarrhea (32% vs 12%), dyspnea (27% vs 16%), nausea (24% vs 43%), decreased appetite (24% vs 25%), cough (23% vs 9%), and pruritus (21% vs 1%). The most common grade 3 or 4 adverse events in the nivolumab/ipilimumab group were diarrhea (6.0%), fatigue (4.3%), and pneumonia (4.0%). The most common grade 3 or 4 laboratory abnormalities were increased lipase levels (13%), hyponatremia (8.0%), and hyperkalemia (4.1%).
Serious adverse events occurred in 54% of the nivolumab/ipilimumab group, with those occurring in at least 2% consisting of pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism.
Adverse events led to withholding of at least one dose in 52% of patients and to permanent discontinuation of treatment in 23%. Fatal adverse events occurred in four patients and included pneumonitis, acute heart failure, sepsis, and encephalitis.
Nivolumab has warnings/precautions for immune-mediated adverse reactions (including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis); infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; and embryofetal toxicity. Patients should be monitored for changes in liver function, changes in thyroid function, hyperglycemia, changes in renal function, and changes in neurologic function. Patients should be advised not to breastfeed while receiving nivolumab.
Ipilimumab has warnings/precautions for severe and fatal immune-mediated adverse reactions. They can occur in any organ system or tissue, including colitis, hepatitis, dermatologic adverse reactions, endocrinopathies, pneumonitis, and nephritis with renal dysfunction, and can occur at any time during treatment or after discontinuation of therapy. Ipilimumab also has warnings/precautions for infusion-related reactions and embryofetal toxicity. Patients should be monitored for symptoms and signs that may be clinical manifestations of immune-mediated adverse reactions. Clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone level, and thyroid function should be evaluated at baseline and before each dose. Patients should be advised not to breastfeed while receiving ipilimumab.
1. U.S. Food and Drug Administration: FDA approves nivolumab and ipilimumab for unresectable malignant pleural mesothelioma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-and-ipilimumab-unresectable-malignant-pleural-mesothelioma. Accessed October 22, 2020.
2. Opdivo (nivolumab) injection prescribing information, Bristol-Myers Squibb Company, October 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125554s089lbl.pdf. Accessed October 22, 2020.
3. Yervoy (ipilimumab) injection prescribing information, Bristol-Myers Squibb Company, October 2020. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125377s115lbl.pdf. Accessed October 22, 2020.