Previously untreated patients. A multicenter, international trial randomly assigned 502 patients untreated for metastatic disease (adjuvant treatment was allowed) in a 1:1 ratio to ipilimumab (10 mg/kg) plus dacarbazine (850 mg/m2) or placebo plus dacarbazine (850 mg/m2) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary endpoint was survival.
Patients were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS) and metastatic stage. Approximately 70% of the patients had an ECOG PS of 0, and the remainder of the patients had an ECOG PS of 1. Approximately 55% of the patients had stage M1c disease. The median OS was 11.2 months (95% confidence interval [CI], 9.4–13.6) versus 9.1 months (95% CI, 7.8–10.5). Estimated survival rates in the two groups respectively were 47.3% and 36.3% at 1 year; 28.5% and 17.9% at 2 years; and 20.9% and 12.2% at 3 years (HR for death with ipilimumab-dacarbazine, 0.72; P < .001). The most common study-drug–related AEs were those classified as immune related. Grade 3 to 4, immune-related AEs were seen in 38.1% of patients treated with ipilimumab plus dacarbazine versus 4.4% in patients treated with placebo plus dacarbazine, the most common being hepatitis and enterocolitis. No drug-related deaths occurred.[Level of evidence: 1iA]
Clinicians and patients should be aware that immune-mediated adverse reactions may be severe and fatal. Early identification and treatment, including potential administration of systemic glucocorticoids or other immunosuppressants according to the immune-mediated–adverse reaction management guide provided by the manufacturer, is necessary.
Anti-PD-1 and PD-L1
Anti-PD-1 and PD-L1 are immune checkpoint inhibitors; however, they inhibit different targets than ipilimumab. Promising early data have supported testing anti-PD-1 against DTIC in a phase III trial (NCT01721772).
Response to high-dose IL-2 regimens generally ranges from 10% to 20%.[12,13,22] Approximately 4% to 6% of patients may obtain a durable complete remission and be long-term survivors; these results were the basis for approval by the FDA in 1998. Phase III confirmatory trials have not been conducted, and there are currently no predictive biomarkers to select who is likely to respond to treatment.