[PMC free article] [PubMed] [CrossRef] [Google Scholar] 6. treatment-related adverse events were reported in 98% and 60% of patients respectively and led to treatment discontinuation in 40% and 28% of patients. Two treatment-related deaths were reported. The 12- and 18-month os rates were 80% [95% confidence interval (ci): 73% to 86%] and 76% (95% ci: 67% to 82%) respectively. Conclusions In this Canadian population, nivolumab plus ipilimumab demonstrated a safety profile and survival outcomes consistent with phase ii and iii clinical trial data. wild-type advanced melanoma5,6. In the randomized, phase iii CheckMate 067 study, nivolumab plus ipilimumab or nivolumab alone, compared with ipilimumab alone, was associated with a significant improvement in the objective response rate, median progression-free survival, and median os in patients with treatment-na?ve advanced melanoma2,7. The combination of nivolumab and ipilimumab was approved for advanced melanoma in 2015 in the United States and in 2016 in Canada. CheckMate 218 (see “type”:”clinical-trial”,”attrs”:”text”:”NCT02186249″,”term_id”:”NCT02186249″NCT02186249 at https://ClinicalTrials.gov/) is a North American expanded-access program (eap) for nivolumab plus ipilimumab in patients with unresectable stage iii or iv melanoma, including cutaneous, ocular or uveal, mucosal, and acral melanoma. The eap provided the combination to patients with treatment-na?ve disease or disease that progressed with other therapies, excluding antiCctla-4 or antiCPD-1 therapies, until market authorization was granted for the combination. The overall patient population for the eap included 754 patients: 580 treated in the United States and 174 treated in Canada. We previously reported earlier os data for the combined U.S. (1-year follow-up) and Canadian (6-month follow-up) cohorts8. Here, we report updated safety and os data for the Canadian cohort, with a median follow-up of 12.9 months. Results from the Canadian cohort support reimbursement decisions in Canada related to this approved treatment. Results from the total North American population (United States and Canada combined) will be published separately. METHODS Patients Eligible patients were 18 years of CD9 age or older with unresectable stage iii or iv metastatic melanoma per the American Joint Committee on Cancer staging system (7th edition)9. Patients were required to have an Eastern Cooperative Oncology Group performance status (ecog ps) of 0 or 1 and to be Mepixanox treatment-na?ve to Mepixanox antiCctla-4 and antiCPD-1 agents. Patients could have received other systemic treatments for localized or metastatic disease, including braf or mek Mepixanox inhibitors. (Initially, patients with mutationCpositive tumours who had received prior treatment with targeted therapy were excluded, but the protocol was amended within a few weeks to remove that exclusion.) Patients were excluded if they had active (symptomatic) or untreated brain metastases or leptomeningeal metastases, a life expectancy of less than 6 weeks, autoimmune disease, or conditions requiring systemic corticosteroids or other immunosuppressive medications within 14 days of drug administration. Patients were also excluded if they required other systemic antineoplastic therapy while receiving nivolumab. EAP Design and Treatment An eap protocol was used for administration of sequential doses of nivolumab plus ipilimumab. Investigators had previous experience with the administration of nivolumab and ipilimumab, either as monotherapy or in combination. Patients received nivolumab (intravenously over 60 minutes at 1 mg/kg) and ipilimumab (intravenously over 90 minutes at 3 mg/kg every 3 weeks) for 4 doses during the induction phase. Subsequently, they continued with single-agent nivolumab (intravenously over 60 minutes at 3 mg/kg every 2 weeks) during the maintenance phase, until disease progression or unacceptable toxicity, or until a maximum of 48 weeks from the first nivolumab monotherapy dose, whichever occurred first (supplemental Figure 1). In Canada, patients who stopped combination therapy because of toxicity were allowed to resume nivolumab monotherapy.
