In the phase II OpACIN-neo study reported in The Lancet Oncology, Rozeman et al identified a promising dosing schedule for neoadjuvant ipilimumab/nivolumab in macroscopic stage III melanoma.
The trial included 86 evaluable patients with resectable stage III melanoma involving the lymph nodes only from three sites in Australia, Sweden, and the Netherlands. Patients were randomly assigned between November 2016 and June 2018 to receive two cycles of ipilimumab at 3 mg/kg plus nivolumab at 1 mg/kg once every 3 weeks (group A = 30), two cycles of ipilimumab at 1 mg/kg plus nivolumab at 3 mg/kg once every 3 weeks (group B = 30), or two cycles of ipilimumab at 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab at 3 mg/kg once every 2 weeks (group C = 26).
The primary endpoints were proportions of patients with grade 3 or 4 immune-related toxicity within the first 12 weeks of treatment and proportions of patients with radiologic objective response and pathologic response at 6 weeks.
Radiologic objective response occurred in 63% of group A, 57% of group B, and 35% of group C.
Pathologic responses were observed in 80% of group A (pathologic complete response in 47%), 77% of group B (pathologic complete response in 57%), and 65% of group C (pathologic complete response in 23%).
Immune-Mediated Adverse Events
Accrual to group C was stopped early upon advice of the data safety monitoring board due to observation of severe adverse events. Within the first 12 weeks, grade 3 or 4 immune-related adverse events occurred in 40% of group A, 20% of group B (P = .158 vs group A), and 50% of group C (P = .591 vs group A).
The most common events were elevated liver enzymes in group A (20%) and colitis in group C (19%); no grade 3 or 4 events occurred in more than one patient in group B. A patient in group A died at 9.5 months after the start of treatment due to consequences of late-onset immune-related encephalitis considered possibly related to treatment.
The investigators concluded, “OpACIN-neo identified a tolerable neoadjuvant dosing schedule (group B: two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg) that induces a pathological response in a high proportion of patients and might be suitable for broader clinical use. When more mature data confirm these early observations, this schedule should be tested in randomized phase III studies vs adjuvant therapies, which are the current standard-of-care systemic therapy for patients with stage III melanoma.”
Christian U. Blank, MD, of the Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit thelancet.com.
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