Updated data confirm the high survival rates after neoadjuvant combination checkpoint inhibition in macroscopic stage III melanoma, especially for patients with pathologic response. Pathologic response is the strongest surrogate marker for long-term outcome.
Median recurrence-free survival (RFS) and overall survival (OS) were not reached in either trial. After a median follow-up of 69 months for OpACIN, 1/7 patients with pathologic response to neoadjuvant therapy had disease recurrence. The estimated 5-year RFS and OS rates for the neoadjuvant arm were 70% and 90% versus 60% and 70% for the adjuvant arm. After a median follow-up of 47 months for OpACIN-neo, estimated 3-year RFS and OS rates were 82% and 92%. Estimated 3-year RFS rate for OpACIN-neo was 95% for patients with pathologic response versus 37% for patients without pathologic response (P<0.001). In multiple regression analyses, pathologic response was the strongest predictor of disease recurrence. Of the twelve patients with distant disease recurrence after neoadjuvant therapy, five responded to subsequent anti-PD-1 and eight to targeted therapy, although seven patients showed progression after initial response.
Neoadjuvant ipilimumab plus nivolumab has yielded high response rates in macroscopic stage III melanoma patients. These response rates translated to high short-term survival rates. However, data on long-term survival and disease recurrence are lacking.
In OpACIN, 20 macroscopic stage III melanoma patients were randomized to ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w four cycles adjuvant or split two cycles neoadjuvant and two adjuvant. In OpACIN-neo, 86 macroscopic stage III melanoma patients were randomized to arm A (2x ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w, n=30), arm B (2x ipilimumab 1 mg/kg plus nivolumab 3 mg/kg q3w, n=30), or arm C (2x ipilimumab 3 mg/kg q3w plus 2x nivolumab 3 mg/kg q2w, n=26) followed by surgery.