Impact of personalized response-directed surgery and adjuvant therapy on survival after neoadjuvant immunotherapy in stage III melanoma: Comparison of 3-year data from PRADO and OpACIN-neo

Background: Pathologic response following neoadjuvant immune checkpoint blockade (ICB) in stage III melanoma serves as a surrogate marker for long-term outcomes. This may support more personalized, response-directed treatment strategies. Methods: The OpACIN-neo and PRADO trials were phase 2 studies evaluating neoadjuvant treatment with ipilimumab and nivolumab in stage III melanoma. In OpACIN-neo, all patients underwent therapeutic lymph node dissection (TLND) without subsequent adjuvant therapy. In contrast, PRADO explored a response- directed strategy, where patients achieving a major pathologic response (MPR) omitted TLND and adjuvant therapy, while those without a pathologic response (pNR) received TLND and adjuvant therapy. Here, we provide a descriptive post-hoc comparison of 3-year survival outcomes between the non-personalized approach in OpACIN-neo and the response-directed approach in PRADO. Results: For patients who achieved an MPR, the 3-year recurrence-free survival (RFS) was 93 % for those without TLND versus 96 % for those with TLND (log-rank p = 0.47), and distant metastasis-free survival (DMFS) was 98 % compared to 96 % (log-rank p = 0.49), respectively. For patients with pNR, 3-year RFS rates were 64 % for those receiving adjuvant systemic therapy and 35 % for patients without (log-rank p = 0.10). DMFS rates were 70 % versus 52 % (log-rank p = 0.24), respectively. Conclusions: These data suggest that TLND and adjuvant therapy may be safely omitted in most patients achieving an MPR, while adjuvant systemic therapy following TLND appears to improve RFS and DMFS in patients with pNR. Although these results are hypothesis-generating and require further validation, they offer a potential foundation for developing personalized neoadjuvant immunotherapy approaches.