Personalization of Neoadjuvant Immunotherapy in High-Risk Resectable Melanoma and Utility of ctDNA as a Biomarker of Immunotherapy Response

BACKGROUND: Randomized trials demonstrated superior outcomes with neoadjuvant immune checkpoint inhibitors (ICI) compared with adjuvant ICI alone for patients with resectable macroscopic melanoma. However, the optimal perioperative strategy remains undetermined, and biomarkers are lacking. Real-world data reporting the feasibility of limited resection and the utility of circulating tumor DNA (ctDNA) in predicting melanoma recurrence could help inform optimal practice. METHODS: Retrospective data regarding treatment, outcomes, and safety were collected for 76 patients who had melanoma treated with neoadjuvant ICI from 2020 to 2024. Signatera ctDNA results were available for 22 patients. RESULTS: Of the 76 patients, 42 (55%) received ipilimumab plus nivolumab (Ipi/Nivo), 31 (41%) received anti-PD1 monotherapy, and 3 (4%) received nivolumab plus relatlimab. The patients included 64 (84%) who underwent planned surgical excision, 25 who underwent upfront total lymph node dissection (TLND), and 32 who underwent index node excision (INE), with reflex TLND performed for 7 patients. The overall major pathologic response (MPR) rate was 55% (49% with Ipi/Nivo and 65% with monotherapy). Six (21%) of 28 non-MPR patients did not receive adjuvant therapy. After a median follow-up period of 15.8 months, recurrence rates were comparable between the INE (9%) and TLND (12%) cohorts. At the time of surgery, ctDNA was undetectable in the majority of the MPR patients (9/11) and the minority of the non-MPR patients (4/11). Postoperatively, ctDNA was detectable in 1 of 20 patients. CONCLUSIONS: A personalized surgical approach to neoadjuvant ICI was feasible, with comparable recurrence rates between the patients who underwent INE and those who underwent TLND. For the patients without MPR, subsequent adjuvant therapy improved recurrence-free survival (p = 0.046). The ctDNA results correlated with the clinical outcomes, suggesting that ctDNA may complement pathologic response in guiding management.