A phase II study of neoadjuvant ipilimumab-nivolumab-relatlimab (INR) combination immunotherapy in high-risk resectable melanoma.

Abstract

9501 Background: Advances in the neoadjuvant (neo) setting of locoregionally advanced melanoma have recently transformed practice. However, there continues to be a need to enhance efficacy while deescalating the duration of systemic therapy for those who achieve major pathologic (path) responses (MPR). Recent data support an important role for triplet INR checkpoint inhibitor therapy targeting CTLA4, PD1 and LAG3 in the treatment of advanced melanoma. Methods: A phase II trial of INR in patients (pts) with resectable clinical AJCC8 stages IIIB-D. It planned to enroll 20 evaluable pts to neo ipilimumab 1 mg/kg x1 dose combined with nivolumab-relatlimab (NR) 480/160 mg every 4 weeks x2 doses, followed by definitive surgery. Primary endpoint was MPR consisting of complete path response (pCR; 0% viable tumor) and near-pCR (< 10%). Secondary endpoints included other path responses, recurrence free survival, overall survival, event-free survival [EFS: disease progression (PD), recurrence or death] and safety. Adjuvant therapy was given in the absence of MPR. Biospecimens for research from consenting pts were banked at baseline, during treatment, at surgery and in follow up. Results: The study enrolled 20 pts August 2024-January 2026, including 7 female, 13 male, 16 cutaneous (2 acral) and 4 unknown primary. Median age was 65 (63-80). Baseline clinical stages were 9 IIIB, 9 IIIC, 2 IIID, including 4 pts with in-transit metastases. Among 19 patients who completed the neoadjuvant phase, all received ipilimumab and the median number of neo NR doses was 2. Among 19 pts who initiated treatment, 5 pts (26%) experienced Gr3 related AEs including colitis (1), encephalitis (1), headache (1), hyperglycemia (1), rash (1), and one pt experienced an event of Gr5 myocarditis. Among 18 pts who completed radiologic tumor response assessment, there were 13 (72%) partial response (PR), 4 stable disease (SD) and 1 disease progression (PD) preoperatively. There was 1 event of death before surgery. One patient declined surgery following deep PR, 1 pt is pending surgery and 1 pt continues in the neo phase. Among 16 pts who had surgery, median time from enrollment to surgery was 73 days. Pathologic responses were 5 path non-response (pNR), 1 near-pCR (microscopic residual disease) and 10 pCR (63%; 95% CI, 38.64 – 81.52). MPR rate (pCR + near-pCR) was 11/16 (69%; 95% CI, 44.40 – 85.84) and none of these patients received adjuvant therapy. Median follow up time from enrollment was 9.8 months. Among all pts, no pt experienced recurrence after surgery to date. Conclusions: Neoadjuvant INR demonstrated encouraging clinical activity in pts with resectable clinical stages IIIB/IIIC/IIID melanoma, warranting further investigation. The toxicity profile was consistent with reported data of INR and other combinations in this setting. Mechanistic and biomarker studies related to response, resistance and toxicity are underway. Clinical trial information: NCT06295159 .