A phase 2 study of neoadjuvant nivolumab (nivo) + relatlimab (rela) in high-risk stage II cutaneous melanoma (NeoReNi).

Abstract

9502 Background: Patients (pts) with stage II melanoma account for ~50% of those who develop metastatic disease. Checkpoint inhibitor neoadjuvant therapy (NAT) is standard for resectable stage III melanoma (NADINA & SWOG 1801) and pathological response correlates with recurrence. Other NAT benefits include personalised prognosis, tailored subsequent management, and collection of translational specimens to explore response and resistance mechanisms. The NeoReNi II trial aimed to determine feasibility, response and safety of NAT nivo+rela in resectable stage II melanoma. Methods: Eligible pts had biopsy (partial) confirmed AJCC (v8) clinical stage IIA (T2b, T3a), IIB (T3b, T4a), or IIC (T4b) cutaneous melanoma with residual macroscopic primary disease at enrolment. IIA pts had ≥20% 5 yr recurrence risk according to Melanoma Institute Australia stage II risk calculator (melanomarisk.org.au). All pts underwent sentinel lymph node (SLN) mapping at baseline and peri-operatively, and resection (wide excision + SLN biopsy [RES]) at wk 6 following 2 doses of nivo (480 mg, IV) + rela (160 mg, IV). Pts without major pathological response (MPR) had 11 cycles (Q4W) of adjuvant nivo/rela. FDG PET/CT was performed at baseline; CT prior RES; dermoscopy and reflectance confocal microscopy (RCM) baseline, wk 3 and prior to RES. The primary endpoint was the path complete response (pCR) rate. Secondary endpoints included feasibility of NAT in stage II, RECIST response, RFS, OS, safety/tolerability, surgical outcomes, QOL. Exploratory; biomarker, dermoscopy and RCM analyses. Results: From 6 Oct 2023 to 21 Oct 2025, 20 pts were recruited and received NAT, demonstrating partial biopsy leaving residual macroscopic stage IIA-C primary melanoma was feasible. Median age 67 yrs (46-81yrs), 9 females, 8 IIA, 8 IIB and 4 IIC. 18 (90%) pts received both NAT doses. 12 (60%) pts had pCR in the primary melanoma, 1 near-pCR (MPR 65%), 1 pPR and 6 (30%) pNR. Drug treatment related adverse events (TRAE) gd ≤ 2 occurred in all 20 pts (100%); 11 (55%) with fatigue, 8 rash (40%) and 5 arthralgia (25%). 3 (15%) pts had gd 3 (secondary adrenal insufficiency, nephritis, pneumonitis). There were no gd 4 or 5 TRAEs. 1 (5%) pt had a gd 3 AE related to surgery (cellulitis). 19 (95%) pts had no change in SLN mapping from pre to RES. 2 pts with pNR in primary melanoma had postitive SLN and 1 pt with pCR had focal fibrosis within a negative SLN, suggestive of possible treatment effect. Dermoscopy showed regression in all 12 MPR (100%) pts; 11 also showed changes in RCM (collagen reorganization and imflammatory infiltrates) concordant with pathology. At datacut off (11 Dec 25) 2 pts recurred, 5 and 11 mo respectively (both pNR);1 died due to melanoma (15 mo after 1 st recurrence; 20 mo after enrolement. Positive SLNBx at pNR). Conclusions: NAT with nivo + rela in resectable stage II melanoma was feasible and induced a high rate of pCR and MPR in the primary melanoma. Clinical trial information: NCT05418972 .