Background: Patients diagnosed with stage II melanoma account for ~50% of those who develop metastatic disease and die (Poklepovic et al., 2020). Neoadjuvant therapy (NAT) is a powerful treatment platform to rapidly assess drug activity in resectable cancers using the International Neoadjuvant Melanoma Consortium (INMC) path response criteria (Tetzlaff et al., 2018), wherein a major path response (≤10% viable tumor) correlates with low risk of recurrence in resectable stage III melanoma (Menzies et al., 2021). Other benefits include early insight into response, feedback to pts regarding their individual response and prognosis, ability to tailor subsequent management, and collection of translational specimens to explore mechanisms of response and resistance (Amaria et al., 2019). NAT for stage II melanoma is an opportunity to improve survival rates beyond the gains achieved with adjuvant therapy, as illustrated by the phase II SWOG 1801 trial (Patel et al., 2022) for pts with stage III melanoma. The NeoReNi II trial will examine whether combination PD-1 blockade plus lymphocyte-activation 3 (LAG3) checkpoint inhibition will achieve a high rate of path response with manageable toxicity. Methods: Pts with histologically confirmed AJCC (8^th ed.) clinical stage IIA (T2b, T3A), IIB (T3b, T4a), or IIC (T4b) primary cutaneous melanoma from a partial biopsy, with residual macroscopic disease at study entry, are eligible (N = 20). Pts with IIA disease must have an estimated ≥20% risk of recurrence at 5 years, according to the Melanoma Institute Australia stage II risk calculator (melanomarisk.org.au). All pts undergo wide excision and sentinel lymph node resection (RES) at wk 6 following NAT with 2 doses of nivo (480 mg, IV) plus rela (160 mg, IV). Pts with no ( > 50% viable tumor) or partial path response ( > 10% - ≤50% viable tumor) receive a further 11 cycles (Q4W) of adjuvant nivo (480 mg) plus rela (160 mg), and radiological and clinical surveillance. Pts with complete (pCR; 0% viable tumor) or near-complete (≤10% viable tumor) path response will undergo radiological and clinical surveillance after RES. All pts will be followed for recurrence (6 monthly CT) and survival for 10 years. Lymphatic mapping, dermoscopy, in vivo confocal microscopy, CT, and FDG PET/CT will be performed at baseline (BL) and prior to RES to measure response to NAT. Tumour and fecal samples are collected at BL, RES, and recurrence. Blood samples are collected at BL, wk 4, RES, and recurrence. The primary endpoint is the rate of pCR at RES after 6 wks of NAT using INMC response criteria (Tetzlaff et al., 2018). Secondary endpoints include assessing the feasibility of NAT in a stage II pt population, RFS, OS, safety/tolerability, surgical outcomes, changes in confocal microscopy and dermoscopy, rate of sentinel node positivity and changes in lymphatic mapping, QOL, and biomarker analyses. Clinical trial information: NCT05418972.