Clinical Summary: 

• Design/Population: The phase 2 NEO-RENI-2 trial evaluated 2 doses of neoadjuvant nivolumab plus relatlimab followed by surgery in 20 patients with resectable stage IIA-C melanoma and residual macroscopic primary disease. Patients without major pathologic response received adjuvant nivolumab plus relatlimab.
• Key Outcomes: The primary end point was met, with a pathologic complete response rate of 60% and a major pathologic response rate of 65%. At data cutoff, only 2 recurrences occurred, both in patients with pathologic nonresponse, and patients achieving major pathologic response experienced no recurrences.
• Clinical Relevance: These findings demonstrate the feasibility and substantial antitumor activity of neoadjuvant checkpoint inhibition in high-risk stage 2 melanoma and support further evaluation in randomized phase 3 studies.

Georgina Long, MD, PhD, Melanoma Institute Australia, Sydney, Australia, discusses results from the phase 2 NEO-RENI-2 trial evaluating neoadjuvant nivolumab plus relatlimab in patients with high-risk stage 2 melanoma. The study tested a novel approach in which patients underwent only a partial diagnostic biopsy before receiving immunotherapy and subsequent definitive surgery, demonstrating that this strategy was feasible without compromising sentinel lymph node mapping or surgical outcomes.

The regimen produced deep pathologic responses, including complete eradication of invasive melanoma in 60% of patients, with recurrences occurring exclusively among patients who failed to achieve a pathologic response. Treatment was generally well tolerated, with no grade 4/5 treatment-related adverse events, supporting continued investigation of neoadjuvant immunotherapy in stage 2 melanoma and highlighting the potential of pathologic response as an early predictor of long-term outcome.

Dr Long presented these results at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois. 

Transcript: 

Hello, my name is Professor Georgina Long from Melanoma Institute Australia and the University of Sydney. I’m here at ASCO 2026, and today in the Melanoma Oral Session I presented the NEO-RENI 2 trial, a phase 2 study evaluating the feasibility and pathological response rate of neoadjuvant nivolumab plus relatlimab in patients with high-risk, resectable stage 2 melanoma. The results were really quite remarkable.

As background, patients with stage 2 melanoma account for approximately 50% of all melanoma patients who ultimately develop metastatic disease. We already know from studies such as NADINA and SWOG S1801 that neoadjuvant checkpoint inhibition is highly effective in resectable stage 3 melanoma and that pathological response strongly correlates with recurrence outcomes. The question was whether this strategy could be moved into high-risk stage 2 melanoma.

The study enrolled patients with AJCC 8th edition stage IIA, IIB, or IIC cutaneous melanoma who had residual macroscopic primary disease after a diagnostic partial biopsy. Importantly, stage IIA patients were required to have at least a 20% five-year recurrence risk according to the Melanoma Institute Australia stage 2 risk calculator. This is a major departure from current standard practice. Normally, if melanoma is suspected, guidelines recommend complete excision biopsy with narrow margins. In this trial, however, patients underwent only a partial biopsy and then proceeded to neoadjuvant therapy, which is why feasibility was such an important end point.

Between October 2023 and October 2025, we enrolled 20 patients: 8 with stage IIA disease, 8 with stage IIB disease, and 4 with stage IIC disease. All patients underwent sentinel lymph node mapping before starting treatment. They then received two doses of nivolumab 480 mg plus relatlimab 160 mg over six weeks, followed by wide local excision and sentinel lymph node biopsy. 

The study clearly demonstrated feasibility. All 20 patients were recruited, all received neoadjuvant therapy, and all proceeded to surgery. In terms of efficacy, 12 of the 20 patients achieved a pathologic complete response in the primary melanoma, representing 60% of patients. One additional patient achieved a near-complete pathological response, giving a major pathological response rate of 65% according to International Neoadjuvant Melanoma Consortium criteria. There was one partial pathological response and six pathological nonresponses. 

These findings suggest that neoadjuvant immune checkpoint inhibition works in stage 2 melanoma very similarly to what we have already observed in stage 3 disease. Only two patients had positive sentinel lymph nodes, both of whom were among the pathological nonresponders. Interestingly, one patient with a pathologic complete response in the primary lesion had fibrosis in a negative sentinel node, suggesting a possible treatment effect.

At a median follow-up of approximately 15 months, only two patients had recurred, both of whom had pathological nonresponse. One patient subsequently died from melanoma. When we looked at outcomes by pathological response, the results were striking. 

Among patients who achieved any major pathological response, there were no recurrences observed. In other words, 12-month event-free survival was 100%. Among patients with pathological nonresponse, 12-month event-free survival was 67%. 

In terms of safety, treatment-related adverse events of grade 1 or 2 occurred in all patients. The most common were fatigue, rash, and arthralgia. Three patients experienced grade 3 treatment-related adverse events, including secondary adrenal insufficiency, nephritis, and pneumonitis. There were no grade 4 or grade 5 treatment-related adverse events. Only one patient experienced a grade 3 surgery-related adverse event, which was cellulitis. 

We also observed that dermoscopy showed regression in all patients who achieved a major pathological response, and reflectance confocal microscopy findings correlated strongly with pathological response, showing collagen reorganization and inflammatory infiltrates. So overall, these are very exciting results.

This is still a small phase 2 feasibility study, and if we want to move this approach into routine practice, we will need a randomized phase 3 trial comparing neoadjuvant versus adjuvant therapy in high-risk stage II melanoma. 

More broadly, my vision for melanoma is that we continue improving prognostic and predictive tools so that when a patient presents with stage I or stage II melanoma, we can accurately identify who is at risk of recurrence, who needs systemic therapy, and which therapy is most likely to benefit them. If we want to achieve a future with no deaths from melanoma—and ultimately no deaths from cancer—we need to start thinking this way.

Source: 

Long G, Lo SN, Spillane AJ, et al. A phase 2 study of neoadjuvant nivolumab (nivo) + relatlimab (rela) in high-risk stage II cutaneous melanoma (NeoReNi). Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. Abstract 9502.