# Adjuvant nivolumab and relatlimab in stage III/IV melanoma: the randomized phase 3 RELATIVITY-098 trial

Georgina Long, Charlie Garnett-Benson, Sonia Dolfi, Paolo Ascierto, Jun Guo, Ahmad Tarhini, Sunandana Chandra, Eva Muñoz-Couselo, Michele del Vecchio, Andreia Cristina de Melo, et al.

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## To cite this version:

Georgina Long, Charlie Garnett-Benson, Sonia Dolfi, Paolo Ascierto, Jun Guo, et al. Adjuvant nivolumab and relatlimab in stage III/IV melanoma: the randomized phase 3 RELATIVITY-098 trial. Nature Medicine, 2025, Online ahead of print. 10.1038/s41591-025-04032-8. inserm-05323324

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# Adjuvant nivolumab and relatlimab in stage III/IV melanoma: the randomized phase 3 RELATIVITY-098 trial

Received: 12 September 2025

Accepted: 26 September 2025

Published online: 18 October 2025

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Georgina V. Long<sup>1, ∗</sup>, Charlie Garnett-Benson<sup>2</sup>, Sonia Dolfi<sup>2</sup>,
Paolo A. Ascierto<sup>3</sup>, Jun Guo<sup>4</sup>, Ahmad A. Tarhini<sup>5</sup>, Sunandana Chandra<sup>6</sup>,
Eva Muñoz-Couselo<sup>7</sup>, Michele Del Vecchio<sup>8</sup>, Andreia Cristina de Melo<sup>9</sup>,
Margaret Callahan<sup>10</sup>, Helen Gogas<sup>11</sup>, Reinhard Dummer<sup>12</sup>,
Dirk Schadendorf<sup>13</sup>, Peter Koelblinger<sup>14</sup>, Gaelle Quereux<sup>15</sup>, Ioannis Thomas<sup>16</sup>,
Jia Xin Yu<sup>2</sup>, Andrew Fisher<sup>2</sup>, Bonnie Wang<sup>2</sup>, Patrick Djidel<sup>2</sup>, Armand Chouzy<sup>2</sup>,
Mark Semaan<sup>2</sup>, Bohang Chen<sup>2</sup>, Alicia M. Y. Cheong<sup>17</sup> & Hussein A. Tawbi<sup>18</sup>

Based on RELATIVITY-047, nivolumab plus relatlimab is approved for advanced melanoma. Here, to address a current unmet need for more efficacious adjuvant regimens for completely resected melanoma, the phase 3, double-blind RELATIVITY-098 trial compared adjuvant nivolumab plus relatlimab to nivolumab after complete resection of stage III/IV melanoma. Patients were randomized 1:1 to receive nivolumab 480 mg plus relatlimab 160 mg (n = 547) or nivolumab 480 mg (n = 546) intravenously every 4 weeks for ≤1 year; safety populations totaled 543 and 545 patients, respectively. The primary endpoint was recurrence-free survival (RFS), and the key secondary was overall survival; translational endpoints were exploratory. There was no difference in RFS for nivolumab plus relatlimab versus nivolumab (hazard ratio = 1.01; 95% confidence interval: 0.83–1.22; P = 0.928); therefore, overall survival was not tested. Translational data across trials showed lower circulating LAG-3+ T cells in the adjuvant setting (RELATIVITY-098) versus advanced melanoma (RELATIVITY-047), where LAG-3+ T cells were enriched in tumor versus blood. The absence of macroscopic tumor and reduced peripheral LAG-3+ T cells may explain the lack of added benefit of nivolumab plus relatlimab over nivolumab in resected versus metastatic melanoma. ClinicalTrials.gov identifier: NCT05002569.

The programmed death 1 (PD-1) immune checkpoint inhibitors nivolumab and pembrolizumab, both administered as monotherapy, and the targeted therapy combination of dabrafenib plus trametinib are standard-of-care adjuvant therapy options for patients with completely resected stage III/IV melanoma¹⁻⁵. However, approximately 50% of patients have disease recurrence, with 5-year RFS rates of 50% for nivolumab⁶, 55% for pembrolizumab⁴ and 52% for dabrafenib plus trametinib⁵. These outcomes highlight the ongoing need to

develop treatments that improve RFS while maintaining a manageable safety profile.

Nivolumab plus relatlimab fixed-dose combination (FDC; 480-mg nivolumab plus 160-mg relatlimab intravenously every 4 weeks) was approved for treatment of advanced melanoma based on the phase 2/3 RELATIVITY-047 trial⁷. In the primary analysis, there was a significant improvement with nivolumab plus relatlimab compared to nivolumab in median progression-free survival (PFS; 10.1 months
<figure><img src="image_5.png" /><figcaption>**Fig. 1 |** Flow diagram depicting the patient numbers in each arm throughout the study. CONSORT diagram. ITT, intention-to-treat.</figcaption></figure>

versus 4.6 months; hazard ratio = 0.75; 95% confidence interval: 0.62–0.92; *P* = 0.006) at a median follow-up of 13.2 months, with a tolerable safety profile⁷. In updated analyses, blinded independent confirmed objective response rates were 43.1% with nivolumab plus relatlimab and 32.6% with nivolumab (odds ratio = 1.6; 95% confidence interval: 1.2–2.2) at a median follow-up of 19.3 months⁸, and median overall survival was 53.3 months and 33.2 months, respectively (hazard ratio = 0.77; 95% confidence interval: 0.64–0.94) at a median follow-up of 34.9 months⁹.

Given the unmet need for more efficacious adjuvant regimens for completely resected melanoma, the phase 3 RELATIVITY-098 trial compared adjuvant treatment with nivolumab plus relatlimab FDC to nivolumab in patients after complete resection of stage III/IV melanoma. Here we present the primary results of RELATIVITY-098, which demonstrate no added benefit of the combination versus nivolumab in the resected setting, and translational evidence from RELATIVITY-098 and RELATIVITY-047 to better understand the differential efficacy of this combination in the resected versus advanced melanoma settings.

## Results

### Patients

From October 2021 to November 2022, a total of 1,093 patients were randomly assigned to receive nivolumab plus relatlimab (547 patients) or nivolumab (546 patients) (Fig. 1) at 163 hospitals and cancer

centers worldwide (list provided in the Supplementary Information) in 24 countries worldwide. Patients were recruited by investigators through enrollment based on prespecified inclusion/exclusion criteria. Eligibility criteria and screening procedures minimized the potential of self-selection bias. Baseline characteristics were generally balanced across the treatment arms (Table 1).

At the 16 December 2024 clinical cutoff date, patients had a minimum follow-up (time from last patient randomized to the cutoff date) of 23.4 months and a median follow-up (median time between randomization and the last known alive date) of 26.7 months. No patient was continuing treatment, and 96 patients (17.7%) in the nivolumab plus relatlimab arm and 78 patients (14.3%) in the nivolumab arm discontinued the study, mainly due to death (72 (13.3%) and 59 (10.8%) patients, respectively) (Fig. 1). Subsequent systemic therapy was received by 27.1% of patients in the nivolumab plus relatlimab arm and by 28.4% of patients in the nivolumab arm (Extended Data Table 1).

### Efficacy

The primary endpoint of RFS was not statistically significantly associated in the intention-to-treat population, with a hazard ratio for nivolumab plus relatlimab versus nivolumab of 1.01 (95% confidence interval: 0.83–1.22; *P* = 0.928) (Fig. 2a) and a similar incidence of recurrence events across the two arms (36.7% (*n* = 201) and 37.7% (*n* = 206), respectively) (Extended Data Table 2). Although overall survival data
<table><caption>**Table 1 | Characteristics of the patients at baseline**</caption><thead><tr><th>Characteristic</th><th>Nivolumab plus<br>relatlimab (n=547)</th><th>Nivolumab (n=546)</th></tr></thead><tbody><tr><td>Median age (range) — years</td><td>59 (18–89)</td><td>59 (19–92)</td></tr><tr><td>Sex — no. (%)</td><td></td><td></td></tr><tr><td>Male</td><td>327 (59.8)</td><td>315 (57.7)</td></tr><tr><td>Female</td><td>220 (40.2)</td><td>231 (42.3)</td></tr><tr><td>Geographic region — no. (%)</td><td></td><td></td></tr><tr><td>United States/Canada</td><td>54 (9.9)</td><td>63 (11.5)</td></tr><tr><td>Australia</td><td>67 (12.2)</td><td>57 (10.4)</td></tr><tr><td>Europe</td><td>318 (58.1)</td><td>319 (58.4)</td></tr><tr><td>Latin America</td><td>76 (13.9)</td><td>72 (13.2)</td></tr><tr><td>China</td><td>32 (5.9)</td><td>35 (6.4)</td></tr><tr><td>ECOG performance status — no. (%)</td><td></td><td></td></tr><tr><td>0</td><td>494 (90.3)</td><td>498 (91.2)</td></tr><tr><td>1</td><td>53 (9.7)</td><td>48 (8.8)</td></tr><tr><td>AJCC stage — no. (%)</td><td></td><td></td></tr><tr><td>IIIA–IIIB</td><td>209 (38.2)</td><td>199 (36.4)</td></tr><tr><td>IIIC</td><td>270 (49.4)</td><td>271 (49.6)</td></tr><tr><td>IIID–IV</td><td>68 (12.4)</td><td>76 (13.9)</td></tr><tr><td>Melanoma subtype — no. (%)</td><td></td><td></td></tr><tr><td>Cutaneous non-acral</td><td>436 (79.7)</td><td>454 (83.2)</td></tr><tr><td>Cutaneous acral</td><td>61 (11.2)</td><td>52 (9.5)</td></tr><tr><td>Mucosal</td><td>10 (1.8)</td><td>8 (1.5)</td></tr><tr><td>Unknown primary</td><td>38 (6.9)</td><td>32 (5.9)</td></tr><tr><td>Other</td><td>2 (0.4)</td><td>0</td></tr><tr><td>LDH — no. (%)</td><td></td><td></td></tr><tr><td>≤ULN</td><td>496 (90.7)</td><td>486 (89.0)</td></tr><tr><td>>ULN</td><td>49 (9.0)</td><td>57 (10.4)</td></tr><tr><td>Not reported</td><td>2 (0.4)</td><td>3 (0.5)</td></tr><tr><td>BRAF status — no. (%)</td><td></td><td></td></tr><tr><td>Mutant</td><td>220 (40.2)</td><td>217 (39.7)</td></tr><tr><td>Wild-type</td><td>195 (35.6)</td><td>200 (36.6)</td></tr><tr><td>PD-L1 status — no. (%)</td><td></td><td></td></tr><tr><td>Positive (≥1%)</td><td>136 (24.9)</td><td>123 (22.5)</td></tr><tr><td>Negative (<1%)</td><td>315 (57.6)</td><td>340 (62.3)</td></tr><tr><td>Indeterminate/not evaluable/<br>not reported</td><td>96 (17.6)</td><td>83 (15.2)</td></tr><tr><td>LAG-3 status — no. (%)</td><td></td><td></td></tr><tr><td>Positive (≥1%)</td><td>352 (64.4)</td><td>352 (64.5)</td></tr><tr><td>Negative (<1%)</td><td>126 (23.0)</td><td>145 (26.6)</td></tr><tr><td>Indeterminate/not evaluable/<br>not reported</td><td>69 (12.6)</td><td>49 (9.0)</td></tr></tbody></table>

ULN, upper limit of normal.

are immature and not tested for significance, they showed a hazard ratio for nivolumab plus relatlimab versus nivolumab of 1.24 (95% confidence interval: 0.90–1.72) (Extended Data Fig. 1). The secondary endpoint of distant metastasis-free survival (DMFS) showed a hazard ratio for nivolumab plus relatlimab versus nivolumab of 1.07 (95% confidence interval: 0.84–1.36) (Fig. 2b). RFS results for patients across prespecified subgroups were generally similar to the overall population (Extended Data Fig. 2). Additional planned secondary endpoint of PFS through next-line therapy is not reported in this paper as the

analyses were not completed due to the primary endpoint not reaching statistical significance.

## Exposure and safety

The median (range) duration of therapy was similar for nivolumab plus relatlimab (11.0 months (0.03–12.06)) and nivolumab (11.0 months (0.03–12.06)). Overall, 89.0% of patients treated with nivolumab plus relatlimab and 80.4% of patients treated with nivolumab had any-grade treatment-related adverse events (TRAEs); grade 3 or 4 TRAEs were reported in 19.0% and 8.4% of patients, respectively (Table 2). The most frequent (≥10%) any-grade TRAEs in the nivolumab plus relatlimab arm were hypothyroidism (25.2%), fatigue (24.3%), pruritus (18.0%), hyperthyroidism (17.5%), rash (15.3%), arthralgia (13.3%) and diarrhea (11.2%); those in the nivolumab arm were fatigue (25.3%), pruritus (18.7%), hypothyroidism (13.6%), rash (13.4%) and arthralgia (12.7%) (Table 2). Any-grade TRAEs led to treatment discontinuation in 17.5% of patients in the nivolumab plus relatlimab arm and in 8.8% of patients in the nivolumab arm; grade 3 or 4 TRAEs led to treatment discontinuation in 9.6% and 3.1%, respectively (Table 2). Treatment-related deaths occurred in two patients (0.4%; gastrointestinal hemorrhage and sinusoidal obstructive syndrome (n = 1) and myocarditis (n = 1)) in the nivolumab plus relatlimab arm and in one patient (0.2%; immune-mediated myocarditis and immune-mediated myositis) in the nivolumab arm. Immune-mediated adverse events (Extended Data Table 3) and adverse events of special interest (Extended Data Table 4) are presented.

## Translational data

Clinical results presented in this report show that there was no added benefit in the resected setting for nivolumab plus relatlimab over nivolumab, although benefit was demonstrated in advanced melanoma in RELATIVITY-047 (refs. 7–9). Therefore, as post hoc analyses, the pharmacodynamic effects of nivolumab plus relatlimab and nivolumab were compared between patients in the adjuvant treatment setting from RELATIVITY-098 and patients in the advanced melanoma treatment setting from RELATIVITY-047.

Similar to results observed in patients with advanced melanoma from RELATIVITY-047 (ref. 10), pharmacodynamic and target engagement evaluation in patients in RELATIVITY-098 demonstrated that inflammatory cytokines (interferon gamma (IFNy), C-X-C motif chemokine ligand 9 and C-X-C motif chemokine ligand 10 (CXCL9 and CXCL10)) were significantly increased by nivolumab plus relatlimab and nivolumab treatment, with greater increases in the nivolumab plus relatlimab arm than in the nivolumab arm (Fig. 3a). In a longitudinal blood analysis, nivolumab plus relatlimab promoted greater expansion of LAG-3+ T cells than nivolumab (Fig. 3b). Additionally, a significant decrease in free soluble LAG-3 was observed with nivolumab plus relatlimab compared to increases with nivolumab, supporting relatlimab target engagement (Fig. 3c). An inverse relationship was observed between free soluble LAG-3 levels in serum and relatlimab exposures, with free soluble LAG-3 levels decreasing as relatlimab trough concentration increased (Extended Data Fig. 3). Immunosuppressive cytokines were significantly increased in the nivolumab plus relatlimab arm but not in the nivolumab arm (for example, IL-10 and C-reactive protein) (Extended Data Fig. 4).

Immune checkpoint expression on T cells in the blood and tumor was investigated to understand whether tumor (which was surgically removed in the adjuvant treatment setting) may be necessary for relatlimab benefit. In samples from patients with advanced melanoma from RELATIVITY-047 the levels of PD-1+ CD8 T cells in the tumor and blood were similar; however, LAG-3+ and LAG-3+PD-1+ CD8 T cells were substantially higher in tumor (multiplex CODEX analysis) versus blood (flow cytometry) (Fig. 4a). The similar multiplex CODEX analyses were not available for the RELATIVITY-098 study. Comparing baseline blood samples of advanced melanoma (RELATIVITY-047) to those of resected
a

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b

<figure><img src="image_7.png" /><figcaption>**Fig. 2 | RFS and DMFS.** a, Kaplan-Meier estimates of RFS defined as the time between randomization and the first date of documented recurrence (local, regional or distant recurrence or new primary melanomas (excluding in situ)) or death due to any cause in all randomized patients. b, DMFS defined as the time between randomization and first distant metastasis or death due to any cause in a subset of intention-to-treat patients, defined as those with resected stage III-IVA-IVB melanoma (those without presence of baseline metastasis prior</figcaption></figure>

to surgical resection—that is, stage III cutaneous and stage IVA-IVB mucosal melanoma). RFS statistical analysis was two-sided log-rank test, with no multiple comparisons. Symbols (circles) indicate censored data. Dashed lines indicate landmark analyses. CI, confidence interval; HR, hazard ratio; mDMFS, median DMFS; mRFS, median RFS; mo, months; NIVO, nivolumab; NR, not reached; RELA, relatlimab.

melanoma (RELATIVITY-098) demonstrated similar PD-1+ T cell levels (Fig. 4b). By contrast, among patients in the advanced disease setting, there were higher levels of LAG-3-expressing T cells in the blood at baseline (Fig. 4b) and a greater magnitude of increase in LAG-3+ T cells upon treatment with nivolumab plus relatlimab than in patients treated in the adjuvant disease setting after tumor resection (Fig. 4c).

When correlating tumor expression with RFS, higher LAG-3 and CD8 expression in resected tumors enriched for RFS benefit in both the nivolumab plus relatlimab and nivolumab arms (Extended Data Fig. 5a,b). In addition, there was a trend toward RFS benefit for nivolumab plus relatlimab compared to nivolumab in CD8 low inflamed tumors (Extended Data Fig. 5c). Overall, CD8 expression was higher in baseline resected tumors compared to recurrent tumors (Extended Data Fig. 6a), and there was a higher proportion of LAG-3- (<1%) tumors in recurrent tumor samples compared to baseline resected tumors (Extended Data Fig. 6a). Expression of CD8 and LAG-3 at baseline was lower in patients who had a recurrence than in those who did not in both arms (Extended Data Fig. 6b).

## Discussion

In RELATIVITY-098, nivolumab plus relatlimab did not significantly improve RFS over nivolumab as adjuvant treatment for patients after complete resection of stage III-IV melanoma. However, in RELATIVITY-047, nivolumab plus relatlimab was shown to be superior to nivolumab in terms of PFS in patients with advanced melanoma⁷. Comparing biomarker results in resected melanoma in RELATIVITY-098 and advanced melanoma in RELATIVITY-047 suggested that the presence of tumor and associated higher levels of LAG-3+ T cells in the blood may be necessary to derive additional clinical benefit with nivolumab plus relatlimab over nivolumab.

There was a similar recurrence pattern in the nivolumab plus relatlimab and nivolumab arms of RELATIVITY-098, and RFS results in prespecified subgroups were generally similar to those in the intention-to-treat population. Overall survival and DMFS were also similar across the treatment arms. The safety profile of nivolumab plus relatlimab in RELATIVITY-098 was similar to that in RELATIVITY-047, with no new safety signals; similar to the metastatic setting, an
<table><caption>Table 2 | Safety summaryª</caption><thead><tr><th rowspan="2">Event</th><th colspan="2">Nivolumab plus relatlimab (n=543)</th><th colspan="2">Nivolumab (n=545)</th></tr><tr><th>Any grade</th><th>Grade 3 or 4</th><th>Any grade</th><th>Grade 3 or 4</th></tr></thead><tbody><tr><td>Any adverse event, n (%)</td><td>522 (96.1)</td><td>155 (28.5)</td><td>520 (95.4)</td><td>100 (18.3)</td></tr><tr><td>Any adverse event leading to discontinuation, n (%)</td><td>102 (18.8)</td><td>55 (10.1)</td><td>65 (11.9)</td><td>28 (5.1)</td></tr><tr><td>TRAEs, n (%)</td><td>483 (89.0)</td><td>103 (19.0)</td><td>438 (80.4)</td><td>46 (8.4)</td></tr><tr><td>TRAEs leading to discontinuation, n (%)</td><td>95 (17.5)</td><td>52 (9.6)</td><td>48 (8.8)</td><td>17 (3.1)</td></tr><tr><td>TRAEs in ≥5% patients, n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Hypothyroidism</td><td>137 (25.2)</td><td>3 (0.6)</td><td>74 (13.6)</td><td>0</td></tr><tr><td>Fatigue</td><td>132 (24.3)</td><td>1 (0.2)</td><td>138 (25.3)</td><td>1 (0.2)</td></tr><tr><td>Pruritus</td><td>98 (18.0)</td><td>0</td><td>102 (18.7)</td><td>1 (0.2)</td></tr><tr><td>Hyperthyroidism</td><td>95 (17.5)</td><td>3 (0.6)</td><td>53 (9.7)</td><td>0</td></tr><tr><td>Rash</td><td>83 (15.3)</td><td>0</td><td>73 (13.4)</td><td>4 (0.7)</td></tr><tr><td>Arthralgia</td><td>72 (13.3)</td><td>2 (0.4)</td><td>69 (12.7)</td><td>3 (0.6)</td></tr><tr><td>Diarrhea</td><td>61 (11.2)</td><td>6 (1.1)</td><td>54 (9.9)</td><td>2 (0.4)</td></tr><tr><td>Increased alanine aminotransferase</td><td>50 (9.2)</td><td>8 (1.5)</td><td>34 (6.2)</td><td>0</td></tr><tr><td>Asthenia</td><td>46 (8.5)</td><td>3 (0.6)</td><td>44 (8.1)</td><td>1 (0.2)</td></tr><tr><td>Dry mouth</td><td>46 (8.5)</td><td>0</td><td>29 (5.3)</td><td>0</td></tr><tr><td>Increased aspartate aminotransferase</td><td>41 (7.6)</td><td>5 (0.9)</td><td>27 (5.0)</td><td>0</td></tr><tr><td>Hypophysitis</td><td>40 (7.4)</td><td>11 (2.0)</td><td>7 (1.3)</td><td>2 (0.4)</td></tr><tr><td>Nausea</td><td>39 (7.2)</td><td>0</td><td>28 (5.1)</td><td>0</td></tr><tr><td>Myalgia</td><td>34 (6.3)</td><td>2 (0.4)</td><td>30 (5.5)</td><td>0</td></tr><tr><td>Infusion-related reaction</td><td>30 (5.5)</td><td>1 (0.2)</td><td>18 (3.3)</td><td>0</td></tr><tr><td>Treatment-related deaths, n (%)</td><td></td><td>2 (0.4)<sup>b</sup></td><td></td><td>1 (0.2)<sup>c</sup></td></tr></tbody></table>

increased frequency of TRAEs for nivolumab plus relatlimab compared to nivolumab alone was reported⁷. Furthermore, similar proportions of patients receiving nivolumab plus relatlimab discontinued treatment because of TRAEs in RELATIVITY-098 and RELATIVITY-047 (17.5% and 14.6%, respectively)⁷.

Results from RELATIVITY-047 established the superiority of nivolumab plus relatlimab over nivolumab in metastatic melanoma⁷⁻⁹. At a follow-up of 4 years, nivolumab plus relatlimab demonstrated a sustained PFS benefit (hazard ratio = 0.78; 95% confidence interval: 0.65–0.93) and a clinically meaningful overall survival benefit (hazard ratio = 0.77; 95% confidence interval: 0.64–0.94) compared to nivolumab⁹ while maintaining a tolerable safety profile. Although there was no added efficacy benefit for nivolumab plus relatlimab in resected melanoma in RELATIVITY-098, pharmacodynamic modulation of IFNγ and target engagement via a reduction in free soluble LAG-3 were similar to those observed in patients with advanced disease in RELATIVITY-047 (ref. 10). In addition, higher levels of biomarkers associated with inflammation (LAG-3 and CD8 expression) in baseline tumors enriched for RFS benefit in both treatment arms, similar to trends observed for PFS in patients with advanced melanoma in RELATIVITY-047 (ref. 9).

Comparative biomarker results from RELATIVITY-098 and RELATIVITY-047 explored why clinical activity differed between resected and advanced disease. In patients with advanced melanoma, there was a higher percentage of LAG-3⁺ and LAG-3⁺PD-1⁺CD8 T cells in tumor samples than in blood samples. In the blood, PD-1⁺CD8 T cells were much higher than LAG-3⁺CD8 T cells, whereas LAG-3⁺T cell levels and PD-1⁺CD8 T cell levels in the tumor were similar. The higher level of LAG-3⁺T cells in the blood of patients with advanced melanoma compared to patients with resected melanoma tumors suggested

that there were more T cells with a relatlimab ‘target’ in the advanced setting than in the resected disease setting, which may have been driven by the presence of tumor. Previous analysis in advanced melanoma revealed that response to nivolumab plus relatlimab, but not nivolumab, was associated with an on-treatment increase in LAG-3⁺T cells¹⁰. When comparing biomarker results from RELATIVITY-047 and RELATIVITY-098, there was a greater magnitude of on-treatment increase of LAG-3⁺T cells in the advanced disease setting than in the resected disease setting. In comparison, there were substantial levels of PD-1⁺T cells in the blood, and the on-treatment changes were similar between the two settings. Although informative, these analyses have inherent limitations preventing adequate conclusions to be drawn, including that multiplex CODEX analyses were not available for the RELATIVITY-098 study. This limitation prevented direct assessment of LAG-3⁺T cells within earlier-stage tumors, leading to insight inferred from the data generated in the advanced setting. The inferences drawn here need to be tested directly comparing resected tumor with blood in patients with adjuvant setting disease.

Published studies support the requirement of tumor presence for increased benefit with the addition of relatlimab to nivolumab, specifically during neoadjuvant therapy administered prior to surgery¹¹⁻¹³. Nivolumab plus relatlimab showed impressive activity as neoadjuvant therapy in a single-arm study in melanoma, with a major pathologic response rate of 63%¹¹, and in MMR-deficient colon cancer, with a major pathologic response rate of 92%¹². In addition, encouraging initial neoadjuvant activity was observed in a randomized phase 2 study with non-small cell lung cancer, with a major pathologic response rate of 30%¹³. Moreover, in advanced melanoma (RELATIVITY-047), responders to nivolumab plus relatlimab were associated with CD8⁺CD103⁺ gene expression signatures indicative of tissue-resident T cells¹⁰.

<footnote>ªThe safety population included all patients who had received at least one dose of a trial drug. Listed are events that were reported between the first dose and 30 days after the last dose. The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. ᵇCauses of deaths were gastrointestinal hemorrhage and sinusoidal obstructive syndrome (n=1) and myocarditis (n=1). ᶜCause of death was immune-mediated myocarditis and immune-mediated myositis (n=1).</footnote>
a

<figure><img src="image_8.png" /></figure>

b

<figure><img src="image_9.png" /></figure>

c

<figure><img src="image_10.png" /></figure>

<table><caption>**Fig. 3 | Pharmacodynamic and target engagement in the periphery for adjuvant treatment of melanoma.** **a**, Expression of serum cytokines.</caption><thead><tr><th></th><th>Baseline (BL)</th><th>4 wks P value vs BL</th><th>8 wks P value vs BL</th></tr></thead><tbody><tr><td>NIVO + RELA, n</td><td>457</td><td>442</td><td>422</td></tr><tr><td>NIVO, n</td><td>458</td><td>446</td><td>430</td></tr></tbody></table>

**b**, Expression of surface LAG-3⁺CD4 and CD8 T cells. **c**, Soluble LAG-3. **a**, Linear mixed-effect models per cytokine. Comparisons were between baseline and each on-treatment mean and of the mean of each arm for each timepoint.

**b**, Linear mixed-effect models per flow populations. Comparisons of mean of each arm for each timepoint. **c**, Linear mixed-effect models for free soluble

LAG-3. Comparisons were between baseline and each on-treatment mean and of the mean of each arm for each timepoint. Tests were two-sided *t*-tests for pairwise comparisons of estimated marginal means with 95% confidence interval (CI). No adjustment was made for multiple comparisons because each biomarker/timepoint was analyzed one at a time. NA, not applicable; NIVO, nivolumab; RELA, relatlimab; wks, weeks.
<figure><img src="image_11.png" /><figcaption>b</figcaption></figure>

<figure><img src="image_12.png" /><figcaption>c</figcaption></figure>

<figure><img src="image_13.png" /></figure>

**Fig. 4 | Comparative analysis of LAG-3' and PD-1' CD8 and CD4 T cells in metastatic and adjuvant treatment of melanoma.** a, Baseline PD-1', LAG-3' and PD-1'LAG-3' CD8 cells in tumor and blood in advanced melanoma (RELATIVITY-047). b, Baseline expression of PD-1', LAG-3' and PD-1'LAG-3' CD8 and CD4 cells in blood in advanced melanoma (RELATIVITY-047) and adjuvant-treated melanoma (RELATIVITY-098). c, Delta change of baseline to on-treatment expression of PD-1', LAG-3' and PD-1'LAG-3' CD8 and CD4 cells in blood in advanced and adjuvant-treated melanoma. a, Tumor CD8 frequencies

from CODEX/PhenoCycler. Blood frequencies from multiparametric flow cytometry. b, Figure is non-log mean and non-log median, and *n* is the number of patients with flow cytometry. Figure is the log-transformed frequencies of each population. c, Figure is non-log mean of delta and non-log median of delta, and *n* is the number of patients with flow cytometry. LAG-3' and LAG-3'PD-1' figures represent the log-transformed frequencies of each population. Statistical tests were two-sided Wilcoxon tests with no multiple comparisons. Error bars are s.e. of the estimated marginal means.
Along with nivolumab plus relatlimab, other immune check-
point inhibitor combinations have proven unsuccessful as melanoma
adjuvant therapy. The KeyVibe-010 trial, which investigated adjuvant
treatment with pembrolizumab plus the anti-TIGIT antibody vibos-
tolimab versus pembrolizumab monotherapy, met the prespecified
futility criteria for RFS and was terminated, with a higher rate of dis-
continuation in the combination arm due to immune-mediated adverse
events¹⁴,¹⁵. Moreover, treatment with nivolumab plus ipilimumab did
not meet the primary endpoint (RFS) of adjuvant therapy for melanoma
(CheckMate-915)¹⁶, whereas it was shown to be effective in neoadjuvant
therapy (NADINA)¹⁷. New modalities, such as mRNA vaccines, may
overcome some of the challenges associated with the lack of tumor
in the resected setting by mimicking the neoadjuvant state and elicit-
ing an immune response against preselected or personalized tumor
neoantigens¹⁸.

As mentioned, higher LAG-3 and CD8 expression in baseline
tumors in patients with resected melanoma (RELATIVITY-098) enriched
for RFS benefit in both the nivolumab plus relatlimab and nivolumab
arms. Interestingly, there were lower levels of these biomarkers in recur-
rent tumors than in baseline tumors (Supplementary Fig. 5a), suggest-
ing that recurring tumors were less inflamed. Moreover, patients with
recurrent disease demonstrated lower levels of these inflammatory
biomarkers in their baseline resected tumors (Supplementary Fig. 5b).

In conclusion, nivolumab plus relatlimab did not significantly
improve RFS compared to nivolumab in patients with resected stage
III/IV melanoma in RELATIVITY-098, despite nivolumab plus relatli-
mab having been proven to provide benefit in patients with advanced
melanoma. Translational evidence suggests that the presence of tumor
may be required for the benefit of nivolumab plus relatlimab com-
pared to nivolumab in melanoma. Nivolumab plus relatlimab remains
a standard-of-care option for patients with advanced melanoma.

Online content

Any methods, additional references, Nature Portfolio reporting sum-
maries, source data, extended data, supplementary information,
acknowledgements, peer review information; details of author contri-
butions and competing interests; and statements of data and code avail-
ability are available at https://doi.org/10.1038/s41591-025-04032-8.

References

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3. Eggermont, A. M. M. et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. *N. Engl. J. Med.* **378**, 1789-1801 (2018).

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7. Tawbi, H. A. et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. *N. Engl. J. Med.* **386**, 24–34 (2022).

8. Long, G. V. et al. Overall survival and response with nivolumab and relatlimab in advanced melanoma. NEJM Evid. **2**, EVIDoa2200239 (2023).

9. Lipson, E. J. et al. Nivolumab plus relatlimab in advanced melanoma: RELATIVITY-047 4-year update. *Eur. J. Cancer* **225**, 115547 (2025).

10. Lipson, E. J. et al. Unraveling relatlimab-specific biology using biomarker analyses in patients with advanced melanoma in RELATIVITY-047. *Clin. Cancer Res.* **31**, 3702–3714 (2025).

11. Amaria, R. N. et al. Neoadjuvant relatlimab and nivolumab in resectable melanoma. *Nature* **611**, 155–160 (2022).

12. de Gooyer, P. G. M. et al. Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial. *Nat. Med.* **30**, 3284–3290 (2024).

13. Schuler, M. et al. Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 trial. *Nat. Med.* **30**, 1602–1611 (2024).

14. Dummer, R. et al. Neoadjuvant anti-PD-1 alone or in combination with anti-TIGIT or an oncolytic virus in resectable stage IIIB-D melanoma: a phase 1/2 trial. *Nat. Med.* **31**, 144–151 (2025).

15. Merck provides update on phase 3 KeyVibe-010 trial evaluating an investigational coformulation of vibostolimab and pembrolizumab as adjuvant treatment for patients with resected high-risk melanoma. https://www.merck.com/news/merck-provides-update-on-phase-3-keyvibe-010-trial-evaluating-an-investigational-coformulation-of-vibostolimab-and-pembrolizumab-as-adjuvant-treatment-for-patients-with-resected-high-risk-melanoma/ (2024).

16. Weber, J. S. et al. Adjuvant therapy of nivolumab combined with ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or stage IV melanoma (CheckMate 915). *J. Clin. Oncol.* **41**, 517–527 (2023).

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**Open Access** This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

© The Author(s) 2025
¹Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. ²Bristol Myers Squibb, Princeton, NJ, USA. ³Istituto Nazionale dei Tumori IRCCS 'Fondazione G. Pascale', Napoli, Italy. ⁴Peking University Cancer Hospital & Institute, Beijing, China. ⁵Moffitt Cancer Center & Research Institute, Tampa, FL, USA. ⁶Northwestern University, Chicago, IL, USA. ⁷Vall d'Hebron Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. ⁸Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. ⁹Brazilian National Cancer Institute, Rio de Janeiro, Brazil. ¹⁰Memorial Sloan Kettering Cancer Center, New York, NY, USA. ¹¹National and Kapodistrian University of Athens, Athens, Greece. ¹²University of Zurich, Zurich, Switzerland. ¹³University Hospital Essen, National Center for Tumor Diseases (NCT-West), Campus Essen, German Cancer Consortium, Campus Essen, and University Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Essen, Germany.

¹⁴Paracelsus Medical University, Salzburg, Austria. ¹⁵CHU Nantes, Nantes University and Immunology and New Concepts in ImmunoTherapy (INCIT), Nantes, France. ¹⁶EDOEAP, Athens, Greece. ¹⁷Bristol Myers Squibb, Uxbridge, UK. ¹⁸The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

<figure><img src="image_14.png" /></figure>

e-mail: georgina.long@sydney.edu.au
# Methods

## Trial oversight and ethics approval

The protocol and amendments for this trial (available in the Supplementary Information) were reviewed by the institutional review board or independent ethics committee for each trial site, and all patients provided written informed consent before enrollment. The trial was conducted in accordance with International Council for Harmonization Good Clinical Practice guidelines and was designed by the trial steering committee and the sponsor. Data were collected by the sponsor and analyzed in collaboration with the authors who vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. An independent data monitoring committee was established to provide oversight to assess the efficacy and safety profile of nivolumab plus relatlimab and nivolumab. All authors contributed to drafting the manuscript, provided critical review and gave final approval to submit the manuscript for publication. Professional medical writing and editorial assistance were funded by the sponsor.

## Patients

Eligible patients were at least 12 years of age with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 and stage IIIA (>1-mm tumor in lymph node), stage IIIB/C/D or stage IV (no evidence of disease) melanoma (per the American Joint Committee on Cancer (AJCC) Cancer Staging Manual (eighth edition) (AJCC-8))¹⁹ completely resected <90 days from randomization. Patient exclusions included prior treatment for melanoma other than surgery; adjuvant brain radiotherapy or adjuvant interferon; prior immunotherapy for any malignancy; concurrent prior malignancy within 2 years of randomization; ocular melanoma, except conjunctival melanoma; or any condition requiring treatment with a systemic corticosteroid within 14 days, or other immunosuppressive medications within 30 days, of randomization.

## Trial design, treatment and endpoints

RELATIVITY-098 was a double-blind phase 3 trial with patients randomly assigned in a 1:1 ratio to receive 480 mg of nivolumab plus 160 mg of relatlimab as FDC or 480 mg of nivolumab administered via intravenous infusion every 4 weeks for a maximum of 1 year (or ≤13 doses) or until recurrence of disease, unacceptable adverse events or withdrawal of consent. Patients were stratified according to AJCC-8 stage (IIIA/IIIB or IIIC or IIID/IV (including mucosal melanoma)) and geographic region (United States/Canada/Australia or Europe or rest of the world). Randomization was carried out via permutated blocks within each stratum. The sponsor, participants, investigator and site staff were blinded to the study therapy administered.

The primary endpoint was investigator-assessed RFS, with computed tomography scans performed every 12 weeks for 2 years and then twice a year; patients who did not undergo complete lymph node dissection required ultrasound surveillance. Overall survival was the key secondary endpoint to be hierarchically tested if the primary endpoint was met. Other secondary endpoints included investigator-assessed DMFS, PFS through next-line therapy and safety. The severity of adverse events was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Included TRAES are those reported between the first dose and 30 days after the last dose. In addition, immune-mediated adverse events and adverse events of special interest reported between the first dose and 135 days after the last dose are reported per category.

## Exploratory translational endpoints

Biomarker analyses were exploratory and were performed on patient blood samples from RELATIVITY-098 and RELATIVITY-047 at baseline and on treatment to assess expression or expansion of biomarker-specific immune cell populations and soluble proteins. The RELATIVITY-047 study (NCT03470922) was previously published⁷⁻⁹ and

can be referred to for additional information on the RELATIVITY-047 study, including study compliance and a link to the protocol. In brief, eligible patients were ≥12 years of age with previously untreated, unresectable stage III or IV melanoma and had tumor tissue that was evaluable for LAG-3 and programmed death ligand 1 (PD-L1) expression. Enrolled patients were randomly assigned 1:1 to receive 480 mg of nivolumab and 160 mg of relatlimab as an FDC or 480 mg of nivolumab alone, administered intravenously every 4 weeks until disease progression, unacceptable adverse effects or withdrawal of consent. Random assignment was stratified according to LAG-3 expression (≥1% or <1%), PD-L1 expression (≥1% or <1%), BRAF V600 mutation status and metastasis stage (M0 or M1 with normal lactate dehydrogenase (LDH) levels versus M1 with elevated LDH levels).

Cytokines and free soluble LAG-3 were measured in whole blood serum samples from RELATIVITY-098 at baseline and on treatment to assess pharmacodynamic activity and target engagement. On-treatment samples in general were taken at cycle 2, day 1 (C2D1), with samples also taken for select analyses on day 1 of cycles 3, 6 and 9.

Analyses of patient tumor samples from RELATIVITY-047 were performed by CODEX/PhenoCycler system to assess expression of marker-specific CD8 T cells. Images were analyzed using HALO AI to segment cells and measure mean marker intensities per cell (Indica Labs). Cell segmentation used a deep learning model trained on DAPI-stained images to segment nuclei, and the cytoplasm compartment was approximated as a 3-µm radius from segmented nuclei. Segmented cells were classified into broad lineages (that is, tumor, immune and other) using a secondary deep learning image classifier model trained on SOX10, CD45, PCNA, Collagen IV and DAPI channels. For each cell, the mean intensities per cellular compartment (that is, nuclear and cytoplasmic) were measured and exported into a tabular format for subsequent phenotyping in R. Cell phenotyping was computed in R by thresholding marker intensities (for example, CD3, CD4 and CD8) and deriving cell classes through logical combinations of binarized markers with the broad cell lineages (tumor, immune and other), resolving conflicts by prioritizing markers with cleaner segmentation profiles.

LAG-3 and PD-1 expression on CD8 and CD4 T cells in the peripheral blood was analyzed on a five-laser Cytek Aurora system (Cytek Biosciences) using a 25-color LAG-3-specific immunophenotyping panel. Flow cytometric analysis for RELATIVITY-047 and RELATIVITY-098 was performed in an exploratory manner. Pre-treatment and on-treatment frozen peripheral blood mononuclear cell (PBMC) samples (RELATIVITY-047) or whole blood (RELATIVITY-098) from patients were sent for immunophenotypic analysis at Q2 Solutions in Atlanta, Georgia. In brief, samples were thawed, stained using a custom antibody panel and subsequently acquired on a five-laser Aurora spectral cytometer from Cytek Biosciences. Data were analyzed in the OMIQ platform from Dotmatics using a hierarchical gating strategy to remove non-cellular debris, spectral artifacts, dead cells and non-lymphocytes before T cell (CD3⁺CD56⁻CD4⁺CD8⁻ and CD3⁺CD56⁻CD4⁻CD8⁺) subsets of interest were identified using specific markers and reported out as relative frequencies. A PBMC sample from the same presumed normal healthy volunteer was included in all experiments to ensure inter-assay consistency.

Peripheral biomarker levels (for example, cytokines and peripheral flow cytometry) were analyzed using linear mixed-effect models for pharmacodynamic changes. Separate models were fitted for each treatment arm to evaluate changes over time, with biomarker concentration/frequency as the dependent variable, study timepoints (for example, screening, C2D1, etc.) as fixed effects and participant-specific random intercepts to account for repeated measures. Within each arm, pairwise contrasts were used to estimate the difference between the screening and each on-treatment timepoint. In addition, differences between treatment arms were assessed at each timepoint.
Tumor biomarker expression was assessed at baseline and at recurrence via immunohistochemistry. Monoplex immunohistochemistry staining was used to evaluate PD-L1, LAG-3 and CD8 expression in resected and recurrent tumor samples from RELATIVITY-098.

## Statistical analysis

An approximate sample size of 1,050 patients was planned to achieve the required 410 RFS events and show a significant difference in investigator-assessed RFS with a two-sided α of 0.05 using a stratified log-rank test with at least 90% statistical power when the average hazard ratio of nivolumab and relatlimab FDC versus nivolumab was 0.72 and an assumed cure rate of 0.52 in the nivolumab arm. The actual events were 427, with a critical hazard ratio of 0.815 and cumulative power of 91.5%. Two interim analyses were performed at a cumulative power of 48% (12 February 2024) and 77% (29 July 2024), but the study had remained blinded. The study significance boundaries were based on an O'Brien–Fleming alpha spending function.

A key secondary endpoint of overall survival was to have been tested hierarchically by stratified log-rank test if the primary endpoint was met. At the time of final RFS analysis, there were 148 deaths, representing 48% of the information fraction.

RFS was compared using a two-sided log-rank test on all randomized patients; hazard ratio and confidence intervals were estimated using a stratified Cox proportional hazards model and survival curves using Kaplan–Meier methodology. Hazard ratio and confidence intervals were estimated using a non-stratified Cox proportional hazards model on the prespecified subgroup analyses of patients. DMFS was similarly compared on a subset of patients defined as those with resected stage III–IVA–IVB melanoma. For biomarker analyses, the Wilcoxon test was used to compare frequencies of T cells in tumor and blood samples and between patients with resected melanoma (RELATIVITY-098) and advanced melanoma (RELATIVITY-047).

Efficacy analysis populations were as stated above. Safety was assessed in all patients who received at least one dose of study drug. Biomarker analyses were performed on patients for whom samples and biomarker data were available. Data collection software used was Meddata Classic Rave (version 2025). All clinical analyses were performed using SAS software (SAS Institute) and R version 4.3.1. Differences in biomarker levels between baseline and recurrence were evaluated using the Wilcoxon signed-rank test. Baseline biomarker expression was also compared between patients with recurrence and those censored (no recurrence) using the Wilcoxon rank-sum test. All statistical tests were two-sided, and *P* < 0.05 was considered significant.

## Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

## Data availability

Bristol Myers Squibb will honor legitimate requests for our clinical trial data from qualified researchers with a clearly defined scientific objective. We share data from phase 2–4 interventional clinical trials completed on or after 1 January 2008 and evaluate medicines and indications approved in the United States, the European Union and other designated markets. Data shared may include non-identifiable patient-level and study-level clinical trial data, full clinical study reports and protocols. Sharing is subject to protection of patient privacy and respect for patient informed consent and publication of the primary results in peer-reviewed journals. Bristol Myers Squibb reserves the right to update and change criteria at any time. Other criteria may apply. For details, please visit Bristol Myers Squibb at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html. The option to submit data requests as well as review criteria for data requests are available at

https://vivli.org/ourmember/bristol-myers-squibb/. The study protocol of RELATIVITY-098 is provided in the Supplementary Information.

## References

19. American Joint Committee on Cancer (AJCC) Cancer Staging Manual, Eighth edn (eds Amin, M. B. et al.) (Springer, 2018).

## Acknowledgements

The RELATIVITY-098 trial was funded by Bristol Myers Squibb, which collected the data and analyzed the data in collaboration with the authors. We thank the patients and investigators who participated in the RELATIVITY-098 trial. We acknowledge ONO Pharmaceutical Company, Ltd. for contributions to nivolumab development and Dako, an Agilent Technologies, Inc., company, for collaborative development of the PD-L1 immunohistochemistry 28-8 pharmDx assay. We would like to acknowledge N. Eddy, P. H. Chen and B. Chen of Bristol Myers Squibb for their contributions to the biomarker analyses and A. Menzies of Melanoma Institute Australia, The University of Sydney and Royal North Shore and Mater Hospitals for his contribution to the clinical trial. Professional medical writing and editorial assistance were provided by M. Kirk and M. Salernitano of Ashfield MedComms, an Inizio Company, funded by Bristol Myers Squibb; specifically, M. Kirk assisted with the development of the first draft and subsequent revisions, under the direction of the authors, and M. Salernitano provided editorial support for formatting and submission.

## Author contributions

G.V.L., C.G.-B., S.D., P.A., J.G., A.A.T., S.C., E.M.-C., A.C.d.M., M.C., J.X.Y., A.F., P.D., A.M.Y.C. and T.A.H. designed the RELATIVITY-098 study in collaboration with the sponsor, Bristol Myers Squibb. G.V.L., P.A., J.G., S.C., E.M.-C., M.D.V., A.C.d.M., M.C., H.G., R.D., D.S., P.K., G.Q., I.T., J.X.Y., A.F. and T.A.H. contributed to data acquisition. J.X.Y., A.F., P.D. and A.C. contributed to data analysis. G.V.L., C.G.-B., S.D., P.A., J.G., A.A.T., S.C., E.M.-C., M.D.V., A.C.d.M., M.C., H.G., R.D., D.S., P.K., G.Q., I.T., J.X.Y., A.F., P.D., A.C., M.S., B.C., A.M.Y.C., B.W. and H.A.T. contributed to data interpretation. The initial manuscript was written in collaboration with G.V.L., T.A.H., C.G.-B. and S.D., and all authors contributed to subsequent drafts and provided final approval before submission. All authors vouch for the accuracy and completeness of the analyses and data reported.

## Funding

Open access funding provided by the University of Sydney.

## Competing interests

G.V.L. discloses consulting fees from Agenus Inc., AstraZeneca, Bayer HealthCare, BioNTech, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion A/S, Fortiva Biologics (USA), GI Innovation, Hexal AG (Sandoz Company), Highlight Therapeutics, IO Biotech, Immunocore Ireland Limited, Innovent Biologics USA Inc., Merck Sharp & Dohme (Australia) Pty Limited, Novartis, PHMR Limited, Pierre Fabre, Regeneron, Scancell, SkylineDX and Strand Therapeutics Inc. and honoraria from Bristol Myers Squibb and Pierre Fabre. C.G.-B., S.D., J.X.Y., A.F., B.W., P.D., A.C., M.S., B.C. and A.M.Y.C. are employees of and hold stock in Bristol Myers Squibb. P.A.A. discloses grants or contracts from Bristol Myers Squibb, Medicenna Therapeutics, Pfizer, Regeneron and Roche-Genentech; consulting fees from BioAI Health, BioNTech, Bristol Myers Squibb, Incyte, ITALFARMACO, Medicenna Therapeutics, Merck KGaA, Merck Sharp & Dohme, Novartis, Philogen, Pfizer, Pierre Fabre, Regeneron, Replimune, Roche-Genentech, Sanofi, Sun Pharma and ValoTx; support for meeting attendance and/or travel from Merck Sharp & Dohme, Philogen, Pierre Fabre and Replimune; and participation on a Data Safety Monitoring Board or Advisory Board for Anaveon, Boehringer Ingelheim International GmbH, Bristol
Myers Squibb, Erasca, Genmab, ImCheck Therapeutics, Menarini Group, Merck Sharp & Dohme, Nouscom, Novartis, Regeneron and Roche-Genentech. J.G. discloses honoraria from Bayer HealthCare, Merck Sharp & Dohme, Novartis, OrienGene, Pfizer, Roche, Shanghai Junshi Bioscience and Simcere. A.A.T. discloses grants or contracts with their institution from Acrotech, Agenus Inc., Bristol Myers Squibb, Dragonfly Therapeutics, Iovance Biotherapeutics, Merck, Moderna, OncoResponse, OncoSec, Regeneron, Roche-Genentech, Pfizer, Sanofi Genzyme, Scholar Rock and Werewolf Therapeutics Inc. and consulting fees from Bristol Myers Squibb, ConcertAl, Merck, Moderna, OncoSec, Regeneron and Sanofi Genzyme. S.C. discloses participation on an Advisory Board for Alkermes, Bristol Myers Squibb, CelltrionUSA, Immunocore, Merck, Moderna, Novartis, Pfizer, Regeneron and Sun Pharma. E.M.-C. discloses consulting fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, PharmaMar, Pierre Fabre, Regeneron, Replimune, Roche and Sanofi; honoraria from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre and Regeneron; and meeting attendance and/or travel support from Merck Sharp & Dohme and Pierre Fabre. M.D.V. discloses consulting fees from Bristol Myers Squibb, Immunocore, Merck Sharp & Dohme, Novartis, Pierre Fabre and Regeneron; honoraria from Bristol Myers Squibb, Immunocore, Merck Sharp & Dohme, Novartis, Pierre Fabre and Regeneron; meeting attendance and/or travel support from Merck Sharp & Dohme and Pierre Fabre; and participation on an Advisory board for Bristol Myers Squibb and Merck Sharp & Dohme. A.C.d.M. discloses grants or contracts with their institution from Amgen, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Daiichi-Sankyo, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Regeneron and Roche; honoraria from AbbVie, Adium Pharma, AstraZeneca, Bristol Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Merck Sharp & Dohme, Novartis and Pfizer; meeting attendance and/or travel support from AbbVie, AstraZeneca, Daiichi-Sankyo and Merck Sharp & Dohme; and participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Bristol Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Merck Sharp & Dohme, Novartis and Roche. M.C. has received consulting fees from Bristol Myers Squibb, Merck, InCyte, Moderna, ImmunoCore and AstraZeneca; receives institutional support from Bristol Myers Squibb; and has a family member who is employed by Merus. H.G. discloses grants or contracts from Amgen, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme and Pfizer; honoraria from Merck Sharp & Dohme, Bristol Myers Squibb and Pierre Fabre; support for meeting attendance and/or travel from Bristol Myers Squibb, Merck Sharp & Dohme and Pierre Fabre; and participation on a Data Safety Monitoring Board or Advisory Board for Bristol Myers Squibb, Merck Sharp & Dohme and Regeneron. R.D. discloses a consulting or advisory role with Amgen, Bristol Myers Squibb, Catalym, Merck Sharp & Dohme, MaxiVAX SA, Novartis, Pfizer, Pierre Fabre, Regeneron, Roche, Sanofi, Second Genome, Simcere, Sun Pharma, T3 Pharma and Takeda and a senior medical advisor role with Oncobit. D.S. discloses consulting fees from 4SC, AstraZeneca, BioAlta, Boehringer Ingelheim International GmbH, BioNTech, Bristol Myers Squibb, Daiichi-Sankyo, Erasca, Fomycon, Immatics, Immunocore, InFlarX, IO Biotech, Iovance, Ipsen, Labcorp, Merck KGaA, Merck Sharp & Dohme, Neracare, Novartis,

Pfizer, Philogen, Pierre Fabre, Regeneron, Replimune, Sanofi, Seagen, SkylineDx and Sun Pharma; honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Pierre Fabre, Pfizer, InFlarX, Regeneron and Sun Pharma; travel support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Pierre Fabre and Regeneron; participation in a Data Safety Monitoring or Advisory Board with 4SC, AstraZeneca, BioNTech, Bristol Myers Squibb, Daiichi-Sankyo, Immatics, Immunocore, InFlarX, Iovance, Labcorp, Merck Sharp & Dohme, Neracare, Novartis, Pfizer, Philogen, Pierre Fabre, Regeneron, Replimune, Sanofi, SkylineDx and Sun Pharma; unpaid leadership role with Dermatologic Cooperative Group, EuMelaREg, NVKH and Deutsche Hautkrebsstiftung/Hiege-Stiftung; and grants to his institution from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme and Novartis. P.K. discloses consulting fees from Bristol Myers Squibb, Merck Sharp & Dohme and Pierre Fabre; payment for expert testimony from Merck Sharp & Dohme; meeting attendance and/or travel support from Bristol Myers Squibb, Merck Sharp & Dohme and Pierre Fabre; and participation on a Data Safety Monitoring Board or Advisory Board for Bristol Myers Squibb and Merck Sharp & Dohme. G.Q. discloses consulting fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Incyte, Checkpoint Therapeutics and Regeneron. I.T. discloses grants or contracts with their institution from 4SC, Amgen, ARGN-X, AstraZeneca, Biotech, BioNTech, Bristol Myers Squibb, CerpassRx, CureVac, Genentech, HUYA, Incyte, Idera, Iovance, InflaRx, Kartos Therapeutics, LEO Pharma, Merck Sharp & Dohme, Nektar Therapeutics, Novartis, Pfizer, Philogen, Pierre Fabre, Regeneron, Replimune, Roche, Sanofi and UCB; honoraria from Bristol Myers Squibb and Pierre Fabre; and participation on a Data Safety Monitoring Board or Advisory Board for Bristol Myers Squibb and Pierre Fabre. H.A.T. discloses grants or contracts from Dragonfly Therapeutics, Eisai, Genentech, GlaxoSmithKline, Merck, Novartis, Regeneron and Syntrix and consulting fees from Bristol Myers Squibb, Corcept Therapeutics, Eisai, Immunocore, IO Biotech, Iovance, Krystal Biotech, Medicenna Therapeutics, Merck, Novartis, Regeneron, Pfizer, Strand Therapeutics and T-Knife Therapeutics.

**Additional information**

**Extended data** is available for this paper at
[https://doi.org/10.1038/s41591-025-04032-8](https://doi.org/10.1038/s41591-025-04032-8).

**Supplementary information** The online version contains supplementary material available at [https://doi.org/10.1038/s41591-025-04032-8](https://doi.org/10.1038/s41591-025-04032-8).

**Correspondence and requests for materials** should be addressed to Georgina V. Long.

**Peer review information** *Nature Medicine* thanks Marco Donia, Tara Mitchell and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ulrike Harjes, in collaboration with the *Nature Medicine* team.

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<table><thead><tr><th></th><th>NIVO + RELA<br>(n = 547)</th><th>NIVO<br>(n = 546)</th></tr></thead><tbody><tr><td>Events</td><td>81</td><td>67</td></tr><tr><td>mOS, mo</td><td>NR</td><td>NR</td></tr><tr><td>(95% CI)</td><td>(NR-NR)</td><td>(36.8-NR)</td></tr><tr><td>HR (95% CI)</td><td>1.24 (0.90-1.72)</td><td></td></tr></tbody></table>

<figure><img src="image_15.png" /></figure>

**Extended Data Fig. 1 | OS.** Kaplan-Meier estimates of OS defined as the time between randomization and death. Symbols (circles) indicate censored data. Dashed lines indicate landmark analyses. mOS, median OS; NIVO, nivolumab; NR, not reached; RELA, relatlimab.
<table><thead><tr><th rowspan="2">Subgroup</th><th rowspan="2"></th><th rowspan="2">N</th><th>NIVO + RELA</th><th>NIVO</th><th>Unstratified</th></tr><tr><th>No. of events (No. of patients)</th><th>No. of events (No. of patients)</th><th>HR (95% CI) NIVO + RELA vs NIVO</th></tr></thead><tbody><tr><td>Overall</td><td>Overall</td><td>1093</td><td>214 (547)</td><td>213 (546)</td><td>1.01 (0.83-1.22)</td></tr><tr><td rowspan="3">Age, years</td><td>≥ 18 and &lt; 65</td><td>722</td><td>129 (354)</td><td>139 (368)</td><td>0.97 (0.76-1.23)</td></tr><tr><td>≥ 65 and &lt; 75</td><td>263</td><td>60 (136)</td><td>53 (127)</td><td>1.06 (0.73-1.53)</td></tr><tr><td>≥ 75</td><td>108</td><td>25 (57)</td><td>21 (51)</td><td>1.12 (0.63-2.00)</td></tr><tr><td rowspan="2">Sex</td><td>Male</td><td>642</td><td>131 (327)</td><td>127 (315)</td><td>0.99 (0.78-1.27)</td></tr><tr><td>Female</td><td>451</td><td>83 (220)</td><td>86 (231)</td><td>1.03 (0.76-1.39)</td></tr><tr><td rowspan="3">AJCC v8 stage at study entry</td><td>Stage IIIA/IIIB</td><td>408</td><td>62 (209)</td><td>61 (199)</td><td>0.96 (0.68-1.37)</td></tr><tr><td>Stage IIIC</td><td>541</td><td>120 (270)</td><td>123 (271)</td><td>1.00 (0.78-1.29)</td></tr><tr><td>Stage IIID/IV</td><td>144</td><td>32 (68)</td><td>29 (76)</td><td>1.21 (0.73-2.00)</td></tr><tr><td rowspan="4">Melanoma subtype at study entry</td><td>Cutaneous nonacral</td><td>890</td><td>148 (436)</td><td>172 (454)</td><td>0.87 (0.70-1.09)</td></tr><tr><td>Cutaneous acral</td><td>113</td><td>42 (61)</td><td>30 (52)</td><td>1.26 (0.79-2.02)</td></tr><tr><td>Mucosal</td><td>18</td><td>7 (10)</td><td>3 (8)</td><td>—</td></tr><tr><td>Unknown primary</td><td>70</td><td>15 (38)</td><td>8 (32)</td><td>1.91 (0.81-4.53)</td></tr><tr><td rowspan="3">Geographic region</td><td>USA/CAN/AUS</td><td>241</td><td>40 (121)</td><td>45 (120)</td><td>0.85 (0.56-1.31)</td></tr><tr><td>Europe</td><td>637</td><td>121 (318)</td><td>121 (319)</td><td>1.01 (0.78-1.30)</td></tr><tr><td>Rest of world</td><td>215</td><td>53 (108)</td><td>47 (107)</td><td>1.18 (0.80-1.75)</td></tr><tr><td rowspan="2">Baseline ECOG PS</td><td>0</td><td>992</td><td>188 (494)</td><td>194 (498)</td><td>0.96 (0.79-1.18)</td></tr><tr><td>1</td><td>101</td><td>26 (53)</td><td>19 (48)</td><td>1.43 (0.79-2.59)</td></tr><tr><td rowspan="2">Baseline PD-L1 status</td><td>≥ 1%</td><td>259</td><td>38 (136)</td><td>31 (123)</td><td>1.22 (0.75-1.97)</td></tr><tr><td>&lt; 1%</td><td>655</td><td>143 (315)</td><td>148 (340)</td><td>1.05 (0.84-1.32)</td></tr><tr><td rowspan="2">Baseline LAG-3 status</td><td>≥ 1%</td><td>704</td><td>129 (352)</td><td>117 (352)</td><td>1.15 (0.90-1.48)</td></tr><tr><td>&lt; 1%</td><td>271</td><td>64 (126)</td><td>79 (145)</td><td>0.86 (0.62-1.20)</td></tr><tr><td rowspan="2">Baseline BRAF status</td><td>Mutant</td><td>437</td><td>86 (220)</td><td>93 (217)</td><td>0.91 (0.68-1.22)</td></tr><tr><td>Wild-type</td><td>395</td><td>78 (195)</td><td>81 (200)</td><td>0.96 (0.71-1.32)</td></tr><tr><td rowspan="2">Baseline LDH level</td><td>≤ ULN</td><td>982</td><td>189 (496)</td><td>191 (486)</td><td>0.97 (0.79-1.18)</td></tr><tr><td>&gt; ULN</td><td>106</td><td>24 (49)</td><td>22 (57)</td><td>1.28 (0.72-2.29)</td></tr></tbody></table>

<figure><img src="image_16.png" /></figure>

**Extended Data Fig. 2 | RFS according to prespecified subgroups.** Shown is a forest plot of hazard ratios for disease recurrence or death among prespecified subgroups of patients in the nivolumab plus relatlimab group and nivolumab group. The hazard ratios were not stratified according to the stratification factors. The horizontal lines indicate 95% confidence intervals with the hazard

ratio represented by the center dot. AJCC-8, American Joint Committee on Cancer; *Cancer Staging Manual*, Eighth Edition; ECOG PS, Eastern Cooperative Oncology Group performance status; LAG-3, lymphocyte activation gene 3; LDH, lactate dehydrogenase; NIVO, nivolumab; RELA, relatlimab.
<figure><img src="image_17.png" /></figure>

**Extended Data Fig. 3** | Decrease in Soluble LAG-3 Levels Driven by Relatlimab Trough Concentration (Ctrough) Exposure. Center lines represent medians, the bounds of the boxes indicate the 25th and 75th percentiles, the whiskers represent the minima and maxima, and dots represent outliers; baseline = last

non-missing result with a collection date-time less than or equal to the date-
time of the first active dose of study medication; Q1 = [0.0892-8.7000);
Q2 = [8.7000-13.2790); Q3 = [13.2790-19.5397); Q4 = [19.5397-50.5000].
<figure><img src="image_18.png" /></figure>

**Extended Data Fig. 4 | Pharmacodynamics Heat Map for Serum Factors in Patients with Melanoma treated with Adjuvant Nivolumab plus Relatlimab versus Nivolumab Alone in RELATIVITY-098.** The figure presents a heatmap summarizing linear mixed effect models for a cytokine panel separated by treatment arm. Each individual box represents the statistical comparison

between the on-treatment time point on the x-axis with the baseline time point, colored by the difference in means, in which blue is lower on treatment and red is higher on-treatment. C, cycle; D, day; ns, not significant/P > 0.1.

*P* ≤ 0.1(trending), *P* ≤ 0.05, **P* ≤ 0.01, ***P* ≤ 0.001, and ****P* ≤ 0.0001.
a

<figure><img src="image_19.png" /></figure>

<figure><img src="image_20.png" /></figure>

b

<figure><img src="image_21.png" /></figure>

<figure><img src="image_22.png" /></figure>

c

<figure><img src="image_23.png" /></figure>

<figure><img src="image_24.png" /></figure>

<figure><img src="image_25.png" /></figure>

**Extended Data Fig. 5 | RFS Association with Baseline TME Biomarkers.**

a, Association with LAG-3 within treatment arms. b, Association with CD8 within treatment arms. c, Association with CD8 between treatment arms. CD8 density is defined as CD8 positive cells/mm². Statistical testing is two-sided log-rank

test with no multiple comparisons and error bars are 95% confidence interval. CD, cluster of differentiation; LAG-3, lymphocyte activation gene 3; TME, tumor microenvironment.
a

<figure><img src="image_26.png" /></figure>

b

<figure><img src="image_27.png" /></figure>

Extended Data Fig. 6 | See next page for caption.
**Extended Data Fig. 6** | **Evaluation of CD8 and LAG-3 Biomarkers in Baseline and Recurrent Tumors.** a, CD8 and LAG-3 expression overall in baseline vs early recurrent tumors. b, Baseline expression of CD8 and LAG-3 in patients who did not have a recurrence vs those who had an early recurrence (prior to the minimum follow-up of 23.4 months). a, Box plot of screening/baseline versus recurrent CD8% and LAG3% in pooled treatment arms. The figure shows each

biomarker, visit, and frequency of patients below and above the 1% cutoff.
b, Negative(n) indicates number of patients with <1% immunohistochemistry and N indicates number of patients with immunohistochemistry. Box plot shows 25%, 50% and 75% quartiles and statistical tests are two-sided Wilcoxon with no multiple comparisons.CD, cluster of differentiation; LAG-3, lymphocyte activation gene 3.
Extended Data Table 1 | Subsequent treatment in all patients who underwent randomizationª

<table><thead><tr><th>Treatment</th><th>Nivolumab Plus Relatlimab (n=547)</th><th>Nivolumab (n=546)</th></tr></thead><tbody><tr><td>Any subsequent therapy, n (%)</td><td>183 (33.5)</td><td>196 (35.9)</td></tr><tr><td>Any subsequent systemic therapy</td><td>148 (27.1)</td><td>155 (28.4)</td></tr><tr><td>PD1/CTLA-4 inhibitors</td><td>76 (13.9)</td><td>92 (16.8)</td></tr><tr><td>Targeted BRAF/MEK (monotherapy and combination therapy)</td><td>64 (11.7)</td><td>58 (10.6)</td></tr><tr><td>Other</td><td>42 (7.7)</td><td>34 (6.2)</td></tr><tr><td>Subsequent radiotherapy</td><td>36 (6.6)</td><td>50 (9.2)</td></tr><tr><td>Subsequent surgery</td><td>84 (15.4)</td><td>103 (18.9)</td></tr></tbody></table>

<footnote>ªPatients may have received more than one type of post-protocol therapy, and more than one agent within each type. All percentages are based on the total number of patients in each arm. CTLA-4, cytotoxic T-lymphocyte antigen 4; PD-1, programmed death-1.</footnote>
Extended Data Table 2 | Pattern of recurrence

<table><thead><tr><th></th><th>Nivolumab Plus<br>Relatlimab<br>(n=547)</th><th>Nivolumab<br>(n=546)</th></tr></thead><tbody><tr><td><strong>First Recurrence</strong></td><td></td><td></td></tr><tr><td>Number of events, n (%)</td><td>214 (39.1)</td><td>213 (39.0)</td></tr><tr><td>Type of events, n (%)</td><td></td><td></td></tr><tr><td>Recurrence<sup>a</sup></td><td>201 (36.7)</td><td>206 (37.7)</td></tr><tr><td>Distant recurrence</td><td>104 (19.0)</td><td>109 (20.0)</td></tr><tr><td>Regional node recurrence</td><td>53 (9.7)</td><td>51 (9.3)</td></tr><tr><td>Local recurrence</td><td>16 (2.9)</td><td>16 (2.9)</td></tr><tr><td>In-transit metastasis</td><td>21 (3.8)</td><td>22 (4.0)</td></tr><tr><td>New primary invasive melanoma</td><td>7 (1.3)</td><td>8 (1.5)</td></tr><tr><td>Death prior to recurrence</td><td>13 (2.4)</td><td>7 (1.3)</td></tr></tbody></table>

<footnote>aFor patients who had multiple recurrences identified on the same day, the most serious type is tabulated according to the displayed prespecified hierarchy.</footnote>
Extended Data Table 3 | Immune-mediated adverse events by categoryª

<table><thead><tr><th rowspan="2">Category, n (%)</th><th colspan="2">Nivolumab Plus Relatlimab (n=543)</th><th colspan="2">Nivolumab (n=545)</th></tr><tr><th>Any Grade</th><th>Grade 3 or 4</th><th>Any Grade</th><th>Grade 3 or 4</th></tr></thead><tbody><tr><td>Hypothyroidism/thyroiditis</td><td>158 (29.1)</td><td>3 (0.6)</td><td>93 (17.1)</td><td>0</td></tr><tr><td>Hyperthyroidism</td><td>96 (17.7)</td><td>2 (0.4)</td><td>56 (10.3)</td><td>0</td></tr><tr><td>Hypophysitis</td><td>51 (9.4)</td><td>16 (2.9)</td><td>13 (2.4)</td><td>3 (0.6)</td></tr><tr><td>Rash</td><td>49 (9.0)</td><td>4 (0.7)</td><td>40 (7.3)</td><td>4 (0.7)</td></tr><tr><td>Adrenal insufficiency</td><td>33 (6.1)</td><td>6 (1.1)</td><td>9 (1.7)</td><td>1 (0.2)</td></tr><tr><td>Diarrhea/colitis</td><td>28 (5.2)</td><td>13 (2.4)</td><td>21 (3.9)</td><td>7 (1.3)</td></tr><tr><td>Hepatitis</td><td>26 (4.8)</td><td>17 (3.1)</td><td>17 (3.1)</td><td>10 (1.8)</td></tr><tr><td>Thyroiditis</td><td>18 (3.3)</td><td>0</td><td>14 (2.6)</td><td>0</td></tr><tr><td>Hypersensitivity</td><td>12 (2.2)</td><td>1 (0.2)</td><td>2 (0.4)</td><td>0</td></tr><tr><td>Diabetes mellitus</td><td>11 (2.0)</td><td>7 (1.3)</td><td>8 (1.5)</td><td>6 (1.1)</td></tr><tr><td>Pneumonitis</td><td>8 (1.5)</td><td>3 (0.6)</td><td>10 (1.8)</td><td>2 (0.4)</td></tr><tr><td>Nephritis and renal dysfunction</td><td>3 (0.6)</td><td>1 (0.2)</td><td>3 (0.6)</td><td>2 (0.4)</td></tr></tbody></table>

<footnote>ªThe safety population included all patients who had received at least one dose of a trial drug. Listed are events that were reported between the first dose and 135 days after the last dose. Includes patients with immune-mediated adverse events where immune modulating medication was initiated by category. The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.</footnote>
Extended Data Table 4 | Other adverse events of special interest by categoryª

<table><thead><tr><th rowspan="2">Category, n (%)</th><th colspan="2">Nivolumab Plus Relatlimab (n=543)</th><th colspan="2">Nivolumab (n=545)</th></tr><tr><th>Any Grade</th><th>Grade 3 or 4</th><th>Any Grade</th><th>Grade 3 or 4</th></tr></thead><tbody><tr><td>Myositis/rhabdomyolysis event<sup>b</sup></td><td>13 (2.4)</td><td>7 (1.3)</td><td>5 (0.9)</td><td>0</td></tr><tr><td>Myocarditis event<sup>c</sup></td><td>11 (2.0)</td><td>6 (1.1)</td><td>5 (0.9)</td><td>1 (0.2)</td></tr><tr><td>Pancreatitis event</td><td>6 (1.1)</td><td>2 (0.4)</td><td>3 (0.6)</td><td>2 (0.4)</td></tr><tr><td>Myasthenic syndrome</td><td>4 (0.7)</td><td>4 (0.7)</td><td>1 (0.2)</td><td>1 (0.2)</td></tr><tr><td>Autoimmune cytopenia</td><td>2 (0.4)</td><td>2 (0.4)</td><td>0</td><td>0</td></tr><tr><td>Demyelination event</td><td>2 (0.4)</td><td>1 (0.2)</td><td>0</td><td>0</td></tr><tr><td>Encephalitis event</td><td>2 (0.4)</td><td>2 (0.4)</td><td>0</td><td>0</td></tr><tr><td>Immune-mediated arthritis</td><td>1 (0.2)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Meningitis event</td><td>1 (0.2)</td><td>1 (0.2)</td><td>0</td><td>0</td></tr><tr><td>Uveitis event</td><td>1 (0.2)</td><td>0</td><td>1 (0.2)</td><td>0</td></tr><tr><td>Guillain-Barre syndrome</td><td>0</td><td>0</td><td>1 (0.2)</td><td>1 (0.2)</td></tr></tbody></table>

<footnote>ªThe safety population included all patients who had received at least one dose of a trial drug. Listed are events that were reported between the first dose and 135 days after the last dose. The table includes patients with immune-mediated adverse events in which immune modulating medication was initiated by category. The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. ´There was 1 grade 5 event in the NIVO arm. This category includes the preferred terms of myositis, rhabdomyolysis, autoimmune myositis, and immune-mediated myositis. cThere was 1 grade 5 event for each arm.</footnote>
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## Software and code

Policy information about [availability of computer code](#)

**Data collection** Medidata Classic Rave (version 2025.1; New York, NY, USA).

**Data analysis** All clinical analyses were performed using Statistical Analysis System software (SAS Institute, North Carolina, USA). All biomarker statistical analyses were performed using R version 4.3.1.

For manuscripts utilizing custom algorithms or software that are central to the research but not yet described in published literature, software must be made available to editors and reviewers. We strongly encourage code deposition in a community repository (e.g. GitHub). See the Nature Portfolio [guidelines for submitting code & software](#) for further information.

## Data

Policy information about [availability of data](#)

All manuscripts must include a [data availability statement](#). This statement should provide the following information, where applicable:

- Accession codes, unique identifiers, or web links for publicly available datasets

- A description of any restrictions on data availability

- For clinical datasets or third party data, please ensure that the statement adheres to our [policy](#)

Data availability: Bristol Myers Squibb will honor legitimate requests for our clinical trial data from qualified researchers with a clearly defined scientific objective. We share data from Phase II-IV interventional clinical trials completed on or after January 1, 2008 and evaluate medicines and indications approved in the US, EU, and other designated markets. Data shared may include non-identifiable patient-level and study-level clinical trial data, full clinical study reports and protocols.
Sharing is subject to protection of patient privacy and respect for the patient's informed consent, and publication of the primary results in peer-reviewed journals. Bristol Myers Squibb reserves the right to update and change criteria at any time. Other criteria may apply, for details please visit Bristol Myers Squibb at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html. The option to submit data requests as well as review criteria for data requests are available at https://vivli.org/ourmember/bristol-myers-squibb/. The study protocol of RELATIVITY-098 is provided in the Supplementary Information.

## Research involving human participants, their data, or biological material

Policy information about studies with human participants or human data. See also policy information about sex, gender (identity/presentation), and sexual orientation and race, ethnicity and racism.

**Reporting on sex and gender**

Both male and female patients were eligible for enrollment. Sex was self-reported. The number of male (n = 642) and female (n = 451) patients randomized in this study is reported in Table 1. Evaluations of recurrence-free survival in several prespecified subgroups, including subgroups defined by sex, are reported in Extended data Fig. 1.

**Reporting on race, ethnicity, or other socially relevant groupings**

There are no analyses based on race or ethnicity reported in this manuscript.

**Population characteristics**

Baseline patient demographics (including age, sex, geographic region) and disease characteristics for patients randomized in this study are reported in Table 1.

**Recruitment**

From October 2021 to November 2022, a total of 1093 patients were randomly assigned to receive nivolumab plus relatlimab (547 patients) or nivolumab (546 patients) (Fig. 1) at 163 hospitals and cancer centers in 24 countries worldwide (site list is provided in the supplement). Patients were recruited by investigators through enrollment based on prespecified inclusion/exclusion criteria. Eligibility criteria and screening procedures minimized the potential of self-selection bias.

**Ethics oversight**

The protocol and amendments for this trial were reviewed by the institutional review board or independent ethics committee for each trial site and all patients provided written informed consent before enrollment. The trial was conducted in accordance with the International Council for Harmonisation Good Clinical Practice Guidelines.

Note that full information on the approval of the study protocol must also be provided in the manuscript.

## Field-specific reporting

Please select the one below that is the best fit for your research. If you are not sure, read the appropriate sections before making your selection.

<figure><img src="image_28.png" /></figure>

Life sciences

<figure><img src="image_29.png" /></figure>

Behavioural & social sciences

<figure><img src="image_30.png" /></figure>

Ecological, evolutionary & environmental sciences

For a reference copy of the document with all sections, see [nature.com/documents/nr-reporting-summary-flat.pdf](https://nature.com/documents/nr-reporting-summary-flat.pdf)

## Life sciences study design

All studies must disclose on these points even when the disclosure is negative.

**Sample size**

An approximate sample size of 1050 patients was planned to achieve the required 410 RFS events and show a significant difference in investigator-assessed RFS with a two-sided alpha of 0.05 using a stratified log-rank test with at least 90% statistical power when the average hazard ratio of nivolumab and relatlimab fixed-dose combination versus nivolumab was 0.72 and an assumed cure rate of 0.52 in the nivolumab arm. The actual events were 427, with a critical HR of 0.815 and cumulative power of 91.5%. A total of 1093 patients were randomly assigned to receive nivolumab plus relatlimab (547 patients) or nivolumab (546 patients).

**Data exclusions**

No data were excluded from the reported clinical analyses. Biomarker analyses were performed on biomarker-evaluable samples.

**Replication**

Attempts of replication were not performed given that RELATIVITY-098 was a clinical trial.

**Randomization**

Randomization was carried out via permutated blocks within each stratum, defined by a combination of geographic region and AJCC v8 stage. Patients were stratified according to AJCC-8 stage (IIIA/IIIB or IIIC or IIID/IV [including mucosal melanoma]), and geographic region (USA/Canada/Australia or Europe or rest of the world).

**Blinding**

This was a double-blind study. Access to treatment codes was restricted for all participants, as well as site and Sponsor personnel, prior to the primary database lock, with exceptions as follows: in the event of a medical emergency or pregnancy involving an individual participant, where knowledge of the investigational product was essential for participant management, the blind for that participant was broken by the investigator. The participant's safety took priority over any other considerations when determining if treatment assignment was to be unblinded.

## Reporting for specific materials, systems and methods
We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response.

## Materials & experimental systems

<table><thead><tr><th>n/a</th><th>Involved in the study</th></tr></thead><tbody><tr><td>☐</td><td>Antibodies</td></tr><tr><td>☒</td><td>Eukaryotic cell lines</td></tr><tr><td>☒</td><td>Palaeontology and archaeology</td></tr><tr><td>☒</td><td>Animals and other organisms</td></tr><tr><td>☐</td><td>Clinical data</td></tr><tr><td>☒</td><td>Dual use research of concern</td></tr><tr><td>☒</td><td>Plants</td></tr></tbody></table>

## Methods

<table><thead><tr><th>n/a</th><th>Involved in the study</th></tr></thead><tbody><tr><td>☒</td><td>ChIP-seq</td></tr><tr><td>☐</td><td>Flow cytometry</td></tr><tr><td>☒</td><td>MRI-based neuroimaging</td></tr></tbody></table>

## Antibodies

<table><tr><td>Antibodies used</td><td>Nivolumab, an anti-PD-1 monoclonal antibody, and relatlimab anti-LAG-3 antibody, were administered as the experimental treatment in this study. Nivolumab and relatlimab administered as part of this study was provided by the study's sponsor (Bristol Myers Squibb).<br/><br/>For the IHC biomarker analyses, the following antibodies were used: PD-L1 immunohistochemistry assay (Dako PD-L1 IHC 28-8 pharmDx assay; Agilent Technologies, Inc.), LAG-3 (17B4) mouse monoclonal antibody, CD8 (mouse clone C8/144B) antibody<br/><br/>For biomarker analyses using CODEX/phenocycler, the following antibodies were employed:<br/>Detection of E-cadherin was performed using the 4250021 (Akoya Inventoried) antibody.<br/>Detection of CD45RO was performed using the 4250023 (Akoya Inventoried) antibody.<br/>Detection of CD8 was performed using the 4250012 (Akoya Inventoried) antibody.<br/>Detection of Ki67 was performed using the 4250019 (Akoya Inventoried) antibody.<br/>Detection of CD163 was performed using the 2450079 (Akoya Inventoried) antibody.<br/>Detection of CD4 was performed using the 4550112 (Akoya Inventoried) antibody.<br/>Detection of CD68 was performed using the 4550113 (Akoya Inventoried) antibody.<br/>Detection of CD45 was performed using the 4550121 (Akoya Inventoried) antibody.<br/>Detection of FOXP3 was performed using the 4550071 (Akoya Inventoried) antibody.<br/>Detection of HLA-DR was performed using the 4550118 (Akoya Inventoried) antibody.<br/>Detection of PCNA was performed using the 4550124 (Akoya Inventoried) antibody.<br/>Detection of Collagen IV was performed using the 4550122 (Akoya Inventoried) antibody.<br/>Detection of PD-L1 was performed using the 4550072 (Akoya Inventoried) antibody.<br/>Detection of CD3e was performed using the 4550119 (Akoya Inventoried) antibody.<br/>Detection of PD-1 was performed using the 4550038 (Akoya Inventoried) antibody.<br/>Detection of LAG3 was performed using the 17b4 antibody.<br/>Detection of CD20 was performed using the 4450018 (Akoya Inventoried) antibody.<br/>Detection of PanCK was performed using the 4450020 (Akoya Inventoried) antibody.<br/>Detection of SOX10 was performed using the 5H7L26 antibody.</td></tr><tr><td>Validation</td><td>Adjuvant nivolumab plus relatlimab for patients with resected stage IIIB/C/D or stage IV melanoma was evaluated vs nivolumab in this study as part of Bristol Myers Squibb's clinical study program.<br/><br/>The majority of the *Akoya Inventoried antibodies were validated by Akoya described on the Akoya website.<br/>Clones chosen by the investigators were well-known and conjugated by Akoya. All antibodies were tested and the staining was validated with Pathologist.</td></tr></table>

## Clinical data

Policy information about clinical studies

All manuscripts should comply with the ICMJE guidelines for publication of clinical research and a completed CONSORT checklist must be included with all submissions.

Clinical trial registration NCT05002569

Study protocol The study protocol is provided in the Supplementary Information.

Data collection From October 2021 to November 2022, a total of 1093 patients were randomly assigned to receive 480 mg of nivolumab plus 160 mg of relatlimab as FDC or 480 mg of nivolumab administered via intravenous infusion every 4 weeks for a maximum of 1 year (or ≤ 13 doses) or until recurrence of disease, unacceptable adverse events, or withdrawal of consent at 163 sites in 24 countries worldwide. At the December 16, 2024 clinical cutoff date, patients had a minimum follow-up (time from last patient randomized to the cutoff date) of 23.4 months and a median follow-up (median time between randomization and the last known alive date) of 26.7 months.

Outcomes The primary endpoint was investigator-assessed RFS, with computed tomography scans performed every 12 weeks for 2 years and
## Outcomes

then twice a year; patients who did not undergo complete lymph node dissection required ultrasound surveillance. Overall survival was the key secondary endpoint to be hierarchically tested if the primary endpoint was met. Other secondary endpoints included investigator-assessed DMFS, PFS through next-line therapy, and safety. The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Included treatment-related adverse events (TRAES) are those reported between the first dose and 30 days after the last dose. In addition, immune-mediated AEs and AEs of special interest reported between the first dose and 135 days after the last dose are reported per category.

Biomarker analyses were exploratory and were performed on patient blood samples from RELATIVITY-098 and RELATIVITY-047 (NCT03470922) at baseline and on treatment to assess expression or expansion of biomarker-specific immune cell populations and soluble proteins. Biomarker analyses were performed on patient tumor samples from RELATIVITY-098 at baseline and at recurrence and RELATIVITY-047 (NCT03470922) at baseline to assess expression of proteins in the tumor microenvironment.

# Flow Cytometry

## Plots

Confirm that:

☐ The axis labels state the marker and fluorochrome used (e.g. CD4-FITC).

☐ The axis scales are clearly visible. Include numbers along axes only for bottom left plot of group (a 'group' is an analysis of identical markers).

☐ All plots are contour plots with outliers or pseudocolor plots.

☑ A numerical value for number of cells or percentage (with statistics) is provided.

## Methodology

**Sample preparation** Whole blood collected on Cyto-Chex BCT tubes

**Instrument** 5-laser Cytek Aurora spectral cytometer

**Software** OMIQ

**Cell population abundance** The parent populations are CD4 and CD8 cells which are highly abundant in the total white cell population. Activation markers were analyzed on a subset of these cells that are LAG3+ or PD1+ populations which can range from 1-20% of the parent cells in normal circumstances.

**Gating strategy** The original files were gated by time. Non-debris cells were selected by FSC and SSC. Doublets were excluded. Dead cells were excluded. Leukocytes were selected by SSC vs. CD45. From leukocytes, T cells were selected by CD3 positivity. T cells were subseted to CD4 or CD8 positive. CD4 and CD8 cells were subseted based on LAG3 or PD1 positivity. Activation markers (i.e Ki67) were measured from these cell subsets as a percent of parent.

☐ Tick this box to confirm that a figure exemplifying the gating strategy is provided in the Supplementary Information.