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Abstract

Background

A phase 2/3 trial — A Study of Relatlimab Plus Nivolumab Versus Nivolumab Alone in Participants With Advanced Melanoma (RELATIVITY-047) — evaluated nivolumab + relatlimab as a fixed-dose combination and found a significant progression-free survival (PFS) benefit over nivolumab monotherapy in previously untreated unresectable or metastatic melanoma. We now report updated PFS and safety data and the first results for overall survival (OS) and objective response rate (ORR).

Methods

Patients were randomly assigned 1:1 to receive nivolumab 480 mg and relatlimab 160 mg fixed-dose combination or nivolumab 480 mg alone, given intravenously every 4 weeks. PFS (primary end point) according to the Response Evaluation Criteria in Solid Tumors, version 1.1, was assessed by blinded independent central review (BICR). Secondary end points, tested hierarchically, were OS and then ORR per Response Evaluation Criteria in Solid Tumors, version 1.1, per BICR.

Results

At a median follow-up of 19.3 months, median PFS according to BICR was 10.2 months (95% confidence interval [CI], 6.5 to 14.8) with nivolumab + relatlimab versus 4.6 months (95% CI, 3.5 to 6.4) with nivolumab (hazard ratio, 0.78; 95% CI, 0.64 to 0.94). Median OS was not reached (NR) (95% CI, 34.2 to NR) with nivolumab + relatlimab versus 34.1 months (95% CI, 25.2 to NR) with nivolumab (hazard ratio, 0.80; 95% CI, 0.64 to 1.01; P=0.059) (prespecified value for statistical significance, P≤0.043). ORRs per BICR were 43.1% (95% CI, 37.9 to 48.4) versus 32.6% (95% CI, 27.8 to 37.7), respectively. Grade 3/4 treatment-related adverse events were observed in 21.1% of patients treated with nivolumab + relatlimab versus 11.1% treated with nivolumab.

Conclusions

The fixed-dose combination of nivolumab + relatlimab showed consistent PFS benefit versus nivolumab with approximately 6 months of additional median follow-up. The combination treatment did not reach the preplanned statistical threshold for OS, with a 10.3 percentage-point difference in ORR. Grade 3/4 treatment-related adverse events were more frequent with nivolumab + relatlimab versus nivolumab. (Funded by Bristol Myers Squibb; ClinicalTrials.gov number, NCT03470922.)

Introduction

Advances in immunotherapy over the last decade have substantially improved patient survival, especially in patients with advanced melanoma treated with programmed death-1 (PD-1) receptor inhibitors, both as monotherapy and in combination with cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors.1,2 In the Phase 3 Study of Nivolumab or Nivolumab Plus Ipilimumab Versus Ipilimumab Alone in Previously Untreated Advanced Melanoma (CheckMate 067; NCT01844505), with a minimum follow-up time of 77 months, combined anti–PD-1/anti–CTLA-4 immunotherapy as first-line therapy in patients with advanced melanoma resulted in a median overall survival (OS) of 72.1 months; this was compared with the median OS of 36.9 months with nivolumab monotherapy (descriptive analysis).2
Despite this progress, approximately 40% of patients with melanoma do not benefit from existing front-line combination immunotherapies.3,4 New therapeutic approaches could help patients with advanced melanoma.1,4-7 PD-1 monotherapy has shown robust efficacy in advanced melanoma, resulting in a high clinical benchmark for further improvement with novel immunotherapy combinations.7,8 However, the effectiveness of PD-1 monotherapy may be limited by compensatory increases in the expression of other immune checkpoint receptors, supporting the potential benefit of novel immunotherapy combinations to overcome immune suppression.9
A global, randomized, double-blind, phase 2/3 trial — A Study of Relatlimab Plus Nivolumab Versus Nivolumab Alone in Participants With Advanced Melanoma (RELATIVITY-047; NCT03470922) — evaluated nivolumab, a PD-1 inhibitor, with relatlimab, a lymphocyte-activation gene 3 (LAG-3)–blocking antibody, as a fixed-dose combination in patients with previously untreated unresectable or metastatic melanoma.10 With a median follow-up of 13.2 months, RELATIVITY-047 met its primary end point of progression-free survival (PFS) by blinded independent central review (BICR), with nivolumab + relatlimab as a fixed-dose combination showing a PFS of 10.1 months (95% confidence interval [CI], 6.4 to 15.7) versus 4.6 months (95% CI, 3.4 to 5.6) for nivolumab alone (hazard ratio, 0.75; 95% CI, 0.62 to 0.92; P=0.006).10 The nivolumab + relatlimab combination had a higher rate of grade 3/4 treatment-related adverse events (AEs) compared with nivolumab alone, but there were no new or unexpected safety signals. These findings supported the U.S. Food and Drug Administration’s approval of the nivolumab + relatlimab fixed-dose combination for use in adult and pediatric patients ≥12 years of age with unresectable or metastatic melanoma.11
Here we report updated PFS and the first results of the secondary end points OS and objective response rate (ORR); we also report the safety profile with additional follow-up.

Methods

Patients

As noted in the prior report,10 eligible patients were ≥12 years of age and had previously untreated, histologically confirmed, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Full eligibility criteria are provided in the previous report and can be found in Sections 6.1 and 6.2 of the study protocol, available with the full text of this article at evidence.nejm.org.

Study Design, Treatment, and Assessments

The study design, treatment description, trial end points, and assessments for RELATIVITY-047 have been reported previously.10 Patients were randomly assigned 1:1 to receive the nivolumab 480 mg and relatlimab 160 mg fixed-dose combination or nivolumab monotherapy 480 mg intravenously every 4 weeks. Stratification factors included LAG-3 expression (≥1% or <1%), programmed death ligand 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) as defined in the AJCC Cancer Staging Manual, Eighth Edition. Treatment was discontinued in the event of disease progression, unacceptable AEs, or withdrawal of consent. Treatment beyond initial progression (as defined by investigators according to Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST v1.1]) was permitted if the investigators assessed that the patient had clinical benefit, if the patient did not have unacceptable adverse effects, and if the patient wished to continue treatment.
The primary end point was PFS according to BICR per RECIST v1.1, and secondary end points included OS and confirmed ORR according to BICR. PFS was defined as the time between the date of randomization and the first date of documented progression or death due to any cause, whichever occurred first. OS was defined as the time between the date of randomization and the date of death due to any cause. ORR was defined as the proportion of randomly assigned patients with the best confirmed overall response by BICR of complete response or partial response before progression or subsequent therapy (per RECIST v1.1). Exploratory end points included duration of response, defined as the time between the date of first response to the date of first documented tumor progression (per RECIST v1.1) or death due to any cause and evaluation of PFS, OS, and ORR in prespecified subgroups. AEs were coded by using the Medical Dictionary for Regulatory Activities, version 24, and were graded for severity according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 5.0. PD-L1 and LAG-3 expression assessments were described previously.10

Trial Oversight

All trial investigators received approval from their respective institutional review boards. RELATIVITY-047 was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Guideline for Good Clinical Practice, and all patients provided written informed consent before participation. The trial was registered at ClinicalTrials.gov (NCT03470922). An independent data monitoring committee provided oversight to assess the efficacy and safety profile of nivolumab and relatlimab. The trial was designed by Bristol Myers Squibb, the trial sponsor, in collaboration with the trial steering committee. Data were collected by the sponsor and subsequently analyzed in collaboration with the authors. The authors vouch that the data and analyses reported here are both accurate and complete. All authors contributed to manuscript draft development, provided critical feedback, and gave their final approval before manuscript submission. The trial sponsor and authors decided to publish the manuscript. Professional medical writing and editorial support were funded by the sponsor. All authors signed a confidentiality disclosure agreement with the sponsor.

Statistical Analysis

Overall analyses were performed in the intention-to-treat population, which included all patients who were randomly assigned to any treatment group. Safety analyses were performed on all patients who received at least one dose of double-blind study treatment. At the time of the primary PFS analysis with a median follow-up of 13.2 months, the approximately 300-event target to trigger the final OS analysis had not been reached; a prespecified interim analysis of the difference in OS was conducted by the data monitoring committee but was not statistically significant. Trial investigators and the sponsor remained blinded to the OS interim results. Per the prespecified hierarchy for statistical analyses, ORR was not analyzed at the time of the primary PFS disclosure, because the difference in OS was not statistically significant, and ORR was to be assessed only after all patients had a minimum of 28 weeks of follow-up required for the analysis.
After a median follow-up of approximately 19.3 months, OS was compared between the randomized groups at final analysis by using a two-sided log-rank test stratified according to LAG-3 expression, American Joint Committee on Cancer metastasis stage, and BRAF mutation status. An O’Brien–Fleming α-spending function determined the nominal significance level for the final analysis to be P<0.043 (two-sided), with a cumulative design power of 69% for a target OS hazard ratio of 0.75. The Kaplan–Meier method was used to estimate OS and PFS curves, as well as both medians and rates for OS and PFS, within each treatment group along with corresponding 95% CI values. Two-sided 95% CIs were computed via the log-log transformation method, and OS rate estimate CIs were derived based on the Greenwood formula for variance derivation and on log-log transformation applied on the survivor function. For OS and PFS, hazard ratios and corresponding two-sided 95% CIs were estimated by using a Cox proportional-hazards model, with the treatment group as a single covariate, stratified according to the aforementioned stratification factors.
A comparison of ORR between treatment groups was performed with a two-sided Cochran–Mantel–Haenszel test stratified according to the aforementioned stratification factors. ORRs and corresponding exact two-sided 95% CIs were determined based on the Clopper and Pearson method, and 95% CIs were calculated for the odds ratio of response and differences in response between the treatment groups. Duration of response for each treatment group was estimated by using the Kaplan–Meier product-limit method for patients who were responders. Updated PFS analyses were conducted as reported previously10 and were descriptive in nature at this database lock. The prespecified PFS, OS, and ORR subgroup analyses were exploratory and descriptive in nature.
The proportional-hazards assumption was tested for OS by using a time-dependent covariate, defined by treatment-by-time interaction, in a stratified Cox regression model. The resulting two-sided Wald chi-square P value was 0.981, which indicates that the proportional-hazards assumption is reasonable.

Results

Patients

Between April 2018 and December 2020, a total of 714 patients were randomly assigned to receive nivolumab + relatlimab (n=355) or nivolumab monotherapy (n=359; Fig. S1 in the Supplementary Appendix). Patient baseline characteristics and demographic characteristics were well balanced across both treatment groups, as previously reported (Table 1), and were largely representative of the global population of patients with previously untreated advanced melanoma (Table S1).10 At the time of database lock (October 28, 2021), median follow-up was 19.3 months, with a minimum follow-up (time from last patient randomly assigned, to last patient’s last visit) of 8.7 months. Median duration of therapy was 8.3 months (95% CI, 5.6 to 10.3) in the nivolumab + relatlimab treatment group compared with 6.5 months (95% CI, 5.0 to 7.9) in the nivolumab treatment group. The median number of doses received was 10 (range, 1 to 43 doses) in the nivolumab + relatlimab group compared with 8 (range, 1 to 44 doses) in the nivolumab monotherapy group. At the time of database lock, 269 (75.8%) patients in the nivolumab + relatlimab treatment group and 267 (74.4%) patients in the nivolumab treatment group had discontinued treatment. The most common reason for discontinuation in both treatment groups was disease progression (146 [41.1%] patients treated with nivolumab + relatlimab and 183 [51.0%] patients treated with nivolumab).
Table 1
CharacteristicNivolumab + Relatlimab (n=355)Nivolumab (n=359)Total (N=714)
Age — median (range), yr63 (20–94)62 (21–90)63 (20–94)
Female — no. (%)145 (40.8)153 (42.6)298 (41.7)
AJCC v8 metastasis stage — no. (%)   
M1a77 (21.7)107 (29.8)184 (25.8)
M1b85 (23.9)88 (24.5)173 (24.2)
M1c151 (42.5)127 (35.4)278 (38.9)
M1d6 (1.7)11 (3.1)17 (2.4)
ECOG PS — no. (%)   
0236 (66.5)242 (67.4)478 (66.9)
1119 (33.5)117 (32.6)236 (33.1)
LDH level — no. (%)   
Above the ULN130 (36.6)128 (35.7)258 (36.1)
>2 × ULN32 (9.0)31 (8.6)63 (8.8)
Prior neoadjuvant/adjuvant — no. (%)33 (9.3)27 (7.5)60 (8.4)
Tumor burden — median (minimum–maximum), mm59.0 (10–317)54.5 (10–548)
Melanoma subtype classification — no. (%)§   
Cutaneous acral41 (11.5)41 (11.4)82 (11.5)
Cutaneous nonacral249 (70.1)254 (70.8)503 (70.4)
Mucosal23 (6.5)28 (7.8)51 (7.1)
Stratification factors — no. (%)   
LAG-3 expression   
≥1%268 (75.5)269 (74.9)537 (75.2)
<1%87 (24.5)90 (25.1)177 (24.8)
PD-L1 expression   
≥1%146 (41.1)147 (40.9)293 (41.0)
<1%209 (58.9)212 (59.1)421 (59.0)
BRAF mutation status   
Mutant136 (38.3)139 (38.7)275 (38.5)
Wild-type219 (61.7)220 (61.3)439 (61.5)
AJCC metastasis stage   
M0/M1any[0]232 (65.4)237 (66.0)469 (65.7)
M1any[1]123 (34.6)122 (34.0)245 (34.3)
Patient Demographic and Baseline Characteristics.*
*
Adapted from Tawbi et al.10 AJCC v8 denotes American Joint Committee on Cancer, version 8; ECOG PS, Eastern Cooperative Oncology Group performance status; LAG-3, lymphocyte-activation gene 3; LDH, lactate dehydrogenase; PD-L1, programmed death ligand 1; and ULN, upper limit of normal.
Most common therapy was interferon.
Sum of reference diameters of target lesions in millimeters.
§
Seventy-eight patients had a melanoma subtype classification of “Other.”
AJCC metastasis stage M0/M1any (LDH not elevated).
AJCC metastasis stage M1any (elevated LDH).

Efficacy

In this update, with a median follow-up of 19.3 months (approximately 6 months of additional median follow-up), the median PFS was 10.2 months (204 events; 95% CI, 6.5 to 14.8) with nivolumab + relatlimab versus 4.6 months (233 events; 95% CI, 3.5 to 6.4) with nivolumab alone (hazard ratio, 0.78; 95% CI, 0.64 to 0.94; Fig. 1A). PFS rates at 12 months were 48.0% (95% CI, 42.5 to 53.4) versus 36.9% (95% CI, 31.7 to 42.1) and at 24 months, they were 38.5% (95% CI, 32.7 to 44.2) versus 29.0% (95% CI, 23.8 to 34.4), respectively.
Figure 1
Kaplan–Meier Curves of PFS and OS.
(Panel A) The statistical model for progression-free survival (PFS) hazard ratios was assessed via a stratified Cox proportional-hazards model. PFS rates at 36 months are not shown because there were less than 10 patients in the analysis sets at this time point. (Panel B) The statistical model for overall survival (OS) hazard ratios and P values was assessed via a stratified Cox proportional-hazards model and stratified log-rank test. The OS boundary for statistical significance was P<0.043 (two-sided) analyzed at 69% power; the target hazard ratio was 0.75. Both analyses were stratified according to lymphocyte-activation gene 3 (LAG-3), BRAF, and American Joint Committee on Cancer metastasis stage. Programmed death ligand 1 was removed from stratification because it led to subgroups with less than 10 patients. Median follow-up was 19.3 months, and minimum follow-up (time from last patient randomly assigned to last patient’s last visit) was 8.7 months. CI denotes confidence interval; and NR, not reached.
Median OS was not reached (NR) (137 events; 95% CI, 34.2 to NR) for nivolumab + relatlimab versus 34.1 months (160 events; 95% CI, 25.2 to NR) for nivolumab (hazard ratio, 0.80; 95% CI, 0.64 to 1.01; P = 0.059; Fig. 1B) and the difference was not statistically significant. OS rates at 12 months were 77.0% (95% CI, 72.2 to 81.1) versus 71.6% (95% CI, 66.6 to 76.0); at 24 months, they were 63.7% (95% CI, 58.1 to 68.7) versus 58.3% (95% CI, 52.7 to 63.4); and at 36 months, they were 55.8% (95% CI, 49.8 to 61.4) versus 48.8% (95% CI, 42.7 to 54.7).
Any subsequent therapy was received by a similar proportion of patients across the nivolumab + relatlimab (40.8%) and nivolumab (42.6%) treatment groups (Table 2). Specifically, subsequent systemic therapy was received by 116 (32.7%) patients treated with nivolumab + relatlimab compared with 124 (34.5%) patients treated with nivolumab; PD-(L)1 and CTLA-4 inhibitors (either in combination or as monotherapy) were given to 11.8% of patients treated with nivolumab + relatlimab versus 15.9% of patients treated with nivolumab. BRAF/MEK inhibitors (either in combination or as monotherapy) were given to 12.4% of patients treated with nivolumab + relatlimab versus 14.8% of patients treated with nivolumab.
Table 2
Subsequent TherapyNivolumab + Relatlimab (n=355)Nivolumab (n=359)
Any subsequent therapy145 (40.8)153 (42.6)
Systemic therapy116 (32.7)124 (34.5)
PD-(L)1 and/or CTLA-4 inhibitors42 (11.8)57 (15.9)
Nivolumab + ipilimumab15 (4.2)24 (6.7)
Nivolumab monotherapy15 (4.2)20 (5.6)
Ipilimumab monotherapy13 (3.7)19 (5.3)
Pembrolizumab monotherapy6 (1.7)10 (2.8)
Avelumab monotherapy01 (0.3)
BRAF and/or MEK inhibitor therapies44 (12.4)53 (14.8)
Other49 (13.8)55 (15.3)
Radiotherapy52 (14.6)44 (12.3)
Surgery25 (7.0)29 (8.1)
Subsequent Therapy.*
*
Values are presented as no. (%). CTLA-4 denotes cytotoxic T lymphocyte antigen-4; PD-1, programmed death-1; and PD-L1, programmed death ligand 1.
Patients may have received more than one subsequent therapy.
Subsequent therapies of radiotherapy and surgery were allowed during study therapy.
Because the difference in OS was not statistically significant, ORR could not be formally tested and was descriptively analyzed. Confirmed ORR per BICR was 43.1% (95% CI, 37.9 to 48.4) for nivolumab + relatlimab compared with 32.6% (95% CI, 27.8 to 37.7) for nivolumab, with an ORR difference of 10.3 percentage points (95% CI, 3.4 to 17.3) between treatment groups and an odds ratio of 1.6 (95% CI, 1.2 to 2.2; Table 3). Complete and partial responses were noted in 16.3% and 26.8% of patients receiving nivolumab + relatlimab, respectively, compared with 14.2% and 18.4% in patients receiving nivolumab alone. The disease control rate for nivolumab + relatlimab was 62.8% (95% CI, 57.6 to 67.9) compared with 50.7% (95% CI, 45.4 to 56.0) for nivolumab, and median duration of response was NR for nivolumab + relatlimab (95% CI, 29.6 to NR) or nivolumab alone (95% CI, 29.9 to NR).
Table 3
ResponseNivolumab + Relatlimab (n=355)Nivolumab (n=359)
ORR — no. (%)153 (43.1)117 (32.6)
95% CI37.9–48.427.8–37.7
Difference of ORR — percentage points (95% CI)10.3 (3.4–17.3)
Odds ratio — (95% CI)1.6 (1.2–2.2)
Confirmed best overall response — no. (%) 
Complete response58 (16.3)51 (14.2)
Partial response95 (26.8)66 (18.4)
Stable disease61 (17.2)59 (16.4)
Progressive disease105 (29.6)149 (41.5)
Unknown27 (7.6)28 (7.8)
DCR — no. (%)223 (62.8)182 (50.7)
95% CI57.6–67.945.4–56.0
Median DoR — moNRNR
95% CI29.57–NR29.93–NR
Response to Treatment.*
*
Objective response rate (ORR) could not be formally tested and was descriptively analyzed. Strata-adjusted difference in ORR based on the Cochran–Mantel–Haenszel method of weighting. Stratified by lymphocyte-activation gene 3 (LAG-3), BRAF, and American Joint Committee on Cancer metastasis stage. CI denotes confidence interval; DCR, disease control rate; DoR, duration of response; and NR, not reached.
Data from prespecified exploratory subgroup analyses of PFS, OS, and ORR for the nivolumab + relatlimab combination compared with nivolumab alone are presented in Figure 2, Figure S2, and Figure S3.
Figure 2
PFS, OS, and ORR across Key Specified Subgroups.
Analyses were exploratory/descriptive. Changes in patient counts between database locks may be due to corrections in data. BICR denotes blinded independent central review; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; LAG-3, lymphocyte-activation gene 3; LDH, lactate dehydrogenase; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; Q, quartile; and ULN, upper limit of normal.

Safety

The safety profile of nivolumab + relatlimab was consistent with the initial report, with no new safety signals observed (Table 4). All-causality AEs were reported in 352 (99.2%) patients treated with nivolumab + relatlimab compared with 344 (95.8%) patients treated with nivolumab alone (Table 4 and Table S2). All-causality serious AEs were reported in 131 (36.9%) patients treated with nivolumab + relatlimab compared with 115 (32.0%) patients treated with nivolumab alone, with grade 3/4 all-causality serious AEs reported in 101 (28.5%) and 75 (20.9%) patients, respectively (Table S3).
Table 4
AEsNivolumab + Relatlimab (n=355)Nivolumab (n=359)
Any GradeGrade 3/4Any GradeGrade 3/4
Any AE352 (99.2)154 (43.4)344 (95.8)126 (35.1)
Any serious AE131 (36.9)101 (28.5)115 (32.0)75 (20.9)
TRAE297 (83.7)75 (21.1)260 (72.4)40 (11.1)
Serious TRAE55 (15.5)38 (10.7)30 (8.4)19 (5.3)
TRAEs leading to discontinuation of treatment54 (15.2)32 (9.0)26 (7.2)13 (3.6)
Treatment-related deaths4 (1.1)02 (0.6)0
TRAE in ≥10% of patients    
Pruritus87 (24.5)059 (16.4)2 (0.6)
Fatigue83 (23.4)5 (1.4)47 (13.1)1 (0.3)
Rash59 (16.6)3 (0.8)48 (13.4)2 (0.6)
Hypothyroidism55 (15.5)046 (12.8)0
Arthralgia53 (14.9)3 (0.8)29 (8.1)1 (0.3)
Diarrhea53 (14.9)4 (1.1)36 (10.0)2 (0.6)
Vitiligo45 (12.7)042 (11.7)0
IMAE    
Hypothyroidism/thyroiditis66 (18.6)053 (14.8)0
Rash39 (11.0)3 (0.8)28 (7.8)5 (1.4)
Diarrhea/colitis25 (7.0)5 (1.4)12 (3.3)5 (1.4)
Hyperthyroidism23 (6.5)025 (7.0)0
Hepatitis21 (5.9)15 (4.2)11 (3.1)6 (1.7)
Adrenal insufficiency19 (5.4)6 (1.7)4 (1.1)0
Pneumonitis14 (3.9)2 (0.6)7 (1.9)2 (0.6)
Hypophysitis10 (2.8)2 (0.6)4 (1.1)1 (0.3)
Nephritis and renal dysfunction7 (2.0)4 (1.1)5 (1.4)4 (1.1)
Hypersensitivity5 (1.4)05 (1.4)0
Summary of AEs.*
*
Values are presented as no. (%). Includes events reported between first dose and 30 days after last dose of study therapy. Other grade 3/4 treatment-related adverse events (TRAEs) that were associated with any-grade TRAEs occurring in less than 10% of patients not shown. AE denotes adverse event; and IMAE, immune-mediated adverse event.
Treatment-related deaths: nivolumab + relatlimab (n=4): hemophagocytic lymphohistiocytosis, acute edema of the lung, pneumonitis, and multiorgan failure; nivolumab (n=2): sepsis and myocarditis and worsening pneumonia.
Includes AEs of any grade occurring in 1% or more of patients considered by investigators to be potentially immune-mediated that met the following criteria: occurred within 100 days of the last dose, regardless of causality; treated with immune-modulating medication with no clear alternate etiology; or had an immune-mediated component. Comprehensive case definitions for IMAEs are presented in Table S4.
Treatment-related AEs were reported in 297 (83.7%) patients treated with nivolumab + relatlimab compared with 260 (72.4%) patients treated with nivolumab alone, with grade 3/4 treatment-related AEs observed in 75 (21.1%) and 40 (11.1%) patients, respectively (Table 4). No additional cases of myocarditis were reported since the initial disclosure; one additional treatment-related death was reported within the nivolumab + relatlimab group due to multiorgan failure.

Discussion

The RELATIVITY-047 trial was designed to evaluate whether the dual immunotherapy combination of nivolumab + relatlimab is superior to nivolumab alone in patients with previously untreated unresectable or metastatic melanoma. RELATIVITY-047 met its primary end point of PFS per BICR (median follow-up, 13.2 months), with nivolumab + relatlimab exhibiting superior PFS versus nivolumab alone (hazard ratio, 0.75; 95% CI, 0.62 to 0.92; P=0.006).10 In this report, with a median follow-up of 19.3 months (approximately 6 months of additional median follow-up), nivolumab + relatlimab continued to show a sustained PFS benefit (hazard ratio, 0.78; 95% CI, 0.64 to 0.94) and consistent PFS rates at 12 and 24 months. This sustained PFS benefit was accompanied by a consistent safety profile compared with the initial report.10
The hazard ratio for death in the combination treatment group compared with the nivolumab group was 0.80 (95% CI, 0.64 to 1.01). The difference in OS did not reach the prespecified statistical threshold to claim significance. ORR was analyzed descriptively within the prespecified data analysis hierarchy because OS was not significant. As noted earlier, the point estimates of ORR were 43.1% for nivolumab + relatlimab versus 32.6% for nivolumab alone. Although the ORR for nivolumab monotherapy we observed is lower than values reported for historical trials that assessed response per investigator in the first-line melanoma setting,4,6 it was similar to the ORR reported for other trials that assessed response per BICR.7,12 Cross-trial comparisons should be made with caution because results can vary due to differences between trials in the patient population evaluated, trial design, and the time at which the trial was conducted. These challenges underpin the importance of a well-designed randomized controlled trial, which permits appropriate comparison between treatment groups in a consistent population under consistent study conditions.
The benefit we observed in patients treated with nivolumab + relatlimab versus nivolumab alone was largely consistent across key prespecified patient subgroups, including those with varying levels of PD-L1 expression (≥1% or <1%), LAG-3 expression (≥1% or <1%), LDH level (equal to or below the upper limit of normal and above the upper limit of normal), and BRAF mutation status and across other key clinical characteristics, including baseline patient age and tumor burden. Overall, the results of this trial suggest that LAG-3 is a third immune checkpoint pathway that can be inhibited to improve outcomes over anti–PD-1 monotherapy for patients with advanced melanoma. Over the last decade, immunotherapy has transformed the treatment landscape of advanced melanoma, specifically with anti–PD-1 and/or anti–CTLA-4 therapy. Our report of the durable effect on PFS and the trends in OS and ORR in the RELATIVITY-047 trial builds upon these advances.

Notes

A data sharing statement provided by the authors is available with the full text of this article.
This article was updated on April 25, 2023 at evidence.nejm.org.
Supported by Bristol Myers Squibb.
Disclosure forms provided by the authors are available with the full text of this article.
Presented in part at the 2022 American Society of Clinical Oncology March Plenary Series, Virtual, March 15, 2022, and the 2022 American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, June 3–7, 2022.
All authors have contributed to the preparation and development of this manuscript and have approved the final draft before submission. Medical writing support and editing support, including first draft development under guidance of the authors, were provided by Ryan Staudt, Ph.D., and Jane Beck, M.A., of Complete HealthVizion, IPG Health Medical Communications, funded by Bristol Myers Squibb.
We thank the patients and families who made this trial possible. We also thank the personnel at Dako, an Agilent Technologies, Inc. company, for collaborative development of the PD-L1 IHC 28-8 pharmDx assay and the personnel at Labcorp for collaborative development of the LAG-3 immunohistochemistry assay, including analytic and clinical assay validations.

Supplementary Material

Protocol (evidoa2200239_protocol.pdf)
Supplementary Appendix (evidoa2200239_appendix.pdf)
Disclosure Forms (evidoa2200239_disclosures.pdf)
Data Sharing Statement (evidoa2200239_data-sharing.pdf)

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Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373:23-34.
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Information & Authors

Information

Published In

History

Published online: March 22, 2023
Published in issue: March 28, 2023

Topics

Authors

Affiliations

Georgina V. Long, M.D., Ph.D. [email protected]
Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, Sydney
F. Stephen Hodi, M.D.
Dana-Farber Cancer Institute, Boston
Evan J. Lipson, M.D.
Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore
Dirk Schadendorf, M.D.
Department of Dermatology, University Hospital Essen, Essen, Germany
German Cancer Consortium, Partner Site Essen, Essen, Germany
Paolo A. Ascierto, M.D.
Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale,” Naples, Italy
Luis Matamala, M.D.
Department of Oncology, Instituto Oncológico Fundación Arturo López Pérez, Santiago, Chile
Pamela Salman, M.D.
Department of Oncology, Instituto Oncológico Fundación Arturo López Pérez, Santiago, Chile
Erika Castillo Gutiérrez, M.D.
FAICIC Clinical Research, Veracruz, Mexico
Piotr Rutkowski, M.D., Ph.D.
Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland
Helen J. Gogas, M.D.
Department of Medicine, National and Kapodistrian University of Athens, Athens
Christopher D. Lao, M.D., M.P.H.
Michigan Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
Juliana Janoski De Menezes, M.D.
Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil
Stéphane Dalle, M.D., Ph.D.
Unit of Dermatology, Hospices Civils de Lyon, Cancer Research Center of Lyon, Pierre-Bénite, France
Ana Arance, M.D., Ph.D.
Department of Medical Oncology, Hospital Clinic Barcelona and IDIBAPS, Barcelona
Jean-Jacques Grob, M.D.
Aix-Marseille University, CHU Timone, Marseille, France
Sarah Keidel, M.B., Ch.B.
Bristol Myers Squibb, Princeton, New Jersey
Anadil Shaikh, M.Sc.
Bristol Myers Squibb, Princeton, New Jersey
Anne Marie Sobiesk, Ph.D.
Bristol Myers Squibb, Princeton, New Jersey
Sonia Dolfi, Ph.D.
Bristol Myers Squibb, Princeton, New Jersey
Hussein A. Tawbi, M.D., Ph.D.
Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston

Notes

Dr. Long can be contacted at [email protected] or at Melanoma Institute Australia, 40 Rocklands Rd., North Sydney, NSW 2060, Australia.

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