Three-Year Overall Survival With Nivolumab Plus Relatlimab in Advanced Melanoma From RELATIVITY-047

Abstract

Nivolumab plus relatlimab demonstrated a statistically significant improvement in progression-free survival (PFS), along with a clinically meaningful, but not statistically significant improvement in overall survival (OS) and a numerically higher objective response rate (ORR) compared with nivolumab in the RELATIVITY-047 trial (ClinicalTrials.gov identifier: NCT03470922). We report updated descriptive efficacy and safety results from RELATIVITY-047 with a median follow-up of 33.8 months. Median PFS was 10.2 months (95% CI, 6.5 to 15.4) with nivolumab plus relatlimab and 4.6 months (95% CI, 3.5 to 6.5) with nivolumab (hazard ratio [HR], 0.79 [95% CI, 0.66 to 0.95]); median OS was 51.0 months (95% CI, 34.0 to not reached) and 34.1 (95% CI, 25.2 to 44.7) months, respectively (HR, 0.80 [95% CI, 0.66 to 0.99]). ORR was 43.7% (95% CI, 38.4 to 49.0) with nivolumab plus relatlimab and 33.7% (95% CI, 28.8 to 38.9) with nivolumab. Efficacy across the majority of prespecified subgroups favored the combination. No new or unexpected safety signals were identified. Overall, at 3-year follow-up, the benefit observed with nivolumab plus relatlimab compared with nivolumab in patients with advanced melanoma was sustained, with the OS HR 95% CI upper bound now <1. This benefit is accompanied by a safety profile consistent with previous reports.

INTRODUCTION

RELATIVITY-047 is a global phase II/III randomized clinical trial that evaluated nivolumab plus relatlimab fixed-dose combination (FDC) compared with nivolumab alone in patients with previously untreated metastatic or unresectable advanced melanoma. A statistically significant improvement in progression-free survival (PFS) with the FDC was observed at a median follow-up of 13.2 months, which led to regulatory approval.¹ At a median follow-up of 19.3 months, the PFS benefit remained consistent, and a clinically meaningful (but not statistically significant) improvement in overall survival (OS), as well as a numerically higher objective response rate (ORR), was observed.² Here, we report updated descriptive efficacy and safety results from RELATIVITY-047 at a median follow-up of 33.8 months.

METHODS

Study Design and Patients

The study design of RELATIVITY-047 (ClinicalTrials.gov identifier: NCT03470922) has been described previously.¹ Eligible patients were age 12 years and older with previously untreated, histologically confirmed, unresectable advanced stage III or IV melanoma, measurable disease according to RECIST version 1.1,³ and tumor tissue evaluable for expression of lymphocyte activation gene 3 (LAG-3) and PD-L1. 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 intravenously once every 4 weeks. 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 v M1 with elevated LDH levels) as defined in the Cancer Staging Manual of the American Joint Committee on Cancer, eighth edition.⁴ The protocol and amendments were approved by the appropriate institutional review board and/or ethics committee at each institution. All patients provided written informed consent.

End Points and Statistical Analysis

The primary end point was PFS as assessed by blinded independent central review (BICR). Secondary end points were OS and confirmed ORR by BICR. Exploratory/post hoc analyses in all randomly assigned patients included melanoma-specific survival (MSS), PFS-2 (PFS2), and efficacy on subsequent second-line (2L) therapy. Post hoc analyses were also performed for receiver-operating characteristic (ROC) analysis of PD-L1 association with efficacy. All efficacy analyses in this 3-year update are exploratory and descriptive. Adverse events (AEs) were assessed continuously throughout the trial for at least 100 days after treatment was discontinued.

Kaplan-Meier methods were used to estimate survival rates. ORR and corresponding 95% CIs were generated by using the Clopper-Pearson method for each arm. In responders, duration of response (DOR) per treatment arm was estimated using Kaplan-Meier product-limit methodology. ROC analyses included a probability curve, with the AUC representing the degree of separability.

RESULTS

Patients

A total of 714 patients received nivolumab plus relatlimab (n = 355) or nivolumab (n = 359; Fig 1). Baseline patient characteristics were well balanced (Data Supplement, Table S1 [online only]). Minimum follow-up was 33.0 months and median follow-up was 33.8 months (range, 0.3-64.2 months). Patient disposition can be found in the Data Supplement (Table S2).

FIG 1.

CONSORT diagram.

Efficacy

Median PFS was 10.2 months (95% CI, 6.5 to 15.4) with nivolumab plus relatlimab compared with 4.6 months (95% CI, 3.5 to 6.5) with nivolumab (hazard ratio [HR], 0.79 [95% CI, 0.66 to 0.95]); 3-year PFS rates were 31.8% (95% CI, 26.6 to 37.1) and 26.9% (95% CI, 22.1 to 31.9), respectively (Fig 2A). Median OS was 51.0 months (95% CI, 34.0 to not reached [NR]) with nivolumab plus relatlimab and 34.1 months (95% CI, 25.2 to 44.7) with nivolumab (HR, 0.80 [95% CI, 0.66 to 0.99]); 3-year OS rates were 54.6% (95% CI, 49.2 to 59.6) and 48.0% (95% CI, 42.7 to 53.1), respectively (Fig 2B). BICR-assessed ORR is depicted in Figure 3A and DOR in the Data Supplement (Fig S1). Median MSS was NR (95% CI, NR to NR) with nivolumab plus relatlimab and 46.7 months (95% CI, 34.1 to NR) with nivolumab (HR, 0.75 [95% CI, 0.60 to 0.94]; Fig 3B).

FIG 2.

Kaplan–Meier estimates of (A) PFS and (B) OS. BICR, blinded independent central review; HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression-free survival.

FIG 3.

(A) Response to treatment and Kaplan–Meier estimates of (B) MSS^a and (C) PFS2. ^aA total of 375 deaths (52.5%) were reported (173 [48.7%] in the nivolumab plus relatlimab arm and 202 [56.3%] in the nivolumab arm), with 133/355 (37.5%) and 166/359 (46.2%) deaths due to melanoma reported in the nivolumab plus relatlimab arm and nivolumab arm (nonmelanoma deaths occurred in 40 patients [11.3%] and 36 patients [10.0%]), respectively. MSS was defined as the time from random assignment to death due to melanoma per investigator assessment, with deaths for any other reason, including death due to study drug toxicity, being censored. PFS2 was defined as the time from random assignment to progression after the next line of therapy, per investigator assessment, or to death from any cause, whichever occurred first. CR, complete response; HR, hazard ratio; MSS, melanoma-specific survival; NR, not reached; PD, progressive disease; PFS2, progression-free survival-2; PR, partial response; SD, stable disease.

Nivolumab plus relatlimab was favored over nivolumab in the majority of clinically relevant subgroups (Data Supplement, Fig S2). In ROC curve analyses, tumor PD-L1 expression was not predictive for efficacy at any PD-L1 cutoff in either arm (Data Supplement, Fig S3).

Subsequent systemic therapy was received by 135 patients (38.0%) in the nivolumab plus relatlimab arm and 141 (39.3%) in the nivolumab arm (Data Supplement, Table S3). Efficacy of 2L therapy is presented in the Data Supplement (Table S4). Median PFS2 was 29.6 months (95% CI, 23.0 to 42.1) with nivolumab plus relatlimab and 20.3 months (95% CI, 16.1 to 24.9) with nivolumab (HR, 0.79 [95% CI, 0.65 to 0.96]; Fig 3C).

Safety

Safety summary is shown in Table 1. Grade 3 or 4 treatment-related AEs (TRAEs) occurred in 22.0% of patients treated with nivolumab plus relatlimab and 12.0% with nivolumab. No new treatment-related deaths were reported since the last analysis.² Time to onset of select TRAEs is shown in the Data Supplement (Figs S4 and S5).

TABLE 1.

AE Summary

Event	Nivolumab Plus Relatlimab (n = 355)		Nivolumab (n = 359)
	Any grade, No. (%)	Grade 3 or 4, No. (%)	Any grade, No. (%)	Grade 3 or 4, No. (%)
Any AE	352 (99.2)	164 (46.2)	345 (96.1)	141 (39.3)
TRAE	302 (85.1)	78 (22.0)	263 (73.3)	43 (12.0)
Leading to discontinuation	63 (17.7)	34 (9.6)	35 (9.7)	14 (3.9)
TRAEs in ≥5% of patients
Pruritus	93 (26.2)	0	61 (17.0)	2 (0.6)
Fatigue	84 (23.7)	5 (1.4)	47 (13.1)	1 (0.3)
Rash	61 (17.2)	3 (0.8)	54 (15.0)	2 (0.6)
Diarrhea	60 (16.9)	5 (1.4)	39 (10.9)	2 (0.6)
Hypothyroidism	59 (16.6)	0	47 (13.1)	0
Arthralgia	56 (15.8)	3 (0.8)	34 (9.5)	1 (0.3)
Vitiligo	49 (13.8)	0	44 (12.3)	0
Asthenia	32 (9.0)	1 (0.3)	18 (5.0)	0
Nausea	32 (9.0)	0	18 (5.0)	0
Increased ALT	31 (8.7)	5 (1.4)	17 (4.7)	2 (0.6)
Increased AST	31 (8.7)	5 (1.4)	10 (2.8)	1 (0.3)
Myalgia	30 (8.5)	1 (0.3)	18 (5.0)	0
Decreased appetite	28 (7.9)	0	10 (2.8)	0
Infusion-related reaction	24 (6.8)	0	13 (3.6)	1 (0.3)
Hyperthyroidism	23 (6.5)	0	24 (6.7)	0
IMAEsa
Hypothyroidism or thyroiditis	70 (19.7)	0	54 (15.0)	0
Rash	48 (13.5)	3 (0.8)	34 (9.5)	5 (1.4)
Diarrhea or colitis	29 (8.2)	6 (1.7)	14 (3.9)	5 (1.4)
Hyperthyroidism	24 (6.8)	0	26 (7.2)	0
Hepatitis	23 (6.5)	18 (5.1)	13 (3.6)	6 (1.7)
Adrenal insufficiency	21 (5.9)	6 (1.7)	4 (1.1)	0
Pneumonitis	15 (4.2)	2 (0.6)	9 (2.5)	2 (0.6)
Hypophysitis	11 (3.1)	2 (0.6)	4 (1.1)	1 (0.3)
Nephritis and renal dysfunction	7 (2.0)	4 (1.1)	5 (1.4)	4 (1.1)
Hypersensitivity	6 (1.7)	0	5 (1.4)	0
Treatment-related deathsb	4 (1.1)		2 (0.6)

NOTE. Data are No. (%) unless otherwise specified.

Abbreviations: AE, adverse event; IMAE, immune-mediated AE; TRAE, treatment-related AE.

^a IMAEs included AEs of any grade that occurred in at least 1% of patients in the nivolumab plus relatlimab arm, that were considered by investigators to be potentially immune-mediated, and that met the following criteria: occurred within 100 days after the last dose (regardless of causality) and were treated with immune-modulating medication with no clear alternate cause or had an immune-mediated component.

^b Treatment-related deaths: nivolumab plus relatlimab (n = 4): hemophagocytic lymphohistiocytosis, acute edema of the lung, pneumonitis, and multiorgan failure; nivolumab (n = 2): sepsis and myocarditis, and worsening pneumonia. No new treatment-related deaths were reported since the last database lock.¹²

DISCUSSION

The updated 3-year descriptive results presented here confirm the sustained efficacy benefit of nivolumab plus relatlimab versus nivolumab. Of note, the HR 95% CI upper bound for the descriptive analysis of OS is now <1. Efficacy results continued to favor nivolumab plus relatlimab across the majority of prespecified subgroups, including in BRAF-mutant and BRAF-wildtype patients. Nivolumab plus relatlimab maintained benefit over time versus nivolumab in low-risk subgroups, where anti–PD-1 monotherapy may have otherwise been considered to balance efficacy with toxicity (low LDH and low tumor burden).^5-7 Additionally, a sustained benefit was observed with nivolumab plus relatlimab in patients with high LDH, high tumor burden, stage M1C disease, and mucosal and acral melanoma subtypes, where combination immunotherapy may be considered.^5-7 The ROC analysis indicated that tumor PD-L1 was not useful in predicting efficacy, indicating that the level of tumor PD-L1 expression alone is a poor predictive biomarker of efficacy.

PFS2 results further support the long-term benefits of nivolumab plus relatlimab, with a median PFS2 of 29.6 months for nivolumab plus relatlimab and 20.3 months for nivolumab. The therapeutic benefit of 2L therapies in this study appears consistent with that of other studies in this setting.^8-12 Moreover, in patients whose disease did not respond to or progressed on first-line therapy, the therapeutic benefit of 2L therapy did not appear to be negatively affected by previous treatment with nivolumab plus relatlimab versus nivolumab. The use of subsequent therapy was not prespecified in the protocol and was based on local standards of care per the investigator's decision. Given the small sample size, and because the use of subsequent therapy was not prespecified in the protocol and was based on local standards of care per the investigator's decision, additional data on patients whose disease is resistant to or progresses on first-line immunotherapy are required.

Although targeting two immune checkpoints in patients with advanced melanoma is a well-established treatment strategy, to our knowledge, RELATIVITY-047 is the first study to test and show a statistically significant improvement in PFS for an immunotherapy combination versus PD-1 monotherapy. Furthermore, to our knowledge, this analysis is the first to demonstrate an OS HR 95% CI upper bound ≤1 for a combination immunotherapy over anti–PD-1 monotherapy. Overall, these descriptive analyses continued to show a benefit for nivolumab plus relatlimab in patients with previously untreated metastatic or unresectable advanced melanoma.

CLINICAL TRIAL INFORMATION

NCT03470922

DATA SHARING STATEMENT

Bristol Myers Squibb's policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.

AUTHOR CONTRIBUTIONS

Conception and design: Hussein A. Tawbi, F. Stephen Hodi, Evan J. Lipson, Dirk Schadendorf, Paolo A. Ascierto, Luis Matamala, Erika Castillo Gutiérrez, Piotr Rutkowski

Administrative support: Jean-Jacques Grob, Barbara Ratto

Provision of study materials or patients: Hussein A. Tawbi, F. Stephen Hodi, Evan J. Lipson, Dirk Schadendorf, Paolo A. Ascierto, Luis Matamala, Erika Castillo Gutiérrez, Piotr Rutkowski, Helen Gogas, Christopher D. Lao, Juliana Janoski De Menezes, Stéphane Dalle, Ana Maria Arance, Saima Rodriguez, Antonella Mazzei, Sonia Dolfi, Georgina V. Long

Collection and assembly of data: Hussein A. Tawbi, F. Stephen Hodi, Evan J. Lipson, Dirk Schadendorf, Paolo A. Ascierto, Luis Matamala, Erika Castillo Gutiérrez, Piotr Rutkowski, Helen Gogas, Christopher D. Lao, Juliana Janoski De Menezes, Stéphane Dalle, Jean-Jacques Grob, Barbara Ratto

Data analysis and interpretation: Hussein A. Tawbi, F. Stephen Hodi, Evan J. Lipson, Dirk Schadendorf, Paolo A. Ascierto, Luis Matamala, Erika Castillo Gutiérrez, Piotr Rutkowski, Helen Gogas, Christopher D. Lao, Juliana Janoski De Menezes, Stéphane Dalle, Ana Maria Arance, Jean-Jacques Grob, Barbara Ratto, Saima Rodriguez, Antonella Mazzei, Sonia Dolfi, Georgina V. Long

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Three-Year Overall Survival With Nivolumab Plus Relatlimab in Advanced Melanoma From RELATIVITY-047

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