Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047).
Abstract
9503 Background: Immune checkpoint inhibitor therapy has revolutionized the treatment of patients with advanced melanoma. However, novel combinations are needed to optimize the benefit-risk profile. Lymphocyte-activation gene 3 (LAG-3) regulates an immune checkpoint pathway, which inhibits T-cell activity, and is upregulated in many tumor types including melanoma. Relatlimab (RELA), a human IgG4 LAG-3-blocking antibody, restores effector function of exhausted T cells. RELA in combination with nivolumab (NIVO; anti-programmed death [PD]-1) modulates potentially synergistic immune checkpoint pathways and can enhance antitumor immune responses. RELATIVITY-047 is a global, randomized, double-blind, phase II/III study evaluating a novel immune checkpoint inhibitor combination of RELA+NIVO as a fixed-dose combination (FDC) treatment in first-line advanced melanoma. Methods: Patients with previously untreated advanced melanoma were randomized 1:1 to receive RELA 160 mg + NIVO 480 mg FDC intravenously (IV) every 4 weeks (Q4W) or NIVO monotherapy 480 mg IV Q4W, stratified by LAG-3 expression, programmed death ligand 1 expression, BRAF mutation status, and AJCC (v8) M stage. The primary endpoint was progression-free survival (PFS) per RECIST v1.1 as assessed by blinded independent central review. Secondary endpoints were overall survival and objective response rate. PFS in prespecified subgroups and safety were additional objectives. Results: 714 patients were randomized to RELA+NIVO FDC (n = 355) or NIVO (n = 359). Patient characteristics were well balanced between treatment groups. Median follow-up was 13.2 months. Median PFS in the RELA+NIVO FDC group (10.1 months [95% CI, 6.4–15.7]) was significantly longer than in the NIVO group (4.6 months [95% CI, 3.4–5.6]; hazard ratio, 0.75 [95% CI, 0.6–0.9]; P = 0.0055). PFS rates at 12 months were 47.7% (95% CI, 41.8–53.2) and 36.0% (95% CI, 30.5–41.6) for RELA+NIVO FDC and NIVO, respectively. PFS favored RELA+NIVO FDC across key prespecified subgroups. The incidence of grade 3/4 treatment-related adverse events (TRAEs) was higher in the RELA+NIVO FDC group (18.9%) versus NIVO (9.7%). There were 3 treatment-related deaths with RELA+NIVO FDC and 2 with NIVO. TRAEs (any grade) led to treatment discontinuation in 14.6% and 6.7% of patients in the RELA+NIVO FDC and NIVO groups, respectively. Conclusions: First-line treatment with RELA+NIVO FDC demonstrated a statistically significant PFS benefit compared to NIVO monotherapy in patients with advanced melanoma. RELA+NIVO FDC was well tolerated with a manageable safety profile and without unexpected safety signals. This is the first phase III study of a novel FDC to demonstrate a clinically meaningful benefit by dual inhibition of the LAG-3 and PD-1 pathways. Clinical trial information: NCT03470922.
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In the phase 2/3 study RELATIVITY-047, relatlimab plus nivolumab therapy demonstrated a significant PFS benefit (10.1 vs. 4.6 months, HR: 0.75) in advanced melanoma, relative to nivolumab monotherapy.
“In the phase 2/3 study RELATIVITY-047, relatlimab (α-LAG-3) plus nivolumab therapy demonstrated a significant PFS benefit (10.1 vs. 4.6 months, HR: 0.75) in advanced melanoma, relatively to nivolumab monotherapy [165].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [165]
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“75) in advanced melanoma, relatively to nivolumab monotherapy [165].”
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Gorabi, A. M., Ravari, M. S., Sanaei, M., Davaran, S., Kesharwani, P., & Sahebkar, A. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109300 · Cited by 18 · see citing works
Veld, R. V. H. I. ‘., Ma, S., Kines, R. C., et al. (2023) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-023-03425-3 · Cited by 19 · see citing works
“In line with this, a phase II and III trial investigated a combination treatment consisting of anti-PD-1 (Nivolumab) together with anti-LAG-3 (Relatlimab) in patients with metastatic or unresectable cutaneous melanoma (NCT03470922) [39], showing a significant increase in progression-free survival for the combination t…”
BackgroundTreatment of Metastatic Melanoma in the Elderly
Seedor, R. S., & Orloff, M. M. (2022) · Current Oncology Reports · doi:10.1007/s11912-022-01257-5 · Cited by 19 · see citing works
TCR-Directed Therapy in the Treatment of Metastatic Uveal Melanoma
Strobel, S. B., Machiraju, D., & Hassel, J. C. (2022) · Cancers · doi:10.3390/cancers14051215 · Cited by 17 · see citing works
Zhong, J., Bai, H., Wang, Z., Duan, J., Zhuang, W., Wang, D., Wan, R., Xu, J., Fei, K., Ma, Z., et al. (2023) · Frontiers of Medicine · doi:10.1007/s11684-022-0976-4 · Cited by 18 · see citing works
Systemic CD4 Immunity and PD-L1/PD-1 Blockade Immunotherapy
Escors, D., Bocanegra, A., Chocarro, L., Blanco, E., Piñeiro‐Hermida, S., Garnica, M., Fernández, L., Vera, R., Arasanz, H., & Kochan, G. T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113241 · Cited by 17 · see citing works
Sun, H., Dai, J., Zhao, L., et al. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-4481 · Cited by 16 · see citing works
“In patients who present with upregulated LAG3 expression and are insensitive to PD-1 blocking treatment, the application of this combined strategy (antiPD-1 and anti-LAG3) may improve prognosis (30,47), as demonstrated in such patients with melanoma (48).”
BackgroundAtkins, M. B., Abu‐Sbeih, H., Ascierto, P. A., Bishop, M., Chen, D. S., Dhodapkar, M. V., Emens, L. A., Ernstoff, M. S., Ferris, R. L., Greten, T. F., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-005413 · Cited by 15 · see citing works
Self-citationTumor-infiltrating γδ T cells as targets of immune checkpoint blockade in melanoma
Simone, M. D., Corsale, A. M., Toia, F., et al. (2024) · Journal of Leukocyte Biology · doi:10.1093/jleuko/qiae023 · Cited by 16 · see citing works
Tarantino, P., Antonarelli, G., Ascione, L., & Curigliano, G. (2021) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2021.1972968 · Cited by 16 · see citing works
“Notably, an anti-LAG3 mAb (relatlimab) has recently demonstrated to significantly prolong PFS in a randomized trial enrolling untreated melanoma patients, representing the first NGIO to improve oncological outcomes in a phase 3 trial [95].”
BackgroundEdwards, C., Sette, A., Cox, C. T., Fiore, B. D., Wyre, C., Sydoruk, D., Yadin, D., Hayes, P., Stelter, S., Bartlett, P. D., et al. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01684-4 · Cited by 16 · see citing works
Schmitt, A. M., Dumas, L., & Larkin, J. (2021) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2022.2017286 · Cited by 15 · see citing works
“the congress of the American Society for Clinical Oncology 2021 showed promising results for the combination of the anti-LAG3 antibody relatlimab with nivolumab compared to nivolumab monotherapy in the treatment of metastatic melanoma [40].”
BackgroundThe Impact of Hyaluronan on Tumor Progression in Cutaneous Melanoma
Takabe, P., Siiskonen, H., Rönkä, A., Kainulainen, K., & Pasonen‐Seppänen, S. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2021.811434 · Cited by 16 · see citing works
Michot, J., Mouraud, S., Adam, J., et al. (2021) · Cancers · doi:10.3390/cancers13215487 · Cited by 14 · see citing works
“Interestingly, recent results of a phase 3 clinical trial in patients with metastatic melanoma showed that anti-LAG-3 antibody combined with anti-PD-1 improves overall survival in patients with metastatic melanoma, compared with anti-PD-1 monotherapy [27].”
BackgroundSequencing Targeted and Immune Therapy in BRAF-Mutant Melanoma: Lessons Learned
Trojaniello, C., Sparano, F., Cioli, E., & Ascierto, P. A. (2023) · Current Oncology Reports · doi:10.1007/s11912-023-01402-8 · Cited by 14 · see citing works
“Recently, the US FDA and EMA approved the combination of relatlimab and nivolumab, which is now available as an adjunctive immunotherapy option for this group of patients with minimal added toxicity [18].”
BackgroundSelf-citationEggermont, A. M. M., Ascierto, P. A., Khushalani, N. I., et al. (2022) · Future Oncology · doi:10.2217/fon-2021-1286 · Cited by 11 · see citing works
Self-citationMahdiabadi, S., Momtazmanesh, S., Karimi, A., & Rezaei, N. (2023) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2023.2278509 · Cited by 11 · see citing works
“Anti-LAG3 antibodies constitute another class of ICIs whose simultaneous use with nivolumab has recently demonstrated improved PFS [47].”
BackgroundAdvances in the drug management of basal cell carcinoma
Ramelyte, E., Restivo, G., Mannino, M., Levesque, M. P., & Dummer, R. (2022) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2022.2032646 · Cited by 10 · see citing works
“Results from a randomized, double-blind, phase III study assessing clinical efficacy of the novel combination relatlimab (anti LAG3) plus nivolumab (anti PD-1) versus nivolumab monotherapy in advanced melanoma patients have been recently published [88].”
BackgroundVenzel, R., Campos, M. C. P., de Oliveira, L. P., Lins, R. V. D., Siena, Á. D. D., Mesquita, K. T., dos Santos, T. P. M., Nohata, N., Arruda, L. C. M., Sales‐Campos, H., et al. (2023) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2023.103988 · Cited by 10 · see citing works
Understanding resistance to immune checkpoint inhibitors in advanced breast cancer
Tarantino, P., Barroso‐Sousa, R., Garrido-Castro, A. C., McAllister, S. S., Guerriero, J. L., Mittendorf, E. A., Curigliano, G., & Tolaney, S. M. (2021) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2022.2020650 · Cited by 10 · see citing works
“hopefully lead to more promising results, as already observed in the context of advanced melanoma [112] and”
ResultZhou, L., Wu, X., Chi, Z., Si, L., Sheng, X., Kong, Y., Mao, L., Lian, B., Tang, B., Yan, X., et al. (2022) · BMC Cancer · doi:10.1186/s12885-022-09663-5 · Cited by 10 · see citing works
“Abbreviations PD-1: Programmed cell death receptor-1; CTLA-4: Cytotoxic T-lymphocyteassociated antigen 4; LAG3: Lymphocyte-activation gene 3; RECIST: Response Evaluation Criteria In Solid Tumors; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; DLT: Dose-limited toxicity; MTD: Maxim…”
BackgroundKelly, D., Rose, A. A. N., Muniz, T. P., et al. (2021) · Cancers · doi:10.3390/cancers13143640 · Cited by 9 · see citing works
“In addition, novel CTLA4-free combinations such as Relatlimab, a human IgG4 LAG-3-blocking antibody in combination with nivolumab may also play a role in uveal melanoma treatment in the future [39].”
BackgroundLecocq, Q., Debie, P., Puttemans, J., Awad, R. M., Beck, L. D., Ertveldt, T., Vlaeminck, Y. D., Goyvaerts, C., Raes, G., Keyaerts, M., et al. (2021) · EJNMMI Research · doi:10.1186/s13550-021-00857-9 · Cited by 9 · see citing works
Adjuvant PD-1 Blockade in Resected Melanoma: Is Preventing Recurrence Enough?
Smithy, J. W., & Shoushtari, A. N. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1593 · Cited by 9 · see citing works
Salani, F., Genovesi, V., Vivaldi, C., Massa, V., Cesario, S., Bernardini, L., Caccese, M., Graziani, J., Berra, D., Fornaro, L., et al. (2022) · Cancers · doi:10.3390/cancers14194896 · Cited by 9 · see citing works
“Being an inhibitor IgG4 monoclonal antibody on the LAG3 signaling pathway, relatlimab combination with nivolumab was recently approved by FDA for advanced unresectable and previously untreated melanoma, thanks to PFS and OS results from Relativity-047 phase 2/3 trial [52].”
BackgroundTargeting Innate Immunity in Glioma Therapy
Gillard, A. G., Shin, D. H., Hampton, L. A., Lopez-Rivas, A. R., Parthasarathy, A., Fueyo-Margareto, J., & Gomez‐Manzano, C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25020947 · Cited by 8 · see citing works
“Preliminary studies have already reported an improved NK cell and CD8+ T-cell anti-tumor response after NKG2A blockade [104,105].”
BackgroundNovel Immunotherapeutics: Perspectives on Checkpoints, Bispecifics, and Vaccines in Development
Kreidieh, F., Tawbi, H. A., Alexaki, A., Borghaei, H., & Kandalaft, L. E. (2023) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_391278 · Cited by 8 · see citing works
Self-citationMarkers of Immune Cell Exhaustion as Predictor of Survival in Surgically-Treated Early-Stage NSCLC
Sellmer, L., Kovács, J., Walter, J., Kumbrink, J., Neumann, J. H. L., Kauffmann-Guerrero, D. E., Kiefl, R., Schneider, C., Jung, A., Behr, J., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.858212 · Cited by 8 · see citing works
Mathematical modeling identifies LAG3 and HAVCR2 as biomarkers of T cell exhaustion in melanoma
Beck, R. J., Sloot, S., Matsushita, H., Kakimi, K., & Beltman, J. B. (2023) · iScience · doi:10.1016/j.isci.2023.106666 · Cited by 7 · see citing works
“This is consistent with findings that blockade of LAG3 as well as PDCD1 receptors is required to prevent relapse in melanoma(31) and with recent clinical results demonstrating that co-administration of PDCD1 and LAG3 inhibitors improves survival compared to administration of PDCD1 inhibitors alone.(35)”
Result
- Authors
- Lipson, E. J., Tawbi, H. A.-H., Schadendorf, D., Ascierto, P. A., Matamala, L., Gutiérrez, E. C., Rutkowski, P., Gogas, H., Lao, C. D., Janoski de Menezes, J., Dalle, S., Arance, A. M., Grob, J.-J., Srivastava, S., Abaskharoun, M., Simonsen, K. L., Li, B., Long, G. V., & Hodi, F. S.
- Affiliations
- Johns Hopkins University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
- Fundación Arturo López Pérez (CL)
- FAICIC Clinical Research, Veracruz, Mexico;
- The Maria Sklodowska-Curie National Research Institute of Oncology (PL)
- National and Kapodistrian University of Athens (GR)
- University of Michigan (US)
- Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil;
- Hospices Civils de Lyon (FR)
- Hospital Clínic de Barcelona (ES)
- Aix-Marseille Université (FR)
- Bristol-Myers Squibb (United States) (US)
- The University of Sydney (AU)
- Dana-Farber Cancer Institute (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2021-05-20
- Volume
- 39
- Issue
- 15_suppl
- Pages
- 9503-9503
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W3169720255
- Cited by
- 150
- References
- 0
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 12 · 2023: 24 · 2022: 68 · 2021: 34
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Funders
- Bristol-Myers Squibb
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- relatlimab, nivolumab, LAG-3 blockade, anti-PD-1 therapy, advanced melanoma, first-line therapy, immune checkpoint inhibitors, fixed-dose combination, progression-free survival, objective response rate, overall survival, PD-L1 expression, BRAF mutation, treatment safety, T cell exhaustion, antitumor immunity, combination immunotherapy
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