Relatlimab Plus Nivolumab More Than Doubles PFS in Frontline Advanced Melanoma

Evan J. Lipson, MD

The addition of relatlimab to nivolumab (Opdivo) more than doubled the median progression-free survival (PFS) compared with nivolumab alone in patients with previously untreated, unresectable or metastatic melanoma, according to the primary results from the phase 3 RELATIVITY-047 (CA224-047) trial (NCT03470922).¹

Results, which were presented during a virtual press briefing ahead of the 2021 ASCO Annual Meeting, indicated that the combination resulted in a median PFS of 10.12 months (95% CI, 6.37-15.74) vs 4.63 months (95% CI, 3.38-5.62) with nivolumab alone (HR, 0.75; 95% CI, 0.62-0.92; P = .0055). Moreover, the 12-month PFS rate with relatlimab/nivolumab was 47.7% (95% CI, 41.8%-53.2%) vs 36.0% with single-agent nivolumab (95% CI, 30.5%-41.6%).

“Our findings demonstrate that relatlimab plus nivolumab is a potential novel treatment option for this patient population,” lead study author Evan J. Lipson, MD, an oncologist and an associate professor of oncology at Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, and Johns Hopkins University, said in a presentation on the data. “Additionally, and importantly, this is the first phase 3 study to validate inhibition of the LAG-3 immune checkpoint as a therapeutic strategy for patients with cancer. It establishes the LAG-3 pathway as the third immune checkpoint pathway in history, after CTLA-4 and PD-1, for which blockade appears to have clinical benefit.”

Because PD-L1 inhibitors have been shown to improve survival in several tumor types, including melanoma, investigators began to examine novel immune checkpoint inhibitor combinations to derive further clinical benefit with manageable risk.

Relatlimab is an antibody that was developed to block LAG-3, which is responsible for T-cell inhibition and helps cancer cells avoid immune attacks.^2-5 The agent is designed to help reinvigorate T cells to target cancer cells.⁶

Previous data on the combination were presented during the 2017 ESMO Congress and showed that the doublet elicited an objective response rate of 11.5% with a disease control rate of 49% among 68 patients with melanoma who received previous immunotherapy. Notably, 57% of these patients had previously received an anti–CTLA-4 agent and 46% had received 3 more prior lines of treatment.⁸

“In support of this approach are results from trials that led up to the current study in which administration of relatlimab plus nivolumab caused tumors to shrink in some patients with advanced melanoma who had already progressed through anti–PD-1 alone,” Lipson noted.^6-8

The global, double-blind, phase 2/3 trial enrolled a total of 714 patients and randomized them 1:1 to receive either a single fixed-dose intravenous (IV) infusion of 160 mg of relatlimab plus 480 mg of nivolumab every 4 weeks or 480 mg of IV nivolumab every 4 weeks.

“[The combination] is administered as a single intravenous infusion to reduce preparation and infusion times and minimize the risk of administration errors,” Lipson explained.

To be eligible for enrollment, patients needed to have previously untreated, unresectable or metastatic disease and an ECOG performance status of 0 or 1. Patients were stratified based LAG-3, PD-L1, BRAF, and American Joint Committee on Cancer v8 M stage.

The primary end point of the trial was PFS by blinded independent central review (BICR), and key secondary end points included overall survival (OS) and objective response rate by BICR.

The combination of relatlimab plus nivolumab was found to have a manageable safety profile, with no unexpected safety signals observed during the course of the study. In the combination arm, 97.2% of patients experienced any grade of AE, while 40.3% experienced grade 3 or 4 AEs; in the monotherapy arm, these rates were 94.4% and 33.4%, respectively.

The most common any-grade treatment-related adverse effects (TRAEs) reported in the investigative and control arms included pruritus (23.4% vs 15.9%, respectively), fatigue (23.1% vs 12.8%), and rash (15.5% vs 12.0%). The most frequently experienced grade 3 or 4 TRAEs in the combination arm included fatigue (1.1%), rash (0.8%), arthralgia (0.8%), and diarrhea (0.8%). In the monotherapy arm, the most notable grade 3 or 4 TRAEs were pruritus (0.6%), rash (0.6%), and diarrhea (0.6%).

Just under 15% (14.6%) of patients on the combination arm experienced any-grade TRAEs that led to treatment discontinuation; 8.5% discontinued treatment due to grade 3 or 4 TRAEs. Comparatively, 6.7% and 3.1% of patients, respectively, discontinued treatment in the nivolumab-alone arm. Three patients in the combination arm died due to treatment-related hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis. In total, 2 patients in the nivolumab arm died due to sepsis and myocarditis, as well as worsening pneumonia.

In March 2021, it was announced that relatlimab/nivolumab met the primary end point of RELATIVITY-047.⁹ Currently, follow-up for OS, a secondary end point of the study, is ongoing.

References

1. Lipson EJ. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047). Presented at: 2021 ASCO Annual Meeting; June 4-8, 2021; Virtual. Abstract 9503.
2. Durham NM, Nirschl CJ, Jackson CM, et al. Lymphocyte activation gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed in vivo. PLoS One. 2014;9(11):e109080. doi:10.1371/journal.pone.0109080
3. Workman CJ, Cauley LS, Kim I-J, et al. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J Immunol. 2004;172(9):5450-5455. doi:10.4049/jimmunol.172.9.5450
4. Grosso JF, Kelleher CC, Harris TJ, et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest. 2007;117(11):3383-3392. doi:10.1172/JCI31184
5. Hemon P, Jean-Louis F, Ramgolam K, et al. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J Immunol. 2011;186(9):5173-5183. doi:10.4049/jimmunol.1002050
6. Lipson E, Gopal A, Neelapu SS, et al. Initial experience administering BMS-986016, a monoclonal antibody that targets lymphocyte activation gene (LAG)-3, alone and in combination with nivolumab to patients with hematologic and solid malignancies. Presented at: 2016 SITC Annual Meeting; November 3-13, 2016; National Harbor, MD. Abstract P232. doi:10.1186/s40425-016-0173-6
7. Ascierto PA, Melero I, Bhatia S, et al. Initial efficacy of anti-lymphocyte activation gene-3 (anti-LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti–PD-1/PD-L1 therapy. J Clin Oncol. 2017;35(suppl 15):9520. doi:10.1200/JCO.2017.35.15_suppl.9520
8. Ascierto PA, Bono P, Bhatia S, et al. Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with melanoma who progressed during prior anti–PD-1/PD-L1 therapy (mel prior IO) in all-comer and biomarker-enriched populations. Ann Oncol. 2017;28(suppl 5):V611-V612. doi:10.1093/annonc/mdx440.011
9. Bristol Myers Squibb announces RELATIVITY-047, a trial evaluating anti-LAG-3 antibody relatlimab and Opdivo (nivolumab) in patients with previously untreated metastatic or unresectable melanoma, meets Primary endpoint of progression-free survival. News release. Bristol Myers Squibb. March 25, 2021. Accessed May 14, 2021. https://bit.ly/3w7PiLu