James W. Smithy, MD, MHS
Margaret K. Callahan, MD, PhD
In the recently published results of the RELATIVITY-047 trial,1 summarized in this issue of The ASCO Post, the addition of relatlimab to nivolumab monotherapy was associated with improved progression-free survival compared with nivolumab alone in patients with previously untreated advanced, unresectable melanoma. Relatlimab is a monoclonal antibody targeting lymphocyte-activation gene 3 (LAG-3), a transmembrane protein expressed on T cells that negatively regulates T-cell proliferation and effector function.2 LAG-3 been found to be co-expressed with PD-1 on tumor-infiltrating lymphocytes in multiple orthotopic murine models of cancer.3 Preclinical data from mouse models suggested that the combination of anti–LAG-3 and anti–PD-1 could generate promising antitumor activity and that this combination would likely be much more active than anti–LAG-3 monotherapy.3 Prior reports from the phase I/II experience showed that combined relatlimab and nivolu-mab could generate objective responses in patients with melanoma that had progressed on or after anti–PD-1 monotherapy.4
Significantly, these results demonstrate the first positive phase III study introducing a novel agent to improve upon the benchmark set by PD-1 inhibition nearly a decade ago.5 Despite considerable effort over the past decade, other clinical programs targeting immunomodulatory pathways such as IDO6 and co-stimulatory receptors such as CD137,7 and GITR8 have failed to demonstrate a strong clinical signal despite initial anecdotal promise. Trials of the anti-TIGIT antibody tiragolumab in combination with the anti–PD-L1 antibody atezolizu-mab in non–small cell lung cancer are also ongoing (ClinicalTrials.gov identifier NCT03563716).
Anti–PD-1 alone (nivolumab or pembrolizumab) or combined CTLA-4 (nivolumab plus ipilimumab) are approved first-line therapies for metastatic or unresectable melanoma. In clinical practice, the selection of monotherapy vs combined checkpoint blockade is based upon clinician judgment; factors such as patient fitness, clinical symptoms, tumor burden, and the presence of liver metastases9,10 or untreated brain metastases11 may influence decision-making. In the CheckMate 067 trial, which compared nivolumab, ipilimumab, and combined ipilimumab/nivolumab, the combination generated a higher response rate (57.6%, 95% confidence interval [CI] = 52.0%–63.2%) than nivolumab alone (43.7%, 95% CI = 38.1%–49.3%).12 With more than 6 years of follow up, there are emerging signals of an overall survival benefit with ipilimumab/nivolumab compared with nivolumab monotherapy,13 and some have argued that this combination should be the standard to which new combinations are compared.12,14
RELATIVITY-047 and CheckMate 067: Cross-Trial Comparisons
In RELATIVITY-047, patients were randomly assigned to either combination therapy with relatlimab and nivolumab or nivolumab monotherapy. The trial enrolled a range of patients with untreated M1a through M1c melanoma. The two study arms were relatively well balanced, with the authors noting a higher percentage of patients with M1c disease in the relatlimab/nivolumab group. Though patients with untreated brain metastases were excluded, a small percentage of patients (1%-3%) with treated M1d disease were represented in the study population. Of note, randomized and nonrandomized clinical trials have demonstrated favorable outcomes with nivolumab and ipilimumab for patients with untreated brain metastases, including CheckMate 20415 and the anti–PD-1 brain collaboration (ABC) trial.11
Additionally, patients with uveal melanoma were excluded from RELATIVITY-047, and a relatively small percentage of patients with mucosal melanoma (7%) were included. Both populations have significant unmet clinical needs and would benefit from additional dedicated investigation.
This study population largely mirrors that of CheckMate 067.12 However, there are some important differences. RELATIVITY-047 allowed for enrollment of patients who had previously received adjuvant BRAF/MEK inhibition, whereas adjuvant BRAF/MEK inhibition was not yet approved by the U.S. Food and Drug Administration during the enrollment period of CheckMate 067. As demonstrated in the recently presented DREAMSeq trial, there is some evidence that prior BRAF/MEK inhibition may be associated with decreased efficacy of checkpoint blockade.16 Additionally, there was a lower percentage of patients with M1c disease in RELATIVITY-047 (39%) compared with CheckMate 067 (58%). Although it is unlikely that either of these differences unduly benefited either the nivolumab monotherapy or combination-therapy arm, they are important to note when making cross-trial comparisons.
RELATIVITY-047: Primary Efficacy Endpoint Met
RELATIVITY-047 met its primary efficacy endpoint, with an impressive median progression-free survival of 10.1 months with relatlimab and nivolumab compared with 4.6 months with nivolumab monotherapy (hazard ratio [HR] = 0.75, 95% CI = 0.62–0.92). The initial prespecified interim analysis for overall survival was negative, and data regarding overall response rate remain blinded. Although some response data from a separate small neoadjuvant trial are available, showing an impressive 59% rate of pathologic complete response with relatlimab plus nivolumab,17 it is possible that responses in the more advanced, unresectable disease setting may differ.
Survival analyses were also stratified by pretreatment tissue protein expression of PD-L1 and LAG-3 by immunohistochemistry. Among patients with PD-L1–positive tumors (defined by positive staining in at least 1% of tumor cells), median progression-free survival was similar and favorable for both treatment arms: 15.7 months with relatlimab/nivolumab and 14.7 months with nivolumab alone (HR = 0.95, 95% CI = 0.68–1.33). Among patients with PD-L1–negative tumors, median progression-free survival was shorter, and there appeared to be a greater benefit with relatlimab/nivolumab than with nivolumab monotherapy (6.4 vs 2.9 months, HR = 0.66, 95% CI = 0.51–0.84). It remains to be seen whether there is a specific biologic benefit to the addition of LAG-3 blockade in PD-L1–negative tumors, or whether the curves in the PD-L1–positive tumor will diverge further as more events occur in this prognostically favorable group. Conversely, the progression-free survival benefit of adding relatlimab appeared to be similar in patients with low LAG-3–positive lymphocyte infiltration (defined as less than 1% LAG-3–positive lymphocyte-appearing cells compared with all nucleated cells; HR = 0.78, 95% CI = 0.54–1.15) and in those with high LAG-3–positive lymphocyte infiltration (at least 1% of cells; HR = 0.75, 95% CI = 0.59–0.95).
Favorable Safety Profile
In addition to encouraging efficacy signals, RELATIVITY-047 was also notable for a favorable safety profile with combined relatlimab plus nivolumab. The most common adverse effects (fatigue, pruritus, and rash) as well as immune-related adverse effects (thyroid dysfunction, rash, diarrhea/colitis, and arthralgias) were similar across the two treatment arms, with absolute rates between 3% and 10% higher in the relatlimab/nivolumab group. Rates of grade 3 or 4 adverse events were similar in the relatlimab/nivolumab group (40%) and nivolumab-alone (33%) group. Although cross-trial comparisons must be interpreted with caution, these rates are considerably lower than the 55% rate of grade 3 or 4 adverse events in the ipilimumab/nivolumab arm in CheckMate 067.12
“The potential application of relatlimab/nivolumab is broad and likely worthy of further exploration across multiple areas of solid tumor oncology.”— James W. Smithy, MD, MHS, and Margaret K. Callahan, MD, PhD
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In terms of less common but clinically significant adverse events, the relatlimab/nivolumab group did have higher rates of adrenal insufficiency (4.2% vs 0.8%) and myocarditis (1.6% vs 0.6%). Although these rates of myocarditis appear high compared with prior immunotherapy trials, routine troponin screening during the first 2 months of therapy was included in the RELATIVITY-047 protocol based on preclinical safety signals, which may have led to an increased rate of detection. Of note, no treatment-related deaths in the relatlimab/nivolumab group were attributed to myocarditis.
Remaining Questions
Though these initial results from RELATIVITY-047 demonstrate an encouraging efficacy signal and a favorable safety profile for relatlimab plus nivolumab, several important questions remain. Most pressingly, further data are needed to inform the decision between combined ipilimumab/nivolumab vs combined relatlimab/nivolumab in the first-line setting. Ipilimumab/nivolumab represents a highly effective regimen with a high response rate and durable survival benefit, with more than 6 years of follow-up.13
Although the safety profile of relatlimab/nivolumab may appear more palatable, it is important to note that there are no randomized trial data comparing the two regimens head-to-head. Furthermore, special attention will be needed in populations in which ipilimumab/nivolumab has demonstrated a benefit compared with anti–PD-1 monotherapy, including patients with liver9 and untreated brain metastases.11 In deciding among first-line regimens, it will also be helpful to know whether ipilimumab/nivolumab has preserved efficacy in the second line following relatlimab/nivolumab, as it does following anti–PD-1 monotherapy.18
The role of biomarkers in selecting first-line therapies also warrants further investigation. With additional follow-up, it will be interesting to note whether the survival curves for relatlimab/nivolumab and nivolumab-alone arms separate among patients with PD-L1–positive tumors. If they do not, it could be worth considering PD-1 monotherapy in patients in this population.
Compared with PD-L1 expression, it is less clear whether LAG-3 positivity will be useful in informing therapy choices. Although LAG-3 positivity was associated with at least a 3.5 times higher objective response rate in the phase I/II study of patients with previously treated melanoma,4 in RELATIVITY-047, it was not associated with a progression-free survival benefit in the first-line setting. It remains to be seen whether an alternate cutpoint may be useful in defining high and low LAG-3 expression, whether all nucleated cells are an optimal denominator, or whether LAG-3 could be incorporated into a multiplex assay that could more precisely identify patients likely to benefit from the addition of relatlimab.
What Next?
Going forward, the efficacy of relatlimab/nivolumab should be examined in populations of patients with melanoma that were either excluded from or minimally represented in RELATIVITY-047—including those with uveal melanoma, mucosal melanoma, and untreated brain metastases. Each of these populations has significant unmet clinical needs and could benefit from the development of additional treatment options.
FDA APPROVAL
On March 18, 2022, the U.S. Food and Drug Administration approved nivolumab and relatlimab-rmbw (Opdualag) for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.
Additionally, relatlimab/nivolumab is under active development in other melanoma disease settings. For example, a small phase II neoadjuvant study was presented at the 2021 ASCO Annual Meeting,17 and the phase III RELATIVITY-098 (NCT 05002569) trial of adjuvant relatlimab/nivolumab will start enrolling patients later this year. Given the wide range of current approvals for PD-1 monotherapy, the potential application of relatlimab/nivolumab is broad and likely worthy of further exploration across multiple areas of solid tumor oncology.
Dr. Smithy is a medical oncology fellow and Dr. Callahan is a medical oncologist, both practicing at the Memorial Sloan Kettering Cancer Center, New York.
DISCLOSURE: Dr. Smithy reported no conflicts of interest. Dr. Callahan has had provision of services with Merck, Moderna, InCyte, Bristol Myers Squibb, Clinical Care Options, Axios, AstraZeneca, and Celldex Therapeutics; a patent filed by Memorial Sloan Kettering; served as a consultant or advisor to AstraZeneca, Moderna, Merck, Immunocore, and Bayer; and has received research funding from Bristol Myers Squibb.
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