Advanced Melanoma: ICI Combo Improves PFS, with No Decrease in HRQoL

Targeting specific immune checkpoints has become de rigueur in the development of new treatments for many forms of cancer, and one such target—lymphocyte activation gene-3 (LAG-3)—has garnered attention as a potential target in patients with metastatic melanoma.

"Two parallel discoveries have significantly changed the treatment paradigm for melanoma. First was the finding that immune checkpoint inhibition (ICI) could improve progression-free survival (PFS) and overall survival (OS) of advanced melanoma patients. The second advance was the identification of the BRAF oncogene being a driver mutation in approximately 45% of melanoma patients AND the ability to selectively block the MAP kinase pathway with BRAF inhibitors in BRAF-mutant melanomas," he wrote. "Over the past decade, these therapies have evolved into a combination of BRAF-MEK inhibitors being less toxic and more effective than single-agent BRAF inhibition. Similarly, ICI has evolved to anti-PD-1 (nivolumab or pembrolizumab) or a combination of both ipilimumab and nivolumab (IPI-NIVO) rather than single-agent anti-CTLA-4. Moreover, these drugs have shifted towards use in the (neo-)adjuvant setting for stage III, and now even more recently, stage II melanoma. All these developments have culminated in a significantly improved OS for advanced melanoma," he wrote.

"However, despite these fantastic improvements, patients still progress and later die due to metastatic melanoma. Therefore, the challenge is on how to target novel immune checkpoints. Lymphocyte activation gene-3 (LAG-3) is such a novel target. LAG-3, similar to PD-1 or CTLA-4 before, is another co-inhibitory receptor on T cells that suppress their activation. Other proposed targets include, for example, T-cell immunoglobulin and mucinodomain containing-3 (TIM-3) and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT)," he continued.

Since 2014, several immune checkpoint inhibitor combinations have been approved for the treatment of advanced melanoma, including atezolizumab plus vemurafenib and cobimetinib, encorafenib plus binimetinib, dabrafenib plus trametinib, nivolumab plus ipilimumab, and vemurafenib plus cobimetinib. The newest of these is a combination of nivolumab (a programmed death receptor-1 [PD-1] blocking antibody) plus relatlimab (a LAG-3 blocking antibody), which was approved in March 2022 for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. Unlike other immune checkpoint inhibitor combinations, nivolumab plus relatlimab is a fixed-dose combination of both agents, delivered intravenously and simultaneously.

In his review, van Akkooi cited results from the phase II/III RELATIVITY-047 trial and phase I/II RELATIVITY-020 trial, adding that the combination of nivolumab-relatlimab is also being studied in the neoadjuvant and adjuvant settings.

"In conclusion, the combination of NIVO-RELA seems to add to the current melanoma systemic therapy drug arsenal, with efficacy shown in both first-line and second-line or higher for advanced melanoma and with promising results in the neoadjuvant setting. How this combination performs against the combination IPI-NIVO or after failing IPI-NIVO and in the adjuvant setting still needs to be determined," wrote van Akkooi.

RELATIVITY and Beyond

In the RELATIVITY-047 trial, researchers found that first-line treatment with a combination of nivolumab and relatlimab improved median progression-free survival (PFS) compared with single-agent nivolumab, at 10.1 versus 4.6 months, respectively (HR for progression or death, 0.75; 95% CI, 0.62-0.92; P=0.006), with a 1-year PFS of 47.7% versus 36.0%. Grade 3/4 adverse events, however, were more common in patients treated with the nivolumab-relatlimab combination versus nivolumab alone (18.9% versus 9.7%).

Dirk Schadendorf, of the University Hospital Essen, German Cancer Consortium, Partner Site Essen and University Alliance Ruhr, Research Center One Health, Essen, Germany, and colleagues presented updated HRQoL results from the phase II/III RELATIVITY-047 trial, in which patients were randomized to treatment with intravenous nivolumab plus relatlimab (480 mg/160 mg) or nivolumab alone (480 mg) every 4 weeks.

"In the phase II/III RELATIVITY-047 trial, a novel fixed-dose combination (FDC) of nivolumab plus relatlimab (NIVO + RELA; a programmed death-1 and a lymphocyte-activation gene 3 inhibitor, respectively) significantly improved progression-free survival (PFS) versus NIVO in patients with previously untreated unresectable or metastatic melanoma (median follow-up, 13.2 months) with stable health-related quality of life (HRQoL), although grade three or four treatment-related adverse events (TRAEs) were more frequent with the combination," they wrote.

For this analysis, Schadendorf and colleagues assessed HRQoL with the Functional Assessment of Cancer Treatment-melanoma (FACT-M) and EQ-5D-3L (one of the most internationally widely used patient reported outcome measures) questionnaires at baseline, before dosing at each treatment cycle, and at follow-up.

Patients were a mean age of 61, most (57%-58%) were men and White (97%), the majority were of American Joint Committee on Cancer (AJCC) stage IV at baseline (89%-94%), and 69%-70% had cutaneous non-acral melanoma. In both treatment groups, 76% of patients had a LAG-3 expression of 1% or greater, 59% had PD-L1 expression of less than 1%, and 62%-63% had wild-type BRAF mutation.

From baseline to week 152 of treatment, researchers found no clinically meaningful differences between treatment groups in overall LS mean changes in FACT-M and DQ-5D-3L scores. They did note that "Across time points, [least squares] LS mean changes from baseline in FACT-M scale/subscale scores initially deteriorated and subsequently stabilized or slightly improved over time but remained within MIDs with both treatments for most time points."

There was an exception in the FACT-M emotional well-being subscale, and while changes remained within the MID for both treatment arms, scores immediately improved and continued improving over time in both treatment arms.

"Although mean changes from baseline in FACT-M scale/ subscale scores were slightly higher (indicating improvement) with NIVO than with NIVO + RELA, particularly from week 96 through week 152, the changes did not exceed MIDs with both treatments. Although LS mean changes in EQ-5D-3L health utility index and VAS scores initially deteriorated and subsequently improved slightly across visits with both treatments, changes remained within MIDs at most time points," noted Schadendorf and colleagues.

They highlighted one item in the FACT-G, "I am bothered by side effects of treatment." Less than 6% of patients reported that they were bothered "quite a bit" or "very much" by treatment-related adverse events, the two worst ratings, a finding that suggests "that overall tolerability was similar with NIVO + RELA and NIVO."

"For most PROs, there was early deterioration in scores followed by stabilization or slight improvement. Thus, cumulative toxicity with NIVO + RELA did not appear to have a negative impact on HRQoL relative to NIVO monotherapy. It can be speculated that improvement in disease symptoms and/or relief due to the perception of active treatment may have had a positive impact on HRQoL," noted Schadendorf and colleagues.

In both the FACT-M total and EQ-5D-3L scores generally remained stable and were similar in the two treatment groups, although researchers noted that fewer patients treated with nivolumab alone had decreases in FACT-M total scores.

"In summary, results from the phase II/III RELATIVITY-047 trial suggest that a novel [fixed-dose combination] FDC of NIVO + RELA has patient-reported HRQoL (melanoma-specific and general health) that is stable and similar to that with NIVO monotherapy while providing significant improvement in PFS in patients with previously untreated unresectable or metastatic melanoma. These findings further support dual PD-1 and LAG-3 inhibition with NIVO + RELA as a first-line treatment option for this patient population," concluded Schadendorf and colleagues.

Study limitations included that patients who remained on treatment at later assessments may have been different than those in the baseline population, ie, they were more likely to have responded to or tolerated treatment; and that since results were based on patient-reported outcomes, whether patients could distinguish between treatment-related adverse events and disease symptoms.

RELATIVITY-047 was funded by Bristol Myers Squibb.

Schadendorf has received personal fees for advisory boards from 4SC, Array Biopharma, Bristol Myers Squibb (BMS), Immunocore, Merck Serono, Merck Sharp & Dohme (MSD), Nektar, Neracare, Novartis, Pfizer, Philogen, Pierre Fabre, Roche, Sandoz, and Sanofi/Regeneron; personal fees as an invited speaker from BMS, Merck, Merck Serono, MSD, Roche, and Sanofi; personal fees (financial interest) for steering committee membership from 4SC, BMS, MSD, Nektar, and Novartis; and institutional support as a coordinating principal investigator (no financial interest) from 4SC, BMS, MSD, Nektar, Novartis, and Pierre Fabre; institutional support as a local principal investigator (no financial interest) from Philogen, Roche, and Sanofi; and institutional research grant support (financial interest) from Array/Pfizer, BMS, MSD, and Novartis; and EORTC-MG Member of Board of Directors (no financial interest).

van Akkooi is a member of the Advisory Board for, and received consultancy honoraria from, Amgen, Bristol-Myers Squibb, Neracare, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical, and 4SC.

Schadendorf D, et al "Health-related quality of life with nivolumab plus relatlimab versus nivolumab monotherapy in patients with previously untreated unresectable or metastatic melanoma: RELATIVITY-047 trial" Eur J Cancer 2023; 187: 164-73.

van Akkooi ACJ "Relatlimab, an immune checkpoint inhibitor that blocks LAG-3 the latest drug to be added to the arsenal of systemic therapies for melanoma: What does a surgical oncologist need to know?" Ann Surg Oncol 2024; 31: 1-3.