What role can LAG-3-blocking antibodies play in melanoma therapy?

KEYWORDS:

• Melanoma
• anti-PD-
• anti-LAG-3
• relatlimab
• fianlimab

1. Introduction

Melanoma accounts for a minority of cutaneous malignancies, but it is related to most deaths of skin cancers [1,2]. The treatment landscape in the metastatic setting has recently dramatically changed due to developments in immunotherapy and targeted agents [2,3]. It has also been translated into approvals in adjuvant treatment in high-risk locoregional disease [4,5]. Despite these advances, advanced melanoma is a deadly disease for approximately 50% of the patients [5]. Until now, combining immune checkpoint blockade with programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors is the most successful strategy, but limiting its use to in routine practice to about half of the patients due to severe toxicity in the majority of patients [6]. Thus, new strategies in immune-oncology drug development are necessary, and melanoma is the pioneering field [7,8]. The current efforts focus on the best integration of combined immunotherapy in different clinical scenarios and the limitation of the toxicity of these drugs [7,9]. Lymphocyte activation gene-3 (LAG-3) is a co-inhibitory receptor on T cells that suppresses their activation, which strongly improves the possibility of immunomodulation in melanoma. LAG-3 contributes to the mechanism of T-cell exhaustion [7,10]. It has been demonstrated that its inhibition may have a synergistic effect with anti-PD-1 antibodies and that LAG-3 may mediate primary or acquired resistance to immunotherapy [7,11]. LAG-3 inhibitor (relatlimab) in combination with anti-PD-1 inhibitor (nivolumab) significantly improved progression-free survival (PFS) when compared to nivolumab monotherapy in patients with previously untreated metastatic or unresectable melanoma, what led to its approval as a new option in melanoma therapy [10].

The registration phase 2–3, double-blind, randomized clinical trial RELATIVITY-047 confirmed that inhibition of LAG-3 is a relevant biological target. Relatlimab was validated as the third immune checkpoint in melanoma. This pivotal trial compared relatlimab (160 mg) in combination with nivolumab (480 mg) at a fixed dose to nivolumab monotherapy (480 mg) – administered in a single intravenous infusion every 4 weeks in patients with metastatic/unresectable melanoma [12,13]. In the first analysis of this study, the impressive efficacy with the median PFS in the nivolumab-relatlimab arm − 10.1 months (95% confidence interval (CI): 6.4–15.7) as compared to 4.6 months (95% CI: 3.4–-5.6) in nivolumab monotherapy arm [hazard ratio, HR for progression or death was 0.75 (95% CI: 0.62–0.92; p = 0.006)] was achieved [12]. The PFS rate at 12 months was 47.7% in relatlimab-nivolumab arm and 36.0% with nivolumab [12]. In exploratory analyses of prespecified subgroups (as LAG-3 or PD-L1 expression, BRAF mutational status) PFS was also improved for the relatlimab-nivolumab group over nivolumab monotherapy [12]. These data led to the approval of relatlimab in combination with nivolumab for therapy of metastatic melanoma by the FDA [14]. Updated data (including OS) were presented during the ASCO Plenary session 2022 and ASCO 2022 and 2023 Annual Meeting and published finally in NEJM Evidence [15]. These updated results confirmed that the RELATIVITY-047 clinical trial achieved its primary endpoint and resulted in a superior PFS benefit in the nivolumab-relatlimab arm as compared with nivolumab monotherapy [15]. Median OS was not reached (NR; 95% CI, 34.2 to NR) in nivolumab-relatlimab arm as compared with 34.1 months (95% CI, 25.2 to NR) in nivolumab (HR 0.80; 95% CI, 0.64 to 1.01; P = 0.059) arm [15]. However, no significant survival benefit has yet been demonstrated with the new combination over nivolumab monotherapy [15]. Overall response rates (ORR) by blinded independent central review (BICR) were higher at 10.3% for the combination arm: 43.1% (95% CI, 37.9 to 48.4) vs 32.6% (95% CI, 27.8 to 37.7), respectively [15]. An exploratory analysis also found a numerical improvement in melanoma-specific survival (MSS) with nivolumab-relatlimab versus nivolumab (HR 0.77, 95% CI [0.61, 0.97]) [15]. MSS was not reached in the combination arm versus 46.6 months in the nivolumab arm (HR 0.77, 95% CI [0.61, 0.97]), 3-year MSS rates were 63% vs 54%, respectively [15]. Nevertheless, patients with programmed cell death ligand 1 (PD-L1) expression ≥ 1% did not benefit more from combined therapy (median PFS 15.7 vs 14.7 months), but in patients with low PD-L1 expression (<1%) therapy with relatlimab–nivolumab combination led to longer PFS compared with nivolumab monotherapy (6.4 vs 2.9 months) [15]. Thus, EMA decided on authorization of this dual immune checkpoint combination for patients 12 years of age and older with unresectable or metastatic melanoma with PD-L1 expression less than 1% [16]. Therapy with relatlimab-nivolumab showed manageable tolerability with an acceptable safety profile with typical immune-related adverse events. Grade 3/4 treatment-related adverse events were observed more commonly in patients treated with nivolumab + relatlimab versus nivolumab (21.1% vs 11.1%), but the safety profile is much more favorable than that of ipilimumab plus nivolumab [15]. The combination relatlimab-nivolumab also showed superiority in terms of ORR and PFS in the groups of patients with the worse prognosis (high tumor burden, elevated lactate dehydrogenase – LDH). Nevertheless, further studies are needed to establish the efficacy of relatlimab-nivolumab in very high-risk patient populations, as with active or untreated brain metastases and/or with rare melanoma subtypes [15].

The indirect treatment comparison of RELATIVITY-047 and CheckMate-067 trial showed similar 1-year PFS and 2-year OS benefits in the combination group of relatlimab and nivolumab (47.7%; 63.7%) and in combined therapy with ipilimumab and nivolumab group (49%; 64.0%) [17,18]. However, this analysis should be interpreted with caution, especially for less favorable groups such as those with LDH elevated levels or BRAF-mutated. Moreover, we still do not know if the same patients not responding to relatlimab-nivolumab also do not respond to ipilimumab-nivolumab or vice versa and if they constitute different groups. In a small, retrospective, multicenter study anti-CTLA-4-based therapy demonstrated less efficacy after treatment failure on relatlimab plus nivolumab (ORR only 11%) [19].

The outcomes of the RELATIVITY-047 trial were further reinforced by a trial investigating the combination of relatlimab-nivolumab in the neoadjuvant setting. Twenty-nine patients with resectable clinical stage III or oligometastatic stage IV melanoma received two neoadjuvant doses followed by surgery, and then 10 doses of adjuvant combination therapy [20]. The combination resulted in 57% pathologic complete responses and a 70% overall pathologic response rate which was similar to those observed with nivolumab-ipilimumab preoperative therapy. No grade 3–4 immune-related adverse events were observed in the neoadjuvant setting for nivolumab–relatlimab combination therapy [20].

In clinical studies, other LAG-3 inhibitors are currently under evaluation. A very interesting agent seems to be fianlimab with a high affinity to LAG-3. Fianlimab in combination with another anti-PD-1 drug cemiplimab in the phase I trial showed high antitumor activity with ORR of 63.8% for anti-PD-1/PD-L1-naive and 13.3% for anti-PD-1/PD-L1-treated patients [21]. The estimated PFS at 12 months follow-up was 60.6% for anti – PD-1/PD-L1-naive patients and 9.5% for anti – PD-1/PD-L1-treated patients. Fianlimab plus cemiplimab also showed high clinical activity in advanced melanoma patients after adjuvant anti-PD-1 therapy [21]. This combination will be evaluated in a phase 3 trial in comparison to pembrolizumab in patients with untreated unresectable locally advanced or metastatic melanoma (NCT05352672). In addition to LAG-3 inhibitors, the use of IMP321 (Eftilagimod alpha) – soluble version of LAG-3 protein, in combination with pembrolizumab is also evaluated in clinical studies of advanced melanoma (NCT02676869), targeting antigen-presenting cells and transducing an MHC-II mediated feedback signal [22].

2. Expert opinion

The current gold standard for first-line treatment of patients with advanced melanoma is the combination of immunotherapy nivolumab and ipilimumab, which was registered as a result of the Checkmate-067 trial [6]. However, in real practice, due to the significant toxicity of this combination, the choice of first-line systemic therapy is more complicated and should include a comprehensive assessment of factors related to disease and for patients to decide between anti-PD-1 monotherapy or combination therapy. Moreover, although the study design did not include a formal comparison of the treatment outcomes of the combination of nivolumab with ipilimumab and nivolumab monotherapy, it was shown that the combination of nivolumab with ipilimumab was the most effective treatment option (with a median OS of 72.1 months and median PFS of 11.5 months after a 60-month follow-up duration) [6,23]. Since this regimen of two-drug immunotherapy is a highly toxic treatment and often leads to the permanent withdrawal of treatment, new, safer therapeutic options are being investigated. Certainly, such an option seems to be the combination of anti-PD-1 and anti-LAG-3 [11]. The RELATIVITY-047 registration trial for this drug combination achieved its primary endpoint and showed a superior PFS in the nivolumab-relatlimab arm as compared to nivolumab alone. The 2-year PFS rate was 38.5% for the nivolumab-relatlimab cohort vs. 29.0% for the nivolumab arm (HR, 0.78 [95% CI, 0.64–0.94]) [13,15]. A clinically profound prolonged OS (this was the secondary endpoint) was observed, although the 20% reduction in the risk of death was not statistically significant. Taking into account the more favorable safety profile of the combination of anti-PD-1 and anti-LAG-3, it seems that these drugs could change the current standard of practice at least in some patients who were previously considered for anti-PD-1 monotherapy and also for those treated with combo-immunotherapy with nivolumab and ipilimumab [13,15].

The mechanisms of resistance to immunotherapy as well as the effect of PDL-1 expression on treatment response have not been well understood so far, thus more detailed analyses are needed [7]. It is not clear whether a group of patients resistant to treatment with anti-PD1 in combination with anti-CTLA4 will not respond to the combination of anti-PD1 with anti-LAG-3 and vice versa. These factors should have an influence on the therapeutic approach. There are only few data on the activity of nivolumab plus relatlimab after progression in patients, who were previously treated with a combination of ipilimumab and nivolumab, or vice versa. It means that the decision regarding the first-line treatment as well as the appropriate sequence for individual patient should be precised [19,24].

A specific and important group of patients are those with poor prognostic factors like brain metastases. Before the era of checkpoint inhibitors, the median OS in patients with brain metastases treated with chemotherapy was no more than 4 months and decreased to only 2 months in patients with additionally elevated levels of lactate LDH [7,25]. It has been proven that anti-PD1 with anti-CTLa4 are highly active in brain metastases, however until now, there have been no studies investigating the combination of anti-LAG3 with anti-PD-1 in this indication. The CheckMate 204 trial evaluated the efficacy of combined therapy with nivolumab and ipilimumab and included patients with at least one measurable, non-radiated brain metastasis without neurological symptoms. In 94 patients evaluated for the primary endpoint 77% of them had one or two target intracranial lesions. The rate of intracranial clinical benefit, which was defined as the percentage of patients with SD for at least 6 months, CR or PR, achieved 57% with 26% complete responses. The use of combined immunotherapy prevented intracranial progression in 64% of the patients for more than 6 months [26]. Another study showing the efficacy of anti-PD-1 and anti-CTLA-4 in patients with brain metastases was the Australian ABC study. Patients with asymptomatic brain metastases who had not received prior local therapy were randomized to receive nivolumab with ipilimumab (cohort A, 35 patients) or nivolumab alone (cohort B, 25 patients), while 16 patients with brain metastases who had failed local therapy or had neurological symptoms or meningeal involvement received nivolumab in the non-randomized cohort C. Intracranial responses were achieved in 46% in the combination treatment arm and 20% in the nivolumab arm. In contrast, only one patient in the unfavorable C cohort had a response to treatment [27]. Thus, it is necessary to investigate the effectiveness of treatment with anti-LAG-3 and anti-CTLA-4 in this indication, especially considering that this group of patients has a very poor prognosis.

Would it be cost-effective to implement anti-LAG-3 in combination with anti-PD1? Relatlimab and nivolumab are given as a single infusion but continuously, when the existing standard of care with ipilimumab and nivolumab combination consists of induction therapy with both agents, but followed by nivolumab alone and stopping the administration of ipilimumab. It is necessary to draw the line between these two combinations, but further clinical trials are needed to make it more clear. Moreover, we still need translational research on possible biomarkers, as well as a more individualized approach to immunotherapy with new therapies, as we cannot forget that still approximately 60% of the patients with metastatic melanoma would die from this disease. Nevertheless, we can anticipate that combination of anti-PD-1 and anti-LAG-3 will replace the relative clinical indications for anti-PD-1 monotherapy (with limitation of low PD-L1 expression in EU) due to acceptable toxicity profile and improved activity, so it will be routinely used in patients with low LDH baseline level, low tumor burden (M1a, M1b stages), BRAF-wild type, desmoplastic melanoma, preexisting autoimmunity, lack of compliance or psychosocial support, not fit for high toxicity/significant comorbidities [28]. This should be discussed with individual patients in other clinical scenarios such as BRAF-mutated patients or with high baseline LDH level.

In summary, the approval of relatlimab plus nivolumab by the Food and Drug Administration and European Medicines Agency expands the armamentarium of treatment options for melanoma, but raises new questions in clinical practice and leads to the necessity of reevaluation of currently established treatment sequences and standards (Table 1).

Table 1. Landmark studies of immunotherapy with LAG-3 inhibitors in advanced melanoma.

Study	Nivolumab + relatlimab RELATIVITY − 047 [16,17]	Cemiplimab + fianlimab (NCT03005782)
N (% 1st line)	355 (100%)	98 (82)
BRAF-mutated	38.3%	30.6%
ORR	43%	61%
Median PFS (months)	10.2	15
1-year PFS rate	48%	52%
1-year OS rate	77%	NR
2-year OS rate	63.7%	NR
3-year OS rate	55.8%	NR
Median 19.3		12.6
TRAEs grade 3/4	21%	15%

NR- not reported, ORR- overall response rate, PFS- progression-free survival, OS-overall survival, TRAE- treatment-related adverse events.

Declaration of interest

P Rutkowski has received honoraria for lectures and Advisory Boards from BMS, MSD, Sanofi, Merck, Pierre Fabre, Novartis, Astra Zeneca, and Philogen outside of the scope of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14712598.2023.2281495.

Additional information

Funding

This paper was not funded.