Paradigm-changing primary Phase III data for malignant melanoma: What to expect from Relatlimab in combination with Opdivo

Bristol’s Relatlimab/Opdivo (anti-LAG-3/PD-1) therapy is poised to make inroads into its own Opdivo/Yervoy (PD-1/CTLA-4) inhibitor combination share for malignant melanoma. As part of our Drugs to Watch™ series, Clarivate oncology experts Liseth Parra and Rachel Webster review new data shared at ASCO 2021, and implications for patients and life sciences companies.

 

Compelling Phase III results were announced at the 2021 ASCO annual meeting for a novel immune checkpoint inhibitor regimen targeted to a lymphocyte activating gene-3 (LAG-3) inhibitor in combination with a programmed cell death 1 (PD-1) inhibitor.¹ This is the first Phase III trial showing clinical benefit of dual inhibition of LAG-3 and PD-1 pathways. Bristol Myers Squibb’s relatlimab (anti-LAG-3) and Opdivo (anti-PD-1) combination is expected to be positioned as a new front-line treatment option for advanced unresectable or metastatic malignant melanoma.

In March 2021, Bristol Myers Squibb announced that the Phase III RELATIVITY-047 trial met its primary endpoint of progression-free survival, resulting in superior clinical outcomes for the LAG-3/PD-1 inhibitor combination compared to the control arm of Opdivo monotherapy.² Primary data analysis from RELATIVITY-047 was presented at ASCO 2021, ¹ and the results did not disappoint (Table 1).

Table 1: Key data from the Phase III KEYNOTE-564 trial presented at the 2021 ASCO Annual Meeting^2,3,6

Trial (identifier) / patient population and enrollment	Trial design	Select efficacy data	Select safety data
Phase II/III RELATIVITY-047 (NCT03470922) Previously untreated unresectable or metastatic melanoma; ECOG PS 0-1* N = 714	Treatment arms: Relatlimab (160 mg IV) + Opdivo (480 mg IV) – FDC Q4W vs. Opdivo (480 mg IV Q4W) Primary endpoint: PFS by BICR Secondary endpoints: OS, ORR by BICR, and biomarkers of response Unique gated Phase II to III design: interim analysis to assess cumulative patient randomization and PFS by BICR – OS and ORR remain blinded	Relatlimab plus Opdivo (n = 355) vs. Opdivo (n = 359) Median follow-up: 13.2 months Median PFS per BICR: 10.1 vs. 4.6 months HR: 0.75 (P = 0.005) 1-yr PFS: 48% vs. 36% Median PFS (LAG-3 > 1%): 12.6 months (n = 268) vs. 4.8 months (n = 269) Median PFS (LAG-3 < 1%): 4.8 months (n = 87) vs. 2.8 months (n = 90)	Relatlimab plus Opdivo (n = 355) vs. Opdivo (n = 359) Any AE: 97% vs. 94% Grade 3/4 AEs: 4 % vs. 33% Grade 3/4 TRAEs: 19% vs. 10% AEs leading to Tx discontinuation: 15% vs. 7%; pruritus (23%), fatigue (16-13%) irAE hepatitis: 4 % vs. 1% irAE hypothyroidism: 18 % vs. 14%
Note: ECOG, Eastern Cooperative Oncology Group; PS, performance status; IV, intravenous; FDC, fixed-dose combination; PFS, progression-free survival; BICR, blinded independent central review; OS, overall survival; ORR, objective response rate; HR, hazard rate; AE, adverse event; TRAEs, treatment-related adverse events; irAEs, immune-related adverse events. *Stratification factors included prespecified subgroups: LAG-3, PD-L1, BRAF, and AJCC v8 M stage. Source:  Journal of Clinical Oncology

 

What is the clinical significance of the RELATIVITY-047 data?

• Data from the global randomized Phase II/III RELATIVITY-047 study showed that the fixed-dose combination of relatlimab plus Opdivo more than doubled progression-free survival compared with Opdivo alone (10.1 vs. 4.6 months, respectively).
• PFS outcomes favored the dual LAG-3/PD-1 blockade vs. anti PD-1 monotherapy across all subsets of patients, regardless of the prespecified subgroups and stratification factors included in the study (i.e., LAG-3, PD-L1, BRAF, AJCC v8 M stage).¹
• This is the first time a clinical trial has provided evidence that the dual inhibition of LAG-3 and PD-1 pathways is synergistic and results in clinically meaningful efficacy improvements over single-agent PD-1 inhibitors.
• The safety data from RELATIVITY-047 demonstrated a favorable toxicity profile for the dual therapy with manageable adverse events typical of immune checkpoint inhibitors.¹ Importantly, the toxicities observed with relatlimab plus Opdivo, appear to be less severe than the onset of immune-related adverse events characteristic of dual PD-1/CTLA-4 blockade, which could be significant for uptake.

 

How will a LAG-3/PD-1 combination therapy impact current treatment practices?

Relatlimab, as an anti-LAG-3 next-generation immune checkpoint inhibitor, is poised to have a significant impact on medical practice when used as an adjunct to standard anti-PD-1 (Opdivo) therapy. This combination is expected to advance the treatment paradigm of malignant melanoma based on the positive outcomes for RELATIVITY-047.

Combination therapies for treating malignant melanoma have set a high bar of treatment success, but we anticipate that the anti-LAG-3/PD-1 combination will prove a strong contender. Although there are no head-to-head data, it would also appear that relatlimab plus Opdivo demonstrates comparable PFS to that of Bristol’s other dual immune checkpoint inhibitor combination, Opdivo plus Yervoy (it showed a median PFS of 11.5 months in its pivotal CheckMate-067 study.)^3,4 However, the marketed anti-PD-1/CTLA-4 combination Opdivo plus Yervoy has achieved an impressive and sustainable median overall survival (OS) of 72.1 months.⁴ Overall survival data for the LAG-3/PD-1 combination are not yet mature, so it remains to be seen how a lack of Overall survival data will impact physicians’ prescribing of this new combination.

Based on the primary clinical data for RELATIVITY-047, we expect that the fixed-dose relatlimab plus Opdivo combination regimen will secure regulatory approval as a front-line treatment for unresectable or metastatic malignant melanoma, even in the absence of overall survival data. The introduction of immune checkpoint inhibitors and targeted therapies has greatly improved survival rates for malignant melanoma, and currently offers a median overall survival of six years with immunotherapy.^3,4 In turn, PFS data is now increasingly used as an attractive surrogate endpoint for OS, as seen with the recent approval of Tecentriq in combination with Zelboraf plus Cotellic, based on the IMspire150 trial which showed a median progression-free survival of 15.1 months for the triplet combo vs. 10.6 months for Zelboraf monotherapy.⁵

In addition, we anticipate that relatlimab in combination with Opdivo will compete with both anti-PD-1 and anti-PD-1/CTLA-4 therapies. Nevertheless, a full dataset analysis of RELATIVITY-047 will likely be required to inform clinical decision-making, especially for determining which specific patient subpopulations will benefit most from LAG-3/PD-1 inhibition.

 

Looking ahead

 

Relatlimab plus Opdivo represents an exciting advancement that will expand the malignant melanoma treatment armamentarium. It is also an important development for the wider oncology landscape, putting LAG-3 on the map as a novel therapeutic target and paving the way for furthering the advancement of anti-LAG-3/PD-1 combination therapies in other indications.

Full data from RELATIVITY-047 will be captured within the Clarivate Malignant Melanoma Disease Landscape and Forecast™, along with other developments from the ASCO 2021 Annual Meeting. Look for an updated malignant melanoma forecast with a new horizon (2020-2030) this fall. Learn more about this research here.

 

References:

1. Lipson EJ, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: Primary Phase III results from RELATIVITY-047 (CA224-047). Journal of Clinical Oncology. 2021; 39: suppl 15; abstr 9503.
2. Bristol Myers Squibb, press release, March 25, 2021.
3. Larkin JM, et al. 5-year survival outcomes of the CheckMate-067 Phase 3 trial of nivolumab plus ipilimumab (NIVO+IPI) combination therapy in advanced melanoma. Annals of Oncology. 2019; 30(5) mdz394.065.
4. Wolchok JD, et al. CheckMate-067: 6.5-year outcomes in patients (pts) with advanced melanoma. Journal of Clinical Oncology. 2021; 39: suppl 15; abstr 9506.
5. Gutzmer R, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, Phase 3 trial. Lancet. 2020; 395(10240): 1835-1844.