Relatlimab/Nivolumab Improves PFS Without Added Toxicity in Metastatic Melanoma, Underscoring Frontline SOC Potential

Hussein A. Tawbi, MD, PhD

The combination of the anti–LAG-3 agent relatlimab plus the PD-1 agent nivolumab (Opdivo) resulted in a superior progression-free survival (PFS) benefit over nivolumab alone, and the efficacy achieved with the doublet did not come at the cost of increased toxicity, according to Hussein A. Tawbi, MD, PhD, who added that these data underscore the potential for this regimen to become a new standard of care if approved.

Primary results from thephase 3 RELATIVITY-047 (CA224-047) trial (NCT03470922) were presented during the 2021 ASCO Annual Meeting and showed that the median PFS of relatlimab/nivolumab per blinded independent central review was nearly double that observed with nivolumab monotherapy, at 10.12 months (95% CI, 6.37-15.74) vs 4.63 months (95% CI, 3.38-5.62), respectively (HR, 0.75; 95% CI, 0.62-0.92; P = .0055).¹

Additional data presented during the 2021 ESMO Congress showed that the addition of relatlimab to nivolumab resulted in prolonged benefit beyond initial treatment and first progression and reduced the risk of progression or death after the next line of systemic therapy vs nivolumab alone.2

In September 2021, the FDA granted a priority review to a biologics license application for the fixed-dose combination for use in the treatment of adult and pediatric patients aged 12 years and older and weighing at least 40 kg who have unresectable or metastatic melanoma based on data from RELATIVITY-047.3

“We now have additional evidence that dual checkpoint inhibitor combinations are appropriate and a good strategy to pursue. We have a novel checkpoint inhibitor, an anti–LAG-3, that seems to be able to give us additional improvement in clinical activity [in patients with melanoma],” Tawbi said. “We [may soon] have a new combination added to our armamentarium for the first-line treatment of melanoma [and we can] potentially [consider this to be a] new standard of care in the coming months or years. [It is exciting] that we can give [this option] to our patients without the added [cost of toxicity].”

In an interview with OncLive^®, Tawbi, professor and deputy chair of the Department of Melanoma Medical Oncology in the Division of Cancer Medicine; director of Melanoma Clinical Research and Early Drug Development; and director of Personalized Cancer Therapy in the Department of Melanoma Medical Oncology of the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discusses the safety and efficacy achieved with relatlimab plus nivolumab in the RELATIVITY-047 trial and sheds light on the clinical significance of the data in the melanoma treatment paradigm.

OncLive^®: What was the rationale for the RELATIVITY-047 trial?

Tawbi: Anti–PD-1 antibodies have changed the way that we treat patients with cancer. In melanoma specifically, we have been very lucky to have single-agent anti–PD-1 [agents] showing clinical activity. We also have single-agent anti–CTLA-4 [agents] showing independent clinical activity. We know that the combination of CTLA-4 and PD-1 is very effective and improves overall survival [OS] in patients with melanoma. That was the first dual checkpoint inhibitor combination to lead to improved OS and to gain FDA approval. We use it widely, especially in patients with brain metastases, and in other settings.

The challenge with this combination has consistently been the fact that it also has significant toxicity, with up to 55% of grade 3 or 4 adverse effects [AEs]. We have been, as a field, working for a significant amount of time to identify novel targets and combinations that could either compare with dual checkpoint inhibition with CTLA-4 and PD-1, or improve upon it, but most importantly, help with decreasing the rate of toxicity.

Anti–LAG-3 antibodies have emerged as 1 of several checkpoint inhibitors that have been in clinical trials that are trying to improve upon single-agent PD-1. The fact that LAG-3 is co-expressed with PD-1 on exhausted T cells made for a very good scientific rationale to try to inhibit LAG-3, just like we inhibit PD-1 and CTLA-4. [Additionally], preclinical models have shown excellent synergy with anti–PD-1 inhibition.

This phase 3 trial was built on safety results from a phase 1 trial that showed that this dose is safe and has clinical activity, and then this randomized phase 2/3 trial was conducted to assess the potential improvement in PFS, and eventually in OS, over single-agent anti–PD-1. The rationale was strong, scientifically, and there was enough clinical data to warrant a phase 3 trial.

The phase 3 trial was conducted globally; it [enrolled] 714 patients who were accrued from several continents. When we saw the data come out from the first analysis [of the trial], we were very pleased to see that it met its primary end point of improvement in PFS [achieved with] nivolumab and relatlimab given as a fixed-dose combination.

Could you expand on the design of the trial? What were the results reported from the initial analysis of the trial?

The study was designed as a seamless phase 2/3 trial, and [randomized patients] 1:1 to receive either nivolumab plus relatlimab or single-agent nivolumab. It was stratified by important factors, such as PD-L1 expression, LAG-3 expression, BRAF [mutational status], and [disease] stage. The first component of the study included approximately 400 patients who were randomized to the phase 2 [portion], and then the enrollment stopped as planned for an interim analysis after 6 months.

The statistical design allowed for an independent data monitoring committee to analyze the PFS data and decide whether the study hit an interim efficacy end point that allowed it to proceed to phase 3. At the first analysis, the study reached that efficacy end point, and this allowed us to open the study to the phase 3 accrual, at which point more than 300 patients were added. The entire cohort [was then analyzed together].

This was an event-driven analysis, and the first analysis was conducted after the expected number of events had happened. Again, the study’s primary end point was met, with an improvement in PFS over single-agent PD-1.

[Results showed that] the median PFS was 10.1 months [with the combination] vs 4.6 for single-agent nivolumab. However, we really focused on comparing the hazard ratios [HRs], which is important. The HR was 0.75 with a very significant P value of .0055. That tells us that if we treat patients with nivolumab and relatlimab, the risk of progression is decreased by 25% compared with nivolumab alone.

The other result that is remarkable is the 1-year landmark. At the 1-year landmark, the PFS rate was 47.7% [with the doublet] compared with 36.0% for single-agent PD-1. Therefore, the benefit is not just early, but is also consistent until the 1-year mark.

What should be taken away regarding the safety profile of the combination?

That is the one of the most remarkable aspects of this combination. In oncology, we are used to the fact that if we want to give a patient more benefit, that must come at the cost of more toxicity. As such, there is the expectation that if you treat with a combination, [patients] may experience more immune-related AEs.

In the phase 3 trial, the observed immune-related AEs in the combination arm were higher than the single-agent arm, with grade 3 or 4 treatment-related AEs [occurring in 18.9% of those who received the combination] vs 9.7% [of those who received single-agent nivolumab]. However, in the context of clinical practice and prior data with nivolumab monotherapy, most studies have shown a grade 3 or 4 AE rate [ranging from] 10% to 15%.

Having a new combination that offers that much more PFS benefit with [just a minimal] increase in toxicity is remarkable. It is indistinguishable from [prior data with] single-agent PD-1 treatment. This is added value because we are used to having to pay the tax of toxicity [with effective combination regimens]. Now, our patients can thankfully have benefit with a limited increase in toxicity.

What are the next steps for this combination?

This is still an early result. Obviously, [the trial] met its primary end point, but it is still early. We still want to see long-term OS data, the durability of these responses, and we want to see this combination work in other settings. For example, this study excluded patients with brain metastases; it only enrolled treatment-naïve patients and it did not include patients with uveal melanoma. As such, [we still have] many questions, but it puts us in a place where we have a new tool in our armamentarium that can help our patients.

Reference

1. Lipson EJ, Tawbi HAH, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047). J Clin Oncol. 2021;39(15):9503. doi:10.1200/JCO.2021.39.15_suppl.9503.

Editor’s Note: This interview was conducted prior to the 2021 ESMO Congress and the FDA’s decision to grant priority review to the fixed-dose combination for use in adult and pediatric patients aged 12 years and older and weighing at least 40 kg who have unresectable or metastatic melanoma.