Relatlimab/Nivolumab Combo Represents ‘Paradigm-Changing’ Advance in Metastatic Melanoma

Hussein A. Tawbi, MD, PhD

The combination of relatlimab and nivolumab (Opdualag) represents a newly approved option for adult and pediatric patients with unresectable or metastatic melanoma, one that offers a stronger safety profile than that of ipilimumab (Yervoy) plus nivolumab (Opdivo) and stronger efficacy than single-agent checkpoint inhibition, according to Hussein A. Tawbi, MD, PhD.

On March 18, 2022, the FDA approved relatlimab/nivolumab for use in this population based on findings from the phase 2/3 trial RELATIVITY-047 trial (NCT03470922), which showed that the doublet (n = 355) resulted in a median progression-free survival (PFS) of 10.1 months (95% CI, 6.4-15.7) vs 4.6 months (95% CI, 3.4-5.6) with nivolumab monotherapy (n = 359; HR, 0.75; 95% CI, 0.62-0.92; P = .0055).¹

“This is a great [advancement] for patients with metastatic melanoma,” Tawbi, who is a professor in the Department of Melanoma Medical Oncology and deputy chair in the Department of Melanoma Medical Oncology, at The University of Texas MD Anderson Cancer Center, said. “[This combination] is paradigm changing, and it is going to affect the way we practice and the way that we conduct [future] research.”

In an interview with OncLive^®, Tawbi, who is also the director of Personalized Cancer Therapy in the Department of Melanoma Medical Oncology of the Division of Cancer Medicine at MD Anderson, discussed the recent approval of relatlimab/nivolumab in metastatic melanoma, the significance of the regulatory decision, and potential avenues for further exploration of the regimen.

OncLive^®: The FDA has approved the frontline combination of relatlimab and nivolumab for use in patients with unresectable or metastatic melanoma. What is the significance of this decision? What impact will it have on the field?

Tawbi: We have known for years, since the original days of ipilimumab [Yervoy], the anti–CTLA-4 [agent], that checkpoint inhibitors can improve patient survival and potentially provide long-term benefit for patients with [this disease].

We have also known that single-agent PD-1 [inhibitors] have improved efficacy over single-agent CTLA-4 [inhibitors], as well as an improved toxicity profile. We were lucky to have a combination like ipilimumab and nivolumab that is more potent and offers a better benefit to patients with metastatic disease, and especially those with brain metastases and other tough [clinical scenarios]. We had the opportunity to do that with [this] combination, but [it is] also quite toxic.

We are happy to [now] have a third option [for our patients,] in the form of the combination of nivolumab and relatlimab; this combination seems to offer benefit above and beyond single-agent PD-1 [inhibitors], as [was] shown in the randomized phase 2/3 RELATIVITY-047 trial. That [efficacy] happens at the [cost] of a small increase in added toxicity [vs single-agent nivolumab, although the toxicity is] not as staggering as it was with the combination of ipilimumab and nivolumab.

The [grade 3/4] toxicity with nivolumab plus relatlimab [was observed in] 18.9% [of patients] compared with about 15% with nivolumab alone. This [combination represents] a new option for patients who were going to be treated with single-agent nivolumab. [The regulatory decision] offers us a new combination in the armamentarium that may be used in other settings, and increases the possibilities for patients [to derive] more benefit from checkpoint inhibitors.

What key data from RELATIVITY-047 supported the approval?

It is remarkable to see that after a longer follow-up of about 19 months, the PFS benefit with the nivolumab/relatlimab combination compared with nivolumab alone remains consistent, with the hazard ratio showing about a 25% improvement in PFS. We also have objective response data that show a significant improvement in the response rate to 43% compared with about 30% for single-agent nivolumab.

[Additionally,] we are seeing a hint of survival benefit, [with] around a 20% improvement in overall survival [OS], although that is not statistically significant yet. In a field where the median OS is now in the [range of 6 years], we already see that potential impact on OS [after 19 months of follow-up].

All that benefit is happening at the expense of [an approximate] 3% to 5% increase in immune-related adverse effects [AEs], which is a modest increase compared with what we are used to [seeing] with the combination of ipilimumab and nivolumab. In terms of the safety profile, it is similar to what we see with single-agent nivolumab in terms of pattern [and] response to immunosuppressive therapy.

Based on the subgroup analysis, is there a population in whom nivolumab/relatlimab would not be recommended, or should it be used in all comers?

We looked specifically at the [question] of whether there was any difference [in efficacy with the regimen] in any population, and the benefit was consistent across all the subgroups. Whether patients had LAG-3 positivity, PD-L1 [expression], a higher tumor burden, or high lactate dehydrogenase levels [did not matter]. All [of those with] typical factors that we consider to be higher-risk disease still experienced a consistent PFS, objective response, and survival advantage [with the combination].

How do you foresee this approval affecting the paradigm? Moreover, accounting for the dual checkpoint inhibitor combination available, how do you see this approval affecting the use of that regimen in practice going forward?

This approval is going to result in most of us using the combination. Any time we consider using single-agent nivolumab, I will find it hard to find a reason to treat a patient without the combination if they are appropriate for [it]. We are still going to have patients for whom the combination of ipilimumab and nivolumab [will be considered], especially those with brain metastases. That is a situation where we still do not have data with relatlimab/nivolumab. We are hoping to generate [that information] in the near future.

There will still be situations where the combination of ipilimumab and nivolumab will be used. [Another example is] a situation where a higher response rate may be required in a patient who is rapidly progressive or symptomatic. There is still a role for ipilimumab and nivolumab, but I do not see an ongoing role for single-agent nivolumab [in this population].

Is there anything that you would like to emphasize or relay to community oncologists about this regimen?

The idea that this is still a [single] 30-minute infusion for a combination will be helpful for community oncologists to adopt relatively quickly. [You] need to remain vigilant [with regard to] immune-related AEs; [you need to] identify them early and act on them early, which helps prevent them from becoming severe. In terms of activity, we do expect an improvement [with this regimen] over a single-agent PD-1 [inhibition].

Could you elaborate on some of the immune-related AEs to watch for?

Similar to single-agent nivolumab, we see pneumonitis, and a much lower incidence of colitis [vs single-agent] ipilimumab or [ipilimumab plus nivolumab]. What we saw from [RELATIVITY-047] is that endocrine abnormalities were similar to that of single-agent nivolumab, [but] maybe a slight increase in adrenal insufficiency.

Adrenal insufficiency is always challenging to diagnose; it is subtle and develops over a period of time. I would keep that in mind as 1 of the potential reasons why patients may present with fatigue, lower blood pressure, and other symptoms.

Generally, our oncologists, both academic and in the community, have become familiar with managing immune-related AEs. This fits well with what we normally [look] for [with a] single-agent PD-1 [inhibitor].

What is your take-home message?

It is an exciting time. We have a new first-line therapy for [our patients with] melanoma. By definition, that starts [re]defining an entire new second line, because now we are going to have patients who are not just resistant to single-agent PD-1 [inhibition], but potentially to the combination [of relatlimab and nivolumab]. We need to continue to develop new approaches for those patients and learn about the role of this combination in other settings, [such as] brain metastases. In the future, [we should also explore the] combination with other therapies, like CTLA-4 antibodies or other checkpoint inhibitors. [Those efforts] may be coming along.

Reference

1. Long GV, Hodi FS, Lipson EJ, et al. Relatlimab and nivolumab vs nivolumab in previously untreated metastatic or unresectable melanoma: overall survival and response rates from RELATIVITY-047 (CA224-047). J Clin Oncol. 2022;40(suppl 36):360385. doi:10.1200/JCO.2022.40.36_suppl.360385