FDA Follow-Up: Utilizing Relatlimab/Nivolumab in Clinical Practice for Metastatic Melanoma

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Oncology Nursing News® speaks with Hussein A. Tawbi, MD, PhD, principal investigator of the phase 2/3 RELATIVITY-046 trial, about the significance of the relatlimab/nivolumab approval for patients with unresectable or metastatic melanoma.

The FDA recently approved the fixed dose of relatlimab plus nivolumab (Opdivo; Opdualag) on the indication of unresectable or metastatic melanoma for adults of at least 12 years of age and who weigh at least 40 kg.1 This approval is particularly novel because relatlimab, a LAG-3 inhibitor, is the first approved checkpoint inhibitor of its class, according to Hussein A. Tawbi, MD, PhD.

The FDA approval was primarily supported by findings from the phase 2/3 RELATIVITY-046 trial (NCT03470922), which showed that the fixed combination yielded a progression-free survival (PFS) that was double of that reached with nivolumab alone.

Specifically, patients with unresectable or metastatic melanoma who received the combination experienced a median PFS of 10.2 months (95% CI, 6.37-15.74). In comparison, patients who received nivolumab alone reached a median PFS of 4.63 months (95% CI, 3.38-5.62; HR, 0.75; 95% CI, 0.62-0.92, = .0055). In addition, by a 12-month follow-up, the PFS rate in the combination and monotherapy cohorts, respectively, were 47.7% % (95% CI, 41.8%-53.2%) and 36.0% (95% CI, 30.5%-41.6%).2

Tawbi, a professor of the Department of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center, and principal investigator in the RELATIVITY-046 trial, recently met with Oncology Nursing News® to discuss the importance of the approval. Tawbi highlighted administration considerations regarding the new agent, the excitement surrounding the novel checkpoint inhibition pathway, and how the new agent will fit into the preexisting treatment landscape for this patient population.

Oncology Nursing News®: How will this approval impact patients with unresectable or metastatic melanoma?

Tawbi: It is an important development for our patients. We know that single-agent PD-1 has been capable of curing almost 40% of our patients with unresectable or metastatic melanoma. We really think that this [agent] will add a significant proportion of [successfully treated patients].

We still don't have the long-term data, but this [agent yielded] a 25% improvement in PFS with a hazard ratio of 0.75 [95% CI, 0.62-0.92]. [Therefore,] nivolumab pus relatlimab is going to be a regimen that I will use very regularly in lieu of single-agent anti–PD-1 for patients in whom I'm considering single-agent PD-1.

Does this agent present any unique administration considerations?

Yes, that is a great question. There was a bit of innovation in the study that is not as well highlighted, which is the fact that the 2 drugs are combined in 1 bag and delivered together. From an administration perspective, it will make it easier for pharmacists, because they don't have to prepare 2 different antibodies and combine them. Relatlimab/nivolumab comes combined in 1 bag.

Nivolumab as a single agent is administered over 30 minutes. Most of the time, in this study, we administered both single-agent nivolumab and the relatlimab/nivolumab combination over 60 minutes. That may be a slight change.

In terms of safety and administration, it follows the same guidelines that we have had with single agent PD-1. We haven't seen a significant increase in infusion-related reactions.

To give you my experience on the clinical trial itself: It was a blinded study, and I honestly could not tell which combination my patients were getting; [their symptoms] were quite similar. I have obviously treated a lot of patients with single-agent PD-1 in my career.

The other important finding which should be highlighted as well is that the improvement of PFS with this combination came with a much lower cost of toxicity than we experience with other combinations. Grade 3 or 4 adverse events with the nivolumab/relatlimab combination [occurred in] 18.9% of patients. With nivolumab alone, [the rate] was 9.7%. [However], [given the typical rate of] grade 3/4 toxicities with nivolumab alone, the incidence of 18.9% is therefore not very far from what we experience in clinical practice with [the single-agent PD-1 inhibitor].

Could you comment on LAG-3 inhibition and why this immunotherapy is a remarkable advance in immune-oncology?

We are very excited that this is the third checkpoint inhibitor after PD-1 and CTLA-4 to show clinical activity. It has been about a 10-year wait to find the third checkpoint inhibitor, and now we have a new agent to consider combining in different patient populations.

One of the challenges with the combination of PD-1/CTLA-4 is that it is highly potent, highly effective, but it also, unfortunately, is highly toxic. We have about 55% of patients reporting grade 3 or 4 adverse events (AEs) with that combination.

[In contrast], what we know about LAG-3 is that it also co-expressed with PD-1 quite regularly on exhausted antigen specific T cells. In preclinical models, when you block PD-1 and you blocked LAG-3 with it, it has shown quite a bit of synergy. Therefore, the idea of being able to combine those to try to improve patient outcomes has been in study for several years now.

RELATIVITY-047 was designed to study the same combination, but this time in patients with previously untreated metastatic melanoma. There were patients who are treatment naîve that have not experienced treatment with anti–PD-1 before.

We observed that after a median follow up of about 13.5 months, patients on the nivolumab/relatlimab arm had a PFS of 10.2 months, compared to the patients that were on the nivolumab alone [who] had a PFS of 4.63 months. That was a statistically significant difference. We feel that this is a great development: we have a new combination that adds efficacy and has toxicity that is relatively modest.

How will the novel regimen fit into the pre-existing treatment landscape?

The one thing that we will always need to be very clear about is that this study did not compare the combination [of nivolumab/relatlimab] to the combination of PD-1/CTLA-4 inhibition.

The PD-1/CTLA-4 combination will remain a very important part of our treatment decision making. We’re probably going to be treating a significant number of patients with that combination still, where we have evidence of definite activity [with] nivolumab and ipilimumab—like patients with brain metastases. RELATIVITY-047 did not include patients with brain metastases. We know that [the combination of] ipilimumab and nivolumab has excellent activity in the brain.

There will be decision making in the first-line setting. [We will ask ourselves]: “Can I rely on nivolumab/relatlimab or do I give nivolumab/ipilimumab despite the toxicity?” From my perspective, that combination of nivolumab/relatlimab will replace single-agent PD-1 inhibitors.

Are there other significant takeaways from RELATIVITY-047?

I would like to highlight the fact that participation in clinical trials has been a critical component to make this happen. It was a very difficult study to run during the pandemic, which is when a good part of it happened. I'm very grateful for the patients who participated. [In light of] all the challenges that were happening, we would just like to commend them for that, and make it another call to action for all patients to consider enrollment in clinical trials, because that is how we bring progress. That's how we will have, hopefully, a new agent in hand to treat all patients.

Clinical trials do make a huge impact, and participating in them is the way to advance the clinical outcomes of our patients.


  1. US Food and Drug Administration approves first LAG-3-blocking antibody combination, Opdualag (nivolumab and relatlimab-rmbw), as treatment for patients with unresectable or metastatic melanoma. News release. Bristol Myers Squibb; March 18, 2022. Accessed March 24, 2022. https://bit.ly/3wk6PDx
  2. Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34. doi: 10.1056/NEJMoa2109970