Nivolumab Combinations Show Best Treatment Options for Advanced Melanoma

Tarhini, MD, PhD, and Tawbi, MD, PhD

A recent Between the Lines program focused on treatment options for patients with melanoma. The discussants examined data from 2 trials: the phase 2/3 RELATIVITY-047 trial (NCT03470922) and phase 3 CheckMate 067 trial (NCT01844505).1,2 With these results, the discussed an indirect comparison that occurred between the 2 trials.

Ahmad Tarhini, MD, PhD; and Hussein A. Tawbi, MD, PhD, sat down to discuss these trials and how they are being used to help treat the current patient population. Tarhini is the director of cutaneous clinical and translational research and leader of the Neoadjuvant and Adjuvant Translational Science Program at Moffitt Cancer Center and a professor of oncologic sciences at the University of South Florida Morsani College of Medicine, both in Tampa. Tawbi is a professor and deputy chair of the Department of Melanoma Medical Oncology and director of personalized cancer therapy in the Department of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

The conversation centered on the data of these 2 trials and how the clinicians are using them to inform their treatment decisions. They briefly discussed the National Comprehensive Cancer Network (NCCN) guidelines and how the RELATIVITY and CheckMate regimens fall into the preferred categories.

Determining a Treatment Choice

Before delving into the RELATIVITY and CheckMate trial data, Tarhini and Tawbi looked at the current NCCN recommendations for patients with metastatic or unresectable melanoma.3 The preferred regimen is nivolumab (Opdivo) plus ipilimumab (Yervoy) or nivolumab plus relatlimab-rmbw (Opdualag). Anti–PD-1 monotherapy recommendations include pembrolizumab (Keytruda) or nivolumab.

For patients with disease progression, intolerance, or projected risk of progression with BRAF-targeted therapy, preferred regimens include anti–PD-1 monotherapy, nivolumab/ipilimumab, nivolumab plus relatlimab, or pembrolizumab plus low-dose ipilimumab for progression following anti–PD-1 therapy. Tarhini asked Tawbi what his current treatment approach is for the first-line treatment.

“We face situations where our patients are highly symptomatic. They have brain metastases that require steroids, and [there are] other reasons that you don’t have the luxury of doing immunotherapy. In those cases, you wish and hope that your patient has a BRAF mutation because you’ll be able to potentially help them more quickly, and then that will give you time to think about what the next step should be,” Tawbi said.

Because immunotherapy is favored, Tarhini wanted to know whether it was worthwhile waiting for the results of a genetic test to determine a BRAF mutation before selecting a treatment. Tawbi cited results from the phase 3 DREAMseq trial (NCT02224781), which allow him to weigh the toxicity profile between targeted therapy and immunotherapy.4 Before the trial, he would wait to get the results from the test before beginning treatment, but now he will send the sequencing and start the immunotherapy.

RELATIVITY-047 Trial

The trial was designed to assess nivolumab plus relatlimab vs nivolumab monotherapy as first-line treatment for patients with advanced melanoma. Investigators enrolled 741 patients into the trial who received either 480 mg of nivolumab plus 160 mg of relatlimab as a fixed dose intravenously every 4 weeks or 480 mg of nivolumab intravenously every 4 weeks.

Top-line data from the trial included a median progression-free survival (PFS) of 10.2 months (95% CI, 6.5-15.4) in the combination arm and 4.6 months (95% CI, 3.5-6.5) in the monotherapy arm (HR, 0.79; 95% CI, 0.66-0.95). The 36-month rate was 31.8% (95% CI, 26.6%-37.1%) vs 26.9% (95% CI, 22.1%-31.9%), the 48-month rate was 29.7% (95% CI, 24.5%-35.1%) vs 22.4% (95% CI, 17.6%-27.6%), and the 60-month rate was 27.7% (95% CI, 22.5%-33.2%) vs 21.6% (95% CI, 16.8%-26.9%).

The median overall survival (OS) was 51.0 months (95% CI, 34.0-not reached) in the combination arm vs 34.1 months (95% CI, 25.2-44.7) in the monotherapy arm (HR, 0.80; 95% CI, 0.66-0.99). The 36-month rate was 54.6% (95% CI, 49.2%-59.6%) vs 48.0% (95% CI, 42.7%-53.1%), the 48-month rate was 52.1% (95% CI, 46.6%-57.2%) vs 43.2% (95% CI, 37.8%-48.5%), and the 60-month rate was 48.7% (95% CI, 43.0%-54.1%) vs 39.4% (95% CI, 33.5%-45.2%). The overall response rate was 43.7% (95% CI, 38.4%-49.0%) in the combination arm and 33.7% (95% CI, 28.8%-38.9%) in the monotherapy arm.

“This was a practice-changing, landmark study, meeting the primary end point of PFS with an HR of 0.79 at 5 years. The differences were significantly different in favor of the combination at 28% and 22%, respectively. With OS, there was a strong trend in improvement in favor of the combination, as well as the HR of 0.8 at 5 [years],” Tarhini said.

Because of these results, Tawbi always chooses combination therapy over monotherapy for this population. He notes the difficulty in treating adverse effects, as the trial findings showed a difference of approximately 10% between the 2 therapies, but in practice, he has only noticed adrenal insufficiency. With the combination, the adrenal insufficiency presents earlier, which allows clinicians to stay on top of it. One instance in which he chose monotherapy was for a patient who had multiple comorbidities and coexisting cancer for which they were receiving treatment.

Tawbi asked Tarhini to consider patients with desmoplastic melanoma and whether a single agent was still widely used in that population. Tarhini noted that it was hard to give up the notion of a “small therapy.” He has seen this population responding well to monotherapy, and if they do not, there are salvage therapy and immunotherapy combinations.

“This combination [of nivolumab plus relatlimab] is new, and it has a shorter timeline of…the data than the ipilimumab plus nivolumab combination. With the 3-year data, I’ve been feeling more confident about the long term looking very consistent. With some recent meta-analysis, you see [that] if a patient is doing well at 3 years, they do well 10 years later,” Tawbi said.

CheckMate 067 Trial

This trial assessed nivolumab plus ipilimumab vs nivolumab monotherapy vs ipilimumab monotherapy for patients with advanced melanoma. At 10 years, the median OS in the combination arm was 71.9 months (95% CI, 38.2-114.4), 36.9 months (95% CI, 28.2-58.7) in the nivolumab monotherapy arm, and 19.9 months (95% CI, 16.8-24.6) in the ipilimumab monotherapy arm.

The median melanoma-specific survival for the combination was over 120 months for nivolumab plus ipilimumab (95% CI, 71.8-not reached), and 37% of patients were alive at the end of the trial. The median melanoma-specific survival for nivolumab monotherapy was 49.4 months (95% CI, 35.1-119.4) and 21.9 months (95% CI, 18.1-27.4) for ipilimumab monotherapy. The 10-year melanoma-specific survival rate was 52% with the combination, 44% with nivolumab monotherapy, and 23% with ipilimumab monotherapy.

Indirect Comparison

When the indirect comparison occurred, efficacy was assessed. The PFS before weighting in the RELATIVITY regimen was 10.2 months (95% CI, 8.2-14.8) vs 11.5 months (95% CI, 8.9-20.8) in the CheckMate regimen (HR, 1.14; 95% CI, 0.94-1.39). Additionally, the median OS was 54.8 months (95% CI, 34.1-not reached [NR]) vs NR (95% CI, 39.1-NR) between each regimen, respectively (HR, 1.02; 95% CI, 0.81-1.28). Of the note, the confirmed ORR was 46% vs 50% between treatment arms (HR, 0.87; 95% CI, 0.70-1.08).

When assessed after weighting, the median PFS in the REALTVITY regimen was 12.0 months (95% CI, 8.2-17.1) vs 11.2 months (95% CI, 8.5-18.1) in the CheckMate regimen (HR, 1.08; 95% CI, 0.88-1.33). The median OS was NR (95% CI, 38.6-NR) vs NR (95% CI, 37.1-NR) between the 2 arms, respectively, (HR, 0.94; 95% CI, 0.75-1.19). The confirmed ORR was 48% vs 50% between arms (HR, 0.91; 95% CI, 0.73-1.14).

“I was surprised to see that the response rate ended up being very close. It was 48% vs 50% so that was one of the things that surprised me. In some respects, it’s nice to see that there are some groups that, intuitively, we were looking to nivolumab plus ipilimumab for.For a patient that has high lactate dehydrogenase levels or has a rapidly progressive disease, you may think, ‘Okay, maybe I need to use a nivolumab plus ipilumumab. It’s a bit more reliable.’ We have 10 years of experience, as opposed to 2 years. It’s nice to see that the data is pointing towards where that population could benefit,” Tawbi said.

For Tarhini, these results further show that nivolumab plus relatlimab can be used in the first line of therapy.

The clinicians also discussed treatment sequencing, and this is where the mechanism of action of these various drugs should be analyzed. LAG-3 inhibition may play a part in early exhaustion, signature expression, and helping to determine an earlier response. When assessing patients with brain metastases, clinicians aren’t sure how the RELATIVITY regimen will do. Tawbi is working on a trial to enroll patients with brain metastates to get concrete data.

“I can tell you that the evidence doesn’t exist. It is easy to slip into saying, ‘Well, ipilimumab plus nivolumab works better in the brain,’ but the truth is we just don’t know how well it works in the brain. I took that as a personal challenge. We’re running a clinical trial of nivolumab plus relatlimab for brain metastases here at MD Anderson. I was trying to make it a multicenter trial, and there’s a discussion around that. Currently, the plan is to accrue 30 patients. We’ve accrued about half of those patients,” Tawbi said.

He noted that a 44% response has been observed so far, but the result should be viewed cautiously. No evidence suggests this is inferior to how the combination works outside the brain. Tawbi asked Tarhini whether he is deterred from using nivolumab plus relatlimab when he sees metastases in the brain.

Tarhini replied that he is encouraged by the RELATIVITY data because they showed central nervous system–free metastases with nivolumab plus relatlimab compared with nivolumab monotherapy. However, outside of a clinical trial, he continues to use ipilimumab plus nivolumab for brain metastases.

References

1. Tawbi HA, Hodi FS, Lipson EJ, et al. Three-year overall survival with nivolumab plus relatlimab in advanced melanoma from RELATIVITY-047. J Clin Oncol. Published online December 13, 2024. doi:10.1200/JCO.24.01124
2. Wolchok JD, Chiarion-Sileni V, Rutkowski P, et al; CheckMate 067 Investigators. Final, 10-year outcomes with nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2025;392(1):11-22. doi:10.1056/NEJMoa2407417
3. NCCN. Clinical Practice Guidelines in Oncology. Melanoma: cutaneous, version 1.2025. Accessed January 10, 2025. https://shorturl.at/dBomq
4. Atkins MB, Lee SJ, Chmielowski B, et al. Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: the DREAMseq trial-ECOG-ACRIN EA6134. J Clin Oncol. 2023;41(2):186-197. doi:10.1200/JCO.22.01763