Response Time and BRAF Status Factor Into IO Selection for Melanoma

Thach-Giao Truong, MD

Medical director, Melanoma Program

Cleveland Clinic

Cleveland, OH

DISCUSSION QUESTIONS

• What are important efficacy and safety data for you from the RELATIVITY-047 trial (NCT03470922) of nivolumab/relatlimab (Opdualag)?
• How do you balance efficacy, safety, patient preference, goals of therapy, and quality of life when recommending a first-line regimen?

Thach-Giao Truong, MD: When you look at this trial, what stands out to you in terms of efficacy vs safety?

Mohammad Muhsin Chisti, MD: It looks like efficacy is comparable [with ipilimumab (Yervoy) plus nivolumab (Opdivo)] and looks like safety is better.^1,2

Truong: Agreed, and I would also say that kinetics matter. If there's a patient in front of you where you're trying to stop very quick growth, even if you get a response rate, you want it as fast as possible. You can have an equivalent response rate, but if it's taking too long, you know that can be an issue.

Tareq Al Baghdadi, MD: Do you have data on that? I've tried to look for that, and I could find that the average duration to a response with ipilimumab/nivolumab was [between 1 and 2 months] or so, but the RELATIVITY-047 investigators did not include that.³ I couldn't find the number. A lot of people quote that if there's high burden or they want a faster response, they opt for ipilimumab/nivolumab, but nobody quotes the data.

Truong: I wholly agree with you. It's because you assess response when you time the CT scans. The reason why ipilimumab/nivolumab has any such data [below 2 months] is because people go off treatment so fast because they have a toxicity, and when they go off treatment, they get a CT scan. If you go off treatment for toxicity, you are probably getting a response. That's why you have a [1 to 2]-month window where you already have a scan. The majority of people don't have a scan that early. That is a very good point to make. I think the reason people reach for it is the higher nominal response rate, although it's not weighted. Once you weight it, it's quite similar.

Al Baghdadi: I find that whatever makes it first to market will be used more frequently because people get used to it. Having said that, the nivolumab/relatlimab trial excluded patients with brain metastases, and brain metastases are not uncommon with melanoma. So just by having that, you [may] opt for [ipilimumab/nivolumab]. About the comparative study, the indirect comparison [of RELATIVITY-047 and CheckMate 067 (NCT01844505)],⁴ I don't like superimposing 2 graphs from 2 different studies and then saying it is an indirect comparison. You're making it direct by superimposing the graph. The best evidence of efficacy was the hazard ratio in progression-free survival. Both studies were exactly at 0.79 when compared with the same competitor, nivolumab.^1,2 They didn't need to see anything more. They have the same hazard ratio for progression-free survival in both trials.

In terms of selection, I make a big deal out of the BRAF mutation. In every forest plot with nivolumab/relatlimab, you will see that the main benefit compared with nivolumab are patients with a BRAF mutation.⁵ They tend to benefit more than patients with wild-type BRAF. So, if there's a BRAF mutation, I tend to use ipilimumab/nivolumab. If there is no BRAF mutation, I favor nivolumab/relatlimab, and in that forest plot, there was no difference. It did not seem that a BRAF mutation enhances the benefit of relatlimab or decreases it, but it seems to enhance the benefit of ipilimumab. I wonder if you feel the same way about the BRAF and the companion immune drug.

Truong: I love that you made that point. Michael Atkins, MD, [of Georgetown Lombardi Comprehensive Cancer Center] would just love to hear you say that. In the DREAMseq trial [NCT02224781]…at the time that trial was accruing, it...was very slow to accrue, and one of the criticisms at the time was that not everyone felt comfortable using ipilimumab/nivolumab, and everyone begged Dr Atkins to consider a third arm where there was an option of single agent, and he said, “I'm not going to do it,”…because of the CheckMate 067 data showing that it looks like it's better for BRAF mutations to get ipilimumab/nivolumab.⁶ Some people say those 2 [groups] weren't meant to be compared; it was exploratory and the [BRAF mutation] stratification wasn’t powered. But you're exactly right.

The other argument is the patients with a BRAF mutation tend to be younger and fitter, and they tend to have a more symptomatic disease burden. For all those reasons, you'll probably end up favoring ipilimumab/nivolumab.

Disclosure: Al Baghdadi previously reported advisory role from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Genentech; Truong and Chisti had no known relevant disclosures.

_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. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23-34. doi:10.1056/NEJMoa1504030}

_{4. Long GV, Lipson EJ, Hodi FS, et al. First-line nivolumab plus relatlimab versus nivolumab plus ipilimumab in advanced melanoma: an indirect treatment comparison using RELATIVITY-047 and CheckMate 067 trial data. J Clin Oncol. Published online August 13, 2024. doi:10.1200/JCO.24.01125}

_{5. Schadendorf D, Tawbi HA, Hodi FS, et al. Nivolumab plus relatlimab vs nivolumab in previously untreated metastatic or unresectable melanoma: 3-year subgroup analyses from RELATIVITY-047. Ann Oncol. 2024;35(suppl 2):S723-S724. doi:10.1016/j.annonc.2024.08.1160}

_{6. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345-1356. doi:10.1056/NEJMoa1709684}