Optimizing Treatment Selection and Sequencing in Metastatic Melanoma

Ahmad Tarhini, MD, PhD

Approved immunotherapy regimens in metastatic melanoma have similar types of toxicities that oncologists have become more experienced with over time, with differing levels of high-grade toxicity depending on the regimen. In a recent virtual Case-Based Roundtable meeting for oncologists in the Great Lakes region, Ahmad Tarhini, MD, PhD, professor of oncologic sciences at the University of South Florida Morsani College of Medicine and director of Cutaneous Clinical and Translational Research and leader of the Neoadjuvant and Adjuvant Translational Science Program at Moffitt Cancer Center, led a discussion with oncologists on their comfort managing immune-related adverse events (irAEs) and how this might sway their treatment choice.

This article is part 2 of a 2-part series from a Case-Based Roundtable event.

DISCUSSION QUESTIONS

• Discuss your comfort level in managing immune-related adverse events (irAEs) in the setting of metastatic melanoma.​
• How has this changed over time? ​
• To what extent does ease/difficulty of managing potential toxicities factor into your recommendations?​
• How has this changed over time? ​

Gowri Ramadas, MD: I'm much more comfortable in managing irAEs. At this point in time, we've been doing it for long enough so not only we know what's going on, but the nurses and the staff do as well. I think it's easier from that standpoint. For me, nivolumab [Opdivo]/ipilimumab [Yervoy] doesn't worry me.

Ahmad Tarhini, MD, PhD​: Great. We obviously want more experience. We're using immune checkpoint inhibitors across many histologies these days, [and we are getting] more and more experience with those. Any other thoughts about toxicity and the choice of agent?

Priya Kumar, MD: What dose of nivolumab and ipilimumab do you use when you start a patient on this combination?

Tarhini​: If I have to use ipilimumab/nivolumab, I use ipilimumab at 3 mg/kg and nivolumab 1 mg/kg. I know in the past we had CheckMate 511 [NCT02714218], which looked at ipilimumab 1 mg/kg and nivolumab 3 mg/kg, the flip-dose ipilimumab/nivolumab. Obviously, it is less toxic than ipilimumab 3 mg/kg and nivolumab 1 mg/kg, but these days, we have nivolumab/relatlimab [Opdualag] given as a half an hour infusion every 4 weeks, etc, with toxicity significantly less than ipilimumab 3 mg/kg and nivolumab 1 mg/kg, and is maybe comparable to the flip dose, or maybe a little bit less.^1,2 I no longer use ipilimumab 1 mg/kg and nivolumab 3 mg/kg. If I have to use something less toxic, I use nivolumab/relatlimab.

Kumar: The trial that was done with nivolumab 3 mg/kg and ipilimumab 1 mg/kg wasn't a noninferiority trial, but it did show equivalent outcomes.¹

Tarhini​: Correct. It was not noninferiority. It was a relatively small study with the primary end point being toxicity. It was not an efficacy study. It showed the response rates were numerically comparable, but it did not significantly demonstrate the value of ipilimumab 1 mg/kg nivolumab 3 mg/kg in terms of efficacy, just for safety. In my practice now, if I have to use something less toxic, I use nivolumab/relatlimab. If I have to use ipilimumab, I go with the ipilimumab 3 mg/kg, nivolumab 1 mg/kg because we know there is…dependency on the dose with ipilimumab/nivolumab. The higher the dose, the more likely it is to work. If I have to use ipilimumab/nivolumab, it means I need ipilimumab/nivolumab, and that's when I use the ipilimumab 3 mg/kg, nivolumab 1 mg/kg [dose].

DISCUSSION QUESTIONS

• From the RELATIVITY-047 trial (NCT03470922), what are the most important efficacy and safety data?​
• ​How do you balance efficacy, safety, patient preferences, goals of therapy, and quality-of-life when recommending a first-line regimen?​

Kurt Demel, MD: I think one point that captivates my interest is the salvage of ipilimumab/nivolumab after nivolumab/relatlimab [24% with overall response second-line].³

Tarhini​: That’s from the RELATIVITY-047 study. This was presented at the American Society of Clinical Oncology [ASCO] 2024 Annual Meeting.

Demel: I don't understand mechanistically how that works, but I need to look into that more.

Tarhini​: Absolutely. I think it's an important observation. But that's the data that were presented.

Mark Walshauser, MD: How many people received ipilimumab in the nivolumab/relatlimab trial as second line? Because no one got nivolumab/relatlimab when the ipilimumab study was done because it wasn't around.

Tarhini​: The numbers were small. The tables that [were presented] were 17 patients. I know data continue to be collected. These are small numbers, but these were the numbers available at the time.

Any thoughts about the indirect comparison? We have the data from CheckMate 067 [NCT01844505] and RELATIVITY-047.⁴ This indirect comparison was presented at ASCO and published in the Journal of Clinical Oncology. We don't have a randomized study, but they have adjusted for baseline characteristics using individual patient-level data, so they derived the data from the actual studies, not from the published data.

Walshauser: It says the subgroup comparison showed larger numerical differences favoring ipilimumab/nivolumab with acral melanoma, BRAF-mutated melanoma, and lactate dehydrogenase greater than 2 times upper limit of normal, but we’re limited by sample size. Those were the results, but they had higher [rates of] AEs. They seem to favor ipilimumab/nivolumab, but I don't know you can make sense of [the subgroups].

Tarhini​: Exactly, but look at the big picture. We showed the Kaplan-Meier curves there [appeared comparable].

Walshauser: Does LAG3 expression have any [effect] on efficacy [of relatlimab]?

Tarhini​: It hasn't been shown to do so. It has not been shown to be predictive of the lack of response, so it's not applied in clinical practice to test for LAG3.

DISCLOSURES: Tarhini previously reported a consulting or advisory role for Bristol Myers Squibb, Merck, Genentech/Roche, Novartis, Sanofi/Regeneron, Partner Therapeutics, Clinigen Group, Eisai, Bayer, Instil Bio, ConcertAI, BioNTech, AstraZeneca, and Nested.

_REFERENCES:

1. Lebbé C, Meyer N, Mortier L, et al. Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 trial. J Clin Oncol. 2019;37(11):867-875. doi:10.1200/JCO.18.01998

2. 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. 2025;43(13):1546-1552. doi:10.1200/JCO.24.01124

3. Tawbi HA, Hodi FS, Lipson EJ, et al. Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma (RELATIVITY-047): Overall survival (OS) and melanoma-specific survival (MSS) outcomes at 3 years. J Clin Oncol. 2024;42(suppl 16):9524. doi:10.1200/JCO.2024.42.16_suppl.9524

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. 2024;42(33):3926-3934. doi:10.1200/JCO.24.01125