Tawbi Discusses the Role of Brain Metastases and PD-L1 Status in Melanoma

DISCUSSION QUESTIONS

Hussein A. Tawbi, MD, PhD (Moderator)

Professor

Deputy Chair

Director of Personalized Cancer Therapy

Department of Melanoma Medical Oncology

Division of Cancer Medicine

The University of Texas MD Anderson Cancer Center

Houston, TX

• From the RELATIVITY-047 (NCT03470922) and CheckMate 067 (NCT01844505) trials, what are the most important efficacy and safety data?
• How do you select a specific immunotherapy (IO) regimen (i.e. nivolumab [Opdivo]/relatlimab [Opdualag] vs ipilimumab [Yervoy]/nivolumab)?
• How do you balance efficacy, safety, patient preferences, goals of therapy, and quality-of-life when recommending a first-line regimen?

Putao Cen, MD: There were fewer grade 3 to 4 adverse events with [nivolumab/relatlimab than ipilimumab/nivolumab in their respective trials];^1,2 is that because RELATIVITY-047 was a later trial, maybe 10 years after ipilimumab/nivolumab, and physicians know how to foresee and prevent the severe toxicity? They stop the treatment or hold the treatment when they see grade 1 toxicity, for example, and they have a better second line with the BRAF inhibitor, and have more and better treatments, so maybe the survival is catching up compared with the ipilimumab/nivolumab trial conducted 10 years ago?

Hussein A. Tawbi, MD, PhD: Those are interesting points. I don't think so. I think the toxicity is less purely based on mechanism for the LAG3 drug. I think the single-agent PD-1 [inhibitor] has less toxicity now than we had in phase 3 trials before. Usually it's about 15% or 16%, and in this trial, it was 12%. I think…the experience is probably accounting for those few percentage points. The survival is not different because you're comparing the 2 arms of it being of nivolumab/relatlimab vs nivolumab; you're comparing them to the same post treatment regimens. We showed that in the poster I presented at the 2024 American Society of Clinical Oncology annual meeting and both arms of the study have the same amount of BRAF [mutations], same amount of ipilimumab/nivolumab in the second line, and there's still a survival advantage.³ I think both the efficacy and the toxicity for LAG3 are mechanism based. I don't think they're just era related.

When we're comparing nivolumab combinations, I'm not comparing the median overall survival. I didn't say that the median overall survival is better. I'm looking at the HR compared with the same control with single-agent PD-1. When I'm discussing how I feel about those kind of treatments in my clinic, ipilimumab/nivolumab is still ipilimumab/nivolumab. It still causes that much high-grade toxicity. It's the same experienced team with the same setup. It is just a toxic regimen; I think that's mechanism based. Just to be clear, I still use ipilimumab/nivolumab a lot. It's not that I don't. It just is now less. There is a real combination that is efficacy wise, highly comparable, and toxicity wise is much better. There are patients in which I favor nivolumab/relatlimab. [Patients with] high LDH and high tumor burden still respond and get more benefits from the combination compared with single agent.

How do you balance these things...such as safety, efficacy, [etc]. If it's a young patient, do you consider that you're more tolerant of toxicity, for instance, compared with treating an older person, even if they're both healthy?

Ananth Arjunan, MD: I would certainly be more willing in a younger patient. Experientially, people who tend to have some of these toxicities also are the ones that may have a complete response. There are probably data on some of that, but I'm just speaking anecdotally. Even when I've had to stop patients early from toxicities, a lot of them do well in terms of the cancer in the long run.

Tawbi: Fair points.

Rohit Kapoor, MD: I would still favor ipilimumab/nivolumab for brain metastases.

Tawbi: At this moment, the data are still very much in favor of ipilimumab/nivolumab [for brain metastases]....⁴ I do think that it's on us to identify the activity of nivolumab/relatlimab in the brain. It was very disappointing that RELATIVITY-047 did not include that population. My goal is to show that the activity in the brain is similar to the activity outside the brain. If we determine that, then that issue is no longer going to be the main factor. I think being able to give patients intracranial response and benefit long term is a priority. And if we can do that more with ipilimumab/nivolumab, then we should. But if we can achieve the same thing with a third of the toxicity, then it would be more appropriate to save the patient from toxicity. The jury's still out for now; [so] please use ipilimumab/nivolumab for brain metastases.

Maryada S. Reddy, MD: Was there a specific reason why the patients with brain metastases were excluded in the study? What was that thinking at that time of enrollment?

Tawbi: I helped design this trial, and I cannot tell you how much I stomped my feet requesting that we allow those patients in, and the most I could get out of all of that pressure is to include a brain MRI at baseline. Believe it or not, they didn't even have a brain MRI at baseline as part of the plan. Unfortunately, it remains the aptitude in the industry to exclude those patients from large phase 3 trials. I'm hoping that would change over time, and we continue to generate the data to convince them, but we haven't made that progress yet. I don't think you should conclude that nivolumab/relatlimab does not work in the brain. We just don't know how well it works in the brain yet, and [with] ipilimumab/nivolumab we know. It's fair to use ipilimumab/nivolumab for now.

Sumit Gaur, MD: Is your understanding that in these patients with melanoma, the response rates and benefit correlate with the PD-L1 expression and the LAG3 expression in this regimen?

Tawbi: Patients with PD-L1–positive disease do better, period. It's better prognostically. They have more T cells in their tumor, so they already are going to do better long term. They get a higher response rate with nivolumab/relatlimab and ipilimumab/nivolumab than single-agent PD-1….

From an individual patient perspective, for patients with PD-L1–positive disease, the response rate for nivolumab/relatlimab was approximately 44% compared with only about 34% for nivolumab alone.³ You still get that additional benefit in that population. LAG3, interestingly, was not of any use in terms of benefit [although] it was prognostically important. If a patient’s disease is LAG3 positive, it means you have more T cell infiltration. Those patients do well long term, but the differential benefit was about the same.

REFERENCES:

1. 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

2. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535-1546. doi:10.1056/NEJMoa1910836

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. Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med. 2018;379(8):722-730. doi:10.1056/NEJMoa1805453