Dosing and Regimen Changes Promote Tolerability in Advanced Melanoma

Michael B. Atkins, MD

Deputy Director, Georgetown Lombardi Comprehensive Cancer Center

The Scholl Professor & Vice Chair, Department of Medical Oncology

Georgetown University

Washington, DC30

DISCUSSION QUESTIONS

• Are you familiar with the RELATIVITY-047 (NCT03470922) data on nivolumab plus relatlimab (Opdualag) vs nivolumab (Opdivo) alone?
• What are your reactions to these data?

TARAL PATEL, MD: I am familiar with the data, but…50% of patients may [have] prolonged remissions...with ipilimumab [Yervoy] plus nivolumab, so how we can follow 2- to 3-year data and change the standard of care?¹ That’s my biggest obstacle to changing the treatment options.

ANKIT MANGLA, MD: I think the data are not mature enough for me to consider changing from ipilimumab/nivolumab from CheckMate 067 [NCT01844505] to the RELATIVITY-047 protocol. The PFS benefit is definitely there; there is a signal.² I think we need to let the data mature for more time to see if there’s a true [overall] survival benefit. Although if you look at CheckMate 067, [which was] also comparison between monotherapy and dual checkpoint inhibition, there is always that area of concern if there is real survival difference between the 2. Even with the familiarity of the data, the [lower] adverse event [AE] rate is very attractive. But with just a PFS benefit at this point, we are not reaching for nivolumab/relatlimab as the first drug of choice.

MICHAEL ATKINS, MD: How about for the patients who you would be giving nivolumab or pembrolizumab [Keytruda] monotherapy—would you consider nivolumab/relatlimab based on these data for those patients?

MARK MARINELLA, MD: Yes, absolutely. That’s where I have used this…. If you’re fit enough to get nivolumab but not fit enough to get ipilimumab/nivolumab, you should be fit enough to get nivolumab/relatlimab. Those differences of 6% to 7%, [for example] in breast cancer, are a big deal. Like in the monarchE study [NCT03155997] and a lot of these other breast cancer studies, an absolute delta of 4% or 5%...is a game changer. So yes, I’m using this where I would use nivolumab alone if I don’t think the patient can handle ipilimumab 3 mg and nivolumab 1 mg.

MANGLA: What are you thinking about if you compare [the RELATIVITY-047 regimen] with pembrolizumab, rather than nivolumab without relatlimab?

ATKINS: I view pembrolizumab and nivolumab, at least in melanoma, as Coca-Cola and Pepsi. There are no solid data that there’s any difference between the efficacy of the 2 different anti–PD-1 [agents]. We may have seen some differences in lung cancer and kidney cancer; maybe some of those are [because of] study design or biomarker design or things like that. But in melanoma, the data overlap in the metastatic setting and in the adjuvant setting all the way down to stage II disease. The only real differences are schedule differences, where now pembrolizumab can be given every 6 weeks, [whereas] nivolumab monotherapy is every 4 weeks, so when we are giving anti–PD-1 monotherapy to patients, we sometimes lean towards pembrolizumab because of the schedule difference.

EVAN LANG, MD: The data are convincing to me and I agree that we don’t have a lot of follow-up. I hope that the [Kaplan-Meier] curves don’t merge with a longer follow-up. If we have long-term follow-up data that show [OS] benefit with combination nivolumab plus relatlimab, I feel like it’s unethical to just treat with a single agent. It’s amazing that the AEs are not much with the combination as compared with a single agent.2 The other question I have is, what about the CNS [central nervous system] activity with this combination? Do we have any data on it?

ATKINS: We have no data on CNS activity with nivolumab/relatlimab. We also don’t have any data yet on stopping therapy and having the benefit persist, the way we have lots of data from CheckMate 067 with nivolumab/ipilimumab.^3,4

MANGLA: If I feel they cannot take ipilimumab 3 mg plus nivolumab 1 mg, in our practice, we usually go to ipilimumab 1 mg plus nivolumab 3 mg. I personally feel that anti–CTLA-4 still has more activity than anti–LAG-3. To use nivolumab/relatlimab, I would have to be hard pressed not to use anti–CTLA-4, which most of the time means [the patient has] autoimmune disease.

ATKINS: How do you compare the toxicity of nivolumab 3 mg plus ipilimumab 1 mg to nivolumab/relatlimab?

MANGLA: There is no direct comparison. But if you look at CheckMate 511 [NCT02714218], [grade 3 or higher treatment-related AEs are in the range of] 25% to 30% and with nivolumab/relatlimab will [be in the range of] 20% to 25%.^1,5 I usually tell patients that [using ipilimumab] may be 5% to 10% extra toxicity. But I feel like anti–CTLA-4 has proven its worth over the last 10 years and more. I’m more comfortable using ipilimumab 1 mg plus nivolumab 3 mg, if I don’t have to use ipilimumab 3 mg. That’s my clinical [approach]. I understand there is this percentage of [high-grade] toxicity of 50% with ipilimumab 3 mg regimen, [but] 30% with ipilimumab 1 mg.⁵ But we don’t have biomarkers to tell who will get a toxicity and who will not. When I approach these patients, I tell them that the chances are there but it’s a very black and white situation. If you get one, then it’s [effectively] 100%. If you don’t get it, then you don’t get it. We have to give it to you to see what’s going to happen.

ATKINS: The other thing I think is true is these studies report toxicity as the worst toxicity you have. You may only have an AE for a day or 2, and then you’re on immunosuppressive drugs and the toxicity is getting better, and within 4 to 6 weeks, you’re off those drugs and the toxicity is resolved. And if you look over a 3- or 5-year period, the average patient is experiencing grade 3 or grade 4 toxicity for 1% of that time, whereas the amount of time that they’re able to be alive and treatment-free can be 30% of that 5-year time period.

PATEL: I think there is plenty of evidence that a patient will also get benefit when they get 1 dose. We [participated in] the phase 2 trial with ipilimumab in melanoma, and we had plenty of patients who got 1 dose, got gastrointestinal toxicity, and said, “We don’t want any other treatment.” Two of those patients, after 1 dose of ipilimumab, are still around 10 years later with no other treatment. Now in hepatocellular carcinoma, we have another CTLA-4 [tremelimumab (Imjudo)] with only 1 treatment. So 4 treatments [of ipilimumab] may be overdone. We don’t need 4 treatments.

ATKINS: That’s true as well.

_References:

_{1. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J Clin Oncol. 2022;40(2):127-137. doi:10.1200/JCO.21.02229}

_{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}

_{3. Schadendorf D, Wolchok JD, Hodi FS, et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. 2017;35(34):3807-3814. doi:10.1200/JCO.2017.73.2289}

_{4. Brahmer JR, Lee JS, Ciuleanu TE, et al. Five-year survival outcomes with nivolumab plus ipilimumab versus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer in CheckMate 227. J Clin Oncol. 2023;41(6):1200-1212. doi:10.1200/JCO.22.01503}

_{5. 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}