Similar Efficacy in Melanoma Shown in Indirect Comparison of PD-1/LAG3 vs PD-1/CTLA-4

Michael A. Postow, MD

Chief, Melanoma Service

Co-Director, Melanoma Disease Management Team

Memorial Sloan Kettering Cancer Center

New York, NY

Targeted Oncology: Why is it valuable to indirectly compare the experimental arms of the RELATIVITY-047 (NCT03470922) and CheckMate 067 (NCT01844505) trials of patients with metastatic melanoma?

MICHAEL POSTOW, MD: We now know nivolumab/relatlimab [Opdualag] is 10% better than nivolumab [Opdivo] alone; that's a loose 10% based upon [overall response rate (ORR) and progression-free survival (PFS)].¹ But ipilimumab [Yervoy] plus nivolumab also looks better than nivolumab monotherapy. So how do we think about 1 combination vs the other in terms of efficacy with the cross-trial comparisons?

The baseline demographics across these different [experimental] groups did vary a little bit [between RELATIVITY-047 and CheckMate 067]….² The rates of patients with M0 or M1 disease [who also had] lactate dehydrogenase [LDH] less than the upper limit of normal was the same between these 2 trials. That's the best prognostic group. But there are differences in the numbers of patients with stage IV vs stage III disease who were treated with ipilimumab/nivolumab vs nivolumab/relatlimab. There is a little difference in the BRAF-mutated patient populations between the 2 [trial groups]. You could argue that wouldn't make a difference here. With different LDH categories, there were some minor differences, but nothing major.

What were the findings of the indirect treatment comparison performed on the 2 regimens?

With that in mind, [this analysis was] trying to compare ipilimumab/nivolumab and nivolumab/relatlimab, and it overlaid the [Kaplan-Meier curves for PFS and overall survival (OS)]. The takeaway point is they don't look that much different in terms of OS and PFS. We have this idea that ipilimumab/nivolumab is very powerful, [demonstrating] the highest efficacy but the worst toxicities. It very well might not be that different from nivolumab/relatlimab, and nivolumab/relatlimab has much better tolerability.

Now, for brain metastases, we have no idea how nivolumab/relatlimab does. So ipilimumab 3 mg/kg plus nivolumab 1 mg/kg [should be used] in that population. Those patients who are so sick that you need to give them everything you have [should also receive] ipilimumab/nivolumab. For patients who have had PD-1 monotherapy, adjuvant PD-1 therapy, for example, it seems like ipilimumab/nivolumab is still better in that context.³ But for those people that have never had any immune therapy, it's very well likely that these [outcomes] could be pretty much the same.

Nivolumab/relatlimab was compared with ipilimumab/nivolumab for ORR, duration of response, and melanoma-specific survival. There was a weighting that was done in this analysis where some of the baseline demographics were weighted in a certain way to try to make it a fair comparison between the 2 trials. But even if you didn't weight between those 2 groups, it's a 4% difference in ORR if you adjudicate the responses similarly between these 2 trials [50% for ipilimumab/nivolumab vs 46% for nivolumab/relatlimab].² Then if you do the weighting, it's only a 2% difference in ORR in favor of ipilimumab/nivolumab [50% vs 48%, respectively].

My takeaway is, maybe nivolumab/relatlimab is better than we think it might be because the toxicities are a little worse than PD-1 [inhibitor] alone, but not nearly as bad as ipilimumab/nivolumab. The efficacy is not quite as good as ipilimumab/nivolumab, but it does look pretty good, and maybe for most patients, it might be enough. That is how I'm thinking about it, for right or wrong. I'm sure people are thinking about it differently. I still give my patients ipilimumab/nivolumab when I feel like they really need it. But I am using a little bit more nivolumab/relatlimab now because of some of these comparisons.

There were much better [rates of] treatment-related adverse events with nivolumab/relatlimab compared with ipilimumab/nivolumab, and that's because of the ipilimumab toxicity rates that are quite high [grade 3/4 TRAE rate: 58.31% for ipilimumab/nivolumab vs 22.06% for nivolumab/relatlimab before weighting; 60.79 vs 22.92%, respectively, after weighting].

REFERENCES:

1. Tawbi HA, Schadendorf D, Lipson EJ, et al; RELATIVITY-047 Investigators. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34. doi:10.1056/NEJMoa2109970

2. Schadendorf D, Tawbi HA, Lipson EJ, et al. Efficacy and safety of first-line (1L) nivolumab plus relatlimab (NIVO + RELA) versus NIVO plus ipilimumab (NIVO + IPI) in advanced melanoma: An indirect treatment comparison (ITC) using patient-level data (PLD). J Clin Oncol. 2023;41(suppl_16):9552. doi:10.1200/JCO.2023.41.16_suppl.955

3. VanderWalde A, Bellasea SL, Kendra KL, et al. Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial. Nat Med. 2023;29(9):2278-2285. doi:10.1038/s41591-023-02498-y