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Novel Immunotherapies in Advanced Melanoma: RELATIVITY-048 and KEYMAKER-U02A
NIVO + RELA + IPI in advanced melanoma: RELATIVITY-048
Dr. van Akkooi: The RELATIVITY-048 study is a small study where patients with advanced melanoma were treated with first-line triplet immunotherapy, and the triplets consisted in this case of nivolumab at 480 mg every 4 weeks, relatlimab, which is an anti–LAG-3, at 160 mg every 4 weeks, and ipilimumab at a low dose of 1 mg per kg and only every 8 weeks. The primary endpoint of this study was overall response rate, but also some other endpoints were looked at like landmark overall survival rates. So, the triplet combination in 46 patients showed an overall response rate of nearly 60%, which perhaps isn’t that spectacular if you compare it to the overall response rate seen for the combination of ipilimumab and nivolumab in the CheckMate 067 study, which is around the similar overall response rate of between 50% and 60%. But the landmark 4-year overall survival rate was 69% in this study with this triplet. Obviously, the numbers are small compared to the CheckMate 067 study, but that would be indicative of a significant improvement by the triplet compared to ipilimumab and nivolumab alone.
How to optimize the combination of anti–PD-1, anti–CTLA-4, and anti–LAG-3?
The triplet combination does add additional toxicity; that we know. No unknown adverse events were found, the typical immune-related adverse events were found, but just at higher rates. This study really is a more hypothesis-generating type of trial where we now have to deal with how to optimize the combinations that we have of anti–PD-1, anti–CTLA-4, and an anti–LAG-3. And the question is how do we combine the three of them? Is the dose level that was used in the RELATIVITY-048 study the best dose level to take forward, or is a sequential treatment the better way to move ahead in these patients? Definitely, it seems that we can improve upon our current standard of care of ipilimumab and nivolumab, with ipilimumab at 3 mg per kg, and nivolumab at 1 mg per kg; but work is yet to be done.
Triplet combinations with pembrolizumab: KEYMAKER-U02A
If we then move to the other study looking at novel immunotherapies, it is the KEYMAKER-U02A study, which is an umbrella-type of protocol where multiple combinations were tested.
In this case, the reporting has been done on three arms. The first arm is pembrolizumab, an anti–PD-1, with quavonlimab, which is an anti–CTLA-4, and vibostolimab, which is an anti-TIGIT; so, that’s another triplet combination. Then, the second arm of that trial looked at pembrolizumab plus, again, quavonlimab and lenvatinib. Then, a third arm was pembrolizumab plus ATRA. Unfortunately, this trial really did not show that any of these novel combinations had a better efficacy compared to what we currently have. Moreover, there was significantly increased toxicity, especially in the anti-TIGIT combination arm, and therefore it was decided by the company that none of these combinations will be taken forward into further development, showing that combining immunotherapies is a really hard task, and we still are aiming to see what the best combination or sequence of immunotherapies is for patients with advanced melanoma.
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