Treatment Goals and Typical Response for Patients with Metastatic Melanoma

Thoughtful comments from Dr Hussein Tawbi on setting first-line treatment goals and typical treatment responses in patients with unresectable or metastatic melanoma.

Hussein Tawbi, MD, PhD: Our treatment goals for patients with first-line metastatic melanoma are absolutely to give them the best chance at a cure. We have now a long-term evidence that we can potentially save up to 50% of those patients with our various approaches. Given that the first line is our kind of first shot on target, so to speak. From principles of oncology perspective, we always start with our most effective regimen first. Combination immunotherapy is our recommendation, and it's either with ipilimumab and nivolumab, which has a response rate of 55%. Unfortunately at the cost of a high rate of immune-related adverse events so about 55% to 59% of toxicity or nivolumab and relatlimab which is a combination. Gives you response rates of 43% at a much less toxicity of 21%. That's the kind of response rates I expect. Again, if we are not getting a response in the first line, obviously we have other regimens to go to in the second line that could help those patients. As I said, we try to choose our most effective regimen first.

It's a really great question in terms of what are the different patterns of progression for patients that are being treated in the first-line setting. There are kind of several, again, patterns that we observe. We observe patients responding very quickly. That does happen and we see that in the first few weeks of treatment. We see patients that may experience even symptomatic progression within the first three to six weeks. That happens in about 10%, 15% of patients. Out of those patients, we really take care to make sure that what we're experiencing is not what is referred to as pseudoprogression. Pseudoprogression is a true phenomenon in metastatic melanoma and it is related to the immune system really mounting a very vigorous immune response to treatment and against the tumors. As it does that, the tumor sizes may increase. We may actually find newer lesions, especially in the liver is a common place where that could happen but that may not be necessarily associated with the tumor getting worse but with again, a vigorous immune response. That happens only about 5% to 10% of the cases. I just want to caution folks that it's not very common so we have to be careful not to be complacent about seeing progression and saying this is pseudoprogression. However, the pattern is also very clear in that in those patients that experience that kind of progression, they should start regressing or stabilizing and getting better within about four to six weeks after the first scan. For those patients where I'm suspecting pseudoprogression, I repeat a short-term scan to see if that's what's happening. Generally with my experience pseudoprogression happens more consistently in a patient that I see maybe one lesion shrinking and others increasing. If I see any shrinkage, then I'm a lot more confident that this is what we are dealing with. If everything is just getting worse, just be careful because that could be very well just progression. Again, the same rate of pseudoprogression is about the rate of what we just discussed about rapid progression. In those patients that you're seeing the tumor progressing fast and you're not sure that the treatment is helping in any way, we try not to switch off of immunotherapy too quickly again, so that we don't call progression too early, but some patients may not have the luxury of waiting. Especially if they have a BRAF mutation, those are patients that you could immediately switch to BRAF and MEK inhibitors.

For this particular patient, let's assume that we started her on treatment with nivolumab and relatlimab, which is our recommendation for a singular lung lesion with elevated LDH is the only poor prognostic factor. If she progresses rapidly then because she has a BRAF mutation, that is the approach that we fall back on and treat her with BRAF and MEK inhibitors. If she experiences say, stability of disease and then over time starts progressing over six or nine months, then I might consider actually switching to the combination of ipilimumab and nivolumab. This has been shown in a second line setting in S1616, which is another randomized phase three trial in the second line setting, that the combination of ipilimumab and nivolumab can have a 28% response in the second line. Mind you, those were patients that are treated with single-agent PD1 and progressed. Obviously, the fact that it's NIVO-RELA or maybe a new population so we're not 100% sure that that would be the response rate, but this is kind of the currently reported response. Again, if a patient has evidence of either a response and then progression or stability and then progression, I would consider ipilimumab and nivolumab as a second line and always knowing that the BRAF and MEK inhibitors are a good fallback option for those patients.

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