How to Treat Cutaneous Melanoma in 2025 - Dr. Omid Hamid

Speaker 1 Hello and welcome back to the Oncology Brothers Podcast. I'm Rahul Ghossein, here with my brother and Co host Rohit Ghossein. In our ongoing series of treatment algorithms, today we're going to dive into the Cron treatment landscape of Melanoma from work up including scans to the importance of NGS testing to neoadjuvant treatment options for resectable disease and then on to sequencing or available options in metastatic settings. We have a lot to cover. And for this we're excited to have doctor Amid Hamid, a Melanoma specialist from Cedar Sinai. Amid thanks for being here today. Speaker 2 Thanks for having me. It's a pleasure really to get on this platform and to speak with both of you. Speaker 3 It welcome. We are looking forward to this conversation. And Rahul, I agree we have decent bit to cover. So let's dive right in. So starting out with our early stage on media for Melanoma, stage 1A wide local excisions remains a standard of care. Stage 1B and beyond, we recommend Sentinel lymph node evaluation. It's usually after stage 2B and beyond where medical oncologists get involved as we have adjuvant treatment options available, that is IO, some role of radiation as well. And also for higher stages, we have B REF and MEC inhibitors. But then over the last one year, what we've seen is our neoadjuvant trials with immunotherapy that is Nadina as well as log as eighteen O 8 for me. Can you start us off here? What is your treatment paradigm and what data do we have to support this for stage 2 and beyond disease? Speaker 2 Great. But the first point is that for a Stage 1 patient, those patients who are younger going around .75 millimeters, a discussion needs to be had about the utility of a Sentinel lymph node. The second part is changes that have been made to our therapeutic paradigm and how to follow patients with a positive Sentinel node. In the past, a wide excision was done and if the Sentinel node was positive, a completion nodal dissection was indicated. Given the findings of MSLT 2 from Doctor Mark Ferry's My surgical counterpart at the Angelus Clinic, that is no longer necessary. A positive node indicates a need to surveil the nodal basin with ultrasound. Their trial, which is in the New England Journal, showed no clear benefit in survival. There was local recurrence that would could have always been surgically addressed. So that's where I go with my early for stage 2, that is stage 2B and 2C. Despite having a negative Sentinel node, the risk of recurrence is so great that adjuvant therapy with a checkpoint inhibitor is indicated. Now what do I say to patients? It's indicated the risk is enough. So we will work you up like we work up a high risk stage 3, we send for next generation sequencing, scan the body. We discuss the pros and cons of adjuvant immunotherapy for stage 2. It is different than stage 3 because there is clearly no indication, no evidence that adjuvant targeted therapeutics to those patients who have a, B, RAFV, 600 E or K mutation are indicated. That trial was started due to poor accrual, it was stopped. Therefore we don't have that information and I don't give that off label. There's no data. So stage 2, we talk about immunotherapy, one year of immunotherapy whether it's nivolumab or pembrolizumab. We talk about immune related adverse events for our younger patients. We talk about those adverse events that are not reversible, whether it's diabetes, the myocarditis risks, the myositis risks and of course the adrenal insufficiency that can happen. That's very important when we talk about this with our younger, more active people because adrenal insufficiency then says this is a person that needs to have any infection, any surgery, any type of high stress environment needs to supplement more or may not have that push to go. This was a talk I had with a young patient of mine who was an active basketball player in college. For the females, the differences that would lead to issues with fertility, Those patients are surveilled like a high risk stage 3 with imaging every three months for the first two years, then every six months for the next three years to make 5 and then every year for ten with six month interval exams. But what else would we talk about? There is some utility now that we're seeing with circulating tumor DNA and my favorite comes from Melanoma Institute of Australia. Before surgery, if you can, you check CTDNA if it's positive, then post surgically you check again if it's gone to negative, a better outcome than if it's gone to if it remains positive. That's how I take care of stage 2. Obviously we don't just check a Graphy 600 and APDL 1. PDL 1 is not that helpful to her mutational burden. Not that helpful. What I found is a comprehensive next generation sequencing because melanomas harbor other mutations and Ras mutations. In 20% there are Ras mutations, ALK mutations, EGFR, her two things like that. Also, my adjuvant discussions are visits that happen in at least halves, which means the first visit we talk, we educate, we discuss risk, five year, 10 year recurrence, what a life looks like. And then I give them information to read about adjuvant therapy and our targets. They go away and they have at least a week to digest that information and come back and have a discussion. There's a wonderful editorial written by Lynn Schuchter in the New England Journal of Medicine. Once the Jeff Weber adjuvant PD1 versus anti CTLA 4 trial. I said it was Checkpoint Checkmate 238 and Georgina Long's Adjuvant debrafenib intermittent trial were presented and that gives a very straightforward discussion about adjuvant therapy. Speaker 1 There's a lot going on here, but a few things to reiterate that patient shared decision, patient informed decision is very critical. I mean, if you brought up the side effects for us to keep in mind with that benefit that we're trying to buy. You also touched on CTDNA. Are you today doing that for all your patients? Speaker 2 Unfortunately, the majority of patients that come to me have come after they've had their surgical procedure. But yes, I, I, I look to do that to begin, it's a risk analysis. And why is that important? Well, show me an adjuvant trial that has shown an overall survival advantage and I will tell you that you're wrong. All of these trials, Jason Luke's 716, Georgina Long's 76K with stage 2 did not show survival advantage, have not shown that yet, have not matured to show that. What about the stage 3/4? They have not shown that they're not there, they're not available. What about the one that was going to answer at Keynote 54 Lex Eggar Mons, You know, high risk stage 3B and above, including four at the time of no evidence of disease randomized to starting or waiting until recurrence that hasn't shown an overall survival advantage yet. It may, but we don't know. If I tell you I believe in it, I do for other reasons, but the reason that I have evidence in hand for survival advantage is not there. Speaker 1 You touched on this, the recurrence rate here is high, particularly for that Stage 2C that looks even higher than Stage 3A. So we have to keep that in mind. OK, moving right along for Stage 3, the treatment landscape has started to shift to the neoadjuvant advances. Roy brought up NADINA trial to SWAG trial today. What does that treatment paradigm look for you? And what about the adjuvant B, ref and MEC inhibitors? Speaker 2 Right. So my Stage 3 treatment paradigm happens like this. If they show up with disease in place, right, you see nodal disease on exam or they come in and you image because of high risk and they have disease to follow. Those are patients where we have a discussion about neoadjuvant versus adjuvant and there are two regimens that are approved at this time. They have not gone head to There are off label neoadjuvant options the downstage, but at the current time the strongest evidence comes from immunotherapeutic whether it's SAPNA Patel's New England Journal of Medicine article with swag 18 O one single agent pembrolizumab 3 doses take to surgery finish the year versus Nadina from Christian Blanc also in the New England Journal a plenary at ASCO flip dose ipilumab, nivolumab and then bringing the surgery in and making a dynamic decision on therapy. Both of these trials have shown that if you get a pathologic complete response, you have about a 98% chance of nothing coming back. Nadina showed the greatest evidence of that, a 60% complete response rate in those patients who are treated. Now, where is the rub? What am I hiding? The the hiding is the toxicity that comes from a dual checkpoint inhibitor combination. So it might not be for everyone. What am I hiding? The idea that we still don't know what that means in relation to long term survival, but clearly it's beginning a discussion for us about where to go forward. Mark Ferries along with Alexander Vanekoi who's at Melanoma Institute of Australia, have put together MSLT 3, which will be a slog study coming forward. If you get a great response, you can biopsy the index node. If that node is a complete response. Also you don't need to do a completion nodal dissection. So that's coming forward. And what about some of the other regimens that are out there? Rodaba Amaria presented a dual LAG in the neoadjuvant setting. That is a whole other discussion. There are not big studies on that yet, so we have that left to consider. What about B RAF targeted agents? We belong to a group, the International Neoadjuvant Melanoma Working Group that has looked at this data and was published in JC AHO I believe by Alex Manzis from Melanoma Institute of Australia that the long term benefits in relapse free survival seem to be better with immunotherapy. So long discussion to have and the next steps are really looking at those people who get a path. CR can we just stop? OK, let's look and see if we can stop. Why less risk, less morbidity from travel and being in my office and sitting in the chair, less cost full and those are major things to consider here. We're not done with stage 3 adjuvant. If you're doing adjuvant, it is only single agent adjuvant. If you're doing adjuvant, it is never lag. 3PD1 never up do a lag. Why that trial was done? Adjuvant stage 3, Stage 4 no difference. Trial stopped. Can't do that. So what's the decision to make? B RAF versus PD1 alone They look the same one year only. Both show that the relapse free survival curves diverge and remain divergent. What have we learned so far? Georgina Long presented the data with the adjuvant debravative tremitinib and the patients with V600K really had no difference. There was no statistical difference. So I look at these patients who have B RAF fusions, non canonical E mutations, and I really don't discuss B RAF with them because we haven't seen it. The V600K patients traditionally have a shorter response to dual targeted agents and they do better with immunotherapy as a first line. Speaker 3 Thanks very much for me for covering the Stage 3 space. Let's dive into the metastatic space where for all comers, we tend to utilize the dual checkpoint inhibitor NEVO EPIC combination even in BRAF positive patients and then utilize B RAF inhibitors in the second line setting while working with the staging here. Do you do MRI brain in all your patients? If there is metastatic disease present, do you rely on a higher dose of epilimab? How about the data from Dream C&C Combat for our B RAF patients? How do you decide which one of the B RAF MEC inhibitors to go for for me? Can you please walk us through your treatment paradigm? Speaker 2 In the metastatic setting, the work up should always in any high risk include an MRI of the brain, a PET scan if you're getting it, if you can get it, ACT scan to look at the contrast enhanced abdomen, sub centimeter liver lesions usually not seen on a PET scan. So that's that part of it. It includes next generation sequencing of the tumor. B RAF is very important despite the fact that multiple trials including secumbent from Palo Esierto and also Dream Seek from Mike Atkins from Georgetown have shown that the right regimen is starting with first line dual checkpoint inhibitor therapy with anti CTLA for anti PD one. Can you argue that it's lag three PD one, yes, if you need less toxicity, what about those population that has rapidly growing disease then those people, the sandwich regimen of you know, two months B RAF MEC and then reimaging and going on tipping Evo and then B RAF MEC on progression. That's a standard that we have seen and that's how I take care of those patients. Yes, what else do we have there? We now have clinical trials, which is beyond the scope of this discussion, but really should be important. A referral to if there's access to a Melanoma center of excellence to evaluate the role of second line adoptive T cell therapies, other clinical trial options and to work with an assist if toxicities ensue. That's where I go. There is one caveat here that is in your slides. What we haven't talked about is stage 4 resected disease adjuvant for stage 4 comes from immuned which was Dirkshadendorf's trial of standard versus single agent PD one versus PD1 CTLA 4 and the PD1 CTLA 4 out shown all of the others. So that's a de facto regimen. What else have when we talked about brain metastases and again checkmate 2O four has shown that that regimen is anti CTLA 4, anti PD1 plus minus radiation. If you need steroids, then you know focal neurosurgical procedure to remove that. If it's one offending agent, remove it, taper off the steroids and begin if B RAF mutant positive. The ability to utilize a sandwich regimen has been something that's been put out there. Speaker 1 I mean the IP dosing also ends up being important here because this is where I'm in place where we're often using 3 mix per keg. I would love to hear your thoughts the. Speaker 2 Flip dose right? Yes for me if it is brain mass, if it's B RAF disease I give full dose because we don't have anything other than that in the second line. If they have not seen anti CTLA 4 based on the trials, that is the next option, anti CTLA 4. If they have failed PD one alone and you take them to a lag 3PD1, the response rates have been 11 to 13%, not enough for us to go there. If you go to CTLA 4 PD one response rates 25 to 28% and better durability. Speaker 1 Made out in the community practice. A common thing ends up being when we're seeing immunotherapy early on, be it part of neoadjuvant or adjuvant. What if the disease has progressed thereafter? This is a common scenario. What's your treatment paradigm if the patient has seen immunotherapy are ready? Speaker 2 These people who are getting adjuvant PD1 and they recur, what are we doing there? I treat them as having seen a single agent PD 1 and in a advanced setting and progressing. I rarely come back to single agent PD one for them if it's if they've my go to is full dose ipilumab, nivolumab, if they can't tolerate it then flip those versus LAG 3PD1. If they have progressed within six months of stopping their adjuvant, I don't go to LAG 3PD1, I'd go to CTLA 4 PD one or second line trials. And I think that this subgroup of patients is what we're going to really focus on to be able to bring forth an intricate therapeutic paradigm which we don't have now. The good news is that we may be taking care of patients in the neoadjuvant setting and obviating the need for metastatic discussions. The next steps are. Clinical trials, I think that really give us an understanding of what to do here. And one of those for me is one that started in the Nordic countries. It's called Grand Slam. Grand Slam is going to look to randomize patients who receive either neoadjuvant single agent PD One or adjuvant PD1 and randomize them to six months of therapy versus 12 months of therapy. These timelines are strictly brought out of thin air. They're arbitrary and we need to figure it out. Speaker 1 I mean, we've covered a lot here for refractory disease. Of course, there's another discussion of pills as well. We've touched on clinical trials that's essential and should be on our radar. Conversations like these continue to make us feel more comfortable out in the community so that we can provide that best care close to home for our patients, for our listeners. Let's go over a quick recap from today's discussion. Speaker 3 In today's episode with Doctor Omid Hamid, we covered the treatment landscape of Melanoma in 2025 for early stages adjuvant immunotherapy or B RAF MEC inhibitors for high risk remains the standard of care. CTDNA was discussed and the use of this time mainly is for prognostication purposes only. Speaker 1 And Rohith for resectable stage 3 and stage 4 neoadjuvant immunotherapy based off NADINA trial, which was presented last year at ASCO as a plenary session is now the standard of care in metastatic settings. Brain MRI as part of staging for all comers is readily being adopted. Then we also touched on our options of dual checkpoint inhibitors and BUREAF MEC inhibitors in metastatic space. Thanks for tuning in. Make sure to check out our other episodes on treatment algorithms, new FDA approvals and conference highlights. We are at the Oncology Brothers.