Metastatic Melanoma — Omid Hamid, MD

DR HAMID: I’d like to thank Dr Love and Research To Practice for allowing me to speak today about new developments for the treatment of advanced melanoma. My name is Omid Hamid. I’m a medical oncologist. I’m Chief of Translational Research and Immuno-Oncology and Co-Director of the Cutaneous Malignancies program at the Angeles Clinic and Research Institute. We’re a Cedar-Sinai affiliate in Los Angeles, California. And over the last 12 months or so, we’ve had major changes into the options that we have for our patients with advanced disease. Any time I talk about malignant melanoma and more dominantly immunotherapy, I mention that melanoma has been the leader in immunotherapy for all solid tumors. And a lot of what you hear here will be coming to other solid tumors. So it translates to care for all solid tumors, so it’s important to think of this as where we are now and where we’re going. And I’ll try to pepper in my discussion with what’s happening in other solid tumors as we go forward.

Now as you’ve heard and you know, the overall survival bar for metastatic melanoma has changed a lot, even during my very early career from before the checkpoint and the targeted therapy era, with a median overall survival for metastatic or advanced melanoma of 6.4 months until now where you see medians at 6 years and past. And what has done that has been targeted therapeutics and PD-1/CTLA-4 inhibition either single agent or combination. And so what we’re looking at here is trying to finetune that, what we’ve learned, what other options we have and where to go.

I spend a very small amount of time talking about targeted therapies with BRAF inhibitors, but there’s major changes that we’ve had here. As you know, there are 3 combinations that are approved whether it’s dabrafenib/trametinib, vemurafenib/cobimetinib or encorafenib/binimetinib. What we have shown in randomized trials is combination therapy is better than single agent BRAF, so BRAF/MEK better than BRAF. What we’ve also shown is that you can get long-term benefit but ultimately, BRAF targeted therapies have progression disease. So how have we relegated that, those therapeutics?

That’s the DREAMseq trial. And this is a trial started and run through ECOG, Mike Atkins is the primary investigator, presented and recently published looking at a randomization between starting with combination immunotherapy, which is CTLA-4/PD-1 with ipilimumab/nivolumab, versus beginning with BRAF/MEK inhibition, dabrafenib/trametinib. And then on progression, transitioning to the other arm. So you can see arm A, combo checkpoint. Arm B, combo targeted agent. And then, on progression going on to the other therapeutic option.

And to make it short here, what this DREAMseq trial showed was significant benefit in overall survival beginning with immune-oncology versus targeted therapies. And this has set the standard for patients who have BRAF mutations and advanced melanoma to begin with combination immune checkpoint with CTLA-4/PD-1. If you look at this overall survival curve, there’s an early flip and these patients here are thought to be patients who could not tolerate the amount of time necessary for immunotherapy to work. And we’ll talk about that later.

What you looked at here in response, the first line with immune-oncology versus targeted therapy was the same. But then upon progression, when you went from immune-oncology arm A to arm C which is targeted, the response rate was the same. But when you went from targeted therapy upon progression to combination checkpoint inhibition, you got a lower response rate. And we’re not sure whether that’s because disease was progressing too quickly or whether there’s this IPRES signature where when you have progression on targeted therapy, you become immune insensitive. And this is the IPRES idea that has been brought forth by Roger Lo and Antoni Ribas that’s an insensitivity. And so what do we do with those patients? Here's the progression free survivals, by the way, where progression free survival with immunotherapy was better. And then if you come from targeted to immuno, the progression free survival is very poor, so clearly indicating starting with immuno except for those patients where you’re not able to, whether it’s because you need steroids, whether it’s because they’re too symptomatic. What do you do?

And that is SECOMBIT. SECOMBIT was presented by Paolo Ascierto in — at ESMO 2021. It was ultimately published in the Journal of Clinical Oncology. And that looks at 3 arms. One is beginning with combination targeted therapy and upon progression, going on to combination immunotherapy which we now know is not the right way. Arm B was beginning with combination immuno and going to combination targeted on progression which we know is the standard now. But what about those other patients? Could you begin with a sandwich protocol starting with targeted therapies to control disease for 2 months and then switching and then moving forward? And what we saw here in short is you could.

And SECOMBIT showed survival at 2 years better for those patients that either did the sandwich regimen or began with immunotherapy combination. Now this was a smaller study, but what’s important here is we’ve shown that you can begin with targeted therapy but before you get resistance, switching over. What we also are waiting to look at here is this, unlike DREAMseq which was a huge trial done in community settings, this one had biopsies, had circulating DNA and we’re awaiting the correlates to tell us where and how to manage these patients to move forward.

DR LOVE: Just to ask, what about combining IO and BRAF therapy?

DR HAMID: Well you can combine IO and BRAF therapy. And there, that’s IMspire that we have down, we’ll talk about later. What we’ve seen there is there was a trial with vemurafenib, cobimetinib and atezolizumab versus just BRAF and MEK, and that led to an approval. But when that was looked at with central review, didn’t show a benefit in PFS where the trial itself did. And that’s really moved away from being a standard. Other trials that were done that way did not show a benefit. And so at this time, that is not a standard that we use. We only utilize it at times for patients where we think that we can never get immunotherapy in. The triplets of BRAF, MEK and PD-1 have been found to be tolerable. And there are trials looking at encorafenib, binimetinib and pembrolizumab versus pembrolizumab alone. And that’s a, the STARBOARD trial which has not fully accrued yet. There’s also a trial looking at the sandwich regimen in a randomized fashion versus ipilimumab/nivolumab, and that’s an EORTC trial. But for at this point, not a lot of survival advantage has been shown there. Not many people utilize this as a standard unless it’s a patient where you feel like you could not ever get them to get both therapies, so I rarely use that.

DR LOVE: Well I wasn’t thinking so much about using them both together until progression. I was thinking about, could you just start the IO and just use 2 months of the BRAF and then stop it and keep the IO going?

DR HAMID: No, you cannot give — now there are, there’s a small trial being done by Jason Luke to try and see if you can give all 4 together. But in the past, when we’ve done BRAF, MEK and anti-CTLA-4, there’s been huge toxicity with colitis. So that’s a no-go for standard. It’s a no-go for community at this time. We really haven’t shown that benefit.

DR LOVE: Please continue.

DR HAMID: Okay, great. So the granddaddy of them all right now is the combination of ipilimumab/nivolumab from CheckMate 067. And that was updated by Jedd Wolchok, as you can see here, at ASCO looking at durable clinical outcomes in patients with advanced melanoma who are progression free at 3 years. What you can see to the left here is the progression free survival in the intent to treat population. And you can see at 3 years, there was a significant proportion of patients that were progression free survival — that had not progressed. What he showed there is their overall survival was phenomenal. They didn’t need another therapy. And their melanoma specific survival was that they didn’t pass for melanoma. So this is a new endpoint, 3-year progression free survival showing that you do really well for many years to come. And that’s important here as possibly a new endpoint for our patients.

That showed that most patients didn’t need subsequent therapy and that at 7.5 years, they had a cut-off, 90% of patients were alive and greater. So what do we take from this is that we have a huge amount of benefit with either single agent or combination and we may have a predictor for long-term survival which is progression free survival at 3 years. What we also took here from this is that those patients that do really well are the ones that have complete response or near complete response. They never progress, and that’s what we’re looking into more. Those patients who have a complete response or a PET negative response with immunotherapy now are the ones that we feel are doing really well. And we have breakdowns from trials like CheckMate 067 showing that if you get a complete response, you do better in the long-term than a patient that gets a partial response and significantly better than a patient that gets a stable disease. So this is a new endpoint and future trials are going to look at whether we can do more to push these patients who have had a long-term durable partial or stable disease towards a complete response if they’re not PET negative. And that’s something that will come in trials in the future.

These are follow-ups from RELATIVITY-047 which was presented and published in the New England Journal and set a standard for advanced melanoma and has become patient — physicians’ go-to for patients with newly diagnosed malignant advanced melanoma.

And this was RELATIVITY. It was combination relatlimab/nivolumab versus nivolumab alone. Both are given every 4 weeks. Both are given as an infusion over 30 minutes. Previously untreated, unresectable or metastatic melanoma looking at PFS as its primary endpoint. And the most recent update showed 21-month follow-up and updated progression free survival.

And it showed progression free survival benefit that continued to be significant many years out, even 3 years out for advanced melanoma. What it also showed is overall survival benefit now is not, still not significant although in advance melanoma, we’re feeling that that’s because there are other therapies in the second line, et cetera, that are pushing that up, but for progression free survival benefit. And what we — what the last time I talked to you about is about at 3 years, we start to see that plateau of survival. And you’re seeing that better here with the relatlimab/nivolumab combination versus nivolumab alone. So hopefully, as we go further out, we’ll see a more significant survival advantage.

And this idea of progression free survival 2 which still needs to be clarified which is what we saw here is the patients who were treated with this combination had a better progression free survival on their secondary treatment. So there may be benefit into seeing these checkpoint inhibitors initially helping you do better upon progression. There are certain nuances here that we can’t get into in an hour. But what I’ll tell you is that we’re starting to look more and more and understanding that possibly the greatest benefit of checkpoint inhibition in advanced melanoma may be optimizing it in the first-line. So is it a discussion about, oh should I just give single agent PD-1? Should I give PD-1/LAG-3? Or should I give PD-1/CTLA-4? Or are there better options? And that is triplets or quadruplets that are coming up. And I’ll transition into that discussion here in other clinical trials that are upcoming.

Let me just say, we’re trying to figure out what’s best for what. And the only thing that we have here in these trials that are randomized to the same control arm is hazard ratios. So you can see here, ipi/nivo having a better hazard ratio for BRAF mutant. RELATIVITY with LAG, PD-1 not as good. And this idea that patients with PD-L1 greater than 1% may do just as well on single agent versus combination. Clearly, there’s a lot more to figure out here, but this tells us that we need to do more, find better regimens and that — find what a — predictive markers on what to do with patients who are low LAG-3 expressors because those have shown a poorer response to LAG-3 inhibition. Those patients who are PD-L1 greater than 1%, do they really need CTLA-4 with these toxicities? Do they really need LAG-3? Because in Europe, if you’re greater than 1%, you cannot get LAG-3 inhibition in the advanced setting. There is no clear benefit there when you look at the subgroup analysis.

Well what are we doing to figure that out? We’re allowing — we’re looking at toxicity. And there’s a significant Grade 3 or 4 toxicity with ipilimumab/nivolumab versus relatlimab/nivolumab. So for patients where toxicity is an issue, you may want to go with LAG-3 inhibition.

This is a slide showing, well what I told you before. If you’re on nivo/ipi, you get a complete response or a partial response, your survival is almost flat, doing well. Stable disease is not doing well long-term. With nivo alone, stable disease is not doing as well long-term. Ipilimumab is no longer a standard first-line. So how can we move these diseases, these partial responses to better responses, to better long-term survival?

Well maybe it’s we need a better dosing of the regimen. So this is fianlimab and cemiplimab. I’m just showing you the early data from ESMO that I presented showing high response rates, rapid deep and durable response and the fact that when you go to LAG-3 when they’ve initially progressed on a PD-1 experienced patient, they’re not great.

So what has happened now is this data has been updated at ASCO. And it brings into question how we’re taking care of patients with LAG-3 inhibition.

Why is that? This is fianlimab at 1,600 mg. That’s a LAG-3 inhibitor that’s given at a 10 times greater dose than relatlimab every 3 weeks which is more frequent dosing and also given with a PD-1 inhibitor that’s more frequent. What did we see in PD-1 untreated patients in a cohort of 80 patients and then those patients who have seen adjuvant PD-1 is important here. The primary endpoint was overall response. Key inclusion and exclusion here are similar. No uveal melanomas.

What did we see here as follow-up was increased was that the response rates here are 63%. Now these are smaller numbers than the RELATIVITY-047, but it’s important to tell you that RELATIVITY had a response rate of 44% not 63%. It’s important to show you here a greater disease control rate of 80%. And what this brings to question is, are we really dosing LAG-3 appropriately and as beset as we can in our patients with melanoma?

And in this PD-1 experienced where they’ve seen adjuvant PD-1, what we saw here was response rates of 56% in those patients who had seen adjuvant therapy. And this is important because in the past, we didn’t know if we gave adjuvant PD-1 would we have a regimen to come to. And that’s important because adjuvant PD-1 is becoming standard in lung cancer, it’s becoming standard in renal cell carcinoma. LAG-3 is a target that’s being looked at in multiple solid tumors including lung cancer and renal cell and other solid tumors. So what this showed is it's a better response rate than we’ve seen with just coming back with single agent PD-1. So there’s nuance here that’s important.

What we also saw here is tumor responses compared with historical controls that are great. When we took all these cohorts together of these advanced melanoma patients seeing PD-1/LAG-3 with fianlimab/cemiplimab, a total overall response rate of 61% which compares favorably with single agent PD-1 with combination LAG-3/PD-1 with relatlimab/nivolumab, and even with ipilimumab/nivolumab which had a 58% response. The caveat here is this is a Phase II with 98 patients, not 300 patients. But the duration of response, still not reached and beneficial. The progression free survival, more similar to ipi/nivo than rela/nivo. So what we’re doing now is a major randomized Phase III trial to find that out so to answer, are we dosing LAG-3 appropriately?

Because these checkpoints are important. They’re important in T cell exhaustion. They’re important in making patients who may have initially been resistant to first-line checkpoint inhibitors responsive. Going forward, we have a lot of options. I’m just going to show you a couple.

What about bringing CTLA-4, PD-1, LAG-3 together? There are many trials. There’s RELATIVITY-048 that’s being done in Europe that has yet to be reported that looked at a combination of ipilimumab, nivolumab and relatlimab. And the question was, was it tolerable? It hasn’t been presented. But because we have looked at ipilimumab and nivolumab with an IL-6 inhibitor, this is a trial ongoing at my institution, NYU, Mass General and Dana-Farber where we’re looking at 4 drugs. So an IL-6 inhibitor, you can understand, has the ability to decrease the risk of immune-related toxicities. But also, IL-6, elevated IL-6 levels have been associated with poor prognosis and resistant to checkpoint inhibition. So we’re looking to push response rates and benefits and try to push people into better partial response and complete response.

At the same time, we’re accruing to a trial like this. This is a study that’s looking at a PD-1 inhibitor + a LAG-3 inhibitor + a TIM-3 inhibitor. So 3 checkpoints together that aren’t CTLA-4 which would possibly be better tolerated in first-line melanoma. So many first-line options, and I’ll get to some more later.

Not to be pushed out, we talked about those patients who may not need dual checkpoint inhibition, may benefit from other approaches. This is a Phase I/II trial which is now in a Phase III setting being compared with just single agent pembrolizumab alone of a vaccine against IDO and PD-L1, so a vaccine type of approach in combination with nivolumab in metastatic melanoma. The Phase I study showed a high response rate. Now small numbers of patients, but a response rate of 80% and a high complete response rate, you can see here, the majority of patients getting a complete response pointed us to looking at this, and this data is coming forward. And this may bring us back to vaccines being important in melanoma and other solid tumors.

What also is now at FDA and is coming forward is looking at adoptive T cell therapy with autologous tumor infiltrating lymphocytes. This is lifileucel data that showed in the heavily, heavily pretreated patients where you get tumor tissue itself and you make a, you grow those T cells that have infiltrated into the tumor, when you bring this together in heavily pretreated patients that had 3 to 10 previous regimens, had failed BRAF/MEK, had failed CTLA-4, had failed PD-1. Most patients were checkpoint resistant so they didn’t even get a response to checkpoint inhibitors. Most patients had seen CTLA-4, PD-1, et cetera, and you had a 31.4% response rate. This showed that in patients, 80% had seen CTLA-4, all had seen PD-1, an option.

Very tolerable. The majority of toxicity comes from the initial lymphodepletion with chemotherapy and the IL-2 that’s necessary. And a long duration of response. Now this is something that’s in clinical trials and is at the FDA for approval. At this point, the FDA has accepted its biological license and is evaluating the data for approval.

Well where does a lot of this data come from? Most of you have seen the New England Journal article that came forward from John Haanen and others in the Netherlands where they looked at tumor-infiltrating lymphocyte trial versus ipilimumab in the second-line. This was a randomized Phase III trial.

How does tumor-infiltrating lymphocytes work? Here’s how it is. Metastatic melanoma patients are seen. The first thing that’s done, the surgical removal of a melanoma lesion. That’s taken and that’s digested. And the T cells that are in the tumor are then taken out of the tumor, digested and grown up. Now why is that important? Because you get tumor-specific T cells that are targeted at not just one tumor-specific antigen, but multiple tumor antigens. And that is then grown to billions of T cells through a rapid expansion protocol. And then those are called TIL, tumor-infiltrating lymphocytes. Those are then pooled into one infusion bag. The patient themselves then is brought into the hospital and receives Flu/Cy. This is a lymphodepleting chemotherapy. It’s nonmyeloablative. It gets rid of T regulatory cells, nonspecific T cells, et cetera. You are infusing the tumor-specific T cells, so that’s how they get those from a single infusion of TIL and then they get IL-2 up to 6 to 8 doses. We know high-dose IL-2 can work in melanoma, but this is — it’s not doing the heavy lifting here. In this trial that was done in the Netherlands, all of this was done centrally. In trials that we have like the lifileucel trial, it allows the tumor harvest, the beginning, and the tumor infusion, the end, to be done at a local area, the surgery done locally and the TILs to be grown centrally.

Companies like this do the rapid expansion protocol. And they obviate the need to have a GCP facility at every site and allow this therapy to come to all patients.

So what we saw here was in this randomized trial between TIL versus ipilimumab, a higher response rate. So the overall response, 41% versus 18%. And a higher clinical benefit, 57 versus 33%. Well that’s amazing. And you say, well why is this response rate higher? Because it was earlier and we’re getting the understanding that earlier and earlier giving adoptive T cell through tumor-infiltrating lymphocytes is important.

What we also saw is progression free survival benefits here. You can see here a median follow-up of almost 3 years, a progression free survival that is at 6 months greater than double in patients who received TIL.

So where are we with this therapy? There’s a first-line trial that’s coming looking at lifileucel plus pembrolizumab versus pembrolizumab alone in patients. It’s a randomized study with 670 patients globally.

We have some early data that was presented on a trial that’s ongoing at this point looking at many different types of tumors in the first-line. You can see here, best overall response, 100% clinical benefit in melanoma. But here’s a transition I want to make to you, that adoptive T cell therapy with tumor-infiltrating lymphocytes is being looked at in cervical cancer, lung cancer, you can see head and neck cancer here, and it is coming for other solid tumors. And so it’s not just melanoma. But you can see here the efficacy early, 100%. Head and neck, 87. Cervical, 85%. And head and neck cancer, cervical cancer, don’t quote me on this because I’m a melanoma oncologist, but is a greater issue for the whole world. Globally, cervical cancer and non-small cell lung cancer is that issue.

And this is just a slide to say that we’re doing more. This is a trial of TIL cells, the tumor-infiltrating lymphocytes, but they’re a PD-1 knockout. So they, the PD-1/PD-L1 access is knocked out so you do not need to utilize a drug like nivolumab. And so we’re looking at this. Cohort 1 is melanoma. Cohort 2 is non-small cell lung cancer. So if you’re listening to this, this is coming for multiple solid tumors. Combinations are coming. Newer TIL therapies are coming. So we’re looking here at the Angeles Clinic and Research Institute first-line checkpoint inhibition whether on trial, combination, triplet, quadruplet, whatever and then some type of T cell therapy moving forward.

Let’s transition because you guys wanted to talk about, what’s the guidelines for another type of melanoma, ocular melanoma? There’s not a lot to say here. If you’re HLA-A2 positive, we know tebentafusp has been approved for those patients based on overall survival advantage. This is a bispecific antibody that targets CD3 on one end and gp100 on the melanoma side. It showed improvement in overall survival with hazard ratio of 0.51. It’s a standard for HLA-A2 positive melanoma. So any ocular melanoma that’s advanced needs an HLA-A2. And if they’re positive, to be treated with tebentafusp.

Here are the patients. This is the trial that was presented in the New England Journal of Medicine. In uveal melanoma, you saw significant overall survival benefit. Despite the fact that you didn’t see a lot of RECIST response, you saw tumor — progression free survival benefit and overall survival benefit. And in these patients, even patients that did not respond had some form of benefit because if you looked at those patients that were progressors, the long-term benefit in patients who were progressors who saw tebentafusp was better than those patients who didn’t. So in ocular melanoma, it is a standard.

These are ImmTACs. You can see here these are bispecifics that target intracellular proteins that are presented. You can see here the ImmTAC itself targeting CD3 on the polyclonal T cell. And then the reason you need to check the HLA typing is the peptides that are presented by the HLA apparatus. And ImmTACs can target greater than 90% of the proteome whereas antibody bispecifics can only target 10% of the proteome. That means it’s got a wider range of applicability in solid tumors. Now with tebentafusp, the protein here is gp100. And I’m telling you that because there’s a lot to understand here because these things are coming.

Here is data that was presented in metastatic cutaneous melanoma with this type of bispecific in combination with just PD-L1 or PD-L1 + CTLA-4. So now, you’re understanding that you can combine these with checkpoint inhibitors. And in this population, you saw response rates, you saw high tumor control, but what we’ve also seen, let me go back to this, that the 1-year survivals are the best that we’ve seen in anything in small studies at 1-year post-progression on checkpoint. Okay? In patients with any type of decrease, 89% in metastatic cutaneous melanoma, and 85% in metastatic uveal melanoma. So this is becoming not just something for uveal, something, it's something for cutaneous melanoma. And this drug is now going to be looked at in a randomized Phase III trial along with a PD-1 inhibitor versus PD-1 alone in HLA positive cutaneous melanoma.

What else is coming? Well maybe there's a better bispecific, and this is IMC-F106. It's an ImmTAC that targets CD3 on one side and PRAME on the other. And this whole thing can show you, well, PRAME is expressed on a lot of solid tumors: endometrial, ovarian, non-small cell lung cancer, uveal melanoma, cutaneous melanoma. And what you see here to the right is clinical benefit that has been seen in uveal melanoma, cutaneous melanoma, serous ovarian cancer, we're looking at it in triple negative non-small cell lung cancer, et cetera. You can see here when we look at it in the peripheral blood when we start treating it, you can see interferon-gamma induction which increases PD-L1. We see T cell trafficking into the tumor. And possibly now, we're understanding that you can get those T cells into prime and maybe boost with a checkpoint inhibitor. And the reason I'm telling you that is this trial now which is HLA-A2 gated has started in monotherapy cohorts but has multiple other cohorts now with chemotherapy in triple negative breast with chemotherapy in ovarian with ImmTAC combinations of tebentafusp + PRAME in uveal melanoma and monotherapy expansions looking at tumors that heavily express PRAME including in sarcomas. So it's coming.

And this is another type of T cell therapy. When you talk about T cell therapies, you're talking about TIL, you're talking about this, you're talking about possibly natural killer type of therapies that are coming forward, and also CAR T in solid tumors which is getting a ground. We won't talk about it, but it's coming also in melanoma.

And just some evaluations here in cutaneous melanoma are patients that have responded that have progressed on checkpoint inhibitors, and other clinical trials.

Interestingly, this is a trial that's courtesy of Dr Richard Carvajal, but it is in uveal melanoma. A patient who had failed ipi/nivo and had failed — uveal melanoma, had failed ipi/nivo and other therapies, went on tebentafusp, and then after progression because there were no other options went back to checkpoint inhibitor therapy and had a significant response that's ongoing. So we're finding out that in those patients that were refractory, if they're treated with a drug like this, you may be able to then bring T cells in and boost again and utilize checkpoint inhibitors again. The prior therapies here you can see, ipilimumab, pembrolizumab, radioembolization, and then a bispecific ImmTAC and then ipi/nivo. So a lot to be found out. And as you know, as I told you, this can be in many solid tumors.

What about adjuvant therapy? And I'm not going to delve into adjuvant Stage II and Stage III because that's exploding in, in early melanoma, but in the metastatic melanoma setting, the IMMUNED study, Dirk Schadendorf and others, has shown combination checkpoint inhibition to be the standard here with anti-CTLA-4/anti-PD-1 at full dose. Look at the relapse free survival here. And look here, BRAF mutation status. It's helping similarly to what we saw in the metastatic setting, really in the adjuvant for patients with metastatic BRAF. In the adjuvant post resection, it's beneficial. And in the overall survival here, you're showing indications of benefit. So IMMUNED has set a standard for the adjuvant therapy of Stage IV patients. This is now standard. This is, this data is irrefutable.

So the checkpoint therapies have changed the whole landscape of advanced melanoma. Standard therapies include PD-1, single agent combinations, newer checkpoint combinations, adoptive T cell therapies, triplet, quadruplet, and more. And also, these ImmTACs, clinical trials, clinical trials, and understanding what predictive markers we have and really trying to push our patients to full complete response or a partial response which is non-PET avid.

Localized Melanoma and Other Types of Skin Cancer — Evan J Lipson, MD

DR LIPSON: Hi everybody. I'm Dr Evan Lipson. I'm an associate professor of medical oncology here at Johns Hopkins in Baltimore, Maryland. And today, we'll talk about localized melanoma and other types of skin cancer.

One of the research efforts that was reported earlier this year was a look at adjuvant nivolumab combined with ipilimumab versus nivolumab alone in patients with resected Stage IIIB-D or IV melanoma. This trial was called CheckMate 915. And this was a question people had asked for a long period of time which is, could combination therapy in the adjuvant setting be better than just plain anti-PD-1 by itself? And what we saw from this study was no difference in recurrence free survival among about 1,800 patients with resected melanoma between nivo + ipi compared with nivo alone. It's important to note that the ipi used in the study was low dose, 1 mg/kg every 6 weeks. But even with that limitation, the recurrence free survival curves as you can see are right on top of each other. So this confirms that anti-PD-1 by itself is the standard for patients with resected melanoma in the immunotherapy space.

It's important also to know that treatment-related Grade 3-4 adverse events were seen in about 30% of people in the combination group versus about 13% in the nivo group. So once again, as we've seen before, combination therapy is more toxic than, than single agent. So what does that mean going forward? Well, as I say, anti-PD-1 monotherapy is a standard of care. That's not changed. But it does bring the question, what other combinations might be effective? For example, anti-LAG-3 agents are sort of the new checkpoint blocker on the block. And so could that in combination with anti-PD-1 have an acceptable toxicity profile and also bring some advantage over anti-PD-1 monotherapy in the adjuvant setting?

Another important study over the past year was looking at pembrolizumab versus placebo as adjuvant therapy, excuse me, adjuvant therapy in patients with resected Stage IIB or C melanoma. This study was called KEYNOTE-716. And the distant metastasis free survival rates were what was reported at ASCO earlier this year. And the bottom line here is that in patients with resected Stage IIB or C melanoma, distant metastasis free survival was improved with adjuvant pembro versus placebo.

And so what does that mean? Well among 1,000 patients, as I say, we saw an improvement in not only distant metastasis free survival but also recurrence free survival compared with placebo. The median follow-up here was quite long, 39.4 months, so the results support the use of adjuvant pembrolizumab in patients with resected IIB or C melanoma. Moving forward though, it does beg the question, could a combination therapy be tolerable and perhaps more effective? So, as I said before, could anti-PD-1 + anti-LAG-3, for example, give us more efficacy without a whole lot more toxicity?

This is a similar study this time using nivolumab instead of pembrolizumab, but this is also versus placebo in the same patient population, resected IIB or IIC melanoma. And you can see the stratification here. This is nivo at the usual dose given for 12 months versus placebo. And again, we see an improvement in recurrence free survival among the patients that received nivo versus those that received placebo.

So this was an 800-patient study which underlines the results from the pembrolizumab study demonstrating improved risk of recurrence versus placebo. So although nivolumab is not FDA approved, it does underline the benefit with anti-PD-1 monotherapy in this patient population. Again, the question about could combination therapy be more useful in this setting without adding a lot of toxicity remains to be seen.

Moving into the neoadjuvant space, this was a really important study that was published in the New England Journal earlier this year. This is a SWOG study so this was a big cooperative group study looking at neoadjuvant and adjuvant therapy versus adjuvant only therapy in patients with resectable Stage III or IV melanoma. And what this compared was rates of event free survival. And you can see here that patients that received neoadjuvant followed by adjuvant therapy had improved event free survival compared with the group that received adjuvant only.

So what does event free survival mean? It's defined as you see on the screen here; disease progression or toxic effects that precluded surgery and inability to resect gross disease, disease progression, recurrence, death, et cetera. So the bottom line is that patients who received neoadjuvant therapy followed by surgery followed by adjuvant therapy had improved event free survival over those that only received adjuvant therapy. So clinically, what does this mean? Well, it means that neoadjuvant therapy is really sort of making its appearance on the stage. It is in many ways ready for primetime. There are though some questions. So, which regimen is best? Is it anti-PD-1 monotherapy? Is it combination immunotherapy? For how long do those therapies need to be administered before surgery takes place? And then, in the setting of a pathologic complete response, for example, do patients need adjuvant therapy or is the neoadjuvant arm alone enough?

DR LOVE: Can I just ask what your thoughts are in terms of what's going on there, why you see the benefit, and whether or not you see the future using neoadjuvant treatment with lower-stage disease?

DR LIPSON: That's a good question about what's going on. What we hypothesize is that while the tumor is in place, what you have are a population of T cells and probably B cells and others that are right at the interface of the tumor. So there is a population of cells, immune cells ready to be activated with anti-PD-1 in this case that then becomes activated at the time of administration of therapy and then can go to the rest of the body and, and kill melanoma wherever it is. You might lose that interface when you take out gross tumor, and then it's, who — perhaps it's less clear which population of T cells you're activating with the administration of anti-PD-1. And, sorry, what was the second part of the question?

DR LOVE: What about lower-stage disease?

DR LIPSON: Lower-stage disease, right.

DR LOVE: Neoadjuvant therapy.

DR LIPSON: Yeah, for sure. So that's sort of a natural progression of, can we use this in Stage III high-risk, bulky resectable? Could we use it in lower-stage where you think you might have micrometastasis? Could you use it in Stage II when you've got a large primary tumor in place? So I think potentially, there is benefit there. When you get to lower and lower stages, the issue really becomes one of toxicity because with lower and lower staged melanoma, the risk of cure from surgery increases more and more the lower the stage goes. So if you can cure a good percentage of people with surgery alone, do you need to expose them to the potential toxicities of neoadjuvant therapy?

DR LOVE: Yeah, that's a great point. All right. Please continue.

DR LIPSON: All right. This next study looked at distant metastasis free survival from a combination of an mRNA vaccine and pembrolizumab. And the schema is as shown here. So patients with resected Stage IIIB through IV cutaneous melanoma were disease free at the time of randomization and were either assigned to receive pembrolizumab + an MRI vaccination or the control arm which was pembrolizumab monotherapy. And the primary endpoint was recurrence free survival with secondary endpoints as you see here, distant metastasis free survival, safety, et cetera. And so, the reason I've got a red box around the statistics, they are designed with 80% power to detect a hazard ratio of 0.5, et cetera, et cetera in a one-sided alpha is because a lot of the debate that went on around this study had to do with the way the stats were designed.

And so I'll show you the curve of the — this is the recurrence free survival curves. So the red is on top, and that's the pembro + the vaccine, and the black is below. That's the pembro control arm. And you see that there's a nice separation between those 2 curves. And there was a reasonable risk in the, in the reduction, but if you look at the statistics to the right, you see that the confidence interval there crosses 1. And what was up for debate at the time that these data were presented and other data similar to this were presented was, did the study in fact meet the statistical criteria that I laid out in the previous slide and were these statistical criteria meaningful? So I don't know that we have an answer to that question yet, but bottom line, the combination of the mRNA vaccine + pembro led to a 44% reduction in the risk of recurrence or death and a 65% reduction in the risk of distant metastasis among this patient population. However, the caveat is because the statistical outcomes were borderline, a larger sample size is needed, further testing is needed. So a Phase III trial is opening soon. So we will know in the next few years whether this technology is beneficial.

DR LOVE: Could you talk a little bit more about exactly how this therapy works? And you said there are other similar therapies. Maybe mention those as well.

DR LIPSON: So the vaccination is a bespoke vaccination which means that with each patient's tumor, the vaccine that is prepared for that patient is based on the genetic makeup of the tumor itself. And so, the idea is that you are showing the body the genetic makeup of the patient's individual tumor and, much like the COVID mRNA vaccination, the body mounts a, in this case, tumor specific presumably antibody and T cell response.

DR LOVE: So yeah, the thing that confused me was the individualization of it. So literally, is it like this cocktail that's based — I know they have like 34 or 36 neoantigens. They come up with an individualized cocktail or? You would think you could come up with one that's, one of the 34 and whatever, but do you know more about how they individualize it?

DR LIPSON: Right. You'd think you could find some commonalities among melanoma generally and just pick something that would sort of be a best fit for 90% of the population or what have you, but the, the bespoke nature of the vaccine is interesting. On one hand, it's really personalized medicine. I guess on the other hand, it, it does mean that there's an extra step involved in manufacturing a therapy for each individual patient.

DR LOVE: And you mentioned other similar agents, like RNA vaccine agents, for example? Is that what you were talking about when you said similar therapies?

DR LIPSON: Well so mRNA vaccination I guess after the COVID era is of great interest and so vaccinations like this are being tested not just in melanoma but also in other skin cancers. So, for example, there are trials being developed in cutaneous squamous cell carcinoma using similar technology, bespoke mRNA-based tumor vaccinations.

DR LOVE: Really interesting. Please continue.

DR LIPSON: Moving on. So as we said at the beginning of the talk here, one of the new immune checkpoint pathways on the block is the pathway comprised of anti-LAG-3 and its ligands. There is 1 FDA approved anti-LAG-3 agent out at the moment but there are others in testing. This is a trial in progress that is a Phase III study that compares fianlimab which is an anti-LAG-3 to, sorry, + cemiplimab which is an anti-PD-1 compared to pembrolizumab, also an anti-PD-1, in patients with resected high-risk melanoma. So this is an adjuvant study looking at anti-LAG-3 + PD-1 compared to unknown PD-1 or PD-1 that is approved for patients with resected melanoma. So an interesting trial in progress. We will see in the coming years whether this combination is, as I said before, has a safety profile that's acceptable and also improves outcomes for patients with resected high-risk disease.

Also in the adjuvant setting, this is a Phase III study of encorafenib + binimetinib. That's a BRAF inhibitor and a MEK inhibitor. And this is being compared to placebo. This patient population is resected Stage IIB and C BRAF V600 mutant melanoma. This study is called COLUMBUS-AD. And so, you can see the randomization here. These are patients with resected IIB or IIC melanoma randomized 1:1 to either receive enco plus bini or matched placebos. And the primary endpoint here is recurrence free survival as is common with many of these adjuvant studies.

So this is an important Phase III study. We want to understand whether BRAF and MEK inhibition can decrease the risk of recurrence, both local and distant, and overall survival versus placebo. If this trial is successful, it could open the door for combination adjuvant targeted therapy for this patient population. We don't have an approved adjuvant therapy for resected Stage II at the moment. We only have an immune based therapy. So many of us prefer to use a targeted combination in resected patients because the risk of long-term toxicity is lower. So this could be a real gamechanger if this study turns out positive. So this is a Phase III trial in progress.

All right, moving on. This is a Phase II study looking at clinical and molecular responses to a drug called tebentafusp. Tebentafusp is a bispecific antibody that was approved not too long ago for patients with metastatic uveal melanoma. So as we know, uveal melanoma is biologically very different than cutaneous melanoma. It does not respond to immune checkpoint agents the same way that cutaneous does. Genetically, the makeup is different. Tumor mutation burden is much lower than cutaneous melanoma. So it's really a different animal despite the fact that it's still melanoma.

So here, we know that tebentafusp improved overall survival in patients with uveal melanoma. One of the investigations that was done on this study was to try to understand whether, for example, reductions in circulating tumor DNA were associated with overall survival in patients with radiographic progression. Why is that important? That's important because in the tebentafusp studies, we see that patients' overall survival is improved even though per RECIST, per the standard imaging criteria, the tumors may be progressing. And so what we're seeing here is a graph demonstrating survival probability in 2 patient populations; 1 is patients whose ctDNA was cleared, and the second on the yellow line is ctDNA was not cleared. And what you can see is that the ctDNA cleared patients were more, more likely to survive. If you look on the left side of the screen, you'll see the historical controls for uveal melanoma. And so, what the results from this study suggest is that tebentafusp improves the 1-year overall survival rate as well as the median overall survival rate when you compare those patients to what we've seen historically for other therapies.

DR LOVE: So just to clarify, you're saying there're patients who have increasing size of their tumors and yet their ctDNA is clear and they have a good prognosis?

DR LIPSON: That's right.

DR LOVE: So is that like a pseudo progression?

DR LIPSON: Yeah, well it's an immune-related response in some way. It's not entirely clear why that is, but this study and others have shown that same thing.

DR LOVE: And do the tumors stay increased or do they eventually come back down?

DR LIPSON: Well ideally, they'll sort of increase and then stabilize. Certainly in patients where it's progressing and continues to progress, at some point it's time to switch therapies. But we're definitely seeing benefit in patients where the tumor progresses and then oftentimes, those patients will see stability, or at least clinically, the patients continue to do well.

DR LOVE: It's interesting how the ctDNA was informative in this situation. Do you find in just melanoma that you see significant numbers of pseudo progression?

DR LIPSON: Not really, not in the same way we do with tebentafusp. We occasionally do see growth before shrinkage or new lesions pop up, but it's really the exception, not the rule.

DR LOVE: And what is the, what are the targets here?

DR LIPSON: Well tebentafusp is a bispecific antibody that draws a T cell on one side of it and the other one is, links to a protein called gp100 which is expressed on a lot of melanomas.

DR LOVE: So this is a CD3 bispecific?

DR LIPSON: Yeah, you got it. CD3 on one side, gp100 on the other. That's right.

DR LOVE: So you get cytokine release?

DR LIPSON: You do, yeah, cytokine release syndrome. Fortunately, the severe toxicities if they're going to happen generally only happen in the first few doses. So once you get beyond about dose number 3, the road is usually pretty smooth. You can treat as an outpatient. You don't need such intense observation.

DR LOVE: Who actually treats uveal melanoma, particularly systemically? Is that mainly in tertiary centers or do community-based oncologists treat it?

DR LIPSON: Well it's certainly something that a lot of tertiary centers do. In talking with community oncs, med oncs around the country, I think more and more it's being used in the community. Like I say, the first 3 doses can be a little bit on the, on the tox, a little bit toxic, but it — I think cytokine release syndrome is actually something docs are pretty familiar with because we see in the, in the CAR Ts for other indications.

DR LOVE: Well there are also a couple bispecifics out there. There's teclistamab in myeloma. Lymphoma has some bispecifics. So also — and they have that same issue of who's going to give it. But you have to have tocilizumab available in order to give it, right?

DR LIPSON: We do, yeah. I would say the majority of cases don't end up needing toci but we, we get away with steroids and some fluids and things. But yeah, you've got to have it on hand.

DR LOVE: Because that's the issue a lot of times with these other bispecifics whether or not the oncologists have access to toci or not.

DR LIPSON: Yeah, for sure.

DR LOVE: Maybe they, maybe as these, maybe as more and more bispecifics come in, it's going to really end up in practice. Because it's the same thing I think with the, myeloma, for example, the first couple doses and then they're fine.

DR LIPSON: Yeah.

DR LOVE: Have you had patients yourself with prolonged responses?

DR LIPSON: Myself? No. And I certainly have colleagues, Rich Carvajal who was one of the lead authors on this study, is certainly seeing that. But myself, no.

DR LOVE: Okay. Please continue.

DR LIPSON: All right. So just to summarize. So here, among 127 patients with previously treated metastatic uveal melanoma, despite this overall response rate that was low, about only 5%, the 1-year overall survival rate was 62% which is much better than historical controls. It also suggests this benefit as we were saying beyond the traditional imaging-based response criteria. And so the exploratory analysis as we discussed, that circulating tumor DNA is associated with better overall survival, that might actually be a better tool to measure what the success of this therapy is rather than repeat MRIs of the patient's liver, for example. So in patients with metastatic uveal melanoma, especially those who have been through several lines of therapy, chemo, liver directed therapy, what have you, this does seem to be a reasonable option. And even in patients where you see progressive disease on imaging, in cases where ctDNA goes down or drops to undetectable, they do seem to benefit. We do need additional studies for validation of some of these data. We also need testing of this therapy in combination with some therapies that might have some synergy, so for example, ipi + nivo which does have a response rate of 10 or so percent in the uveal melanoma patient population. We need combo trials.

All right, moving on. So this is not a trial. This is just a set of guidelines, practice guidelines that a bunch of us were involved in putting together. This is the Society for Immunotherapy of Cancer, or SITC clinical practice guideline on immunotherapy for patients with nonmelanoma skin cancers. And so this goes through in some detail guidelines, expert consensus, multidisciplinary advice about treating patients with basal cell, cutaneous squamous, and Merkel cell carcinoma. So we looked at studies that had been published. We drew on our own experience. We talked about best practices as we see it from the big academic centers that see a lot of these patients. So these are evidence and consensus-based guidelines, recommendations for cancer care professionals in treating patients with nonmelanoma skin cancers. Like any set of guidelines where you've got consensus based on experience, we're always in search of data that will inform our recommendations. And so as those data mature, we will update the guidelines.

DR LOVE: This paper is like epic. It’s got like 27 pages. There's like a ton of stuff there. Can you summarize some of the, you know, and there's a lot of detail there, but from the point of view of oncologists in practice, could you maybe summarize a few of the things, of the conclusions of the therapies that maybe the average oncologist might not be aware of?

DR LIPSON: Sure. So, for example, one of the patient populations that I'm interested in are patients who have had organ transplants. And this is a solid organ transplant. So this is always a question that comes up. These patients are very, very likely to get particularly cutaneous squamous cell carcinoma. And so, what do you do in a patient who has unresectable cutaneous squamous cell carcinoma and has had, for example, a kidney transplant? So in the guidelines, we talk about frank conversations about the risk of rejection of the organ. We talk about the likelihood that the therapy might work. We talk a little bit about what immunosuppression that we think has worked in the past and what's reasonable to try and — before you'd consider immunotherapy. So guidelines for these small patient populations where there's just not a lot in the literature about what to do.

DR LOVE: It's interesting you brought that up in terms of that. What kinds of transplants are you talking about? It seems — and when this topic comes up sort of outside melanoma, people differentiate renal versus everything else. Is that sort of the way you look at it? In other words, are there situations for transplant that are outside of renal where an IO is a consideration? You know, cardiac, hepatic, I'm not sure what else there might be.

DR LIPSON: Yeah, that's a good question. So I think there are, you're right, there are transplants that fall into the life enhancing category and then, the, then there are the transplants where if you lose the transplant, that's it. So the life enhancing would be renal and pancreas. You can replace renal with dialysis. You can replace pancreas with pancreatic enzymes and, and insulin. But the conversation is different as you suggest for sure between those 2 and everything else. I think there are a lot of kidney transplant recipients where they're considering embarking on an immune checkpoint inhibitor course with the knowledge that they may have to go on dialysis or back on dialysis in some cases. And for some patients, that's perfectly acceptable. And then there's the liver and the cardiac and the lung. And we've had conversations that go both ways there. Some organ transplant recipients, liver for example, will come in and say, this cancer is going to take my life and I'm going to go down swinging. I'm not going to go down looking so I'm going to try and if it ends up that we knock out the liver, well, so be it. At least I tried. And then there are other patients that say, I'm not going to do anything that's going to potentially further jeopardize my health. The cancer is eventually going to take my life but whatever time I have left I'm not going to spend it trying to combat acute cardiac rejection or something like that.

DR LOVE: Just out of curiosity, I know it's not related to transplant, but I was just thinking about a case I heard about. What are your thoughts and what do we know about some of the neurologic diseases that patients have and what happens when you give IO? And the one in particular I'm curious about, and I kind of feel like I've asked, I asked you about this in the past, is multiple sclerosis.

DR LIPSON: Right. I guess the question there is, is there a risk of exacerbating some underlying neurological condition whether it's MS or myasthenia gravis or anything else.

DR LOVE: Right.

DR LIPSON: So in general, the answer is yes there is a risk but no, it does not happen to everybody. And so we have pretty detailed conversations with each patient about what does that mean if we were to exacerbate whatever the condition is that somebody has. We also reach out to the patient's neurologist or rheumatologist or what have you to mitigate as best we can right from the get-go. If somebody is on an immunosuppressive therapy that seems to be holding their disease at bay, we generally keep them on that therapy and then add on immune checkpoint inhibitor therapy. We can always peel back the immunosuppressive later on if the therapy isn't working.

DR LOVE: All right. Please continue.

DR LIPSON: All right, moving on. So this is an interesting study. This was a trial called CheckMate 358 that looked at nivo + ipi, nivolumab + ipilimumab in patients with recurrent or metastatic Merkel cell carcinoma. And it, it was not comparative but there was another arm that was nivo by itself. So I'll show you what that schema looks like. Here are the patients that were treated. So remember, as I said, this is a nonrandomized noncomparative study, but on the left side in the green is nivo by itself and on the right side in orange is nivo + ipi. You can see the population is about half, 25 nivos and about 43 nivo + ipis. But if you look at the overall response rates, you see at 60% in the nivo arm and 58.1% in the nivo + ipi arm. And then if you look at the median duration of response in months on the right side of the screen, you see it's 60 in the nivo and 26 in the nivo + ipi.

So why was this important? This is important, this multicenter international Phase I/II study was important because we don't really have a good handle on whether adding ipilimumab to patients with advanced Merkel cell carcinoma is of benefit. There was one study that was out of Moffitt that demonstrated a 100% response rate in patients with Merkel cell who received ipi + nivo. This study did not do that. This study demonstrated that both nivo and nivo and low dose ipi were associated with frequent and durable responses. And as I said before, this was nonrandomized and so you can't really compare between the cohorts but there was not a suggestion of additional efficacy either in response rates or PFS or OS in the combination arm. So, this study does not support the administration of ipi + nivo to patients with advanced Merkel cell carcinoma. This is contradictory to results from other groups that do suggest some benefit with the combination. So for now, anti-PD-1 or anti-PD-L1 monotherapy remains the standard of care. Sometimes we do consider the addition of ipilimumab in patients with MCC that is refractory to anti-PD-1.

DR LOVE: So I know this was a small number of patients and it's an indirect comparison, but do you make anything out of the duration of response difference?

DR LIPSON: Yeah, that's curious. That caught my eye as well. You would expect if anything they would potentially be equivalent there. I don't know if ipi is having a deleterious effect or if just the numbers are too small to sort of make heads or tails.

DR LOVE: Yeah. The numbers really are small, for sure.

DR LIPSON: They are, for sure.

DR LOVE: And it's indirect.

DR LIPSON: Yeah, for sure. And so we need bigger patient, patient populations. The trouble is, this is a rare tumor type, so it's really difficult to amass the hundreds of patients or whatever that you'd really need to do a solid trial like this. As I said before, we do in patients with PD-1 refractory Merkel cell carcinoma add ipi, and in some cases, we actually have seen responses to that.

DR LOVE: Interesting.

DR LIPSON: All right. Moving on, this is a cutaneous squamous cell carcinoma trial, and this was a fascinating study for several reasons. So this is the schema for this study. So this took patients with cutaneous squamous cell carcinoma and it randomized them to 2 arms. The top arm, you can see arm A, that's nivolumab monotherapy. And the arm B in the middle of the screen is combo nivo + low dose ipilimumab. So patients get you can see 2 doses and then they are supposed to go to surgery. But some very interesting things happened along the way. The first is that 10 patients withdrew consent to surgery because the patients themselves noticed that their tumors had regressed after 2 infusions of the immunotherapy. I will say, this is not uncommon. We have had patients on similar trials that have seen their tumors melt away with immunotherapy and have opted not to go to the operating room. We don't really understand whether that is equivalent or not to having a remarkable response to immunotherapy and then going to surgery. There really has not been a comparison. So when a patient says, well if I’ve had this remarkable response to immunotherapy, do I need to go to the OR? We have to say we don’t really know.

So if you look at relapse free survival among the patients here that did go to surgery and then the ones that had the complete clinical response, that’s the CCR patients, what you see on these top bars here, the green, the major pathologic responses and the clinical complete responses, everybody does really, really well. And so it may be that, granted this is a relatively short follow-up, but it may be that if you have a patient with a clinical complete response, you actually don’t need to send them to the operating room. That data by itself might be enough to say that their longer-term relapse free survival rate is going to be excellent and they could spare themselves a trip to the OR.

DR LOVE: I’m just kind of curious who these patients are. Are these tumors generally neglected or are they socioeconomically disadvantaged patients? Who are these people?

DR LIPSON: That’s a great question. Some of the nonmelanoma skin cancers are patients where, you’re right, it’s neglected for a period of time. And by the time it gets to us, it’s gotten into lymph nodes and other local structures. Other patients just have really aggressive biology where despite having gotten on top of things in a timely fashion, before you know it, it’s gotten into other structures or metastasized.

DR LOVE: And any correlation with PD-1 levels or TMB?

DR LIPSON: Good question. So most of the cutaneous squamous cell carcinomas have a very high TMB to start with, so that’s one of the reasons we think that there are such high response rates. In fact, in a study that was published earlier this year, we saw a 51% complete pathologic response rate to cemiplimab monotherapy. And so the squamous cell population, cutaneous squamous cell population in general is just really sensitive to anti-PD-1 probably for that reason.

DR LOVE: When you say high PD — TMB, like how high?

DR LIPSON: Well the numbers are a little bit all over the place, but we certainly see numbers as high as 20, 25, 30, 40 mutations per megabase. So it’s among the highest of the cancers we see.

DR LOVE: Yeah, interesting. Yeah, that’s definitely a little bit higher — I guess MSI-high is a little bit higher. Does that sound right?

DR LIPSON: Yeah. MSI-high is way up there. Non-virus associated Merkel cell is way up there. Basal cell is way up there. Yeah, a lot of the UV damage tumors are pretty high.

So anyway, among 40 patients with locally advanced cutaneous squamous cell. We see major pathologic response rates in 40 to 50% of patients depending on the therapy they received. And as I said, I think the most, one of the most interesting parts about this is that the 9 patients that declined surgery because they themselves noticed the remission tended to do very well longer-term. So this does suggest that, A, neoadjuvant therapy is becoming, if not has become, the standard of care for patients with locally advanced resectable cutaneous squamous cell and, B, that in a setting of substantial tumor regression, it might be that surgical resection is unnecessary. So, again, like everything else in the neoadjuvant space, we need to know what regimen is best, for how long we need to give it. Do you really need to go to surgery? Do you really need adjuvant therapy, especially in the setting of a substantial tumor regression?

All right. So sticking with the cutaneous squamous cell population set, this is a longer-term analysis of the data from a Phase II study of cemiplimab which is anti-PD-1 for patients with advanced cutaneous squamous cell carcinoma. As you can see, the x-axis on this graph here goes out quite far. This is data presented at ESMO in 2022. So what you’re seeing here are 2 populations of patients, the mCSCC is metastatic and the laCSCC is locally advanced. So this is true in most tumors, the locally advanced patients generally do better than the metastatic which is what you see here. The red is the locally advanced. The green and blue are metastatic. But in any case, just generally, the whole population does quite well over this long period of time. I should say, the bottom is measured in months. So what you’re seeing is as far as 5 and almost 6 years out in some cases.

So of 193 patients with advanced cutaneous squamous cell carcinoma with a median duration of almost 16 months, we saw median progression free survival of 22.1 months and then the median OS was not reached. So this is really impressive results for cutaneous squam.

DR LOVE: When you — when these patients die, what do they die of? Do they get metastatic disease?

DR LIPSON: Yeah, some of them do get metastatic disease. So the 2 green and blue curves here, these are patients with metastatic disease. So sometimes, they die of their tumor, as a result of the tumor. Other times, when it’s locally advanced, the patients die of infection or if the tumor erodes a critical structure, for example, into the skull or something like that.

DR LOVE: Interesting.

DR LIPSON: So this study just went on to confirm the efficacy and durability of response of cemiplimab in patients with advanced cutaneous squamous cell. This for sure benefits a large percentage of the patient population, but not everybody. So could other combinations like PD-1 blockade and LAG-3 blockade provide additional benefit to compared to anti-PD-1 alone without increasing the toxicity signal too much?

This is a similar study except in the neoadjuvant space. And I brought this up a couple of, a few slides ago. This is neoadjuvant cemiplimab for patients with Stage II through IV cutaneous squamous cell carcinoma. This was published in the New England Journal back in 2022.

This here is a waterfall plot demonstrating what the best percent change of the target lesions were for each of these patients. And you can see the inflexion point is way over to the left, at the 80% mark or something like that. So this is 79 patients with advanced cutaneous squam. They received neoadjuvant cemiplimab. And what we saw was a complete response or major path response in 64, so almost two-thirds of patients, with an objective response seen on imaging in 68%. So this is quite an impressive waterfall plot for these patients who received neoadjuvant cemiplimab.

So the results were exciting for sure. As I said before, neoadjuvant therapy I think probably has at this point become standard of care for patients with locally advanced resectable cutaneous squamous cell carcinoma. I think we are helping the majority of patients but as I say, not everybody. There are these patients on the left side of this curve here where the tumor grows despite cemiplimab. So will the addition of additional checkpoint agents help to increase the percent of patients that we are helping? We need larger trials to address these questions. The other thing that comes out of this is with such a high path complete response rate, do we need to take all those patients to the operating room? Could we just judge by imaging alone whether somebody could use the cemiplimab as their primary and only therapy?

Moving on, so this is also a cemiplimab trial except this time, it’s in basal cell carcinoma. This is an interesting study looking at health-related quality-of-life in patients with metastatic basal cell carcinoma who were treated with cemiplimab. This was a Phase II study.

So this is an interesting patient population. These patients were either progressed on or intolerant to a hedgehog inhibitor. The response rate in this trial of cemiplimab was only 24.1% so that is awfully low compared to the response rates that we’re seeing in, say, squamous cell where 50 or 60% of our patients are responding. So this is probably lower than many of us anticipated. What the investigators did here is evaluated health-related quality-of-life data using a couple of validated questionnaires. The reassuring part of this was that the baseline scores showed moderate to high levels of functioning and low symptom burden right from the get-go. And as we went on in time, what we saw was that the analyses showed clinically meaningful either improvement or at the very least, maintenance of function and symptoms in 75 or 80 or almost 90% of patients that was maintained for at least 6 months or so.

So what this suggests is that most patients with metastatic basal cell carcinoma that are treated with cemiplimab either maintain or improve their function and global health status and quality-of-life. So cemiplimab does for sure remain a standard of care therapy for patients with metastatic or advanced basal cell carcinoma who have previously received a hedgehog inhibitor or for whom a hedgehog inhibitor is not appropriate. However, these data do beg the question, why are response rates in basal cell carcinoma so low? Why is it only 24% as opposed to 40 or 50 or 60% like we see in other cutaneous tumors. So here at Hopkins, we have an ongoing trial of front-line anti-PD-1. And as we presented at ESMO last year, we’re seeing about a 50% response rate in the untreated setting, the untreated basal cell carcinoma setting. So it may be that anti-PD-1 up-front as opposed to second-line may be beneficial in this patient population. 

DR LOVE: Any trials combining hedgehog inhibitor + PD-1? And what is your experience with hedgehog inhibitors? And do most patients, for example, in this study, about how many of them were progressing and how many came off because of toxicity from the hedgehog inhibitor?

DR LIPSON: Great question. Yeah, there have been studies, they’re small, but there have been studies looking at PD-1 + hedgehog. It did not seem that there was any additive impact there. Yeah, the tox from hedgehog inhibitors is important. A good percentage of the population, I want to say 35 or 40% or something like that, generally comes off of the drugs because of, not because of progression, but because of the toxicities. We see hair loss. We see taste changes. We see muscle cramps. We see weight loss. So it’s — they’re not dangerous, but they really do impact quality-of-life, the toxicities from hedgehogs. So I think the question about could we avoid hedgehog up-front and just go right to anti-PD-1 becomes important, not just in an efficacy sense, but also in a toxicity sense.

DR LOVE: And your point about the response rate is great. But in lung cancer, the response rate is around 20% also and they use that all the time. So maybe you guys get spoiled because you get such great results. And outside of melanoma, they’re not — it’s hard for me, other than MSI-high, it’s hard for me to think of anything that has more than a 20% response rate to IO other than melanoma.

DR LIPSON: Yeah, we’re pretty spoiled in cutaneous onc. We’re used to effectively treating about half of patients. So when something comes in at the 20 or 25% mark, we scratch our heads and wonder why.

DR LOVE: Yeah, the lung people are just excited that they have a few people surviving 5 years. With you guys, it’s all the time.

DR LIPSON: Right. Right, we’re shooting for the fences. Yeah, for sure.

All right. So moving on, this is also a cemiplimab study like some of the trials we had discussed previously except here, this is a trial looking at whether cemiplimab is safe and effective in patients with advanced cutaneous squamous cell carcinoma who also happen to have kidney transplants, kidney transplant recipients. So this is a fascinating study led by Glenn Hanna in Boston. And what he did was he normalized everybody to get the same 2 immunosuppressive drugs to start with and that’s an mTOR inhibitor + prednisone. And the way he dosed the prednisone is as you see on the screen here as a pulse around the time of the dosing of the cemiplimab and then it sort of tapers down to 10 mg. And then he started everybody on cemiplimab at the standard dose, as you can see. And the question was, could you avoid rejection of the allograft and are we going to see antitumor responses with all of this immune suppression on board?

So here are the efficacy measurements. You can see the waterfall plot on the left side of the screen showing about half of the patients that saw their tumor shrink. You can see the swimmer plot in the middle seeing — showing that some of these responses are actually quite durable. And then the spaghetti plot on the right side showing the split between the responders and the non-responders. So when you take this all together, what does this mean?

Well it was a small study. It was only about a dozen patients or so. The good news is they did not see any kidney rejection which is really impressive. So an mTOR + pulsed prednisone does seem to sort of get you where you need to be with regard to preventing rejection of the organ. The other side of the coin, of course, is efficacy. So the overall response rate here is 50%. It’s only 10 patients so it’s a small study, but in any case. As we discussed a few minutes ago, that is approximately what we’re seeing in the general population. So a 50% response rate and no rejection of the allograft is really impressive. And the durability, of course, is as you’d expect. So these patients that are on chronic immunosuppression can still maintain these durable antitumor responses. A caveat, of course, is the small patient population. So an mTOR inhibitor + pulsed prednisone at this point does seem to be the regimen associated with the lowest risk of organ rejection that does not preclude responses to cemiplimab. So when somebody calls me and says I have a kidney transplant patient who needs therapy, this is the regimen that I say, this is what we have the most data about that’s proven efficacious and safe. What does it mean in terms of research? We need larger studies for sure. So this patient population is in dire need. There have only been 2 prospective studies really that have investigated this patient population, one that we led here at Hopkins and then Dr Hanna’s study as I just described. So there is a lot to learn about how to thread this needle to keep the allograft safe and still allow for antitumor immunity.

DR LOVE: What’s the prevalence of people with status post renal transplant in the United States? I guess it’s probably quite a bit.

DR LIPSON: It is, yeah. So if you look at the stats comparing the general population to the transplant, organ transplant set, what you see is for cutaneous squamous cell carcinoma, the solid organ transplant recipients are between 65 and 250 times more likely to wind up with a cutaneous squamous cell carcinoma compared to the general population, so much, much higher. Beyond that, cancer is the third most common cause of death among kidney transplant recipients. So this is a growing patient population. I think back in 2017, there was something like 35,000 solid organ transplants performed in the United States and these patients are living longer and longer on these immunosuppressive agents. And so this is a growing population who are at hugely high risk of getting particularly cutaneous squam, but all cutaneous malignancies, melanoma, Merkel cell cancer, basal cell, they’re at much higher risk than the general population.