Targeting PD-1 in Non-Melanoma Skin Cancers - Episode 3
Shubham Pant, MD:You talked a little bit about checkpoint inhibitors and immunotherapy as a new target; immunotherapy is used for everything. Can you tell us a little bit more about immunotherapy being used in these kinds of cancers?
Michael R. Migden, MD:Right. Let’s talk about cutaneous squamous cell carcinoma first [cSCC]. It has the highest tumor mutational burden of any cancer in the Cancer Genome Atlas, many times higher than melanoma, which is sometimes compared because it has somewhat of a higher tumor mutational burden. But squamous cell carcinoma of the skin is much higher than that.
Shubham Pant, MD:These are really hot tumors.
Michael R. Migden, MD:Well, in terms of tumor mutational burden, which could generate a lot of neoantigens. And in other cancers, the higher tumor mutational burden has been associated with increased response. Then interestingly, basal cell carcinoma has an even higher tumor mutational burden but it’s not part of the Cancer Genome Atlas, so not everybody is aware of that. And the thought is again, that higher mutational tumor burden is associated with better response, so it makes at least squamous cell and perhaps basal cell very good targets. The literature in squamous cell, here at ASCO [the American Society of Clinical Oncology], the releases just today and 2 days ago, are confirming that we’re not only seeing good point estimates of response, but we’re seeing indications of better durability of response.
So referring back to our discussion of standard chemotherapy and epidermal growth factor receptor targeted agents, they typically don’t have as high of response rates. But more importantly, besides the point estimates response, they just don’t have long durations of response, progression-free survival, overall survival. Then what we’re seeing so far in the data with antiPD-1 [anti–programmed cell death protein 1] is that they do have more durable responses.
The other issue about that is the standard chemotherapy and epidermal growth factor receptor agents have tolerability issues, as we know. With the antiPD-1 agents, such as cemiplimab, most patients have better tolerability day by day. Of course, there’s risk for immune-related adverse events, which can be serious or life-threatening. But the day by day tolerability with the majority of patients is good. Most of the reported, more frequent adverse events include some fatigue, maybe some GI [gastrointestinal] complaints, and so on, but nothing severe in most cases.
Shubham Pant, MD:I know you led the study that was presented and published in theNew England Journal of Medicine. Could you tell us a little bit about the study, about the patient population, response rates? The quality of response, and then follow-up from there?
Michael R. Migden, MD:Yes. So we’ll go back to the phase I trial of cemiplimab. This was a dose escalation initial part of the study that was open to patients with multiple solid tumor types. During that dose escalation phase, a patient with advanced cSCC was found to have a durable complete response, and that led to expansion cohorts in the phase I trial that were exclusively for locally advanced and metastatic cSCC. And favorable results from those expansion cohorts led to the development of the pivotal phase II registration trial, of which I was involved and had a leadership role.
Shubham Pant, MD:Can you tell me about if you have any follow-up from that trial and everything you see? Was there durability of these responses like we see with other checkpoint inhibitors or do they stop responding after some time? When did you stop giving the checkpoint inhibitor, was it a 2-year point or do you continue to give them?
Michael R. Migden, MD:The phase II trial is designed to give people treatment for 2 years and then if after 1 year they had a complete response, they had the option of stopping active therapy and going on follow-up.
It’s a very common question to ask now that we have an agent that’s released for commercial use, how long should we keep patients on? And there’s not a known answer to that. I’ve seen people respond rather quickly. We know that the median time to response is 1.9 months, and so the majority of patients respond starting at 2 or 3 months. In the group 2, locally advanced patients, out of the 34 responders shown on a swimmer plot, 7 patients had a more unconventional slower response. So, instead of starting at 2 months, those 20% of responders had responses ranging anywhere between 6 and 10 months and that’s important. Because when people start patients, there might be a temptation to say, “Well, I’ve given the patient a few months and I don’t see anything changing.” But what if they were to be one of those unconventional later responses, say it could happen 20% of the time, you wouldn’t want to take the treatment away without making sure that the patient really won’t respond. And it might take longer to decide if that’s the case.
Shubham Pant, MD:One of the checkpoint inhibitors works well. What about other trials utilizing other checkpoint inhibitors in this space?
Michael R. Migden, MD:In addition to cemiplimab, there’s pembrolizumab trials. There’s the KEYNOTE-629 that has finished enrollment, but there haven’t been data released yet. There’s the CARSKIN study of 39 patients. They did a much earlier 5-week assessment, and the objective response rate was around 38%. And the disease control rate was in the low 50% range. That’s a small study, so it’s hard to compare to a larger multicenter study, and we really don’t know yet. There’s no head-to-head comparisons, but certainly that would be the other agent that is being tried in advanced cSCC.
Shubham Pant, MD:What about patients who did not respond to immunotherapy or had a response but stopped responding, are there resistant mechanisms like with some other trials? There are other checkpoint inhibitors that are in the works. Is there any research going on in that avenue?
Michael R. Migden, MD:Yes, actually combination therapy, as we know from melanoma treatments, will be more prevalent as time goes on, I believe. And there’s already a trial combining cemiplimab antiPD-1 with a LAG3 agent. There’s also a trial of RP1, which is a modified herpes virus oncolytic vaccine in combination with cemiplimab anti–PD-1. The thought there is that these anti–PD-1 agents take the brakes off the immune response, so to speak, that the tumor can put the brakes on so the agent takes the brakes off. But you might think, well, how revved up is the immune response itself? What are you taking the brakes off of? So, if you give an oncolytic virus and it “revs up” the immune response and then you take the brakes off, the hope is that you can get a better response than just having the brakes taken off regardless of how much immune stimulation there is in the tumor.
Shubham Pant, MD:So more like an additive or hopefully synergistic approach to tackling this cancer.
Michael R. Migden, MD:Yes.
Shubham Pant, MD:What about basal cell? You said basal cell had a higher tumor mutational burden than cutaneous squamous cell. What kind of research is going on in basal cell with checkpoint inhibitors?
Michael R. Migden, MD:There is a trial, a phase II trial of cemiplimab with advanced basal carcinoma, both locally advanced and metastatic. The locally advanced cohort has filled, the metastatic cohort is still open. We don’t have results yet. So the fact that the tumor mutation burden is higher in basal carcinoma may or may not make a difference in terms of efficacy. And as has been discussed by some of my colleagues, basal carcinoma has a different tumor architecture than squamous cell carcinoma. There’s a potential that the basilar cells form some sort of barrier, and we know that there are these clefts that can occur around basal cell carcinoma. So whether that plays a role in the response is unknown at this time. But it’s certainly an area that can be investigated further.
Shubham Pant, MD:Very interesting because it may have a higher tumor mutational burden, more antigen load, but it might not be as responsive because of the tumor microenvironment or something going on in the basal cell, which would give it less response.
Michael R. Migden, MD:And this is speculation, but this has been the comments by some of my colleagues who do a lot of the skin oncology research.
Shubham Pant, MD:What about topical agents like topical Hedgehog inhibitors? Any topical inhibitors out there that have been developed?
Michael R. Migden, MD:Well, yes. And actually, there have been agents tried in the past and nothing was approved. The thought was that there were penetration issues. So there is an agent, patidegib, that is a topical 2% gel. It’s been studied previously in the United Kingdom and found to have good efficacy both in reducing the numbers of new lesions as well as the size of new lesions. So we have a phase III trial that’s opening in the United States. Actually it’s open already in the United States, and we are one of the sites and should be opening our site soon.
Transcript edited for clarity.