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Treatment Approaches in Non-Melanoma Skin Cancers - Episode 11

Using Other Therapies and the Future of Systemic Therapy for the Treatment of Advanced CSCC

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Drs In, Cohen, and Bakst discuss the use of other therapies for cutaneous squamous cell carcinoma, as well as what they believe is the future of systemic therapy for this disease.

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Glenn J. Hanna, MD: Let’s talk about the unusual scenario or the example where cemiplimab or pembrolizumab develops progression, or there’s a significant autoimmune condition where we don’t feel comfortable administering this medication. We heard about the transplant setting, where that might be a concern given the risk of rejection. There are some other agents before these drugs with activity in this disease, such as cytotoxic and EGFR antibodies. Dr In, how do you think about using some of these other therapies with activities and advanced cutaneous squamous cell?

Gino K. In, MD, MPH: A lot of the data to support these other agents historically comes from regimens that were developed in patients with squamous cell carcinoma in the head and neck who had tumors that weren’t cutaneous—tumors that were located on the mucosal surfaces. Active agents included platinums, taxanes, and antimetabolism drugs. Also, EGFR-targeting agents have also shown some efficacy. There have been retrospective studies to point out their use in this setting and a few phase 2 studies looking atEGFR inhibitors. We know that those treatments have some efficacy, but as it has been mentioned a few times, this is a delicate patient population. And without standard studies or guidelines correcting these things, it becomes a personalized approach, at least in my practice. If it’s a robust patient with high-volume disease that’s very symptomatic, that may be a scenario where I tend to employ a platinum-based regimen. I may be more aggressive for a more frail patient, somebody with more comorbidities. I may consider just using a single-agent EGFRinhibitor. It becomes a personalized approach. There are certainly options available.

Glenn J. Hanna, MD: What’s the future of what might be available in this systemic category building on the PD-1 backbone? I’ll let Dr Cohen comment about 2 areas that are evolving quickly. One is the synergism and potential benefits of combining EGFR and antibody therapy with immunotherapy. There are at least 1 or 2 trials going on that combine PD-1 inhibitors with the monoclonalEGFR inhibitor, cetuximab. The other question becomes where I see a host of trials focusing on adding in local injectable intratumoral stimulant. Some immunostimulatory agent, whether it’s a toll-like receptor or some cytokine cocktail mRNA of active immune stimulants in combination with PD-1 inhibitors. Obviously, skin-type cancers are ripe for that mechanism of delivery to minimize the risk of toxicity but also turn a lukewarm tumor a little hot. Dr Cohen, are there any particular agents or combinations that are of interest to you of late in this space building on the PD-1 backbone?

Ezra Cohen, MD, FRCPSC, FASCO: You touched on the potential for intratumoral injection with these agents. Then there are innate immune agonists being looked at, like receptor agonists. I know of 1 study with TLR9 in combination with anti–PD-1 that’s being looked at in cutaneous squamous cell. There are oncolytic viruses that are being looked at. To be honest, I’m more excited with the second- and third-generation oncolytic viruses that are loading in more than just 1 cytokine. We’ve seen some experience with talimogene laherparepvec, which is an HSV [herpes simplex virus] inactivated virus that delivers GM-CSF.

The next wave of oncolytic viruses may be even more effective as they employ agonists of androgen-presenting cells, different cytokines, and perhaps even some other T-cell stimulators that may induce an even more vigorous immune response. There are CTLA4 antibodies in combination with anti–PD-1 that are being tried in these agents. The last area to think about with moving these agents is not necessarily new mechanisms, but there are studies looking at neoadjuvant approaches using anti PD-1 or even combination immunotherapies with the hope that we may turn patients’ tumors into ones that are more easily resectable. In some patients, we may even treat the neoadjuvant with the hope of sparing potentially morbid local therapies.

Glenn J. Hanna, MD: The third and final case will illustrate those points for you to discuss. I just thought of this last piece, and it’s worth spending a moment on before we finish with the last case. Dr Bakst, immunotherapy in the advanced setting is becoming much more common. A lot of us feel comfortable reaching out to our radiation oncologists to integrate radiation into the approach with checkpoint inhibitors. I want to give you a chance to comment. This patient is on an immunotherapy agent. They have benefited for a fair amount of time. Maybe it’s decided that they need a little boost or some local control, and the medical oncologist isn’t ready to give up on the systemic I/O [immuno-oncology] agent. What do you think about in terms of radiating these patients in complement with I/O?

Richard Bakst, MD: It’s 2-fold. For 1, radiation is a great tool for palliation for complete ulceration, even if they’re all for I/O. We always encourage the medical oncologist, whoever is treating them, to refer them to us. In combination with I/O, we’re comfortable giving concurrent therapy. Obviously in a palliative setting it’s about how long we have to give the radiation. Do we hypofractionate or give a shorter course? We have several clinical trials with combination RT [radiation therapy] and I/O. Less commonly we’ll do it off-trial, but if you poll most of us we feel comfortable giving it concurrently.

Glenn J. Hanna, MD: That’s helpful. I wanted to highlight that point because it isn’t often in our practice, and most of you seem to agree that we integrate that strategy in lieu of switching systemic therapies in some instances where we’re getting long-term benefit.

This transcript has been edited for clarity.

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