What’s New in Clinical Trials for Cutaneous Squamous Cell Carcinoma?

Q&A with Dr. Neil D. Gross, MD, FACS

Dr. Neil D. Gross, M.D., FACS, is a professor, scientist, and surgeon in the Department of Head and Neck Surgery at MD Anderson Cancer Center in Houston. He treats patients with head and neck cancers and has an interest in cutaneous squamous cell carcinoma with a focus on surgery-related clinical trials. Dr. Gross completed his B.A. at Washington University in St. Louis and his M.D. at the Oregon Health and Science University in Portland. His post-graduate training includes clinical and research fellowships at Mount Sinai in New York City and Memorial Sloan-Kettering Cancer Center, also in New York City. He has published important foundational research in The New England Journal of Medicine and Lancet Oncology. He recently co-authored a paper appearing in the April 2025 publication of the journal Cancer Discovery titled, “Depletion of effector regulatory T cells associates with major response to induction dual immune checkpoint blockade” that described a Phase 2 clinical trial (NCT03799445) using Ipilimumab (Yervoy) and nivolumab (Opdivo).

AIM at Skin Cancer recently spoke to Dr. Gross about current clinical trials in cutaneous squamous cell skin cancer.

Is nonmelanoma skin cancer common in the U.S.?

To give some context, nonmelanoma skin cancers dwarf every other cancer–they are incredibly common. If you add all other solid tumors together, they don’t equal the number of skin cancers diagnosed each year. Non-melanoma skin cancers in the U.S. are so common they are not tracked in registries. It’s not feasible.

In addition, it’s not uncommon for some patients to have 10 to 100 different skin cancers in their lifetime. Some patients come into the clinic every month—the number of tumors can be overwhelming.

What do you find to be most challenging in treating nonmelanoma skin cancer?

As a head and neck surgeon, I see and treat patients with cancers of the head and neck, and 80% of skin cancers develop in this area because it gets so much sun exposure. I see and treat patients who have their cancers come back. These cancers have spread to lymph nodes and are more advanced. They’re more aggressive cancers.

These can be really challenging cases, and these patients can suffer a lot, especially if they have a tumor close to their eyes, ears, or mouth. It’s very hard to sort out which patients will end up with a severe form of cutaneous squamous cell carcinoma, that threatens function or might have cosmetic changes. It’s been a passion of mine for a long time to develop better options for these patients.

Unfortunately, these patients have had almost nothing in terms of drug therapies for a long time. There has been a lack of data, and therefore, very little change in the treatment strategy for this disease over decades.

How do clinical trials for nonmelanoma skin cancer compare to other cancers?

The clinical trial space is very limited. In short, there have been very few trials for patients with nonmelanoma skin cancer. If we look specifically at cutaneous squamous cell cancer, there’s only been one published randomized phase 3 clinical trial ever for that disease, period. Only one, and it was negative. This means that a negative clinical trial offers nothing new to change standard treatments.

If we look at basal cell cancer, the most common nonmelanoma skin cancer, the data are equally sparse. For example, drug approval for hedgehog inhibitor drug therapy was based on a non-randomized single-arm study of only 33 patients. That study was published in the New England Journal of Medicine over a decade ago! That fact proves there is a huge discrepancy for an extremely common cancer and its lack of clinical trials testing out new treatment ideas.

Is there positive news on the horizon?

Yes, the lack of clinical trials is changing. A lot of movement is going on and a lot is in development or coming soon.

Immunotherapy is now a cornerstone of treatment in melanoma and it also works really well for cutaneous squamous cell carcinoma. Not as much for basal cell cancer, although there is an FDA approval for patients with recurrent, unresectable basal cell cancer that has failed a hedgehog inhibitor.

What’s exciting is the earlier application of immunotherapy to nonmelanoma skin cancers. There is a lot of research on the horizon testing a variety of novel immunotherapy combinations for cutaneous squamous cell carcinoma, particularly before surgery or even an intertumoral injection of immunotherapy for really early disease.

What is your interest related to clinical trials?

My interest has been treating aggressive cutaneous squamous cell carcinomas of the head and neck. My research tests giving single-agent immunotherapy before surgery for those patients. So far, it’s shown a lot of promise. That’s led to what will soon become the fourth randomized clinical trial for cutaneous squamous cell carcinoma. It is a Phase 3 randomized trial, which is now open and started enrolling within the last few months of winter/spring 2025.

What can you tell us about this new clinical trial?

It is an FDA registrational-intent randomized Phase 3 clinical trial (NCT03565783) that is hoped to change the standard of care for patients diagnosed with Stage II-IV (recurrent, metastatic, or high-risk) cutaneous squamous cell carcinoma.

The current standard of care for these patients is upfront surgery. We are testing whether or not giving immunotherapy prior to surgery improves survival. For most patients with advanced disease, they will then get radiation after surgery. So, the current standard is surgery and radiation.

In this trial, all patients will receive surgery. After surgery, some will receive radiation. Since it is a randomized trial, the patients who enroll will be equally split into one of two arms. Some will receive the first arm, the standard of care treatment—surgery and radiation.

The second arm is the experimental arm of the trial. The experimental portion will give immunotherapy before the surgery. This group of patients will get up to four doses of anti-PD-1 therapy. The therapy is cemiplimab. They will be given two doses, and then they will be checked.

If they’re responding and not having toxicity, they can get up to four doses of immunotherapy. In this case, a patient could have four doses, and then go to surgery.

Is there anything different about the timing or the extent of surgery?

Yes—the surgery can be tailored to the response. And that’s important because a lot of these tumors just melt away. We expect roughly two-thirds of patient will have a dramatic response. It’s amazing the number of patients that have responded. They responded so much that it allows for a much less invasive surgery.

This is important because when we did the Phase 2 part of the trial, some patients who, for example, have a tumor very near their eye, might have lost that eye without having received immunotherapy before their surgery. Because of their response to immunotherapy (the shrinking of the tumor) in the Phase 2 part of the trial, these patients were able to keep their eyes.

In the experimental arm, the surgery is tailored to the treatment. They have four doses of treatment, a tailored surgery, and that might be it. Depending on the patient’s response to immunotherapy, they may be done with treatment altogether. We anticipate that half of the patients will have no evidence of cancer left behind—they will be done with treatment.

But not everyone responds the same way. Patients who still have some evidence of cancer left or didn’t respond; they may still need radiation or even adjuvant (meaning post-surgery) cemiplimab. The trial is designed to determine which approach is better for survival.

There’s also a huge opportunity to decrease the toxicity of treatment for patients with advanced cutaneous squamous cell carcinoma. The side effects from surgery and radiation can be substantial. We want to improve the quality of life with this approach, too. To do this, we are measuring quality of life outcomes using questionnaires.

What is the timeframe between treating a patient with immunotherapy and then seeing a tumor “melt away” as you said?

The responses are pretty quick. Usually, you’ll hear from patients or see the decrease within a couple of doses. Since the medicine is given intravenously every three weeks, by the time people are ready for their third dose, there’s usually been response. We’ve seen the tumor shrink in many cases, sometimes a lot. By the end of fourth dose, it’s maxed out.

At surgery, we remove what’s left. After you remove whatever’s left, you test it. Ideally, there’s no cancer under the microscope.

What makes you excited about what you are seeing currently?

I’m enthusiastic about the trial running right now. I’m excited about anything that improves the standard of care for these patients, again, because there have been so few advancements.

I’m also interested to see how treatments shift to earlier stages of disease. This would parallel what has already been done, or is being done, in melanoma. With melanoma, immunotherapy started with advanced, incurable cases of the disease for which there was nothing else to give. And now? Immunotherapy is being given as a neoadjuvant (before surgery) treatment.

For even earlier stage nonmelanoma skin cancers, I think there is a promising opportunity for intratumoral therapy. Instead of patients getting surgery, patients get an intratumoral shot—a shot directly in their tumor rather an infusion. There are trials for early-stage disease testing, which I think is really exciting.

In conclusion—any last thoughts you want to share?

I think we are in a really exciting time in cancer medicine.

We’re at the early part of a big change in how we treat cancers broadly. We are becoming smarter about delivering treatments, particularly before surgery. We are trying to make surgery better and figure out when we can eliminate surgery. We are also trying to reduce the use of radiation for select patients who need it and eliminate it for those who don’t. We are seeing glimpses of major changes.