Resectability Status Drives Treatment Decisions Amid Expanding Immunotherapy Use in CSCC

With anti–PD-1 therapies serving as a new standard of care (SOC) for unresectable or metastatic cutaneous squamous cell carcinoma (CSCC) and an emerging option for resectable disease, determining resectability remains the key initial decision point, according to Neil D. Gross, MD, FACS, who emphasized that careful patient selection, multidisciplinary evaluation, and vigilant toxicity monitoring remain essential during the wait for longer-term survival data.

“It is important that patients are seen in a multidisciplinary fashion to help figure out the right treatment,” Gross said in an interview with OncLive^®. “As a surgeon, I believe strongly that these patients should get a surgical opinion early, because one of the first branch points is to sort out if they are resectable or not. If they are unresectable or metastatic, the [treatment course] is clear: it is now FDA-approved for these patients to receive anti–PD-1 therapy as first-line treatment, and the responses are excellent.”

In addition to discussing how to identify patients who are optimal candidates for immunotherapy, Gross detailed key differences between CSCC and basal cell carcinoma (BCC) in terms of metastatic potential, immune responsiveness, and systemic therapy selection; and spotlighted upcoming research presentations and developments that could shift the treatment paradigm for CSCC.

Gross is a surgeon-scientist and the director of clinical research in the Department of Head and Neck Surgery at The University of Texas MD Anderson Cancer in Houston.

OncLive: How do you frame the key biological and clinical differences between CSCC and BCC?

Gross: Nonmelanoma skin cancers are ubiquitous; if you put them together, they dwarf all other solid tumors combined. The most common nonmelanoma skin cancers are BCCs, which fortunately tend to be more indolent, slower-growing tumors that are far less likely to become metastatic. On the flip side, BCCs are also far less responsive to treatments other than surgery, including radiation and systemic therapies. The SOC for advanced unresectable or metastatic BCC remains hedgehog inhibitors, with immunotherapy serving as a second-line treatment because responses are relatively muted for that disease.

In contrast, CSCC tumors have a propensity for regional lymph node metastasis and distant metastasis. They can also develop significant perineural involvement, sometimes even without significant other disease. These tumors are life-threatening and can be challenging [to treat], particularly in immunosuppressed patients. Fortunately, immunotherapy has become the SOC for patients with unresectable or metastatic CSCC because the responses are remarkable, with [approximately] half of patients having a significant response to treatment.

Which clinical or pathological features most strongly predict nodal involvement and advanced disease?

[Patients with] advanced CSCC can develop nodal metastasis, but there is also a separate group of patients that seems to behave biologically differently. Instead of nodal metastasis, they can have very advanced local disease or significant perineural disease without regional or distant metastasis. This heterogeneous presentation of cancers is one of the reasons there has been a paucity of research in this area, and that’s why it’s not included, for example, in the National Cancer Database or the SEER databases; it has been a blind spot for industry for a long time.

These patients, as common as the disease is, have been relatively underserved, particularly those who present with advanced disease. Why is that? It’s because there are so many skin cancers to start, and only a fraction of those will develop into lymph node metastasis or significant perineural disease.

Predicting which tumors [will develop into lymph node metastasis or significant perineural disease] depends on several factors. Obviously, larger tumors, as well as locally advanced or recurrent tumors, are more likely to become metastatic. The immunosuppressed population is also at very high risk for recurrent disease, metastatic disease, and even dying of the disease. Finally, perineural spread or lymphovascular invasion are significant predictors of both recurrence and metastasis.

How do you identify the best candidates for CSCC immunotherapy and determine the surgical branch points?

It is great that we now have tools that we can apply for these patients with advanced or unresectable disease. There are patients who are borderline resectable, where surgery may be possible, but the functional implication of surgery could leave patients with significant morbidity. You can think of a tumor, for example, encroaching on the eye, where surgery requiring orbital exenteration is life-altering functional loss. We would [also] treat [these patients] with upfront systemic anti–PD-1 therapy to give them a chance to preserve function. If they respond—and we have shown this in the phase 2 setting—then they can preserve function and be cured of disease at the same time.

Patients with resectable CSCC—[such as] a patient with a locally advanced tumor on the scalp, for example, or lymph node metastasis to the parotid or neck—are the vast majority of patients who we see. The SOC for those patients is still upfront surgery. Many of these patients, after surgery, would require radiation if [the disease] is at an advanced stage. Based on new data published [in 2025] from the [phase 3] C-POST trial [NCT03969004], some of these patients would be candidates for adjuvant cemiplimab-rwlc [Libtayo] as well.¹ These would be patients who have extracapsular spread, nerve involvement, or in-transit disease, to name some examples. [Treatment] depends on resectability.

Whether [patients] are resectable upfront is an early branch point. We now have a [phase 3] trial that is open and accruing for patients with advanced resectable CSCC. These patients are eligible for NRG-HN014 [C-PRE; NCT06568172], [which] is National Cancer Institute–sponsored and is a cooperative group trial through NRG.³ It is open broadly in the United States, Canada, and Australia, and it is accruing well. This is to test the neoadjuvant approach vs the SOC, which is upfront surgery.

What are considerations for toxicity management in elderly or immunocompromised patients with CSCC?

In general, anti-PD-1 therapies are well tolerated in patients, even elderly patients, and that has been to the betterment of the community at large. But they are not perfectly safe, and there are patients who can have significant toxicities and even grade 4 or grade 5 deaths with immunotherapy. People have asked me: ‘Why even do a randomized phase 3 trial? Why even test a neoadjuvant approach? We should give neoadjuvant immunotherapy to all patients with advanced CSCC.’ The answer is that we don’t know it is safe.

Not only do we not know if it is safe, we do not know if it is any better than the current SOC in terms of survival. There are toxicities. One potential benefit of a neoadjuvant approach with a short neoadjuvant window is that the exposure is less. We have shown with a neoadjuvant approach that you see responses quickly. On the flip side, some of the toxicities can be delayed, so careful monitoring of any patient who is getting immunotherapy—whether it is neoadjuvant, which is still experimental and in trials, or adjuvant, which is FDA-approved for high-risk patients—is required. In both cases, patients require monitoring.

Which developments will most significantly shift the treatment paradigm over the next few years?

C-POST is the trial that led to the FDA indication for adjuvant cemiplimab [for the treatment of patients with CSCC] based on an interim analysis.³ We will be seeing more mature data from that trial, and everyone will be looking to see how overall survival [OS] looks long-term in that study. [Of note, the study] did not [show] a difference in OS between the treatment arms in that, but perhaps it was early. Also, crossover was allowed in the trial.

We are planning to present the phase 2 data from a single-arm neoadjuvant trial [NCT04154943]; this was the basis for the current randomized trial. The long-term phase 2 data will probably be presented later [in 2026].

There is also a lot of interest in exploring what combination strategies can be applied to these patients safely. We worry about toxicity and tolerance of treatment [in elderly patients], so combining dual-agent immunotherapy, for example, is being explored further to test the safety of this approach. The combination of stereotactic body radiation therapy plus immunotherapy in patients who are borderline unresectable is also something that we hope to see in the future. Finally, the immunosuppressed population is such a high-risk group of patients that is very much underserved, so we hope to see more data for those populations.

References

1. Rischin D, Porceddu S, Day F, et al. Adjuvant cemiplimab or placebo in high-risk cutaneous squamous-cell carcinoma. N Engl J Med. 2025;393(8):774-785. doi:10.1056/NEJMoa2502449
2. Testing the addition of an immunotherapy drug, cemiplimab (REGN2810), plus surgery to the usual surgery alone for treating advanced skin cancer. ClinicalTrials.gov. Updated May 13, 2026. Accessed May 21, 2026. https://clinicaltrials.gov/study/NCT06568172
3. FDA approves cemiplimab-rwlc for adjuvant treatment of cutaneous squamous cell carcinoma. FDA. October 8, 2025. Accessed May 21, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-cemiplimab-rwlc-adjuvant-treatment-cutaneous-squamous-cell-carcinoma