Redefining the Standard: Adjuvant and Neoadjuvant Immunotherapy in High-Risk, Advanced CSCC
As immunotherapy continues to transform cancer care, its role in high-risk and advanced cutaneous squamous cell carcinoma (CSCC) is becoming increasingly clear. Historically managed with surgery and radiation, advanced CSCC often recurs despite aggressive local treatment. But with the advent of immune check-point inhibitors and clinical trial data supporting both adjuvant and neoadjuvant approaches, the paradigm is shifting. Dermatologists are now key players in identifying candidates and helping guide and coordinate care. In this in-depth discussion, Dr Vishal A. Patel outlines how cemiplimab is addressing long-standing clinical gaps, why disease-free survival (DFS) is the right endpoint for this patient population, and what future innovations could further improve outcomes. For dermatologists, the implications are direct: Understanding, initiating, and even potentially administering immunotherapy may soon be central to the management of high-risk and advanced CSCC.
The Dermatologist: What specific clinical gap or unmet need in managing high-risk and advanced CSCC prompted your investigation into adjuvant cemiplimab after surgery and radiation?
Dr Patel: For decades, surgery plus radiation has been the default for high-risk or advanced CSCC. That approach was based largely on expert consensus rather than randomized data, and outcomes were variable. We have long suspected that some patients derive limited benefit from radiation, yet which specific cases may benefit most remained unclear. Until recently there was no way to improve upon the variable impact of adjuvant radiation, and chemotherapy was shown to not improve outcomes in a robust randomized clinical trial in Australia (TROG 05.01 trial).
When those local modalities were exhausted, we had limited effective systemic options. Chemotherapy was nonspecific and largely unreliable for durable responses. The introduction of immunotherapy changed everything. It was truly game changing, not only because we suddenly had a therapy that worked, but because it illuminated the biology of CSCC as a high mutational burden and immune-driven tumor. We see this most clearly in transplant patients who lose immune surveillance and then develop multiple, very aggressive CSCCs.
With the approval of cemiplimab and later pembrolizumab for unresectable disease, the next logical step was to investigate their role earlier in the disease course. Could we improve cure rates by integrating immunotherapy into curative-intent treatment? That was the fundamental question that launched the C-POST trial of adjuvant cemiplimab.
Another key gap, especially for dermatologists, is that we often suspect tumors to be high risk, but do not recognize how high risk a tumor truly is until after surgery. A lesion that appears resectable and straightforward can be upstaged to very high risk once pathology reveals deep bone invasion, extensive perineural or lympho-vascular spread, or even in-transit metastasis. Even for tumors with nodal involvement, sometimes the extent of nodal disease is not fully understood until after lymph node dissection. By then, radiation was the only option to help prevent recurrence but did so at unreliable rates. Adjuvant systemic therapy could offer more to address that residual risk.
Our thinking was also informed by the melanoma model. For almost 2 decades, melanoma has been managed with resection, nodal staging, and then adjuvant therapy (first targeted agents, then immunotherapy). CSCC shares melanoma’s immunogenicity and high mutational burden, so it was natural to ask whether a similar approach could yield benefit.
When we launched C-POST, enrollment was challenging. These were some of the highest-risk patients we see, and practice patterns varied globally. For example, radiation is far more common in Australia and far less common in parts of Europe. Still, the need was obvious: We needed something beyond surgery and radiation to reduce recurrence risk.
While C-POST was enrolling, other trials exploring immunotherapy in unresectable or borderline-resectable CSCC emerged and enrolled rapidly. Investigators were seeing dramatic tumor shrinkage, sometimes converting previously inoperable lesions to operable ones, or even avoiding surgery entirely. That observation drove us to explore immunotherapy before surgery as well, while we were still trying to answer if immunotherapy after surgery could be helpful.
The Dermatologist: What did we learn from those neoadjuvant trials, and how have they influenced current practice?
Dr Patel: While we were investigating C-POST, we also investigated neoadjuvant immunotherapy, specifically in high-risk, advanced CSCCs that had not yet been resected, but could be. We had these 2 trials running in parallel, with the adjuvant trial starting first because it addressed the primary clinical gap and the neoadjuvant one enrolling quickly and giving remarkable results to consider. In the main phase 2 trial, the pathologic complete-response rate was about 50%, whereas the major pathologic response (≤10 percent viable tumor) occurred in approximately 63% of patients after only 4 cycles of cemiplimab, with some responding after only 2. Other neoadjuvant studies have shown major pathologic response rates around 64% to 75% in cemiplimab cohorts, underscoring how reproducible these responses are.
We followed these patients for almost 3 years and saw that roughly 90% of those who achieved a major or complete pathologic response remained recurrence free, even without subsequent adjuvant therapy. Those findings truly changed the landscape.
Neoadjuvant immunotherapy is now adopted in many centers, including ours, for tumors that are large, difficult to resect, or borderline operable. It is not yet guideline mandated per se but suggested for borderline resectable tumors. The enthusiasm for this approach is strong because the outcomes are compelling and durable. For some patients, the tumor shrinks enough to allow less-morbid surgery; in others, pathologic clearance raises the question of whether surgery is even necessary at all.
What is equally important is how these results redefine timing and coordination. We now must think carefully about sequencing systemic and local therapy and about how dermatologists fit into that workflow, from identifying appropriate cases to assisting with post-immunotherapy surgical assessment, sometimes via Mohs evaluation of residual disease.
The Dermatologist: How did the adjuvant findings from C-POST build upon the neoadjuvant experience?
Dr Patel: Eventually, the adjuvant C-POST trial caught up and addressed a different but complementary question: Can we improve outcomes after definitive surgery and radiation in those with the highest-risk features? And the results were exceptionally strong. In patients who received surgery and radiation, adding adjuvant cemiplimab vs placebo produced a 68% reduction in the risk of recurrence or death, which corresponds to a hazard ratio of 0.32. This is one of the best hazard ratios we have ever seen for an adjuvant immunotherapy trial in any solid tumor.
And it raised the question: Is neoadjuvant or adjuvant better? My interpretation is not whether one is better than the other, but rather that we have clearly pivoted to recognizing skin cancer as an immunotherapy-treated disease, and dermatologists can help guide patients to optimal care. This applies to the full spectrum of high-risk tumors that dermatologists manage. Historically, these patients would be referred to head and neck surgeons or academic centers. Now, dermatologists may be able to identify candidates for neoadjuvant therapy or suggest adjuvant therapy to patients who have already undergone surgery and radiation by an outside provider. Dermatologists can coordinate with local oncologists and even help surgically evaluate residual tumor to determine response. If a Mohs surgeon encounters a patient with a very high-risk tumor with positive deep margins into bone or extensive perineural invasion after undergoing surgery, we now have evidence that immunotherapy could be added to prevent recurrence.
Together, the adjuvant and neoadjuvant data demonstrate that immunotherapy is not just an option for metastatic disease, it is now part of the conversation for curative-intent treatment in selected patients.
The Dermatologist: What were some of the biggest challenges in identifying and enrolling truly high-risk patients for C-POST?
Dr Patel: To answer the question of whether adjuvant cemiplimab could help, we needed to start with the highest-risk patients and C-POST was designed to focus on those most likely to recur. These specific high-risk features included patients with multiple involved lymph nodes (greater than 3), a large node with extracapsular extension, deeply invasive T4 tumors, in-transit metastases, large-caliber clinical or radiographic perineural invasion producing neurologic symptoms such as facial droop or numbness, and recurrent tumors with multiple high-risk features. These are not typical high-risk cases as we think of in dermatology; they represent the extreme end of the spectrum. It is important to understand that distinction, because we do not recommend adjuvant therapy for all high-risk CSCC.
The trial criteria were developed in collaboration with other investigators and the sponsor, drawing on lessons from the TROG trial in Australia, which compared chemoradiation with radiation alone. While that study did not show a clear benefit for chemotherapy, it did identify the features predicting poor outcomes, which helped us refine our inclusion parameters.
Timing was also critical. We mandated a narrow window between surgery, completion of radiation, and initiation of systemic therapy to avoid confounding by early recurrence. These tumors can relapse within months, so any delay could blunt the apparent benefit.
That detail may explain why the KEYNOTE-630 trial with adjuvant pembrolizumab did not meet its primary endpoint and was discontinued for futility at interim analysis. It allowed patients with lower-risk features and a longer post-radiation interval of up to several months, which likely diluted the effect. Still, exploratory analyses of KEYNOTE-630 hinted at fewer local and distant recurrences among higher-risk subsets.
My takeaway is that the C-POST trial clearly defined who benefits from adjuvant immunotherapy. The KEYNOTE-630 data support this in high-risk subgroups, even if the trial overall did not meet its endpoint. The message is: Not all high-risk tumors qualify. If you are going to use radiation and immunotherapy, you need to do both early and in the right high-risk patients.
The Dermatologist: Can you walk us through your rationale for selecting DFS as the primary endpoint, and how you expect this outcome to influence treatment decisions in dermatologic oncology?
Dr Patel: Unlike endpoints focused on skin clearance or recurrence in low-risk skin cancers, DFS captures both recurrence and the duration of survival without disease. This is especially relevant in CSCC, where patients tend to be older and have comorbidities that may affect overall survival. DFS tells us how well we are controlling the cancer itself and how long patients remain functional and free of recurrence.
High-risk recurrences can be locally destructive, painful, and disfiguring. Preventing those events has profound quality-of-life implications, even if the patient ultimately dies of another cause. So DFS reflects a clinically meaningful measure of benefit. Longer-term follow up will of course clarify overall-survival impact, but even now, the DFS data give dermatologists a powerful argument for considering systemic therapy in the right setting. This is also especially important in a disease like CSCC that disproportionately impacts older patients where the goal may not be overall survival from their tumor, but DFS and improved quality of life during their remaining years.
The Dermatologist: How do you foresee adjuvant cemiplimab altering the current standard of care for dermatologists treating high-risk and advanced CSCC in collaboration with multidisciplinary teams?
Dr Patel: I think it is going to have a substantial impact. Many of these patients do not present with a single tumor; they have field cancerization, chronic UV damage, and will likely continue to develop new primaries. They rely on dermatologists for long-term surveillance, which makes us central to their ongoing care.
In some cases, a patient may complete surgery and radiation and return for follow up with their dermatologist, and systemic therapy was never discussed. If the tumor had nodal involvement, extracapsular extension, or symptomatic perineural invasion, that patient may benefit significantly from adjuvant immunotherapy. This is where dermatologists can re-engage and advocate for the patient.
Dermatologists often serve as the central figure in long-term care. Patients may trust their dermatologist more than anyone else and look to them for guidance. If a patient comes back and no one has discussed immunotherapy, the dermatologist should say, “You had a high-risk tumor. There is new evidence suggesting you could benefit from immunotherapy.” This conversation may ultimately be lifesaving.
Of course, dermatologists will continue managing low-risk tumors. But this is a major intervention for preventing recurrence and improving survival in patients with advanced disease, and one we should at least be aware of.
The Dermatologist: Based on what you have learned so far, what areas of future research do you think are most promising for improving outcomes in this patient population?
Dr Patel: Neoadjuvant therapy remains the most exciting frontier, and it has really changed the landscape. It is now being adopted globally. The responses we have seen are dramatic and durable, and they are reshaping surgical planning. We are considering neoadjuvant immunotherapy for tumors that previously required extensive surgery and radiation. If the tumor shrinks enough, we may avoid surgery altogether or perform a much smaller, more manageable operation. If it does not respond, we can still proceed with resection and follow up with systemic therapy. It is a flexible, patient-tailored, treatment-response approach.
Another promising direction is intralesional immunotherapy, where agents are injected directly into the tumor to minimize systemic toxicity. This could be especially valuable for tumors in cosmetically sensitive locations, patients with multiple lesions, those who are poor surgical candidates, or those who are contra-indicated for systemic immunotherapy.
Dermatologists are already experts in this type of procedure, so this modality aligns perfectly with our existing skill set. This is particularly important as we treat an aging population with increasing tumor burden. Surgery remains the gold standard, but it may not make sense for every patient. Expanding our therapeutic arsenal is critical for frontline dermatologists.
We are also studying shorter treatment durations, lower dosing schedules, and combination approaches, including tumor-specific vaccines, topical immune modulators, and novel checkpoint combinations. The broader goal is to personalize therapy, manage toxicity, and eventually address field cancerization by preventing new lesions before they appear.
Ultimately, we are shifting from the purely reactive approach of treating tumors as they arise to a proactive, preventive strategy that maintains immune surveillance across chronically sun-damaged skin and field cancerization control.
The Dermatologist: Is there anything else you would like to share with your colleagues?
Dr Patel: Over the past decade, some questioned whether dermatologists really needed to understand systemic immunotherapy. I think that debate is over. As these therapies move earlier into the disease spectrum, dermatologists must be fluent in identifying appropriate candidates, initiating referrals, and managing adverse events.
We already manage the majority of skin cancer cases; we are experts in injectable and cutaneous treatments; and we are comfortable monitoring skin toxicities, which are the most common immune-related events. As intralesional formulations and localized immunotherapies become available, our role will only expand.
The future of dermatologic oncology is immunotherapy driven. Dermatologists should lead the discussion, not just as referring physicians but as core members of the treatment team guiding patients through increasingly complex, multidisciplinary care. This is where we can have the greatest impact.
Disclosure: The author has been a consultant or paid advisory board member for Regeneron, Sun Pharma, Almirall, Biofrontera, Verrica, Replimune, and Palvella.
