Before, After, or Both? Rethinking the Timing of Immunotherapy in Cutaneous Squamous Cell Carcinoma

As head and neck surgeons, for advanced skin cancer, we have long used the resection/reconstruction followed by radiation paradigm. But immunotherapy is challenging us to rethink the sequence of care. The central question in managing high-risk cutaneous squamous cell carcinoma (cSCC) today is not just the resectability of the disease, but also the timing of surgery in the overall management plan.

Checkpoint inhibitors have revolutionized the management of advanced skin cancers. Their success in metastatic cSCC has prompted exploration in earlier settings, in operable locally advanced cases. But do we administer immunotherapy before surgery (neoadjuvant), after surgery (adjuvant), or both?

Adjuvant Immunotherapy: A Proven Path?

The cPOST trial, a randomized phase III study, recently demonstrated that adjuvant cemiplimab, given for 1 year after surgery, significantly improves disease-free survival in patients with high-risk resected cSCC¹. This reinforces a sequence of surgery followed by RT and systemic therapy and has solidified the role of adjuvant immunotherapy in our guidelines.

But questions remain:

• How many patients truly need a full year of treatment?
• What if the disease had already responded completely to prior therapy?

These are not theoretical concerns—especially as neoadjuvant data continue to evolve.

Neoadjuvant Immunotherapy: Less is more?

Multiple phase II trials have reported pathologic complete response (pCR) rates of ~50% with just 2–4 doses of preoperative anti–PD-1 therapy.

• In a pilot study (Ferrarotto et al.), 55% of patients achieved pCR, and another 20% had major pathologic response (MPR) after two cycles of cemiplimab². None of the responders recurred at 3.5 years.
• In the Gross et al. multicenter trial, 79 patients with Stage II–IV cSCC received up to four cycles of neoadjuvant cemiplimab³. The pCR rate was 51%, and none of those with pCR recurred at a median follow-up of 1.5 years. Many avoided adjuvant radiation altogether.

This raises the possibility of response-adaptive treatment: patients with robust responses might forgo adjuvant therapy and even extensive surgery.

Biologically, it makes sense. cSCCs are typically UV-induced tumors with high mutational burden, providing abundant neoantigens. Leaving the tumor in place during initial immunotherapy acts like an in-situ vaccination, allowing the immune system to be primed more effectively.

Professional Guidelines Are Evolving

The National Comprehensive Cancer Network (NCCN) now supports consideration of neoadjuvant immunotherapy in locally advanced or very high-risk cSCC, such as T3, T4, N+ tumors or in-transit metastases. This reflects a growing consensus that neoadjuvant IO can not only downstage tumors, but also potentially transform long-term outcomes and enable organ preservation.

What About Both? Neoadjuvant + Adjuvant

In the Gross et al. trial, adjuvant treatment was investigator-dependent: some patients received cemiplimab, some radiation, and others observation³. While combining neoadjuvant and adjuvant immunotherapy theoretically maximizes immune surveillance, we must ask whether it’s necessary for all.

Recent experiences in melanoma (e.g., SWOG S1801, NADINA) suggest early delivery of IO (before surgery) may be more effective than the same agent delivered adjuvantly^{4, 5}. That logic may also apply to cSCC—but we need randomized trials to confirm, which will be challenging to justify.

De-Escalation: A New Goal in Skin Cancer?

One of the most exciting frontiers is whether surgery or radiation can be omitted altogether in select patients who achieve a clinical complete response after neoadjuvant IO.

• In the DE-SQUAMATE trial, presented at ASCO 2024, patients achieving PET-based clinical complete response + negative biopsy mapping were able to avoid surgery and radiation⁶. None recurred at 6-month follow-up.
• The NEO-CESQ and MATISSE trials also exploring/explored the selective omission of surgery or radiation in patients with strong neoadjuvant responses (no final publication available for either)^{7, 8}.

This shift—toward organ preservation and immunologic cure—is unprecedented in cSCC, where until recently, disfiguring or morbid surgery was the only curative path.

Cautions and Considerations

We must remain cautious. Cure rates for early-stage cSCC with surgery alone are high, and immune-related adverse events (e.g., pneumonitis, colitis, endocrinopathies) are nontrivial, with ~10% experiencing grade ≥3 toxicity.

For smaller, localized tumors, neoadjuvant IO may introduce unnecessary complexity. But for T3/T4 or borderline resectable lesions, neoadjuvant therapy may convert unresectable cases into curative ones, while also reducing surgical morbidity.

Conclusion: Timing Is the New Terrain

In the management of cSCC, the timing of immunotherapy is no longer a matter of academic debate—it’s a rapidly evolving clinical question.

• Adjuvant IO is supported by phase III evidence and is becoming the new standard.
• Neoadjuvant IO offers transformative potential for tumor regression, margin optimization, and biologic insight.
• Combined and de-escalation strategies are under active investigation and may soon redefine our approach.

As surgeons, we are no longer just masters of margins and flaps—we’re now partners in immunologic decision-making. The timing of therapy is becoming as important as the therapy itself.

And as more trials mature, we may soon find ourselves selecting not only how much to resect, but when to stop.

References:

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