Citation
Miller DM, Patel VA, Sondak VK, Tchekmedyian V, Merkin RD, Brownell I, Drews RE, Gupta S, Khushalani NI, Nghiem PT, Kaufman HL, Emerick KS. Evolving standards for resected high-risk CSCC: Integrating insights from C-POST and KEYNOTE-630. Journal of Cutaneous Oncology. Published September 3, 2025. doi:10.59449/joco.2025.09.03.
Why this article matters
C-POST delivered the first phase 3 evidence that adjuvant anti–PD-1 therapy can substantially reduce recurrence after surgery and postoperative radiation for patients with high-risk cutaneous squamous cell carcinoma. At the same time, the futility result from KEYNOTE-630 created an unusual and clinically important tension: two trials testing similar strategies in closely related populations produced very different conclusions.
This perspective highlights the major findings, places them in the context of current multidisciplinary practice, and focuses on the questions that remain unresolved rather than attempting to reproduce the full article.
C-POST changes the conversation by establishing a clear disease-free survival benefit for adjuvant cemiplimab. It does not, however, establish that every patient with resected high-risk CSCC should receive postoperative immunotherapy—or resolve whether treatment is best given before surgery, after surgery, or alongside postoperative radiation.
C-POST at a glance
Adjuvant cemiplimab
Compared with 64.1% among patients assigned to placebo.
Hazard ratio
A 68% relative reduction in the hazard of disease recurrence or death.
Adjuvant anti–PD-1 therapy
Treatment followed complete resection and postoperative radiation.
What C-POST establishes
- Adjuvant cemiplimab substantially reduces recurrence risk in a carefully selected, very-high-risk population.
- The benefit extended across major prespecified subgroups.
- Locoregional and distant recurrence were both reduced.
- The safety profile was consistent with prior experience using PD-1 blockade.
- Overall survival remains immature and was not significantly different at the reported analysis.
Why KEYNOTE-630 still matters
The divergent result of KEYNOTE-630 prevents an overly simple conclusion that all adjuvant PD-1 strategies are interchangeable. Differences in eligibility, enrolled risk, trial execution, treatment timing, follow-up, statistical variation, and unmeasured patient characteristics may all have contributed.
Exploratory reconstruction of published survival curves suggested that the placebo populations may have had broadly similar recurrence trajectories, while the active treatment curves appeared to diverge more clearly. These analyses are hypothesis-generating rather than definitive, but they reinforce the need to understand why apparently similar trials produced different outcomes.
The decisions C-POST does not settle
Neoadjuvant or adjuvant therapy?
Preoperative treatment offers biologic and response-assessment advantages, while adjuvant therapy now has phase 3 evidence for patients who reach surgery without prior immunotherapy.
Can radiation be omitted?
Both C-POST arms received postoperative radiation. The study therefore does not establish that adjuvant cemiplimab can replace radiation in otherwise radiation-eligible patients.
Who is being overtreated?
Many placebo-treated patients remained disease free, meaning some patients exposed to a year of systemic therapy would never have recurred without it.
Does delayed treatment preserve survival?
Immature overall survival and frequent use of anti–PD-1 therapy after recurrence leave open whether observation with treatment at relapse may be reasonable for selected patients.
Adjuvant cemiplimab is now a serious evidence-based option—not an automatic default. The most useful question is no longer whether postoperative immunotherapy works, but which patients derive enough absolute benefit to justify treatment when neoadjuvant therapy, radiation, observation, and salvage remain competing strategies.
What clinicians emphasized
- Multidisciplinary teams already vary widely in how they sequence surgery, radiation, and anti–PD-1 therapy.
- Many clinicians remain more enthusiastic about neoadjuvant than adjuvant immunotherapy.
- Toxicity, treatment burden, competing mortality, and patient preference remain central to decision-making.
- Biomarkers such as gene-expression profiling and circulating tumor DNA may eventually improve patient selection.
- Longer follow-up and cancer-specific outcomes will be essential to define the full clinical value of recurrence prevention.
Authors
David M. Miller, Vishal A. Patel, Vernon K. Sondak, Vatche Tchekmedyian, Ross D. Merkin, Isaac Brownell, Reed E. Drews, Sameer Gupta, Nikhil I. Khushalani, Paul T. Nghiem, Howard L. Kaufman, and Kevin S. Emerick.