The treatment algorithm for cutaneous squamous cell carcinoma (CSCC) has shifted markedly over the past year, from a positive phase 3 adjuvant trial to an expanding neoadjuvant paradigm that is changing when and how surgery is used, according to faculty who participated in a recent OncLive® Scientific Interchange and Workshop held during the 2026 ASCO Annual Meeting (ASCO 2026).1
"I think it's pretty impressive how this field has changed," Adil I. Daud, MBBS, the co-director of the Melanoma Center and director of melanoma clinical research at UCSF Medical Center in San Francisco, California, said during the workshop. “[In terms of our] surgical colleagues and dermatologists, I feel there's been a major change in their impression. Over the last couple of years, I think it’s the most I've treated anybody. It's been pretty impressive.”
Moderated by Soo Park, MD, an associate professor in the Division of Hematology-Oncology and a hematologist and medical oncologist in the Cutaneous Oncology Program at the University of California San Diego Moores Cancer Center, the multidisciplinary panel worked through the current guideline landscape, high-risk definitions, and emerging biomarker data across the adjuvant, neoadjuvant, and advanced-disease settings.
Top Takeaways From an OncLive Workshop on Evolving Decision-Making in CSCC
- Neoadjuvant immunotherapy is reshaping surgical decision-making, allowing surgery to be deferred, de-escalated, or in some cases omitted in patients who achieve a pathologic or clinical complete response.
- Adjuvant cemiplimab cut the risk of recurrence or death by 68% vs placebo in high-risk resected CSCC in C-POST (HR, 0.32; 95% CI, 0.20-0.51; P < .001), while adjuvant pembrolizumab missed its primary end point of RFS in KEYNOTE-630 and the trial was stopped for futility.
- Cosibelimab produced ORRs of 50% in metastatic and 54.8% in locally advanced CSCC with a favorable toxicity profile, offering a PD-L1-directed option alongside PD-1 inhibitors.
Does C-POST support adjuvant cemiplimab as a new standard in high-risk CSCC?
The faculty first acknowledged that no single, universally accepted staging or high-risk definition exists for CSCC. NCCN, EADO, AJCC, and Brigham and Women's Hospital criteria each capture different features, and none account for nodal or distant disease.
Against that backdrop, the phase 3 C-POST trial (NCT03969004) randomly assigned 415 patients with high-risk resected CSCC to adjuvant cemiplimab-rwlc (Libtayo; n = 209) or placebo (n = 206). Data from C-POST demonstrated that cemiplimab reduced the risk of recurrence or death by 68% vs placebo (HR, 0.32; 95% CI, 0.20-0.51; P < .001).2
In contrast, in the phase 3 KEYNOTE-630 trial (NCT03833167), adjuvant pembrolizumab (Keytruda) produced a relapse-free survival HR of 0.76 compared with placebo (95% CI, 0.53-1.10; P = .07) and was stopped for futility, a result faculty attributed to trial design and a lower-risk population rather than inferior drug activity.3 “This is a population that is lost in being able to see us because a lot of these patients are actually seen by dermatology and then sometimes just get recurring Mohs [surgery]. Most surgeons and dermatologists don't necessarily know these data and then [patients] see us a little too late,” Park noted.
How is neoadjuvant immunotherapy changing the role of surgery in CSCC?
John Haanen, MD, PhD, the head of the Division of Medical Oncology at the Netherlands Cancer Institute/Antoni van Leeuwenhoek in the Netherlands summarized the field's direction by noting that investigators are moving away from surgery and radiotherapy and towards curative treatment.
In a phase 2 trial (NCT04154943) of neoadjuvant cemiplimab in patients with stage II to IV CSCC (n = 79), 40 patients achieved a pathologic complete response and the 24-month event-free survival rate reached 92% (95% CI, 78%-97%) in that group vs 64% (95% CI, 35%-83%) among non-responders/not evaluable patients (n = 22).⁴ The phase 2 De-Squamate trial (NCT05025813) evaluated neoadjuvant pembrolizumab to guide de-escalation, with 63% of patients (n = 27) achieving a clinical or pathologic complete/major response and no recurrences at 18-month median follow-up among responders.⁵
The phase 2 MATISSE trial (NCT04620200) is testing neoadjuvant nivolumab (Opdivo) with or without ipilimumab (Yervoy), and the phase 3 NRG-HN014 trial (NCT06568172) is comparing neoadjuvant cemiplimab against standard surgery, though faculty reported enrollment challenges given how effective neoadjuvant cemiplimab appears in practice.6 Faculty described neoadjuvant therapy as preferred over up-front surgery for T3, nodal, or in-transit disease, or tumors in functionally sensitive sites.
What emerging agents and biomarkers are on the horizon in advanced CSCC?
In the phase 1 CK-301-101 trial (NCT03212404), the PD-L1 inhibitor cosibelimab (Unloxcyt) produced an objective response rate of 50.0% in patients with metastatic CSCC (n = 78; 95% CI, 38.5%-61.5%) and 54.8% in locally advanced disease (n = 58; 95% CI, 36.0%-72.7%), with median duration of response that was not reached in either group.⁷ Faculty noted that the agent's PD-L2-sparing mechanism may explain its favorable toxicity profile, though a 60-minute infusion and roughly 10% infusion-reaction rate remain practical considerations, alongside inconsistent payer coverage.
Circulating tumor DNA (ctDNA) data presented at ASCO 2026 showed that a decline in pre-operative ctDNA correlated with pathologic response (P = .03), and detectable post-operative minimal residual disease was associated with markedly worse recurrence-free survival (HR, 11.9; 95% CI, 2.2-65.8; P < .01).⁸
Faculty underscored that the findings are hypothesis-generating rather than practice-changing, citing the absence of assay standardization and prospective validation.
What unmet needs did the panel identify?
The panelists noted that patients are frequently referred to medical oncology only after repeated failure of local and surgical therapy, which is often too late to be candidates for neoadjuvant systemic treatment. They pointed to inconsistent tumor board pathways and a lack of community oncology awareness as key drivers of delayed referral.
“Treating patients with CSCC in 2026 is a team sport. Get everybody involved early on,” Evan Lipson, MD, an associate professor of oncology at Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine in Baltimore, Maryland, said in summary.
References
- Evolving decision-making in cutaneous squamous cell carcinoma. An OncLive Scientific Interchange and Workshop. OncLive. May 29, 2026. Accessed July 14, 2026.
- 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
- Koyfman SA, Lee JHJ, Mortier L, et al. Phase 3 randomized trial (KEYNOTE-630) of adjuvant pembrolizumab (pembro) versus placebo (pbo) for high-risk locally advanced cutaneous squamous cell carcinoma (LA cSCC) following surgery and radiation (RT). J Clin Oncol. 2025; 43(16; suppl):6000. doi:10.1200/JCO.2025.43.16_suppl.6000
- Gross ND, Miller DM, Khushalani NI, et al. Neoadjuvant cemiplimab for stage II to IV cutaneous squamous-cell carcinoma. N Engl J Med. 2022;387(17):1557-1568. doi:10.1056/NEJMoa2209813
- Ladwa R, Lee JH, McGrath M, et al. Response-adapted surgical and radiotherapy de-escalation in resectable cutaneous squamous cell cancer using pembrolizumab: the De-Squamate study. J Clin Oncol. 2025;43(26):2888-2896. doi:10.1200/JCO-25-00387
- Breukers SE, Traets JJH, van Dijk SW, et al. Neoadjuvant ipilimumab and nivolumab in resectable cutaneous squamous cell carcinoma: a randomized phase 2 trial. Nat Med. 2025;31(12):4055-4064. doi:10.1038/s41591-025-03943-w
- Ruiz ES, Muñoz-Couselo E, Montaudié H, et al. Efficacy and safety of cosibelimab in advanced cutaneous squamous cell carcinoma: results from a pivotal open-label study with a median follow-up of ≥2 years. J Am Acad Dermatol. 2026;94(1):48-56. doi:10.1016/j.jaad.2025.09.009
- Vest LS, Liu M, Goyal A, et al. Circulating tumor DNA (ctDNA) as a biomarker for pathologic response and clinical outcomes in patients with cutaneous squamous cell carcinoma (CSCC) receiving neoadjuvant anti–PD-1 therapy. J Clin Oncol. 2026;44(suppl 16):9587. doi:10.1200/JCO.2026.44.16_suppl.9587
