Non-Melanoma Skin Cancer: Deep Dive into Treatment Strategies for Cutaneous Squamous Cell Carcinoma

Session Overview and Highlights

cSCC: Adjuvant and High-Risk Treatment

Faculty agreed that outside clinical trials, adjuvant management of cSCC hinges on multidisciplinary discussion: radiation is still the default for strictly locoregional disease, yet many clinicians now favor perioperative or adjuvant immunotherapy (IO) to spare older patients the long-term morbidity of extensive fields. High-risk status was defined pragmatically by bulky nodal involvement, symptomatic or MRI-visible perineural invasion, in-transit or recurrent lesions, and immunosuppression (especially solid-organ transplant or chronic lymphocytic leukemia carriers), with surgeons increasingly referring such cases earlier. Participants lauded the C-POST trial for demonstrating disease free–survival benefit and flexible 6-week dosing of adjuvant cemiplimab in rigorously selected high-risk cohorts, predicting rapid practice adoption. Conversely, the group viewed KEYNOTE-630’s negative pembrolizumab result as a cautionary tale of broad eligibility, delayed radiation, and event-free survival end points, reinforcing the need for tighter trial designs to avoid harming lower-risk patients.

cSCC: Neoadjuvant Treatment

Faculty agreed that neoadjuvant IO suits resectable cSCC cases for which surgery threatens function or cosmesis, because the benefit is age agnostic, and early imaging allows rapid salvage if tumors fail to shrink. They now favor single-agent cemiplimab, citing frequent downstaging and modest toxicity; the faculty often forgo further treatment after complete pathologic response. Pembrolizumab shows comparable activity, but clinicians question prolonged postoperative dosing and advocate response-guided de-escalation in future studies.

cSCC: Metastatic Treatment

Faculty cited CONTRAC-1’s kidney-transplant data showing that pulsed steroids plus mTOR inhibitors allowed cemiplimab control of cSCC without rejection, flagging a promising yet small template. They viewed KEYNOTE-629’s 5-year update as validation that single-agent anti-PD-1 agents yield durable benefit for a substantial minority of metastatic cases. Consensus favored exploring PD-1 combinations—especially cetuximab or novel checkpoints—in patients who progress on frontline therapy rather than exposing most elderly responders to extra toxicity.

Discussion Themes and Expert Insights

Faculty redefined high-risk cSCC, debating postoperative radiation versus immediate PD-1 inhibition; C-POST supports adjuvant cemiplimab for aggressive tumors, but clinician education is vital to avoid over- or undertreatment. Surgeons now embrace neoadjuvant therapy after seeing dramatic responses to brief cemiplimab or pembrolizumab therapy, yet speakers stressed that biomarkers (UV signature mutations, clinical perineural invasion) and salvage surgery for nonresponders remain urgent.

Metastatically, 5-year KEYNOTE-629 confirmed durable single-agent PD-1 inhibition, while CONTRAC-1 showed that steroid-pulsed, mTOR-based IO can protect kidney grafts. Experts advocate post–PD-1 inhibition trials combining PD-1 inhibitors with EGFR inhibitors, LAG-3 partners plus de-escalation studies to refine sequencing.

Unmet Needs and Recommendations

Clear, consensus-driven criteria for high-risk cSCC are required to guide adjuvant PD-1 inhibition versus radiation and to avoid over- and undertreatment.

Robust predictive biomarkers—UV mutational signature, clinical perineural invasion, or emerging molecular assays—should be integrated into neoadjuvant trials to identify likely responders and flag patients who need rapid salvage surgery.

Dedicated strategies for PD-1 inhibition–refractory and immunosuppressed populations, including transplant recipients, remain a priority; steroid-pulsed, mTOR-based regimens and novel IO/IO or IO/targeted combinations warrant formal study.

Second-line and perioperative trials should test PD-1 inhibitors with inhibitors of EGFR, LAG-3, or other checkpoints while embedding patient-reported outcomes to support therapeutic de-escalation.

Finally, broad education of surgeons, dermatologists, and payers is essential to implement evolving protocols and ensure timely access to systemic therapy.

Conclusion

Management of cSCC is rapidly shifting from surgery plus radiation toward IO-anchored care across adjuvant, neoadjuvant, and metastatic settings. Cemiplimab’s C-POST victory, dramatic neoadjuvant responses with both cemiplimab and pembrolizumab, and durable 5-year KEYNOTE-629 outcomes validate PD-1 blockade as the backbone of therapy.

The next frontier will pair checkpoint inhibitors with rational partners and refine treatment intensity, aiming to maximize cure while minimizing morbidity for this predominantly older patient population.

References

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