The phase II NEO-CESQ trial reveals that neoadjuvant cemiplimab achieves a 44% major pathological response rate in high-risk cutaneous squamous cell carcinoma, with investigators identifying interferon-γ and WNT5A biomarkers associated with treatment recurrence risks.
Immunotherapy Shrinks Tumors and Predicts Survival Through Biomarkers
- Neoadjuvant Immunotherapy: Giving PD-1 checkpoint inhibitors like cemiplimab before surgery shrinks tumors while active antigens remain present to train the immune system.
- Major Pathological Response: Finding less than 10% viable cancer cells in resected tissue strongly predicts better recurrence-free survival.
- Biomarker Discovery: Elevated baseline interferon-γ signals immune activation and response, whereas WNT5A and CD276 expression indicate potential drug resistance.
Trial Design and Patient Demographics in the NEO-CESQ Study
Led by Paolo A. Ascierto and colleagues across seven Italian centers, the multicenter trial evaluated 25 patients with resectable stage III or IV cutaneous squamous cell carcinoma of the head and neck. Oncodaily reported that enrollment took place between May 2021 and October 2022.
The patient cohort had a median age of 82 years, and 88% of the participants were men. Participants received cemiplimab at a dose of 350 milligrams intravenously every three weeks for two cycles prior to surgical resection.
Following surgery, patients were scheduled to receive adjuvant cemiplimab for up to one year, while postoperative radiotherapy was administered based on multidisciplinary clinical assessments. The primary endpoint of the trial was the major pathological response rate, defined as specimens showing less than 10 percent residual viable tumor. Researchers also tracked secondary outcomes including recurrence-free survival, overall safety, and exploratory biomarker profiles through blood draws and tissue analysis.
| Trial Parameter | NEO-CESQ Result (Intention-to-Treat) |
|---|---|
| Total Enrolled Patients | 25 |
| Major Pathological Response (MPR) Rate | 44% (11 patients) |
| Objective Radiological Response Rate | 52% |
Pathological Responses Versus Radiological Imaging Discrepancies
Out of the 25 enrolled patients, 23 underwent surgical resection after receiving neoadjuvant cemiplimab. Oncodaily reported that the intention-to-treat population achieved an 11-patient major pathological response and a 9-patient complete response. Among the subset of 23 surgical patients, the descriptive major pathological response reached 47.8 percent, with a pathological complete response of 39.1 percent. Radiological scans showed an objective response rate of 52 percent, including six complete and seven partial responses.
However, imaging often failed to match actual surgical pathology findings. Only two of the six patients who achieved a radiological complete response actually showed no remaining cancer cells under the microscope.
Treatment-induced fibrosis, inflammation, and immune cell infiltration frequently mimic residual tumors on scans. With a median follow-up of 42 months, all three recurrence events occurred exclusively in patients who failed to achieve a major pathological response, yielding a hazard ratio of 0.16 for event-free survival.
Transcriptomic Signatures and Mechanisms of Immunotherapy Resistance
Baseline tumor tissue profiling via the NanoString PanCancer IO 360 panel revealed distinct molecular patterns separating responders from nonresponders. Patients achieving major pathological responses showed enrichment in interferon-γ gene signatures. Interferon-γ, produced by activated T cells and natural killer cells, stimulates antigen presentation and upregulates PD-L1 through JAK-STAT signaling pathways. This biological environment indicates pre-existing immune activity that checkpoint blockade successfully reactivates.
Conversely, nonresponding tumors exhibited elevated expression of WNT5A and CD276, pointing toward alternative mechanisms of immune escape. WNT5A participates in noncanonical WNT signaling, which influences tissue remodeling and immune cell exclusion.
CD276, also recognized as B7-H3, correlates with aggressive tumor biology and resistance pathways across several malignancies. These findings led investigators to construct an exploratory 10-gene signature named NeoSquamos to evaluate recurrence risk more effectively in future clinical evaluations.
Autoimmune Disorders and Specific Symptoms Require Medical Consultation
Patients with severe autoimmune disorders, active infections, or those taking systemic immunosuppressive medications like high-dose corticosteroids are typically excluded from PD-1 inhibitor trials due to the risk of severe immune-related adverse events. Anyone experiencing persistent fatigue, severe gastrointestinal changes, unexplained pulmonary symptoms, or dermatologic rashes during immunotherapy must immediately notify their oncology care team for clinical triage and intervention.
