Pilot Phase II Trial of Neoadjuvant Immunotherapy in Locoregionally Advanced, Resectable Cutaneous Squamous Cell Carcinoma of the Head and Neck

Abstract

Purpose: In locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck (CSCC-HN), surgery followed by radiotherapy is standard but can be cosmetically and functionally devastating, and many patients will have recurrence.

Patients and methods: Newly diagnosed or recurrent stage III-IVA CSCC-HN patients amenable to curative-intent surgery received two cycles of neoadjuvant PD-1 inhibition. The primary endpoint was ORR per RECIST 1.1. Secondary endpoints included pathologic response [pathologic complete response (pCR) or major pathologic response (MPR; ≤10% viable tumor)], safety, DSS, DFS, and OS. Exploratory endpoints included immune biomarkers of response.

Results: Of 20 patients enrolled, 7 had recurrent disease. While only 6 patients [30%; 95% confidence interval (CI), 11.9-54.3] had partial responses by RECIST, 14 patients (70%; 95% CI, 45.7-88.1) had a pCR (n = 11) or MPR (n = 3). No SAEs ocurred during or after the neoadjuvant treatment. At a median follow-up of 22.6 months (95% CI, 21.7-26.1), one patient progressed and died, one died without disease, and two developed recurrence. The 12-month DSS, DFS, and OS rates were 95% (95% CI, 85.9-100), 89.5% (95% CI, 76.7-100), and 95% (95% CI, 85.9-100), respectively. Gene expression studies revealed an inflamed tumor microenvironment in patients with pCR or MPR, and CyTOF analyses demonstrated a memory CD8⁺ T-cell cluster enriched in patients with pCR.

Conclusions: Neoadjuvant immunotherapy in locoregionally advanced, resectable CSCC-HN is safe and induces a high pathologic response rate. Pathologic responses were associated with an inflamed tumor microenvironment.

Trial registration: ClinicalTrials.gov NCT03565783.

Figure 1.. Efficacy of neoadjuvant cemiplimab.

A) Waterfall plot of percentage change from baseline in target lesions per RECIST 1.1 and color-coded for pathologic response in the same subject; *, indicates recurrence after surgery and radiation. B) Representative pretreatment (left) and post-treatment (right) photographs, coronal computed tomography (CT) images, and micrographs of tumor specimens of a patient who achieved a major pathologic response (6-mm foci of residual viable tumor) following neoadjuvant cemiplimab treatment. pCR, pathologic complete response; MPR, major pathologic response; SD/PD, stable or progressive disease.

Figure 2.. Oncologic outcomes following neoadjuvant cemiplimab and surgery.

Interval event chart aligned by diagnosis date indicating treatment procedures and patient outcomes following surgery.

Figure 3.. Favorable immune microenvironment prior to cemiplimab treatment is associated with pathological responses.

Pretreatment tumor specimens from pathological responders (R, red, n=10) and pathological non-responders (NR, blue, n=4) were analyzed for gene expression using a custom NanoString panel. (A) Heat map showing supervised clustering of immune cell infiltrates by response. (B) Scatter plots showing significantly different immune cell phenotypes between NR and R patients. Asterisks denote statistically significant differences. (C) Volcano plot of differentially expressed genes (Log2 FC>1.5 and P<0.05) by response. (D) Immune pathways with significantly different expression between R and NR patients per gene set enrichment analysis. NES, normalized enrichment score.

Figure 4.. Association of changes in tumor immune microenvironment after cemiplimab treatment with pathological responses.

CyTOF analysis of pre-and post-treatment tumor specimens. (A) Dot plot showing percentage of a memory CD8-T cell subset (CD8+Eomes+CD45RO+) in pre-and post-treatment tumor specimens of patients with pathologic complete response (pCR) and pathologic nonresponders (NR, pathologic stable or progressive disease). (B–C) Dot plots showing percentages of (B) regulatory T cells (CD3+CD4+FOXP3+) and (C) a myeloid cell subset expressing inhibitory marker VISTA (CD68+CD14+VISTA+) in pre-and post-treatment tumor specimens of patients with pathologic response and NR. P<0.05 denotes statistically significant changes.