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, 15 patients (75%; 95% CI, 50.9–91.3) had a pCR (n = 11) or MPR (n = 4). 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.

Immunotherapy to Avoid Orbital Exenteration in Patients With Cutaneous Squamous Cell Carcinoma

“…Immunotherapy has the ability to gain rapid oncological responses as was highlighted by Ferrarotto et al in their neoadjuvant study where 70% of patients (14/20) achieved a complete or major pathological response post two cycles of cemiplimab 350 mg/3-weekly ( 17 ). Rapid clinical response is of particular importance for patients who have symptoms.…”

“…The only published neoadjuvant cemiplimab study utilizing cemiplimab 350 mg/3-weekly with a response assessment post two cycles followed by surgery demonstrated a remarkable 70% major pathological response rate with 55% of patients achieving a complete pathological response ( 17 ). All patients in this study received curative surgery as part of the study design; however, these impressive results raise the pertinent question of whether less extensive surgery is feasible following immunotherapy, a potential area of investigation for future studies.…”

“…The impressive response rates seen with immunotherapy in advanced CSCC, and evidence supporting a neoadjuvant application in other tumor types such as melanoma ( 16 ), have provided more confidence in usage in those patients who wish to avoid disfiguring or morbid curative surgery. The results of a recent phase II study exploring the role of neoadjuvant cemiplimab in patients with locoregionally advanced resectable head and neck CSCC yielded a high major pathological response rate of 70% ( 17 ). Other studies of neoadjuvant immunotherapy are ongoing.…”

Biology and Treatment Advances in Cutaneous Squamous Cell Carcinoma

“…Furthermore, neoadjuvant studies allow for earlier assessment, using pathologic response, compared to adjuvant studies, where survival data can take many years to mature. A pilot phase II study of two doses of neoadjuvant cemiplimab for patients with locally advanced, curable CSCC resulted in 14/20 patients (70%; 95% CI 45.7–88.1) with a pathological complete response ( n = 11) or major pathological response ( n = 3) [ 160 ]; this was despite only 30% (95% CI 11.9–54.3) showing a partial response by RECIST, highlighting the challenges of assessing ICI response using current radiological criteria. Neoadjuvant studies of other ICIs, as well as combination neoadjuvant treatment with dual anti-PD(L)1 with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade, are ongoing [NCT04154943] [ 161 , 162 ].…”

Surgery for Cutaneous Squamous Cell Carcinoma and its Limits in Advanced Disease

“…Finally, the use of systemic immunotherapy in an attempt to reduce tumoral burden, thereby allowing for a less extensive surgery (neoadjuvant therapy), is being assessed in ongoing clinical trials on advanced cSCC. A recently published phase II pilot trial of neoadjuvant immunotherapy with cemiplimab has shown pathologically complete responses in 70% of the patients [40]. Although these results were obtained from patients with advanced but resectable tumors, it can be hypothesized that the same neoadjuvant approach can be applied to borderline resectable or even unresectable advanced cSCC in the future.…”