Phase II Clinical Trial of Neoadjuvant and Adjuvant Pembrolizumab in Resectable Local-Regionally Advanced Head and Neck Squamous Cell Carcinoma

Abstract

Purpose: Patients with resected, local-regionally advanced, head and neck squamous cell carcinoma (HNSCC) have a one-year disease-free survival (DFS) rate of 65%-69% despite adjuvant (chemo)radiotherapy. Neoadjuvant PD-1 immune-checkpoint blockade (ICB) has demonstrated clinical activity, but biomarkers of response and effect on survival remain unclear.

Patients and methods: Eligible patients had resectable squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or oropharynx (p16-negative) and clinical stage T3-T4 and/or two or more nodal metastases or clinical extracapsular nodal extension (ENE). Patients received neoadjuvant pembrolizumab 200 mg 1-3 weeks prior to surgery, were stratified by absence (intermediate-risk) or presence (high-risk) of positive margins and/or ENE, and received adjuvant radiotherapy (60-66 Gy) and concurrent pembrolizumab (every 3 weeks × 6 doses). Patients with high-risk HNSCC also received weekly, concurrent cisplatin (40 mg/m2). Primary outcome was one-year DFS. Secondary endpoints were one-year overall survival (OS) and pathologic response (PR). Safety was evaluated with CTCAE v5.0.

Results: From February 2016 to October 2020, 92 patients enrolled. The median age was 59 years (range, 27-80), 30% were female, 86% had stage T3-T4, and 69% had ≥N2. At a median follow-up of 28 months, one-year DFS was 97% (95% CI, 71%-90%) in the intermediate-risk group and 66% (95% CI, 55%-84%) in the high-risk group. Patients with a PR had significantly improved one-year DFS relative to patients without response (93% vs. 72%, hazard ratio 0.29; 95% CI, 11%-77%). No new safety signals were identified.

Conclusions: Neoadjuvant and adjuvant pembrolizumab increased one-year DFS rate in intermediate-risk, but not high-risk, HNSCC relative to historical control. PR to neoadjuvant ICB is a promising surrogate for DFS.

Figure 1.. Survival Stratified by Pathological Adverse Features.

KM curves representing all patients DFS (A), as well as DFS (B) and OS (C) stratified by high and intermediate risk disease. P value by KM method provided. Hazard ratios (HR) were calculated by comparing high-risk to intermediate-risk.

Figure 2.. Pathological responders have increased survival.

A. Representative H&E pictures of patients with no (NPR), partial (PPR) and major (MPR) pathological response characterized by <20%, 20-90% and ≥ 90% treatment effect (TE) respectively. Images were all at 200x. TE was defined as tumor necrosis with associated histiocytic inflammation and/or giant cell reaction to keratinaceous debris. TE percentage was determined by dividing estimates of area showing these features by the total area showing residual viable (VT) and TE. B. Proportion of patients with NPR, PPR or MPR. C. Percent treatment effect in intermediate and high-risk patients. Survival curves comparing NPR and PPR/MPR for DFS (D) and OS (E).

Figure 3.. PD-L1 expression and immune gene expression signature compared to pathological response.

A. PD-L1 was measured using the 22c3 antibody and CPS was determined. Comparison of PD-L1 CPS in intermediate and high-risk groups. There was no statistical difference between groups. B. Comparison of most differentially expressed gene signatures in NPR versus PPR/MPR tissues at baseline prior to treatment. The values are row-centered by subtracting average scores for each signature. C. Comparison of the gene signatures most changed between pre and post treatment tissues in NPR versus PPR/MPR patients. Red designates an increase in expression while blue designates a decrease in gene expression. Changes in B and C were highly significant at FDR <0.1.