Neoadjuvant chemoimmunotherapy with afatinib for locally advanced head and neck squamous cell carcinoma (neoCHANCE-2): an open-label, single-arm, phase 2 study.

While immune checkpoint inhibitor-based neoadjuvant therapy shows promise in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), the optimal regimen has yet to be established. We report, for the first time, a neoadjuvant treatment that combines chemotherapy with dual blockade of the programmed cell death protein 1 and epidermal growth factor receptor pathways in LA-HNSCC. In this single-arm phase 2 trial (NCT05516589) conducted at a single academic center, patients with LA-HNSCC were enrolled and received two cycles of tislelizumab and TP chemotherapy (nab-paclitaxel and cisplatin), administered on day 1 of each 3-week cycle, along with afatinib during the interval between chemoimmunotherapy cycles, followed by surgical resection. The primary endpoint was the complete pathologic response (pCR) rate. Secondary endpoints included the major pathologic response (MPR) rate, objective response rate (ORR), event-free survival, overall survival (OS), and safety. A total of 40 patients were enrolled and received neoadjuvant treatment, 32 of whom proceeded to surgical resection; among these patients, the pCR rate was 40.6% (95% CI 23.7% to 59.4%). The ORR was 82.5% (95% CI 67.2% to 92.7%). The 1-year OS rate was 97.3% (95% CI 92.2% to 100%). The most common treatment-related adverse event (TRAE) of grade 3-4 was lymphopenia (5/40, 12.5%). No grade 5 TRAEs leading to death occurred, and no treatment-related surgical delays were observed. In the prespecified exploratory biomarker analysis, increased cytotoxic T lymphocytes and B cells in the tumor immune microenvironment may be associated with pCR/MPR. Neoadjuvant treatment induced a significant increase in the proportion of peripheral CD8+T cells, along with a reduction in B cells. We report, for the first time, the promising efficacy and acceptable safety profile of neoadjuvant chemoimmunotherapy combined with afatinib in patients with LA-HNSCC. Neoadjuvant treatment potentially induced an immune-enhanced tumor microenvironment. Further evaluation in large-scale clinical trials with longer follow-up periods is needed. NCT05516589.