Neoadjuvant Chemoimmunotherapy With Pembrolizumab Is Active in Resectable HNSCC

Neoadjuvant pembrolizumab (Keytruda) in combination with docetaxel and cisplatin was effective in providing an encouraging survival benefit and a manageable safety profile in patients with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC), according to data from a phase 2 study published in Frontiers in Immunology.¹

Efficacy-evaluable patients (n = 49) experienced an overall response rate (ORR) of 87.8% (95% CI, 75.2%-95.4%). Patients who underwent resection (n = 27) achieved a pathologic complete response (pCR) rate of 44.4% (95% CI, 25.5%-64.7%). The 6-, 12-, and 18-month progression-free survival (PFS) rates were 89.8% (95% CI, 77.2%-95.6%), 87.5% (95% CI, 74.2%-94.2%), and 72.7% (95% CI, 50.6%-86.1%), respectively. The overall survival (OS) rates at these respective timepoints were 95.9% (95% CI, 84.7%-99.0%), 93.6% (95% CI, 81.5%-97.9%), and 84.9% (95% CI, 65.0%-93.9%).

“In this prospective, single-arm phase 2 clinical trial, neoadjuvant chemoimmunotherapy with pembrolizumab plus docetaxel and cisplatin demonstrated promising efficacy and safety for resectable, locally advanced HNSCC, with an ORR of 87.8% and generally manageable treatment-related adverse effects [TRAEs],” Jing Wang, MD, an assistant professor in the Department of Head and Neck Surgery at the Cancer Hospital of China Medical University/Liaoning Cancer Hospital and Institute in Shenyang, China, and coauthors wrote in the publication.

In June 2025, the FDA approved pembrolizumab monotherapy as a neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy with/without cisplatin after surgery, and then as a single agent, for adult patients with resectable, locally advanced HNSCC whose tumors express PD-L1 with a combined positive score of at least 1, as determined by an FDA-approved test.² The regulatory decision was supported by data from the phase 3 KEYNOTE-689 trial (NCT03765918).

How was the phase 2 study designed?

The prospective single-center, single-arm, open-label study enrolled adult patients with histologically confirmed, previously untreated, resectable, locally advanced HNSCC (stage II-IVB).¹ Patients were also required to have an ECOG performance status of 0 or 1, at least 1 measurable lesion per RECIST 1.1 criteria, and adequate organ function.

Patients received pembrolizumab at 200 mg plus docetaxel at 50 mg/m² and cisplatin at 50 mg/m² on day 1 of each 3-week cycle, for 2 cycles. Following 2 cycles of neoadjuvant therapy, patients proceeded to or refused surgery and continued with chemoimmunotherapy and/or chemoradiotherapy. The primary end point was ORR. Secondary end points included pCR rate, PFS, OS, and safety.

At baseline, the median age in the overall population was 61 years (range, 49-76). Most patients were male (85.7%), were current or former smokers (81.6%), had used alcohol (91.8%), had N2 clinical stage disease (51.0%), underwent surgery (55.1%), and received adjuvant radiotherapy and immunotherapy (51.0%). Primary tumor locations consisted of oral (16.3%), oropharyngeal (32.7%), hypopharyngeal (32.7%), laryngeal carcinoma (12.2%), sinus (4.1%), and surface mass (2.0%).

What were the further efficacy and safety data?

Additional findings from the phase 2 study revealed that 55.6% (95% CI, 35.3%-74.5%) of patients who underwent surgery achieved a major pathologic response. Among patients who experienced a pCR, 9 had completely negative lymph nodes. As of October 31, 2024, no instances of metastasis, recurrence, or death due to HNSCC had been reported in the surgery subgroup.

In terms of safety, the most common any-grade TRAEs included nausea/vomiting (12.2%), fatigue (10.2%), rash (8.2%), neurotoxicity (8.2%), and elevated aminotransferase levels (8.2%). Grade 3 and 4 TRAEs occurred at respective rates of 24.5% and 4.1%. No previously unknown or unexpected TRAEs were reported. Notably, there were no other immune-related adverse effects besides rash and myocarditis, and no patients were forced to cancel surgery due to treatment-related toxicity.

“In conclusion, neoadjuvant chemoimmunotherapy with pembrolizumab plus docetaxel and cisplatin presented encouraging efficacy regarding radiographic and pathological antitumor response and a favorable safety profile,” Wang and her coauthors wrote. “However, the mechanistic insights underlying the treatment response remain largely unexplored.”

References

1. Wang J, Zhang W, Huang D, Liu Z, Zhang W, Li Z. Efficacy and safety of the neoadjuvant chemoimmunotherapy with pembrolizumab plus docetaxel and cisplatin in resectable locally advanced squamous cell carcinoma of the head and neck. Front Immunol. 2025;16:1664892. doi:10.3389/fimmu.2025.1664892
2. FDA approves neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck squamous cell carcinoma. FDA. Updated June 13, 2025. Accessed February 5, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-and-adjuvant-pembrolizumab-resectable-locally-advanced-head-and-neck