Earlier this year, the first interim analysis of the phase III KEYNOTE-689 trial showed that the use of the PD-1 inhibitor pembrolizumab as part of a perioperative treatment regimen with standard-of-care surgery plus adjuvant radiotherapy (with or without cisplatin alone) improved event-free survival compared with the standard-of-care radiotherapy alone in patients with resectable locally advanced head and neck squamous cell carcinoma (median event-free survival of 51.8 vs 30.4 months, respectively).1 And now the results of exploratory efficacy analyses for the intention-to-treat population of this trial, which were presented at the 2025 ASCO Annual Meeting,2 have demonstrated an improvement in distant metastases–free survival with this neoadjuvant/adjuvant treatment strategy.
“Distant metastases–free survival and incidence of second cancers favored the addition of neoadjuvant/adjuvant pembrolizumab to standard-of-care surgery and adjuvant (chemo)radiotherapy, consistent with the primary event-free survival results of the study,” according to Douglas Adkins, MD, of Washington University Division of Oncology, John T. Milliken Department of Medicine, and colleagues. “These results are notable as they mark the first time an anti–PD-1 therapy has demonstrated a statistically significant and clinically meaningful improvement in event-free survival in the neoadjuvant and adjuvant setting in earlier stages of head and neck squamous cell carcinoma,” he said in a press release.
“For patients with newly diagnosed, locally advanced head and neck cancer, treatments haven’t changed in over two decades,” said study coauthor Kevin Joseph Harrington, MBBS, PhD, Professor of Biological Cancer Therapies at The Institute of Cancer Research and a consultant clinical oncologist at The Royal Marsden NHS Foundation in London, in an institutional press release. “The results of this trial show that pembrolizumab dramatically increases the duration of disease remission—for years longer than the current standard treatments. It works particularly well for those with high levels of immune markers, but it’s really exciting to see that the treatment improves outcomes for all head and neck cancer patients, regardless of these levels,” he stated.
Study Details
In the KEYNOTE-689 trial, a total of 714 patients were included, with 363 randomly assigned 1:1 to receive pembrolizumab plus the standard of care and 351 randomly assigned to the standard of care alone. These adults had squamous cell carcinoma of the larynx, hypopharynx, and oral cavity (stage III or IVA) or the oropharynx (stage III or IVA p16-negative or stage III T4 N0–2 p16-positive).
“The results of this trial show that pembrolizumab dramatically increases the duration of disease remission—for years longer than the current standard treatments.”— KEVIN JOSEPH HARRINGTON, MBBS, PhD
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The standard of care consisted of surgery plus postoperative radiotherapy with or without concurrent cisplatin at 100 mg/m2 every 3 weeks. Pembrolizumab was given neoadjuvantly in two cycles, concurrently in three cycles with postoperative radiotherapy with or without cisplatin, and adjuvantly as 12 cycles at 200 mg intravenously every 3 weeks.
The primary endpoint was event-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review. Safety was a secondary endpoint. Prespecified exploratory efficacy endpoints—the focus of this presentation at the ASCO meeting—included locoregional control (time from randomization to first locoregional radiographic disease progression or recurrence by imaging or biopsy), distant metastases–free survival (time from randomization to first distant metastasis or death), and incidence of second head and neck or other cancers.
Key Results and Safety
With a data cutoff date of July 2024, the median follow-up at the first interim analysis was 38.3 months (range, 9.0–66.5 months). At 36 months, the cumulative incidence of locoregional disease progression or recurrence in all patients was 13.4% with pembrolizumab plus the standard of care vs 14.3% with the standard of care alone. In terms of locoregional failure events, the hazard ratio (HR) for risk with pembrolizumab plus the standard of care vs the standard of care alone was 0.92 (95% confidence interval [CI] = 0.61–1.41).
In addition, the median distant metastases–free survival with pembrolizumab plus the standard of care was 51.8 months, compared with 35.7 months with the standard of care alone (HR = 0.71; 95% CI = 0.56–0.90). At 36 months, the estimated distant metastases–free survival rate was 59.1% vs 49.9%, respectively. Second head and neck or other cancers were reported in 9 and 18 patients, respectively.
As for toxicity, the incidence rates of treatment-related adverse events were similar with pembrolizumab plus the standard of care and with the standard of care alone (any grade, 81.4% vs 81.9%; grade ≥ 3, 44.6% vs 42.9%). No new safety signals for pembrolizumab were observed by the investigators.
DISCLOSURE: The study was funded by Merck Sharp & Dohme LLC. Dr. Adkins has served as a consultant or advisor to Adlai Nortye, Boehringer Ingelheim, CUE Biopharma, Exelixis, Genmab/Seattle Genetics, Immunitas, InhibRx, Kura Oncology, Merck, Merck KGaA, Merus, NATCO Pharma, Purple Biotech, Regeneron, Sanofi, Seagen, and TargImmune Therapeutics; and has received institutional research funding from Adlai Nortye, Alentis Therapeutics, AstraZeneca, AVEO, BeiGene, BioAtla, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Calliditas Therapeutics, Celgene, Cofactor Genomics, Coherus Biosciences, CUE Biopharma, Daiichi Sankyo Europe GmbH, Debiopharm Group, Epizyme, Erasca, Exelixis, Genmab, Gilead Sciences, GlaxoSmithKline, Hookipa Biotech, Immutep, InhibRx, ISA Pharmaceuticals, Johnson & Johnson/Janssen, Kura Oncology, Lilly, Merck, Merus, NATCO Pharma, Novartis, Pfizer, Rgenta, Roche, Seagen, Takeda, Tempus, Tizona Therapeutics, Vaccinex, and Xilio Therapeutics; and has received institutional reimbursement for travel expenses from NATCO Pharma. For full disclosures of the other study authors, visit coi.asco.org.
REFERENCES
- Uppaluri R, Haddad RI, Tao Y, et al: Neoadjuvant and adjuvant pembrolizumab plus standard of care in resectable locally advanced head and neck squamous cell carcinoma: Phase 3 KEYNOTE-689 study. 2025 AACR Annual Meeting. Abstract CT001. Presented April 27, 2025.
- Adkins D, Haddad R, Tao Y, et al: Neoadjuvant and adjuvant pembrolizumab plus standard of care in resectable locally advanced head and neck squamous cell carcinoma: Exploratory efficacy analyses of the phase 3 KEYNOTE-689 study. 2025 ASCO Annual Meeting. Abstract 6012. Presented June 1, 2025.
EXPERT POINT OF VIEW
Parth A. Desai, MD, MBBS, Assistant Professor in the Department of Hematology/Oncology at Fox Chase Cancer Center, Philadelphia, shared these comments on the KEYNOTE-689 trial.
“The KEYNOTE-689 study marks a significant advancement in the treatment of resectable, locally advanced head and neck squamous cell carcinoma with stage III or IVA disease. The addition of perioperative pembrolizumab to standard care led to meaningful improvements in both event-free and distant metastases–free survival. Of note, the neoadjuvant immunotherapy component reduced the incidence of high-risk pathologic features after surgery (32.5% vs 44.4% in the control arm), translating to a lower proportion of patients requiring adjuvant high-dose cisplatin (38.9% vs 50.5%)—a promising step toward mitigating long-term treatment-related toxicity.”
Dr. Desai continued: “Surgical feasibility was preserved, with completion rates comparable between the arms (~88%). Although surgical delays were more frequent in the pembrolizumab group, they did not appear to compromise the timing of adjuvant therapy initiation or negatively impact overall outcomes, reinforcing the logistical practicality of incorporating immunotherapy in the preoperative setting. Although locoregional control gains were modest—especially when contrasted with the adjuvant-only immunotherapy approach explored in the NIVOSTOP study1—the pronounced reduction in distant recurrence highlights the biological benefit of early systemic immune activation in a preoperative setting.”
Although the overall survival data remain immature and have not yet reached statistical significance, Dr. Desai noted there is a favorable trend emerging that may solidify with extended follow-up. “It is also worth noting that regulatory approval was granted for patients whose tumors had a PD-L1 combined positive score (CPS) ≥ 1 at baseline—reflecting approximately 95% of the trial population—making these results broadly applicable in clinical practice,” he concluded.
Additional Commentary
Patrick Ha, MD, Irwin Mark Jacobs and Joan Klein Jacobs Distinguished Professor and Chief of Head and Neck Oncologic Surgery, Department of Otolaryngology–Head and Neck Surgery, University of California, San Francisco, also offered these thoughts on this clinical trial. “The exciting results of KEYNOTE-689 have set the place for immunotherapy in the upfront treatment of locoregionally advanced head and neck squamous cell carcinoma. The main benefits of this neoadjuvant and adjuvant immunotherapy paradigm are found in preventing distant metastases and the development of second cancers, both of which are often incurable states. Although there is still much to learn, we now have a platform upon which to build and can continue to explore the role of multimodality treatment in managing this deadly disease.”
DISCLOSURE: Dr. Desai has served as a paid consultant or advisor to Abdera Therapeutics, Rigel Pharmaceuticals, and Sermo; and has received payment for a book chapter for GO2 for Lung Cancer. Dr. Ha has served as a consultant for IIAM Health, Privo Technologies, and Johnson & Johnson; and has received additional educational support from Stryker, Medtronic, and Johnson & Johnson.
REFERENCE
- Bourhis J, Auperin A, Borel C, et al: NIVOPOSTOP (GORTEC 2018-01): A phase III randomized trial of adjuvant nivolumab added to radiochemotherapy in patients with resected head and neck squamous cell carcinoma at high risk of relapse. 2025 ASCO Annual Meeting. Abstract LBA2. Presented June 1, 2025.
