Advancing Head and Neck Cancer Treatment: Insights From KEYNOTE-689

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The landscape of locoregionally advanced resectable head and neck squamous cell carcinoma (HNSCC) treatment has remained largely unchanged for over 2 decades, with cure rates persistently below 50% despite aggressive multimodal therapy. This significant unmet need led to the development of the pivotal KEYNOTE-689 study (NCT03765918), results of which were a major discussion point at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

Douglas Adkins, MD, professor in the Division on Oncology at Washington University in St. Louis, provided insightful commentary on the study's design, findings, and implications for clinical practice in an interview with Targeted Oncology^TM.

Globally, HNSCC accounts for approximately 750,000 new cases annually, with 40,000 to 50,000 occurring in the US. The conventional standard of care for patients with locoregionally advanced disease has historically involved surgery followed by radiotherapy or chemoradiotherapy. While these approaches aim for curative intent, the limited success rates underscore the urgent need for therapeutic advancements.

“There's been a long interval of absence of improvements and outcomes in the standard care treatment of patients with locally advanced head and neck cancer,” Adkins said.

He emphasized that the lack of significant improvement in outcomes served as the compelling rationale for the design and execution of the KEYNOTE-689 trial.

KEYNOTE-689: A Global Effort to Improve Outcomes

KEYNOTE-689 is a global, randomized, phase 3 trial specifically designed to evaluate the addition of pembrolizumab (Keytruda), an immune checkpoint inhibitor, to the established standard of care (SOC) for patients with resectable, locoregionally advanced HNSCC. The study enrolled 714 patients across 190 participating sites worldwide, a testament to the collaborative effort in addressing this challenging malignancy.

The primary end point of the trial was event-free survival (EFS), defined broadly as the time to recurrence or death from any cause. Adkins highlighted that the initial readout of the trial, presented last year, demonstrated a statistically significant improvement in EFS for patients receiving pembrolizumab in combination with SOC. Specifically, the regimen incorporating neoadjuvant pembrolizumab, followed by surgery and subsequent adjuvant pembrolizumab, even concurrently with radiotherapy and chemoradiotherapy, led to a notable 27% reduction in the risk of death or cancer recurrence across the entire study population. This represents a substantial clinical benefit in a disease setting with historically stagnant outcomes.

Safety Profile: Managing Immunotherapy-Related Effects

A critical aspect of introducing novel therapies is a thorough understanding of their safety profile. Adkins addressed several key points regarding the safety of the pembrolizumab-containing regimen in KEYNOTE-689. Importantly, the proportion of patients who were able to proceed to standard of care surgery was similar between the pembrolizumab arm and the SOC alone arm. This suggests that the addition of neoadjuvant pembrolizumab did not impede the feasibility of subsequent surgical intervention.

Furthermore, the overall rates of treatment-related adverse events (TRAEs) of any grade, as well as grade 3 or higher TRAEs, were comparable between the 2 treatment arms. As anticipated with immune checkpoint blockade, the rates of immune-related adverse events (irAEs) were higher in the pembrolizumab plus SOC arm. Adkins clarified that these irAEs were predominantly characterized by thyroid disorders, such as hypothyroidism or hyperthyroidism. He underscored that these conditions are typically manageable with appropriate medical intervention, often involving thyroid hormone supplementation, and generally have a minimal impact on a patient's quality of life.

An intriguing observation from the safety analysis was a numerically lower risk of certain AEs, particularly neutropenia and rash, in patients receiving pembrolizumab plus standard of care compared with standard of care alone. This finding warrants further investigation to elucidate the underlying mechanisms.

Future Directions and Clinical Implications

The KEYNOTE-689 trial remains in active follow-up to assess the impact of the treatment regimen on overall survival (OS), a crucial secondary end point. Adkins noted that the timing of the OS readout is event-driven and cannot be precisely predicted, but it remains an important area of ongoing analysis.

“This trial, in my opinion, provides the justification for altering the current standard care to neoadjuvant pembrolizumab, followed by surgery, followed by adjuvant pembrolizumab with radiotherapy and chemoradiotherapy for patients with resectable, locally advanced head and neck cancer,” Adkins said in the interview.

This regimen holds the promise of significantly improving long-term outcomes for patients facing this aggressive and often debilitating cancer, marking a long-awaited advancement in a field that has seen limited progress for over two decades. The oncology community now awaits OS results and the potential for integration into treatment guidelines.

REFERENCE:

Adkins D, Haddad RI, Tao Y, et al. Neoadjuvant and adjuvant pembrolizumab plus standard of care (SOC) in resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC): Exploratory efficacy analyses of the phase 3 KEYNOTE-689 study. J Clin Oncol. 43, 6012-6012(2025).doi:10.1200/JCO.2025.43.16_suppl.6012