Merck recently announced that KEYTRUDA (pembrolizumab) has been approved by the U.S. Food and Drug Administration (FDA) for the perioperative treatment of adults with surgically resectable locally advanced head and neck squamous cell carcinoma (HNSCC) whose tumors express PD-L1 and have a Combined Positive Score (CPS) of 1 or More. Specifically, KEYTRUDA can be used as a single agent in the neoadjuvant setting (before surgery) and continued administration in the adjuvant setting, along with radiotherapy, with or without cisplatin, and then as monotherapy.
This approval makes KEYTRUDA the first perioperative treatment approved for HNSCC, which indicates a significant improvement in the standard of care. Traditionally, surgery followed by adjuvant radiation, with or without cisplatin, was the primary treatment for resectable, locally progressed HNSCC. The inclusion of KEYTRUDA highlights the increasing importance of immunotherapy in improving outcomes by reducing the risk of disease progression and mortality in high-risk patients.
The KEYNOTE-689 trial – a multicenter, randomized, phase 3 study- supported this approval by evaluating the effectiveness and safety of adding KEYTRUDA to the standard of therapy for surgically resectable, locally advanced HNSCC. The trial included 714 patients, most of whom had stage III or IVA disease, with a CPS score of 1 or higher. Participants were stratified based on original tumor location, stage, and PD-L1 expression before being randomly allocated in a 1:1 ratio to either the KEYTRUDA or control arms.
In the KEYTRUDA arm, 200 mg of KEYTRUDA was administered as monotherapy for two cycles in the neoadjuvant setting, followed by adjuvant KEYTRUDA in combination with radiotherapy, with or without cisplatin, and then KEYTRUDA monotherapy for up to 12 cycles (approximately 9 months). The control arm received the standard of care without KEYTRUDA.
The primary outcome of the study was event-free survival (EFS), defined as the period from randomization to the first recorded disease progression, recurrence, or death from any cause in the population with a PD-L1 CPS of 1 or higher. At the first prespecified interim analysis, KEYTRUDA reduced the risk of an EFS event by 30% (HR, 0.70; 95% CI, 0.55-0.89; p = 0.00140). The median EFS in the KEYTRUDA group was 59.7 months, approximately twice the 29.6 months seen in the control group.
The most frequently reported adverse reactions (occurring in 20% or more of KEYTRUDA participants) were stomatitis (48%), radiation skin injury (40%), weight loss (36%), fatigue (33%), dysphagia (29%), constipation (27%), hypothyroidism (26%), nausea (24%), rash (22%), dry mouth (22%), diarrhea (22%) and musculoskeletal pain (22%).
Serious adverse reactions were not rare. During the neoadjuvant phase, 11% of KEYTRUDA participants experienced a serious adverse reaction like pneumonia (1.4%), tumor hemorrhage (0.8%), dysphagia (0.6%), immune-mediated hepatitis (0.6%), cellulitis (0.6%), and dyspnea (0.6%). 1.1% of patients died during this phase from complications like respiratory failure, Clostridium difficile, septic shock, or myocardial infarction.
During the adjuvant phase, 38% of KEYTRUDA participants experienced serious adverse reaction like pneumonia (2.7%), pyrexia (2.4%), stomatitis (2.4%), acute kidney injury (2%), pneumonitis (1.6%), diarrhea (1.2%) and immune-mediated hepatitis (1.2%). 5% of fatal adverse reactions have been seen, such as deaths from sepsis, respiratory failure, COVID-19, and multiorgan dysfunction. 17% of patients discontinued adjuvant KEYTRUDA permanently because of adverse reactions, such as predominantly pneumonitis, colitis, and hepatitis.
Other, less frequently reported (<1%) but clinically significant immune-mediated adverse reactions include diabetes mellitus, pancreatitis, neurotoxicity (such as Guillain-Barré syndrome, myasthenia gravis, and peripheral neuropathy), uveitis, hematologic abnormalities (including autoimmune anemia), and severe skin disorders (such as exfoliative rash).
Several problems with KEYTRUDA, a medicine used in haematopoietic stem cell transplantation, were addressed following therapy and cessation. Complications related to infusion were rare (0.2%) in the KEYTRUDA population. KEYTRUDA was well tolerated in this scenario, and the majority of side effects were controlled with adequate care. Nearly 79% of hepatitis cases and 59% of pneumonitis cases were cleared with adequate therapy and KEYTRUDA cessation.
The approval of KEYTRUDA, an immunotherapy, in select patient groups represents a significant advance in the standard of care for HNSCC. It demonstrates KEYTRUDA’s potential to prolong event-free survival, reduce the risk of disease progression, and extend its role in early disease management.
Reference: Merck & Co. FDA Approves KEYTRUDA® (pembrolizumab) for PD-L1+ Resectable Locally Advanced Head & Neck Squamous Cell Carcinoma as Neoadjuvant Treatment, Continued as Adjuvant Treatment Combined With Radiotherapy With or Without Cisplatin Then as a Single Agent. Merck. Published June 13, 2025. FDA Approves KEYTRUDA® (pembrolizumab) for PD-L1+ Resectable Locally Advanced Head & Neck Squamous Cell Carcinoma as Neoadjuvant Treatment, Continued as Adjuvant Treatment Combined With Radiotherapy With or Without Cisplatin Then as a Single Agent
