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
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
Approval introduces the first perioperative anti-PD-1 treatment regimen for adults with resectable locally advanced head and neck squamous cell carcinoma whose tumors express PD-L1 (CPS ≥1)
RAHWAY, N.J.–(BUSINESS WIRE)–$MRK #MRK–Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy, for the treatment of adult patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC) whose tumors express PD-L1 (Combined Positive Score [CPS] ≥1) as determined by an FDA-approved test, as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy (RT) with or without cisplatin and then as a single agent.
The approval is based on data from the pivotal Phase 3 KEYNOTE-689 trial, the results of which were presented at the American Association for Cancer Research (AACR) Annual Meeting on April 27, 2025. At the trial’s first pre-specified interim analysis, KEYTRUDA before surgery (neoadjuvant), then continued after surgery (adjuvant) in combination with standard of care (SOC), RT with or without cisplatin, followed by KEYTRUDA alone, reduced the risk of event-free survival (EFS) events (defined as disease recurrence, disease progression, or death) by 30% (HR=0.70 [95% CI, 0.55–0.89]; p=0.00140) in patients whose tumors expressed PD-L1 (CPS ≥1) compared to adjuvant SOC. Among the CPS ≥1 population, median EFS was 59.7 months (95% CI, 37.9-not reached) in the KEYTRUDA arm versus 29.6 months (95% CI, 19.5-41.9) in the SOC arm.
“The introduction of KEYTRUDA as a perioperative treatment option for certain patients with resectable locally advanced head and neck squamous cell carcinoma represents a potentially significant shift in how we manage this disease,” said Dr. Ravindra Uppaluri, the study’s overall principal investigator, director of Head and Neck Surgical Oncology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute. “With this approval, we can now offer appropriate patients with resectable locally advanced head and neck squamous cell carcinoma a new treatment regimen that has been shown to reduce the risk of recurrence, progression, or death by 30%, compared with standard of care adjuvant chemoradiotherapy or radiotherapy alone.”
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, other transplant (including corneal graft) rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of KEYTRUDA. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see “Selected Important Safety Information” below.
“As the first perioperative anti-PD-1 treatment option for appropriate patients with resectable locally advanced head and neck squamous cell carcinoma, this new treatment regimen has the potential to shift the treatment paradigm for patients and their families affected by this disease,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “Based on these trial results, KEYTRUDA as part of this regimen shows potential to change long-standing standards of care for treating certain patients with locally advanced HNSCC.”
This approval was reviewed under Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent review of oncology drugs among its international partners. Under Project Orbis, marketing authorization applications for KEYTRUDA based on the results of KEYNOTE-689 are under review by health authorities in Israel, Canada, Australia, Singapore, Brazil and Switzerland. Marketing Authorization Applications are also under review by regulatory authorities worldwide, including Europe and Japan.
In the U.S., KEYTRUDA is currently approved as monotherapy and in combination regimens for certain patients with recurrent or metastatic HNSCC as follows:
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KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC;
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KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test; and
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KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.
Study design and additional data supporting the approval
KEYNOTE-689 is a randomized, multicenter, open-label, active-controlled Phase 3 trial (ClinicalTrials.gov, NCT03765918) evaluating KEYTRUDA as neoadjuvant treatment, continued as adjuvant treatment in combination with standard of care (SOC), radiotherapy (RT) with or without cisplatin, then as a single agent in patients with resectable locally advanced (Stage III-IVA) head and neck squamous cell carcinoma (HNSCC). Patients with active autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by primary tumor site (oropharynx/oral cavity vs. larynx vs. hypopharynx), tumor stage (III vs. IVA) and PD-L1 status (Tumor Proportion Score [TPS] ≥ 50% vs. TPS<50%). The study enrolled 714 patients who were randomized 1:1 to receive:
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Neoadjuvant KEYTRUDA 200 mg for 2 cycles prior to surgical resection. Within 6 weeks following surgery, 3 cycles of adjuvant KEYTRUDA 200 mg every 3 weeks in combination with RT with or without 3 cycles of cisplatin 100 mg/m2 every 3 weeks. This was followed by KEYTRUDA 200 mg every 3 weeks for up to 12 cycles; or
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No neoadjuvant treatment prior to surgery. Within 6 weeks following surgery, adjuvant RT with or without 3 cycles of concurrent cisplatin 100 mg/m2 every 3 weeks.
On both treatment arms, patients received cisplatin with adjuvant RT if high-risk pathological features (i.e., positive margins <1 mm or extranodal extension) were present at surgery.
Treatment with KEYTRUDA continued until disease progression by RECIST v1.1 per BICR during the neoadjuvant phase that precluded surgery, local or metastatic recurrence during the adjuvant phase, completion of treatment, or unacceptable toxicity. Assessment of tumor status was performed prior to surgery at Week 6 in the neoadjuvant phase. Following the start of the adjuvant phase, assessment of tumor status was performed 12 weeks after end of RT with or without cisplatin treatment and then every three months until the end of Year 3; then every six months thereafter up to the end of Year 5.
The trial was not designed to isolate the effect of KEYTRUDA in each phase (neoadjuvant or adjuvant) of treatment.
The major efficacy outcome measure was event-free survival (EFS) by BICR defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precluded definitive surgery, local or distant disease progression or recurrence, or death due to any cause. Among the CPS ≥1 population, at the time of the first pre-specified interim analysis, the EFS hazard ratio (HR) was 0.70 (95% CI, 0.55-0.89; p=0.00140) and the number of events was 128 (37%) in the KEYTRUDA arm versus 156 (47%) in the SOC arm. In an exploratory subgroup analysis of patients with PD-L1-positive (Combined Positive Score [CPS] ≥1) hypopharyngeal tumors who were randomized (n=51), the EFS HR was 2.28 (95% CI, 0.79-6.56).
Additional efficacy outcome measures were major pathological response (mPR) as assessed by BIPR, and overall survival (OS). While OS results were not mature at this interim analysis, with 76% of pre-specified OS events in the CPS ≥1 population, no trend towards a detriment was observed.
The most common adverse reactions (≥ 20%) on the KEYTRUDA arm 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%).
The median duration of exposure to KEYTRUDA in the neoadjuvant phase was 3.1 weeks (range: 1 day to 4.9 weeks). The median duration of exposure to KEYTRUDA in the adjuvant phase was 42 weeks (range: 1 day to 82 weeks).
Of the 361 patients who received KEYTRUDA as neoadjuvant treatment, 11% (n=38) did not receive surgery. Of the 351 patients randomized to SOC, 12% (n=43) did not receive surgery. In the adjuvant phase of the KEYTRUDA arm, 100 patients received KEYTRUDA and cisplatin with concurrent RT while 154 patients received KEYTRUDA alone with concurrent RT. In the SOC arm, 139 patients received cisplatin with concurrent RT while 136 patients received RT alone. For the KEYTRUDA arm, a total of 222 patients received single-agent KEYTRUDA following RT.
Of the 361 patients who received at least one dose of single agent KEYTRUDA as neoadjuvant treatment, 11% of patients experienced serious adverse reactions. Serious adverse reactions that occurred in more than one patient were pneumonia (1.4%), tumor hemorrhage (0.8%), dysphagia (0.6%), immune mediated hepatitis (0.6%), cellulitis (0.6%), and dyspnea (0.6%).
Of the 255 patients who received at least one dose of KEYTRUDA in the adjuvant phase, 38% experienced serious adverse reactions. The most frequent serious adverse reactions reported in ≥1% of KEYTRUDA-treated patients were pneumonia (2.7%), pyrexia (2.4%), stomatitis (2.4%), acute kidney injury (2.0%), pneumonitis (1.6%), COVID-19 (1.2%), death not otherwise specified (1.2%), diarrhea (1.2%), dysphagia (1.2%), gastrostomy tube site complication (1.2%), and immune-mediated hepatitis (1.2%).
About head and neck cancer
Head and neck cancer describes a number of different tumors that develop in or around the throat, larynx, nose, sinuses and mouth. In the U.S., it is estimated there will be approximately 72,680 new cases of head and neck cancer diagnosed and more than 16,680 deaths from the disease in 2025. These data include cancers of the oral cavity, pharynx and larynx. Most head and neck cancer is squamous cell carcinoma which begins in the flat, squamous cells that make up the thin mucosal lining of the head and neck. Locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is cancer that has spread from where it started to nearby tissue or lymph nodes but has not yet spread to distant parts of the body. There are several factors that greatly increase the risk of developing head and neck cancer, including tobacco and alcohol use and human papillomavirus (HPV).
About KEYTRUDA® (pembrolizumab) injection, 100 mg
KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD- L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.
Selected KEYTRUDA® (pembrolizumab) Indications in the U.S.
Head and Neck Squamous Cell Cancer
KEYTRUDA is indicated for the treatment of adult patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC) whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy (RT) with or without cisplatin and then as a single agent.
KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC.
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.
See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.
Selected Important Safety Information for KEYTRUDA
Severe and Fatal Immune-Mediated Adverse Reactions
KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.
Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.
Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.
Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.
Hepatotoxicity and Immune-Mediated Hepatitis
KEYTRUDA as a Single Agent
KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.
KEYTRUDA With Axitinib
KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Hypophysitis
KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Thyroid Disorders
KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.
Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.
Contacts
Media Contacts:
Julie Cunningham
(617) 519-6264
Sienna Choi
(908) 873-4311
Investor Contacts:
Peter Dannenbaum
(732) 594-1579
Steven Graziano
(732) 594-1583
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