Clinical trialPhase 3Head and neck cancers

Neoadjuvant and Adjuvant Pembrolizumab in Locally Advanced Head and Neck Cancer

N Engl J Med · 2025714 patients

Uppaluri R, Haddad RI, Tao Y, Le Tourneau C, Lee NY, Westra W, et al. N Engl J Med. 2025. 393:37-50

Study type: Clinical trial
Study name: KEYNOTE-689
Phase: Phase 3
Design: Randomised, open-label trial, 1:1 ratio
Sample size: 714 patients
Source: N Engl J Med · 2025
Trial registration: NCT03765918

In plain words

In patients with head and neck cancer that can be operated on, receiving the immunotherapy drug pembrolizumab before surgery and continuing it after surgery together with radiotherapy lowered the chance of the disease coming back or growing at 3 years, without delaying surgery.

Key results

59.8% vs 45.9%

36-month event-free survival – CPS 10 or higher

HR 0.66 (95% CI 0.49–0.88); two-sided P=0.004

58.2% vs 44.9%

36-month event-free survival – CPS 1 or higher

HR 0.70 (95% CI 0.55–0.89); two-sided P=0.003

57.6% vs 46.4%

36-month event-free survival – all patients

HR 0.73 (95% CI 0.58–0.92); two-sided P=0.008

About 88% in both groups

Completion of surgery

Drugs in this study:Cisplatin (Platinol)Pembrolizumab (Keytruda)

Dose and schedule cards

Pembrolizumab before and after surgery (KEYNOTE-689)

Resectable locally advanced head and neck cancer (stage III to IVA) with PD-L1 CPS ≥1Cycle length: Every 21 daysOn the page “Head and neck cancers” · Resectable locally advanced (excluding nasopharynx): treatment before and after surgery

Resectable locally advanced head and neck cancer (stage III to IVA) with PD-L1 CPS ≥1

Drug	Dose	Route	Schedule
Neoadjuvant: 2 cycles (6 weeks)
Pembrolizumab	200 mg every 3 weeks (or 400 mg every 6 weeks)	IV	Day 1
Adjuvant: 3 cycles concurrent with radiotherapy
Pembrolizumab	200 mg	IV	Every 3 weeks, before cisplatin on the same day
Adjuvant: 3 cycles (only with high-risk features)
Cisplatin	100 mg/m²	IV	Every 3 weeks, concurrent with radiotherapy
Maintenance: up to 12 cycles
Pembrolizumab	200 mg	IV	Every 3 weeks

Cycle length: Every 21 days
Duration: 17 cycles of pembrolizumab in total (2 before and 15 after surgery); per the label, until recurrence, unacceptable toxicity or up to 1 year

Adjuvant therapy was started within 6 weeks after surgery; in both groups, cisplatin was given only for positive margins (less than 1 mm) or extranodal extension.

On the page “Head and neck cancers” · Resectable locally advanced (excluding nasopharynx): treatment before and after surgery

Resectable locally advanced HNSCC with CPS 1 or more (KEYNOTE-689)

Resectable stage III to IVACycle length: Every 3 weeksOn the page “Pembrolizumab (Keytruda)” · Early stages: before and after surgery or with chemoradiotherapy (FDA label)

Resectable stage III to IVA

Drug	Dose	Route	Schedule
Before surgery
Pembrolizumab	200 mg	IV infusion over 30 minutes	2 cycles every 3 weeks (6 weeks)
After surgery, with radiotherapy
Pembrolizumab	200 mg	IV infusion over 30 minutes	3 cycles every 3 weeks
With high-risk pathology
Cisplatin with radiotherapy	100 mg/m²	IV, after pembrolizumab	Every 3 weeks, 3 cycles
Maintenance
Pembrolizumab	200 mg	IV infusion over 30 minutes	Every 3 weeks for up to 12 cycles

Cycle length: Every 3 weeks
Duration: Up to one year in total, or until recurrence or unacceptable toxicity

High-risk pathology: positive margin of less than 1 mm or extranodal extension.

On the page “Pembrolizumab (Keytruda)” · Early stages: before and after surgery or with chemoradiotherapy (FDA label)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Pembrolizumab + standard therapy (363 patients)

Neoadjuvant: pembrolizumab 200 mg IV day 1 every 21 days, 2 cycles (up to 6 weeks) before surgery.

Adjuvant (starting within 6 weeks after surgery): pembrolizumab 200 mg IV every 3 weeks, 3 cycles concurrent with radiotherapy (with or without cisplatin), then single-agent pembrolizumab 200 mg every 3 weeks for up to 12 cycles (15 adjuvant cycles in total, about 45 weeks). On shared days, pembrolizumab is given before cisplatin.

Radiotherapy (IMRT, 2 Gy per fraction): 60 Gy in 30 fractions for low risk; 66 Gy in 33 fractions for high risk; 70 Gy in 35 fractions for gross residual disease.

Concurrent cisplatin: 100 mg/m² IV day 1 every 21 days, 3 cycles; only with high-risk pathological features (positive margin of less than 1 mm or extranodal extension).

Treatment continued until the cycles were completed, progression precluding surgery, local or metastatic recurrence, or intolerable toxicity.

2Standard therapy (351 patients)

No treatment before surgery. Within 6 weeks after surgery: IMRT radiotherapy (60 Gy in 30 fractions for low risk, 66 Gy in 33 fractions for high risk, 70 Gy in 35 fractions for gross residual disease) with or without concurrent cisplatin 100 mg/m² IV day 1 every 21 days, 3 cycles (cisplatin for a positive margin of less than 1 mm or extranodal extension).

Source of the regimen details: ClinicalTrials.gov NCT03765918 (arms, radiotherapy and cisplatin doses), the FDA label for Keytruda (DailyMed, section 14.4) and the abstract of the paper

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with resectable, non-metastatic locally advanced head and neck squamous cell carcinoma (stage III to IVA, AJCC 8th edition) of the oral cavity, oropharynx, larynx or hypopharynx: HPV-positive (p16) oropharynx only stage III with T4 and N0 to N2; HPV-negative oropharynx and other sites stage III or IVA. ECOG 0 or 1; no previous radiotherapy or systemic therapy and no previous anti-PD-1/PD-L1 therapy. Exclusion criteria: T4b and/or N3, tumours of the nasopharynx or sinuses or of unknown primary, active autoimmune disease requiring systemic treatment in the past 2 years or a need for immunosuppression. Randomisation was stratified by tumour site, stage (III versus IVA) and PD-L1 (TPS ≥50% versus lower).

Endpoints

Primary endpoint: event-free survival, tested in order in the CPS 10 or higher population, the CPS 1 or higher population and all participants.

Safety and side effects

Treatment-related grade 3 or higher adverse events occurred in 44.6% of the pembrolizumab group and 42.9% of the control group, including deaths in 1.1% and 0.3%. Potentially immune-mediated grade 3 or higher adverse events occurred in 10.0% of the pembrolizumab group.

According to the FDA label: in the neoadjuvant phase, permanent discontinuation of pembrolizumab for adverse events was 2.8% and fatal adverse events 1.1%; 11% of the pembrolizumab group (4% because of disease progression) and 12% of the control group did not undergo surgery; surgery was delayed because of adverse events in 1.2% of operated patients in the pembrolizumab group. In the adjuvant phase, serious adverse events were reported in 38% of pembrolizumab recipients (most common: pneumonia, pyrexia, stomatitis, acute kidney injury and pneumonitis).

Clinical significance and place in guidelines

On 12 June 2025 the FDA approved perioperative pembrolizumab for resectable locally advanced HNSCC with PD-L1 CPS 1 or higher; the first perioperative approval in this disease. Overall survival data are still immature and its clinical benefit is debated by some experts.

Limitations

Open-label design; interim analysis; immature overall survival; smaller benefit in the overall population than in the high PD-L1 groups.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.