Latest Cancer TreatmentsDr. Mohammadreza Dabiri
Dr. Mohammadreza Dabiriفارسی
Clinical trialPhase 3Head and neck cancers

Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: 5-year follow-up from the randomized phase III KEYNOTE-048 study

Eur J Cancer · 2025882 patients
Tahara M, Greil R, Rischin D, Harrington KJ, Burtness B, de Castro G, et al. Eur J Cancer. 2025. 221:115395
Study type
Clinical trial
Study name
KEYNOTE-048
Phase
Phase 3
Design
Randomised (1:1:1), open-label trial; 5-year follow-up report
Sample size
882 patients
Source
Eur J Cancer · 2025
Trial registration
NCT02358031

In plain words

After 5 years of follow-up, among people with head and neck cancer that had come back or spread, 16.0% of those who received pembrolizumab with chemotherapy were alive, compared with 5.2% with the older regimen of cetuximab and chemotherapy. Pembrolizumab alone was also more effective, especially in PD-L1-positive tumours.

Key results

HR 0.61 (CPS ≥20); 0.74 (CPS ≥1); 0.82 (total)
Overall survival, pembrolizumab vs EXTREME
95% CI 0.46–0.81; 0.61–0.89; 0.69–0.97
HR 0.63 (CPS ≥20); 0.65 (CPS ≥1); 0.72 (total)
Overall survival, pembrolizumab + chemotherapy vs EXTREME
95% CI 0.47–0.84; 0.53–0.79; 0.60–0.86
14.4% vs 6.5% (pembrolizumab); 16.0% vs 5.2% (pembrolizumab + chemotherapy)
5-year overall survival (all patients)
Compared with EXTREME
Drugs in this study:Carboplatin (Paraplatin)Cetuximab (Erbitux)Cisplatin (Platinol)Fluorouracil (5-FU)Pembrolizumab (Keytruda)

Dose and schedule cards

Pembrolizumab + platinum + 5-FU (KEYNOTE-048)

First line for unresectable recurrent or metastatic disease; per the FDA label, regardless of PD-L1; ESMO recommends it for CPS ≥1 and considers it an alternative option in tumours without PD-L1 expressionCycle length: Every 21 daysOn the page “Head and neck cancers” · Recurrent or metastatic (excluding nasopharynx): first line and after platinum

First line for unresectable recurrent or metastatic disease; per the FDA label, regardless of PD-L1; ESMO recommends it for CPS ≥1 and considers it an alternative option in tumours without PD-L1 expression

DrugDoseRouteSchedule
Pembrolizumab200 mg every 3 weeks (or 400 mg every 6 weeks)IVDay 1, before chemotherapy
Up to 6 cycles
Cisplatin or carboplatinCisplatin 100 mg/m² or carboplatin AUC 5IVDay 1
5-Fluorouracil1000 mg/m² per dayContinuous IV infusion over 96 hoursDays 1 to 4
Cycle length
Every 21 days
Duration
Platinum and 5-FU up to 6 cycles; pembrolizumab until progression, unacceptable toxicity or up to 24 months

Patients with autoimmune disease requiring systemic treatment within the past 2 years were excluded.

On the page “Head and neck cancers” · Recurrent or metastatic (excluding nasopharynx): first line and after platinum

Pembrolizumab monotherapy (KEYNOTE-048)

First line for unresectable recurrent or metastatic disease with PD-L1 CPS ≥1 (greater benefit with CPS ≥20); also after progression on platinumCycle length: Every 21 or 42 daysOn the page “Head and neck cancers” · Recurrent or metastatic (excluding nasopharynx): first line and after platinum

First line for unresectable recurrent or metastatic disease with PD-L1 CPS ≥1 (greater benefit with CPS ≥20); also after progression on platinum

DrugDoseRouteSchedule
Pembrolizumab200 mg every 3 weeks or 400 mg every 6 weeksIVDay 1
Cycle length
Every 21 or 42 days
Duration
Until progression, unacceptable toxicity or up to 24 months

The choice between monotherapy and combination with chemotherapy is based on CPS, tumour burden and symptoms [V, C].

On the page “Head and neck cancers” · Recurrent or metastatic (excluding nasopharynx): first line and after platinum

First-line metastatic or recurrent HNSCC (KEYNOTE-048)

Unresectable; with chemotherapy (or as a single agent with CPS 1 or more)Cycle length: Every 3 weeksOn the page “Pembrolizumab (Keytruda)” · Standard doses and combination regimens (FDA label)

Unresectable; with chemotherapy (or as a single agent with CPS 1 or more)

DrugDoseRouteSchedule
Pembrolizumab200 mg every 3 weeks or 400 mg every 6 weeksIV infusion over 30 minutesDay 1
Up to 6 cycles
Cisplatin or carboplatin + fluorouracil100 mg/m² or AUC 5 + 1000 mg/m²/dayIV; fluorouracil as a continuous 96-hour infusionEvery 3 weeks
Cycle length
Every 3 weeks
Duration
Until progression, unacceptable toxicity or up to 24 months

On the page “Pembrolizumab (Keytruda)” · Standard doses and combination regimens (FDA label)

Pembrolizumab + platinum + fluorouracil

Recurrent or metastatic head and neck cancer, first lineCycle length: Every 21 daysOn the page “First-line regimens for recurrent or metastatic head and neck cancer: pembrolizumab and EXTREME”

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

Pembrolizumab 200 mg IV day 1 every 3 weeks, for up to 35 cycles (about 2 years) or until disease progression or intolerable toxicity; continuation after radiological progression was allowed in stable patients with clinical benefit (301 patients).

2Pembrolizumab + chemotherapy

Pembrolizumab 200 mg IV day 1 every 3 weeks for up to 35 cycles (about 2 years), plus cisplatin 100 mg/m² IV or carboplatin AUC 5 IV (investigator's choice) on day 1 and 5-fluorouracil 1000 mg/m² per day as a continuous IV infusion on days 1 to 4 (96 hours); every 3 weeks, up to 6 cycles of platinum and 5-FU; then pembrolizumab alone up to a maximum of 35 cycles in total (281 patients).

3EXTREME (cetuximab + chemotherapy)

Cetuximab 400 mg/m² IV as the first dose (day 1), then 250 mg/m² IV weekly until progression or intolerable toxicity, plus cisplatin 100 mg/m² or carboplatin AUC 5 IV on day 1 and 5-FU 1000 mg/m² per day as a continuous infusion on days 1 to 4; every 3 weeks, up to 6 cycles of platinum and 5-FU (300 patients).

Source of the regimen details: Regimen of the original KEYNOTE-048 trial (this paper is the 5-year follow-up report of the same trial and gives no doses): ClinicalTrials.gov NCT02358031 and the FDA label for Keytruda (DailyMed, section 14)

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

(Criteria of the original KEYNOTE-048 trial) Patients with recurrent or metastatic HNSCC not amenable to local therapy, with a primary tumour in the oropharynx, oral cavity, hypopharynx or larynx (nasopharynx excluded); no prior systemic therapy for recurrent or metastatic disease (systemic therapy given as part of multimodal treatment for locally advanced disease was allowed if completed more than 6 months earlier; progression within 6 months of curative systemic therapy was an exclusion criterion); ECOG 0 or 1; measurable disease; adequate organ function. Active autoimmune disease requiring systemic treatment in the past 2 years or a need for immunosuppression was an exclusion criterion. PD-L1 positivity was not required for entry (85% had CPS ≥1 and 43% CPS ≥20).

Endpoints

Primary endpoints: overall survival and progression-free survival.

Safety and side effects

The abstract of this update reports no new safety data.

Clinical significance and place in guidelines

Confirms the durability of the survival benefit of pembrolizumab and pembrolizumab–chemotherapy in the first line and consolidates their place as the standard of care.

Limitations

Open-label trial; progression-free survival was not improved; comparisons of PD-L1 subgroups in this update are descriptive.

Related pages:Head and neck cancers
Original article (DOI)PubMedClinicalTrials.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.