Clinical trialPhase 3Head and neck cancers

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study

Lancet · 2019882 patients

Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, et al. Lancet. 2019. 394:1915-1928

A newer report of this study has been published: 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 (2025)

Study type: Clinical trial
Study name: KEYNOTE-048
Phase: Phase 3
Design: Randomised, open-label, three-arm trial (1:1:1) at 200 centres in 37 countries
Sample size: 882 patients
Source: Lancet · 2019
Trial registration: NCT02358031

In plain words

In head and neck cancer that has come back or spread to distant parts of the body, the standard treatment used to be chemotherapy with cetuximab. This study showed that pembrolizumab (alone in tumours that express the PD-L1 protein, or with chemotherapy in all patients) helps people live longer. Pembrolizumab alone causes far fewer severe side effects. Before treatment is chosen, a PD-L1 test (CPS score) is done on a tumour sample.

Key results

14.9 vs 10.7 months

Pembrolizumab monotherapy, overall survival (CPS ≥20)

HR 0.61; 95% CI 0.45–0.83; p=0.0007

12.3 vs 10.3 months

Pembrolizumab monotherapy, overall survival (CPS ≥1)

HR 0.78; 95% CI 0.64–0.96; p=0.0086

11.6 vs 10.7 months

Pembrolizumab monotherapy, overall survival (all patients)

Non-inferior; HR 0.85 (95% CI 0.71–1.03)

13.0 vs 10.7 months

Pembrolizumab + chemotherapy, overall survival (all patients)

HR 0.77; 95% CI 0.63–0.93; p=0.0034

14.7 vs 11.0 / 13.6 vs 10.4 months

Pembrolizumab + chemotherapy, overall survival (CPS ≥20 / CPS ≥1)

HR 0.60 and 0.65 (final analysis)

No significant improvement

Progression-free survival

At the second interim analysis, for neither pembrolizumab regimen

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

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg every 3 weeks (or 400 mg every 6 weeks)	IV	Day 1, before chemotherapy
Up to 6 cycles
Cisplatin or carboplatin	Cisplatin 100 mg/m² or carboplatin AUC 5	IV	Day 1
5-Fluorouracil	1000 mg/m² per day	Continuous IV infusion over 96 hours	Days 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

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg every 3 weeks or 400 mg every 6 weeks	IV	Day 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)

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg every 3 weeks or 400 mg every 6 weeks	IV infusion over 30 minutes	Day 1
Up to 6 cycles
Cisplatin or carboplatin + fluorouracil	100 mg/m² or AUC 5 + 1000 mg/m²/day	IV; fluorouracil as a continuous 96-hour infusion	Every 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”

Recurrent or metastatic head and neck cancer, first line

Drug	Dose	Route	Schedule
Phase 1: 6 cycles
Pembrolizumab	200 mg	IV	Day 1
Cisplatin 100 mg/m² or carboplatin AUC 5		IV	Day 1
Fluorouracil	1000 mg/m² a day	Continuous infusion	Days 1 to 4
Phase 2
Pembrolizumab	200 mg	IV	Every 21 days

Cycle length: Every 21 days
Duration: Pembrolizumab up to 35 cycles

As in KEYNOTE-048.

Dose source:.

On 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 monotherapy

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 + platinum + 5-fluorouracil

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).

3Cetuximab + platinum + 5-FU (EXTREME regimen)

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: ClinicalTrials.gov NCT02358031 (arms and interventions) 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

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 in the intention-to-treat population; 14 primary hypotheses, including superiority in the CPS ≥20, CPS ≥1 and total populations, and non-inferiority (margin 1.2) in the total population.

Safety and side effects

All-cause grade 3 or worse adverse events (final analysis): 55% with pembrolizumab monotherapy, 85% with pembrolizumab–chemotherapy and 83% with cetuximab–chemotherapy. Deaths due to adverse events: 8%, 12% and 10%.

Clinical significance and place in guidelines

KEYNOTE-048 led to FDA approval (June 2019) of pembrolizumab with platinum–5-FU for all patients and of pembrolizumab monotherapy for tumours with CPS ≥1 in the first-line treatment of recurrent or metastatic HNSCC (the EMA restricted the approval to CPS ≥1). The ESMO and NCCN guidelines consider these regimens the first-line standard, and the EXTREME regimen (cetuximab–platinum–5-FU) remains an option for tumours without PD-L1 expression.

Limitations

Open-label design; the benefit in the CPS below 1 population is limited or unclear; pembrolizumab monotherapy may be associated with early progression in some patients in the first months (the survival curves overlap at first); progression-free survival was not improved.

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.