Review articleHead and neck cancers

Comparative review of KEYNOTE-689 and NIVOPOSTOP trials and their impact on perioperative immunotherapy in locally advanced head and neck cancer

Cancer Treatment Reviews · 2025Not given in the abstract

Imamura Y, Kanno M, Fujieda S. Cancer Treatment Reviews. 2025. 140:103018

Study type: Review article
Study name: KEYNOTE-689 / NIVOPOSTOP
Design: Narrative review comparing the design, patient populations, treatment protocols and outcomes of the two randomised trials KEYNOTE-689 and NIVOPOSTOP
Sample size: Not given in the abstract
Source: Cancer Treatment Reviews · 2025

In plain words

This article compares two large studies in which immunotherapy drugs (pembrolizumab or nivolumab) were used together with surgery and radiotherapy for advanced squamous cell cancers of the head and neck. In both studies, adding immunotherapy lowered the chance of the disease coming back or getting worse. Data on overall length of life are not yet complete. The choice of the best approach depends on the risk of the cancer coming back, PD-L1 status and the opinion of the multidisciplinary care team.

Key results

HR 0.73

Event-free survival (EFS) in KEYNOTE-689

95% CI 0.58–0.92

HR 0.76

Disease-free survival (DFS) in NIVOPOSTOP

95% CI 0.60–0.98

KEYNOTE-689 reduced distant recurrence; NIVOPOSTOP improved locoregional control

Pattern of recurrence

Data still immature; favourable trends in both trials

Overall survival

Drugs in this study:Cisplatin (Platinol)Nivolumab (Opdivo)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

Nivolumab + postoperative chemoradiotherapy (NIVOPOST-OP; not approved)

After complete resection of oral cavity, oropharyngeal, laryngeal or hypopharyngeal cancer with at least one high-risk feature (extracapsular extension, microscopically positive margins, 4 or more involved nodes, multiple perineural invasion); age 19 to 74 years, ECOG 0 to 1On the page “Head and neck cancers” · Resectable locally advanced (excluding nasopharynx): treatment before and after surgery

Drug	Dose	Route	Schedule
Before chemoradiotherapy
Nivolumab	240 mg	IV	One dose
Concurrent: 3 cycles
Nivolumab	360 mg	IV	Every 3 weeks
Cisplatin	100 mg/m²	IV	Every 3 weeks
Concurrent
Radiotherapy	66 Gy	External beam
Adjuvant: 6 cycles
Nivolumab	480 mg	IV	Every 4 weeks

Cycle length: 21 days during the concurrent phase; then 28 days
Duration: 1 + 3 + 6 doses of nivolumab

Overall survival data are not yet conclusive, and this use of nivolumab is not approved.

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

1KEYNOTE-689 (broad perioperative strategy)

Pembrolizumab was given both before and after surgery, and (chemo)radiotherapy was given according to pathological risk. Dosing details in the full text of the paper.

2NIVOPOSTOP (focused adjuvant strategy)

Nivolumab with postoperative chemoradiotherapy, only in high-risk patients. Dosing details in the full text of the paper.

Source of the regimen details: 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 locally advanced head and neck squamous cell carcinoma (HNSCC) studied in the two randomised trials KEYNOTE-689 and NIVOPOSTOP. In NIVOPOSTOP, nivolumab with postoperative chemoradiotherapy was used only in high-risk patients. Exact eligibility criteria are not given in the abstract and are in the full text of the paper.

Endpoints

The main outcomes reported in this review were event-free survival (EFS) in KEYNOTE-689 and disease-free survival (DFS) in NIVOPOSTOP. The pattern of recurrence (distant versus locoregional), overall survival, treatment adherence and serious treatment-related adverse events were also examined.

Safety and side effects

Higher treatment adherence and fewer serious treatment-related adverse events were reported in KEYNOTE-689. Exact rates of grade ≥3 adverse events are not given in the abstract.

Clinical significance and place in guidelines

According to this review, perioperative immunotherapy is becoming the first new standard of care in two decades for resectable locally advanced head and neck squamous cell carcinoma. KEYNOTE-689 represents the pre-‎ and postoperative approach with pembrolizumab, and NIVOPOSTOP the targeted postoperative approach in high-risk patients with nivolumab. The choice should be based on the risk of recurrence, PD-L1 and multidisciplinary assessment. The status of regulatory approvals and clinical guideline recommendations should be checked separately, as the abstract does not address them.

Limitations

This study is a narrative review, not a primary trial or meta-analysis. Overall survival data are still immature, and direct comparison between the two trials is limited by differences in design, population and treatment strategy. Some of the data come from conference presentations. The authors also stress the need for cost-effectiveness assessment and refinement of patient selection and treatment timing. Some authors have financial relationships (speaker) with pharmaceutical companies.

Original article (DOI)PubMed

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.