Is Pembrolizumab Becoming a New Standard for Locally Advanced Head and Neck Cancer?

Head and neck squamous cell carcinoma (HNSCC) can progress rapidly and substantially affect quality of life. It develops in tissues of the mouth, throat, larynx and around the nose.

Among patients diagnosed with head and neck cancer, approximately 60-70%present with locally advanced disease.

Locally advancedmeans the cancer has grown at its original site and spread to nearby tissues or lymph nodes, but has not yet spread to distant organs (metastasized).

To control disease at this stage, surgery, radiotherapy and/or drug therapy must be used as multiple treatment modalities in combination.

Despite current standard treatment, recurrence or progression risk remains high after diagnosis at a locally advanced stage.

New strategies are therefore needed to increase treatment success and improve long-term survival.

Against this background, treatments that activate immunity against cancer, immunotherapies, especially drugs such as the PD-1 inhibitor pembrolizumab , are emerging as important sources of hope.

Conducted to address this need, the phase 3 KEYNOTE-689 studyaimed to improve event-free survival (EFS) with perioperative pembrolizumab, before and after surgery. At the 2025 AACR Annual Meeting,the presented data showed important clinical benefits in this patient population.

Study Design and Main Findings

Participant Profile and Number

A total of 714 patients were enrolled.

Participants had newly diagnosed, stage III or IVA, resectable locally advanced head and neck squamous cell carcinoma.

Tumors were nonmetastatic, with no distant-organ spread (M0).

Treatment Arms and Schedule

1. Experimental Arm (Pembrolizumab + Standard Treatment)

Neoadjuvant phase:

• Pembrolizumab 200 mg every three weeks for a total of two cycles.

Surgery:

• All patients underwent surgical resection.

Adjuvant phase (according to risk):

• High-risk patients:

  • Pembrolizumab 200 mg every three weeks for 15 cycles

  • Radiotherapy + Cisplatin

• Low-risk patients:

  • Pembrolizumab 200 mg every three weeks for 15 cycles

  • Radiotherapy alone

2. Control Arm (Standard Treatment Alone)

No neoadjuvant treatment.

Postoperative adjuvant treatment:

• High-risk patients: Radiotherapy + Cisplatin

• Low-risk patients: Radiotherapy alone

Primary Endpoints

1. Event-free survival (EFS): Time until events such as radiological or clinical progression, recurrence or death from any cause.

2. Major pathological response (mPR): Less than 10% viable tumor cells in the resected primary tumor and regional lymph nodes.

Key Findings

• EFS improvement (overall population):

  • Pembrolizumab + Standard Treatment: 51.8 months

  • Standard Treatment Alone: 30.4 months

  • Risk reduction: 27% (HR = 0.73; p = 0.0041)

• EFS in the PD-L1 CPS ≥10 subgroup:

  • Pembrolizumab + Standard Treatment: 59.7 months

  • Standard treatment group: 26.9 months

  • Difference in mPR rate: 13.7% (p < 0.00001)

• Overall survival (OS):

  • Although not yet statistically significant, an OS trend favored pembrolizumab in patients with CPS ≥10 (HR = 0.72).

Safety Profile

• Severe (Grade ≥3) treatment-related adverse events:

  • Pembrolizumab + SOC: 44.6%

  • SOC alone: 42.9%

• Most common adverse event: hypothyroidism (24.7%)

• Treatment-related deaths: 1.1% with pembrolizumab and 0.3% in controls

Clinical and Scientific Significance

The study showed that head and neck cancer management may involve not only surgery and radiotherapy combinations, but also perioperative immunotherapies in an important role.

The findings:

• Again emphasized the need for a multidisciplinary approach.

• Highlighted pembrolizumab timing (neoadjuvant vs adjuvant) as a question requiring further study.

FDA Process and Approval Expectations

In February 2025, Merck filed an application based on these findings with the US Food and Drug Administration (FDA). This was a supplemental biologics license application (sBLA).

• The FDA accepted the application for Priority Review .

• The target decision date was June 23, 2025 .

If approved by the FDA, pembrolizumab could become a standard perioperative option for resectable locally advanced head and neck cancer.

Conclusion: Is a New Era Beginning in Head and Neck Cancer?

KEYNOTE-689 suggests that perioperative immunotherapy could gain a lasting place in head and neck cancer management.

The survival advantage with pembrolizumab is particularly evident in patients with high CPS scores.

This development, through significantly improved event-free survival , may lead to important changes in clinical practice and the design of later-phase trials.