Addition of Neoadjuvant and Adjuvant Pembrolizumab Improves Event-Free Survival in Locally Advanced HNSCC

This article was originally published on December 11, 2025 on On a Mission.

In 2004, cisplatin was made part of standard care for resectable locally advanced head and neck squamous-cell carcinoma (HNSCC) with high risk features, but there’s been no major advance since then.

Ravindra Uppaluri, MD, PhD, surgeon scientist and physician lead at Brigham and Women’s Hospital, and colleagues recently demonstrated the efficacy and safety of adding neoadjuvant and adjuvant pembrolizumab to standard care in this setting. Their data from the first interim analysis of KEYNOTE-689 appears in The New England Journal of Medicine.

Methods

The phase 3, open-label KEYNOTE-689 trial was conducted at 192 sites across three world regions. Between December 2018 and October 2023, the investigators enrolled 714 adults who had newly diagnosed, nonmetastatic, resectable locally advanced HNSCC and an Eastern Cooperative Oncology Group performance status score of 0 or 1.

Participants were randomly assigned 1:1 to receive:

• Standard care (surgery and adjuvant radiotherapy ± concomitant cisplatin)
• 2 cycles of neoadjuvant pembrolizumab and 15 cycles of adjuvant pembrolizumab, both at a dose of 200 mg every 3 weeks, in addition to standard care. Adjuvant pembrolizumab was started concurrently with postoperative radiotherapy or chemotherapy.

Tumor PD-L1 expression was measured in all participants. 65% had a combined positive score (CPS) ≥10 and 96% had a CPS ≥1. The CPS is the number of PD-L1–staining cells divided by the total number of viable tumor cells, multiplied by 100.

Efficacy of Pembrolizumab

The primary endpoint of KEYNOTE-689 is event-free survival (EFS), defined as time from randomization to disease progression or recurrence, or death from any cause. Key secondary efficacy endpoints are major pathological response (≤10% residual viable invasive disease) and overall survival. The median follow-up for this first analysis was 38.3 months (range, 9.0–66.5):

CPS ≥ 10

• Median EFS—60 months in the pembrolizumab group vs. 27 months in the control group (HR, 0.66; P=0.004)
• Estimated percentage of participants alive and event-free at 3 years—60% vs. 46%
• Major pathological response—14% vs. 0% (P<0.001)

CPS ≥1

• Median EFS—60 vs. 30 months (HR, 0.70; P=0.003)
• Estimated 3-year EFS rate—58% vs. 45%
• Major pathological response—9.8% vs. 0% (P<0.001)

Total population

• Median EFS—52 vs. 30 months (HR, 0.73; P=0.008)
• Estimated 3-year EFS rate—58% vs. 46%
• Major pathological response—9.4% vs. 0% (P<0.001)

Results for overall survival were not mature at the time of the analysis.

Consistent with similar trials, the pembrolizumab group was more likely than the control group to have immune-related adverse events (irAEs) of any grade (43% vs. 10% of participants), irAEs of grade ≥3 (10.0% vs. 0.6%), and treatment-related serious AEs (19% vs. 10.5%).

Because of the trial design, therapy lasted about three times longer in the pembrolizumab group than in the control group, which extended the time for reporting AEs. Nevertheless, the risk of serious irAEs with immunotherapy is genuine and should be discussed with patients by their treating physicians.

Clinical Impact

Based on these results, the U.S. Food and Drug Administration (FDA) approved pembrolizumab in this setting for patients with locally advanced HNSCC. The approval specifies use in patients with a CPS of at least one, a biomarker present in more than 95 percent of cases, making the regimen widely applicable.