Neoadjuvant Pembrolizumab May Redefine Standard of Care in Locally Advanced Head and Neck Cancer

At the American Association for Cancer Research Annual Meeting 2025 in Chicago, Illinois, Douglas Adkins, MD, a WashU Medicine medical oncologist at Siteman Cancer Center, presented data from the 3 KEYNOTE-689 trial evaluating the impact of perioperative pembrolizumab plus standard-of-care (SOC) treatment for patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC). In this QA with Pharmacy Times, Adkins discusses the study’s design, results, and potential implications for clinical practice.

Molecular model of pembrolizumab | Image Credit: © Dr_Microbe - stock.adobe.com

Pharmacy Times: Can you provide an overview of the phase 3 KEYNOTE-689 study and its objectives in evaluating pembrolizumab in combination with standard of care for resectable locally advanced HNSCC?

Douglas Adkins, MD: The Phase 3 KEYNOTE-689 trial was an open-label randomized trial comparing perioperative pembrolizumab and standard of care (SOC) to SOC among participants with resectable locally advanced head and neck cancer. The primary objective was to compare the event-free survival (EFS) among participants randomized to receive pembrolizumab and SOC or SOC across three participant groups (those with tumor PD-L1 combined positive score [CPS] >10, >1, and among all participants). The key secondary objectives were to compare the major pathologic response rate (mPR: <10% viable tumor in the resection specimen), overall survival (OS), and safety (adverse events) among participants randomized to receive pembrolizumab and SOC or SOC. SOC included surgery followed by adjuvant radiation +/- chemotherapy (each directed by pathology risk features).

Pharmacy Times: How was pembrolizumab administered in the neoadjuvant and adjuvant settings, and what were the dosing regimens?

Adkins: Two cycles of pembrolizumab 200 mg IV Q3W were administered before surgery, then 3 cycles concurrent with adjuvant radiation (+/- chemotherapy), then 12 cycles after adjuvant radiation (+/- chemotherapy). Total: up to 17 cycles of pembrolizumab.

Pharmacy Times: What were the primary and secondary end points of the KEYNOTE-689 study, and how were they measured?

Adkins: The primary endpoint was EFS assessed by BICR. The key secondary endpoints were mPR (assessed by BIPR) and OS (assessed by BICR) and safety (assessed by NCICTC).

Pharmacy Times: Can you give an overview of the key findings? Were there any data that stood out?

Adkins: Primary Objective: Among participants whose tumors had PD-L1 CPS >10, the median EFS was 59.7 months with pembrolizumab and SOC and 26.9 months with SOC (HR 0.66, 95% CI 0.49-0.88, p=0.0022) and the landmark 3-year EFS were 59.8% and 45.9%, respectively. Among participants whose tumors had PD-L1 CPS >1, the median EFS was 59.7 months with pembrolizumab and SOC and 29.6 months with SOC (HR 0.70, 95% CI 0.55-0.89, p=0.0014) and the landmark 3-year EFS were 58.2% and 44.9%, respectively. Among all participants, the median EFS was 51.8 months with pembrolizumab and SOC and 30.4 months with SOC (HR 0.73, 95% CI 0.58-0.92, p=0.0041) and the landmark 3-year EFS were 57.6% and 46.4%, respectively.

Key Secondary Objective (mPR): In the CPS 10 or greater population, mPR was 13.7% in the pembrolizumab plus SOC arm and 0% in the SOC arm with a p-value of 0.00001. Similar differences in major pathologic response were observed among participants in the CPS 1 or greater population and all participants.

Key Secondary Objective (OS): At the first interim analysis, the OS was not significantly different between the two arms with a hazard ratio of 0.72 (95% CI 0.52-0.98, p=0.02). The median OS in the pembrolizumab plus SOC arm was not reached and was 61.8 months in the SOC group. The landmark three-year data showed 68.2% OS in the pembrolizumab plus SOC arm versus 59.2% in the SOC arm. Additional follow-up is ongoing and will be tested in future analysis.

Pharmacy Times: What were the most common adverse events observed in patients receiving pembrolizumab plus SOC, and how did they compare to SOC alone?

Adkins: The incidence of any treatment-related adverse events and grade 3 or 4 adverse events was similar in both arms. The incidence of radiation skin injury and stomatitis tended to be higher in the SOC arm versus the pembrolizumab plus SOC arm. Among the treated population, the incidence of thyroid disorders was more common in the pembrolizumab plus SOC arm versus SOC.

Pharmacy Times: What are the implications of these findings for the clinical management of resectable locally advanced HNSCC?

Adkins: In summary, neoadjuvant and adjuvant pembrolizumab added to SOC significantly improved EFS in resectable locally advanced head and neck squamous cell carcinoma in all three pre-specified analyses (population CPS 10 or greater, CPS one or greater, and all participants). OS did not reach statistical significance at the first interim analysis, and additional follow-up is ongoing. Neoadjuvant pembrolizumab did not alter surgical completion rate, and we did observe that fewer participants in the pembrolizumab group had postoperative high-risk pathological features and thus did not have to receive adjuvant chemoradiotherapy. No new safety signals were observed in the neoadjuvant, concurrent with chemo radiotherapy, or adjuvant pembrolizumab settings.

In conclusion, neoadjuvant pembrolizumab followed by surgery and adjuvant pembrolizumab concurrent with and after postoperative radiotherapy without or with chemotherapy represents a new standard of care in the treatment of patients with resectable locally advanced head and neck cancer.

Pharmacy Times: What are the next steps in the research pipeline following the KEYNOTE-689 study?

Adkins: Future studies will likely utilize the perioperative pembrolizumab platform to investigate the addition of other therapeutic agents, which may include inhibitors or co-stimulators of immune checkpoints, ADCs, therapeutic vaccines, chemotherapy, and molecules that target the TME.