Periop Pembrolizumab's Results for HNSCC Raise Questions

Medscape

06-05-2025

Adding pembrolizumab to standard-of-care treatment improved event-free survival (EFS) in locally advanced head and neck squamous cell carcinoma (HNSCC), according to new results of the KEYNOTE-689 trial.
'This new information supports changing the current standard of care to now include neoadjuvant and adjuvant pembrolizumab. For the first time in more than 20 years, patients with this challenging disease have a new therapeutic approach,' said lead investigator Ravindra Uppaluri, MD, PhD, head and neck surgical oncologist, Dana-Farber Cancer Institute, Boston, at the American Association for Cancer Research (AACR) Annual Meeting 2025.
Pembrolizumab — which already carries indications for unresectable/metastatic HNSCC — is currently under review by the US Food and Drug Administration (FDA) for a perioperative HNSCC indication based on the trial. A decision is expected by June 23, 2025.
Methods and Results
KEYNOTE-689 trial randomized 714 patients with stage III-IVa HNSCC; almost all patients were human papillomavirus–negative, about equally to either standard-of-care treatment — surgery followed by radiation plus chemotherapy for high-risk features on pathology — or standard of care plus perioperative pembrolizumab.
The perioperative regimen included two 3-week cycles of 200 mg neoadjuvant pembrolizumab followed by surgery, then three cycles of pembrolizumab concurrent with radiation plus/minus cisplatin, with 12 cycles of maintenance pembrolizumab afterward.
At a median follow-up of 38.3 months, EFS — defined as no recurrence or death — was a median of 59.7 months in the pembrolizumab arm, compared with 26.9 months in those receiving standard of care alone arm among the 465 patients with a programmed death ligand 1 combined positive score combined positive score (CPS) of ≥ 10. Similar results were seen among patients with a CPS of ≥ 1, with EFS of 59.7 months vs 29.6 months for the pembrolizumab vs standard of care alone groups, respectively. Across all patients, including the less than 5% of those patients with a CPS < 1, EFS was 51.8 months with perioperative pembrolizumab vs 30.4 months without it.
Neoadjuvant pembrolizumab also seemed to downstage tumors; a third of pembrolizumab patients had high-risk features — for instance, positive margins or extranodal involvement — on surgical pathology vs 44.4% in the standard of care arm. Subsequently, the use of adjuvant chemotherapy in the pembrolizumab group was lower at 29.6% vs 44.1%.
With pembrolizumab, 13.7% of patients with a CPS of ≥ 10, 9.8% of those with a CPS of ≥ 1, and 9.3% of all patients had a major pathologic response, defined as a tumor reduction of 90% or more.
Median overall survival has not been reached in the pembrolizumab add-on group, but it was 61.8 months in the standard of care arm. Follow-up for overall survival is ongoing.
Discussion of Results
'I think this trial does constitute a leap forward and a new standard of care,' said study discussant Robert Ferris, MD, PhD, a head and neck surgical oncologist at UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina.
However, 'we have a great deal of new things we need to do' to get the most from the approach, he said.
For one, the hazard ratio for EFS benefit among 528 stage IVa patients was not statistically significant, so further study is necessary to identify stage IVa patients who do benefit, he said. Further work is also needed to identify the optimal treatment after progression, the risk for hyperprogression during programmed cell death 1 monotherapy, and the possibility of deintensifying surgery if patients who respond strongly to neoadjuvant treatment can be identified. It's also unknown if adjuvant pembrolizumab is best given with chemoradiation or afterward, Ferris said. Some studies have shown benefit by separating them, he added.
There might be a role for combining neoadjuvant pembrolizumab with chemotherapy or another immunotherapy, but further research is needed, noted Uppaluri. He added that it's unclear how long the maintenance phase of pembrolizumab should be, and the study did not address whether patients need pembrolizumab both before and after surgery, or if one or the other will do.
The FDA has also raised the question about the need for treatment on both sides of surgery in other perioperative immunotherapy trials. Ferris and Uppaluri said they both look forward to future related investigations for clarity.
The grade 3 or higher treatment-related adverse event rate was 44.6% with pembrolizumab add-on vs 42.9% without it. Immune-mediated adverse events occurred in 43.2% of pembrolizumab patients, most commonly hypothyroidism in 24.7%; grade 3 or higher immune-mediated adverse events occurred in 10%, including one fatal case of pneumonitis. There were four fatal adverse events with the pembrolizumab add-on and one in the standard-of-care group.
The work was funded by Merck, manufacturer of pembrolizumab, and KEYNOTE-689 investigators included Merck employees. Uppaluri reported receiving research funding and consulting fees from the company. Ferris is a Merck advisor.