AACR 2025 | First therapeutic advancement in 20 years for patients with head and neck cancer
Phase III trial findings suggest perioperative pembrolizumab is to be incorporated into the standard of care for head and neck cancer patients.
The results of a Phase III trial presented at the AACR Annual Meeting (25–30 April; Chicago, IL, USA) by Ravindra Uppaluri, the director of head and neck surgical oncology at the Dana-Farber Brigham Cancer Center (MA, USA), revealed that administering pembrolizumab before and after surgery significantly improves outcomes in head and neck cancer patients. This trial, funded by Merck (NJ, USA), represents the first major treatment advancement for this patient population in over two decades.
Currently, patients newly diagnosed with locally advanced head and neck squamous cell carcinoma (HNSCC) typically undergo surgery, followed by radiation therapy and, in some cases, chemotherapy. This treatment approach has remained largely unchanged for the past 20 years, yet patient outcomes have remained poor, with only 40% to 50% of patients surviving 5 years after treatment.
Immunotherapy has shown promise for HNSCC patients when delivered perioperatively, both before and after standard of care treatment. Administered early, when the tumor burden is higher, immunotherapy can enhance the immune response and begin targeting and killing tumor cells. After standard treatment, it can help eliminate any remaining cancer cells that may still be present.
Building on the success of a Phase II trial that demonstrated the safety and interesting clinical responses of perioperative pembrolizumab – an immunotherapy targeting the PD-1 pathway – in HNSCC patients, Uppaluri and his colleagues conducted the Phase III KEYNOTE-689 trial. The aim of the trial was to determine whether incorporating perioperative immunotherapy into standard treatment for HNSCC could improve event free survival (reduce disease recurrence and death).
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A total of 714 patients with stage III/IV HNSCC from 192 centers across multiple countries participated in the trial. All patients underwent the current standard of care regimen consisting of surgery followed by pathology directed adjuvant therapy, with approximately half also receiving pembrolizumab before and after surgery. The patients were followed after treatment, with more than half of them being monitored for over 38 months.
The investigators also assessed the levels of PD-L1, in tumors to determine whether higher PD-L1 expression would influence the response to treatment.
The results showed that patients treated with pembrolizumab were at least 27% less likely to experience recurrence compared to those receiving standard care. Additionally, patients with high PD-L1 expression experienced a 13.7% increase in major pathologic response (defined as a 90% or more tumor reduction) before surgery and were 34% less likely to relapse. Researchers also noted that fewer patients required chemotherapy as part of standard of care after receiving immunotherapy before surgery.
Reflecting on the impact of these findings, Uppaluri stated, “For the first time in more than 20 years, patients with this challenging disease have a new therapeutic approach. Now that we know this is a safe approach, we can start thinking about how we can potentially modify surgery and/or adjuvant therapy to reduce the challenges patients face from the side effects of our treatments.”
The trial did not evaluate the relative impact of neoadjuvant versus adjuvant pembrolizumab, so the specific contribution of each treatment stage to clinical outcomes remains unclear for now.
Following these results, the FDA is reviewing perioperative pembrolizumab for potential approval in patients with locally advanced HNSCC, meaning that the standard of care for this patient population could soon change.