Approved drug that revolutionized melanoma treatment may change standard of care for yet another cancer type
Research presented at the annual meeting of the American Association for Cancer Research (AACR) in April provides the strongest clinical evidence to date that standard of care therapy could soon be updated for the treatment of resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC).
Results from KEYNOTE-689, a global phase 3 randomized clinical trial of 714 patients with LA-HNSCC demonstrated statistically significant and clinically meaningful improvement in event-free survival (EFS: defined as relapse, progression or death) with the administration of the immunotherapy drug pembrolizumab (KEYTRUDA®) before and after standard of care surgery and adjuvant (chemo)radiation therapy as compared to standard of care therapy alone.
In the KEYNOTE-689 trial, 714 patients at 192 sites across the globe were randomized 1-to-1 to pembrolizumab plus standard of care or standard of care. Standard of care included surgery and adjuvant radiation with or without chemotherapy. In the pembrolizumab plus standard of care arm, pembrolizumab was given for two cycles before (neoadjuvant) surgery and then concurrent with adjuvant (chemo)radiation therapy, followed by maintenance pembrolizumab.
At the first interim analysis, the median follow-up was 38.3 months. Among the PD-L1 combined positive score (CPS) 10 or greater patient population, EFS was better in the pembrolizumab plus standard of care arm versus the standard of care arm with a hazard ratio of 0.66 and a P value of .0022, which met the intention to treat significance boundary. The three-year EFS was 59.8% in the pembrolizumab plus standard of care arm versus 45.9% in the standard of care arm. Median EFS was 59.7 months in the pembrolizumab plus standard of care arm versus 26.9 months in the standard of care arm. A similar benefit was observed among participants in the CPS one or greater population and among all participants. High-risk adverse pathologic features were observed in 32.5% of pembrolizumab plus standard of care treated patients versus 44.4% in the standard of care arm. As a result, adjuvant cisplatin with radiation therapy was administered to fewer patients in the pembrolizumab plus standard of care arm than the standard of care arm (27.5% versus 37.6%, respectively). Also, the incidence of radiation skin injury and stomatitis was higher in the standard of care arm versus the pembrolizumab plus standard of care arm.
The authors concluded that 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 neck cancer.
The co-principal academic investigators of the trial were:
- WashU Medicine medical oncologist Douglas Adkins, MD, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine, and
- His former WashU Medicine colleague Ravindra Uppaluri, MD, now at Dana-Farber Brigham Cancer Center
They co-led the preceding Merck-funded phase 2 investigator-initiated trial (IIT) that began in 2013 at WashU Medicine and Siteman and were the first to test the perioperative immunotherapy treatment strategy specifically for head and neck cancer. Researchers found that the one-two punch of administering pembrolizumab before and after surgery and (chemo)radiation therapy greatly intensified the degree of tumor cell kill in the surgical specimen of patients with LA-HNSCC and resulted in a lower-than-expected risk of disease relapse.
“What we’ve seen in the global KEYNOTE-689 trial is exciting and groundbreaking,” Adkins said. “I anticipate that with these latest results we will see approval of the change in standard of care therapy for LA-HNSCC by summer.”
With clinically significant results documented in the global phase 3 trial, the federal Food and Drug Administration has granted a priority review and is set to announce a decision in late June 2025 as to whether this will become a new standard of care therapy for the treatment of certain head and neck cancers. Adkins notes that the research now is on track to establish the first change in standard-of-care therapy for locally advanced head and neck cancers in more than 20 years.
Almost 900,000 new cases of head and neck cancer are diagnosed globally each year, with more than 58,000 of those cases diagnosed in the U.S.
Adkins co-leads the Robert Ebert and Greg Stubblefield Head & Neck Tumor Center at Siteman along with WashU Medicine head and neck surgeon Sidharth Puram, MD, PhD, and radiation oncologist Wade Thorstad, MD. Adkins said most patients who come to the center are diagnosed with LA-HNSCC.
“Presentation and publication of this research, along with anticipated FDA approval, will help spread the word so that the treatment strategy can rapidly be incorporated into practice guidelines here and elsewhere,” he said. “We have a history of conducting highly novel and relevant cancer research, and this is an example of how we investigate and push promising results into clinics where it can impact patient care. It’s exciting to see our initial research at this institution move forward with such impressive and potentially life-changing results.”
To search all available clinical trials Siteman, visit siteman.wustl.edu/clinical-trials.