Pre- and post-surgical immunotherapy improves survival in head and neck cancer patients

Pre- and post-surgical immunotherapy improves survival in head and neck cancer patients

Patients with locally advanced head and neck cancer who received the immune checkpoint inhibitor pembrolizumab before, during and after standard-of-care surgery had longer event-free survival without the cancer coming back and higher rates of substantial tumor shrinkage prior to surgery, according to the first interim analysis of a randomized, open-label phase 3 clinical trial led by investigators from Dana-Farber Brigham Cancer Center and Washington University School of Medicine in St. Louis.

This study, called Keynote-689, is the first study in more than 20 years to show improvements in outcomes over standard of care for this patient population. The current standard of care for resectable head and neck cancer includes surgery, radiation and chemotherapy, although only 40% to 50% of patients survive five years.

“This is a practice-changing study,” said Robert Haddad, MD, chief of the Division of Head and Neck Oncology and McGraw Chair in Head and Neck Oncology at Dana-Farber and professor of medicine at Harvard Medical School. Haddad is the principal investigator of the Dana-Farber Brigham Cancer Center and a member of the Keynote-689 Steering Committee. “Not only did this regimen improve survival-free survival, but we also observed that fewer patients required chemotherapy after receiving immunotherapy before surgery.”

The results will be presented by study Global Chair Ravindra Uppaluri, MD, PhD, director of Head and Neck Surgical Oncology at Dana-Farber and Brigham and Women's Hospital, and Brigham and Women's Hospital chairs of Otolaryngology, at the American Association of Cancer Research (AACR) Announcement. A press conference will be held on Sunday, April 27th from 12:00-1:00 ET / 11:00-12:00 CT. Uppaluri will then present the study in clinical trials plenary session CT001 on Sunday, April 27, 2025, from 2:00 p.m. to 10:00 p.m. ET / 1:00 a.m. - 1:15 a.m. CT.

Douglas Adkins, MD, professor of medicine and director of Head and Neck and Thyroid Medical Oncology at Washu Medicine, who worked closely with the team at Dana-Farber Brigham Cancer Center in a previous phase 2 study, is the co-senior author.

The Keynote 689 trial randomized 714 patients with newly diagnosed stage III or stage IVA head and neck squamous cell cancer to receive either pembrolizumab before (called neoadjuvant), during and after (called adjuvant) standard of care, or standard of care alone. The researchers also measured the presence of pembrolizumab's target, PD-L1, in tumors to determine whether higher levels of PD-L1 in tumors would affect response to treatment.

They found that patients who received pembrolizumab had longer event-free survival, regardless of their PD-L1 levels. Median event-free survival for all patients was 51.8 months with pembrolizumab and 30.4 without a median of 38.3 months of follow-up. The team also observed significantly higher rates of major pathologic reaction, a major immune-mediated tumor destruction during surgical resections, in all patients taking pembrolizumab.

The treatment was safe with no new side effects observed. In addition, patients who took pembrolizumab underwent surgery on time and were not delayed by immunotherapy-related side effects before surgery.

The ability to operate without delay was a very important observation. “

Robert Haddad, MD, Chief of Head and Neck Oncology and McGraw Chair in Head and Neck Oncology at Dana-Farber

Based on these results, the US Food and Drug Administration is reviewing the potential approval of this regimen for this patient population.

“It is very exciting to see this first positive upfront immunotherapy study with the potential to become the new standard for head and neck cancer patients worldwide,” said Uppaluri, who expects further analysis of the study data later this year after a longer follow-up.

This new regimen would represent a significant change in the workflow for head and neck cancer care. Currently, patients see a surgeon for a definitive diagnosis via biopsy and, if positive, move straight into surgery. The addition of immunotherapy before surgery requires a robust multidisciplinary approach.

“The value of multidisciplinary care in head and neck cancer becomes even more important with this approach to immunotherapy before surgery,” Haddad said. “The mindset of many surgical oncologists in the United States and the world must evolve to embrace this paradigm shift.”

“Our multidisciplinary teams are now focused on determining whether this progress can be improved with different agents or with combinations of neoadjuvant and adjuvant therapies in head and neck cancer,” said Uppaluri. “This study has really opened the door to the potential for neoadjuvant treatment to make a difference for our head and neck cancer patients.”

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