In a groundbreaking advancement for head and neck cancer treatment, a new phase 3 clinical trial led by Dana-Farber Brigham Cancer Center has unveiled compelling evidence that immunotherapy administered before, during, and after surgery significantly improves patient outcomes. This landmark study, known as KEYNOTE-689, demonstrates for the first time in over two decades that integrating the immune checkpoint inhibitor pembrolizumab into the standard treatment regimen not only prolongs event-free survival but also induces remarkable tumor shrinkage prior to surgery. The trial’s findings, poised to redefine clinical approaches, have the potential to transform the therapeutic landscape for patients battling locally advanced head and neck squamous cell carcinoma.
Head and neck cancers, particularly squamous cell carcinomas, have long challenged oncologists due to their aggressive nature and high rates of recurrence. Standard treatments traditionally involve a combination of surgery, chemotherapy, and radiation. However, despite these intensive interventions, five-year survival rates have stubbornly hovered between 40 and 50 percent, underscoring an urgent need for innovation. The advent of immunotherapy, which leverages the body’s immune system to target and destroy cancer cells, offered promise, yet its integration into early-stage surgical care had not been definitively proven until this pivotal trial.
The KEYNOTE-689 trial enrolled 714 patients diagnosed with stage III or stage IVA locally advanced head and neck squamous cell carcinoma. Participants were randomized to receive either the immune checkpoint inhibitor pembrolizumab in a neoadjuvant (pre-surgery) and adjuvant (post-surgery) setting alongside standard care, or standard care alone. Pembrolizumab specifically blocks the PD-1 receptor on immune cells, releasing the brakes on the immune system and enhancing its ability to identify and eradicate tumor cells. The study also meticulously evaluated the expression of PD-L1 within tumor tissues to assess whether this biomarker influenced treatment response.
Significantly, the trial revealed that pembrolizumab extended median event-free survival to 51.8 months, compared with just 30.4 months in patients receiving standard therapy alone, marking a remarkable improvement across the study population regardless of PD-L1 tumor proportion scores. This suggests that pembrolizumab’s efficacy is not confined to tumors with high PD-L1 expression, broadening its applicability. Another notable finding was the substantially increased rate of major pathologic response among patients treated with pembrolizumab, indicating profound immune-mediated tumor destruction before surgical resection.
Safety and treatment feasibility were important considerations in the trial’s design. Concerns often arise that introducing immunotherapy before surgery could delay critical operative interventions or cause adverse immune-related effects complicating recovery. However, the study reported no new safety signals attributable to pembrolizumab, and surgical timelines remained unaffected. Patients proceeded to surgery without delays, dispelling apprehensions and underscoring the compatibility of neoadjuvant immunotherapy within multidisciplinary treatment workflows.
The clinical implications of these findings are profound. Robert Haddad, MD, chief of the Division of Head and Neck Oncology at Dana-Farber and a principal investigator in the trial, articulated the transformative potential of this regimen. With pembrolizumab reducing the need for postoperative chemotherapy and enhancing long-term cancer control, the study inaugurates a paradigm shift in managing resectable head and neck cancers. This evolution necessitates robust collaboration among surgeons, medical oncologists, radiation oncologists, pathologists, and allied care providers to optimize sequencing and integration of multimodal therapies.
Furthermore, the trial’s outcomes have accelerated regulatory scrutiny, with the U.S. Food and Drug Administration currently reviewing pembrolizumab’s approval for this indication. Such endorsement would mark the first major therapeutic advance in this patient population in over twenty years and pave the way for the adoption of neoadjuvant immunotherapy as a new standard of care. It also sets a precedent for exploring similar strategies in other tumor types where surgery remains central to curative intent.
At the upcoming American Association for Cancer Research (AACR) Annual Meeting, Ravindra Uppaluri, MD, PhD, director of Head and Neck Surgical Oncology at Dana-Farber and Brigham and Women’s Hospital, will present the detailed trial data, illuminating the scientific and clinical nuances that underscore the regimen’s success. Dr. Uppaluri anticipates that ongoing analyses with extended follow-up will further elucidate long-term benefits and may inform combination approaches involving immunotherapy with other agents to augment anti-tumor efficacy.
This study also highlights a critical evolution in the conceptual framework of cancer care. Traditionally, patients with suspected head and neck cancers proceed expeditiously from diagnosis via biopsy to surgical resection. Introducing neoadjuvant immunotherapy requires inserting a systemic treatment phase prior to surgery, necessitating careful coordination and patient monitoring to ensure timely intervention. This challenge reinforces the importance of multidisciplinary oncology teams capable of delivering complex, integrated treatment plans tailored to individual patient profiles.
Looking ahead, the success of pembrolizumab in this context opens fertile avenues for research into optimizing immunotherapeutic strategies. Ongoing and future trials may investigate varying durations, dosages, and combinations with radiation or targeted agents to maximize therapeutic gain. The integration of molecular and immune biomarkers will be pivotal in refining patient selection and predicting responses, moving towards personalized medicine in head and neck oncology.
In summary, the KEYNOTE-689 trial embodies a watershed moment that reframes the therapeutic landscape of locally advanced head and neck cancer. By harnessing the power of immunotherapy in a perioperative setting, this approach delivers durable remissions and enhanced survival, addressing a critical unmet clinical need with a strategy grounded in rigorous science and collaborative care. As the oncology community embraces this novel paradigm, patients stand to benefit from more effective, less toxic regimens—and a renewed hope for long-term cure.
Subject of Research: Locally advanced head and neck squamous cell carcinoma treatment with pembrolizumab immunotherapy.
Article Title: Immunotherapy Enhances Survival Outcomes in Resectable Head and Neck Cancer: Landmark Results from the KEYNOTE-689 Phase 3 Trial.
News Publication Date: April 27, 2025
Web References:
Dana-Farber Brigham Cancer Center: https://www.brighamandwomens.org/cancer
American Association of Cancer Research (AACR) Annual Meeting Presentation Flyer: https://dfci.widen.net/s/phr2qkqkc2/aacr-oral-presentation-2025-flyer.pdf
Robert Haddad, MD profile: https://www.dana-farber.org/find-a-doctor/robert-i-haddad
Ravindra Uppaluri, MD, PhD profile: https://www.dana-farber.org/find-a-doctor/ravindra-uppaluri
Image Credits: Courtesy of Dana-Farber Cancer Institute
Keywords: Head and neck cancer, immunotherapy, pembrolizumab, neoadjuvant therapy, adjuvant therapy, event-free survival, PD-L1, squamous cell carcinoma, surgical oncology, clinical trial, cancer immunotherapy, phase 3 trial
Tags: Dana-Farber Brigham Cancer Center researchevent-free survival improvementhead and neck cancer recurrence ratesimmune checkpoint inhibitors in oncologyimmunotherapy in head and neck cancerinnovative cancer treatment strategiesKEYNOTE-689 clinical triallocally advanced squamous cell carcinomapembrolizumab treatment outcomespre and post-surgery cancer therapysurvival rates for head and neck cancerstumor shrinkage prior to surgery
