By Jennifer Jang, MHS, ASTRO Communications
For yesterday’s keynote, Ravindra Uppaluri, MD, PhD, Dana-Farber Cancer Center, Boston, spoke on the “Evolving Role of Neoadjuvant Immunotherapy in Curative-Intent Head and Neck Cancer.” Ari Rosenberg, MD, University of Chicago, introduced Dr. Uppaluri, noting his illustrious roles as Director of Head and Neck Surgical Oncology at the Brigham and Women’s Hospital and Dana-Farber Cancer Institute, and as the PI of multiple clinical trials integrating small molecule and immunotherapeutics in the surgical management of head and neck cancers.
Dr. Uppaluri gave a rich talk sharing numerous developments in neoadjuvant immune checkpoint blockade (ICB) and combination approaches prior to the definitive surgery of head and neck carcinomas. For emphasis, he shared the meme of Travis Kelce yelling at Coach Reid at the Super Bowl with the caption: “There is no indication for neoadjuvant ICB use in mucosal HNSCC outside of a clinical trial.”
That said, a primary motivation for exploring this area is the continued poor outcomes for primarily surgically managed patients for head and neck cancers, especially in the HPV-negative setting in the oral cavity. Dr. Uppaluri shared numerous studies that reveal neoadjuvant immunotherapy as an exciting frontier for locally advanced head and neck cancers but remains investigational. Key points that make it an intriguing area of study include that neoadjuvant immunotherapy takes advantage of an intact immune axis to induce pathologic tumor regression and helps vaccinate for durable immune responses. Two mechanistic aspects come into play, one where the preexisting anti-tumor immunity is “unleashed,” and another where direct cytotoxicity leads to pathologic response. In this latter instance, ICB with tumor antigen burden is in place and “functional” lymph nodes provide vaccination with enhanced durable immune response.
Meanwhile, monotherapy anti-PD(L)1 approaches have had a modest impact on pathologic responses, and combination approaches hold promise to enhance these changes. In addition to complete pathologic responses, partial pathologic responses are associated with favorable clinical responses. Dr. Uppaluri shared studies that explored whether pathologic responses could be increased, issues that have been considered since the 1960s.
Neoadjuvant trials offer unprecedented opportunities to examine immune cell dynamics, exploring biomarkers of responders and non-responders. Key questions include the safety of neoadjuvant ICB prior to surgery, defining the right window of time and whether dosing should be extended. When examining outcomes, similar features have emerged across head and neck pathologic response: tumor cell necrosis, giant cell/histiocytic reaction to keratinous debris, and infiltrating lymphocytes. In this scenario, a grading scale was crafted to capture the partial responses that were emerging. It appears that a combination approach increases pathological responses, and additional checkpoints are prime for future exploration.
Dr. Uppaluri concluded by noting the progress that has been made in this area, where seven years ago, he and his colleagues presented their first findings on how pembrolizumab combined with standard of care contributed to the treatment of head and neck cancers. Fast forward to now, we have a study that has completed accrual and will likely be published in the next two years, showing definitively the role of neoadjuvant therapy in HPV-negative resectable head and neck cancers. This is an exciting frontier as yet in the investigational phase but has the potential to influence how surgeons view treatment.
Dr. Uppaluri emphasized the difficulty of these trials and shared his appreciation for the patients who enroll and their families, in addition to his colleagues. During the Q&A time, colleagues reciprocated their gratitude to Dr. Uppaluri, while also extrapolating on what they had just learned with more questions. Dr. Uppaluri concluded by noting the importance of a multidisciplinary approach to treatment.
