EA3211 – A Phase III Randomized Trial of Immunotherapy with or without Consolidative Radiotherapy for Oligometastatic Head and Neck Squamous Cell Carcinoma

The study chair for this trial is David J. Sher, MD, MPH (UT Southwestern Medical Center) and the study co-chair is Jessica R. Bauman, MD (Fox Chase Cancer Center).

Selecting treatment for patients with newly diagnosed but metastatic head and neck squamous cell carcinoma (HNSCC) can be a clinical conundrum for the treatment team. Patients commonly have significant symptoms at the primary site (sore throat that does not go away, difficulty swallowing, hoarseness in the voice, and mouth/tongue sores that do not heal). At the same time, clinicians seek treatments that will also be effective against metastases. The goal is to extend patients' survival while alleviating symptoms and improving their quality of life.

Over the past 5 years, anti-PD1/PD-L1 immunotherapy has changed the landscape of treating metastatic head and neck cancer patients. Medicines such as pembrolizumab and nivolumab have significantly improved overall survival for these patients—both in the first-line and platinum-refractory settings. Yet despite the excitement over their use in this group of patients, long-term survival is still poor, approximately 30% at 2 years. And while novel therapeutics and immunotherapy combinations may offer potential, such approaches are not proven and may be associated with significant toxicity.

One promising approach is the addition of radiotherapy to both the primary site and metastatic lesions, which has shown marked, meaningful overall survival benefits in recent randomized trials. Thus, determining the role of consolidative radiotherapy (CoRT) in patients with oligometastatic HNSCC treated with chemoimmunotherapy is the central question that study EA3211 seeks to answer.

This randomized phase 3 trial will enroll 290 patients. To be eligible, patients must have biopsy-proven metastatic HNSCC originating in the oral cavity, larynx, oropharynx, or hypopharynx, with active disease present in both the head/neck and distant sites, four or fewer metastatic sites, and have had no prior head and neck radiotherapy.

For Step 1 (registration), patients who have not started any systemic therapy (or who have started but not finished it) will complete three cycles of chemotherapy plus pembrolizumab. Patients who have already completed three rounds of initial systemic therapy will register and proceed directly to Step 2.

For Step 2 (randomization), patients will have imaging (neck, chest, and abdomen CT) for restaging/to verify the cancer status. Patients with progressive disease will discontinue protocol therapy. Patients with stable disease will be randomized to one of two arms: Arm A (CoRT to the primary and metastatic sites plus pembrolizumab) or Arm B (pembrolizumab monotherapy). After randomization, patients on both arms will receive an additional fourth cycle of chemotherapy plus pembrolizumab before starting the study treatment.

The primary objective of EA3211 is to compare overall survival between immunotherapy plus CoRT and immunotherapy alone following non-progression with systemic chemoimmunotherapy. As a secondary objective, researchers hope to establish the prognostic value of quantitative PET biomarkers at baseline for overall survival in both arms.

Consolidative head and neck radiotherapy is known to increase short-term treatment-related toxicity but may improve long-term quality of life by reducing the risk of tumor progression. Moreover, the impacts of locoregional and distant CoRT on immunotherapy-related toxicities, such as fatigue and pneumonitis, are not well understood. The EA3211 study includes a health-related quality-of-life assessment to measure both the upfront effects of CoRT as well as long-term differences in patient-reported outcomes between the arms.

EA3211 is a pivotal clinical trial. If this study is positive, it could have the potential to immediately change clinical practice for the management of HNSCC and improve patients' quality of life. If negative, the finding would halt the not uncommon practice of irradiating these patients at the beginning of their treatment course.

Learn more about EA3211 at ecog-acrin.org.