Robert Ferris, MD, PhD
Investigators are evaluating the safety of chemoradiation in combination with nivolumab (Opdivo) in intermediate and high-risk head and neck squamous cell carcinoma (RTOG 3504, NCT02764593).
The trial, which is currently ongoing, randomizes 176 patients to cisplatin with radiation with nivolumab or placebo.
Nivolumab has shown an improvement in overall survival in patients with platinum-refractory, recurrent or metastatic head and neck squamous cell carcinoma, compared to standard therapy. The PD-1 inhibitor is approved by the FDA for this indication.
In an interview with OncLive
at the 2017 ASCO Annual Meeting, Robert Ferris, MD, PhD, vice chair for Clinical Operations, associate director for Translational Research, and co-leader of the Cancer Immunology Program at the University of Pittsburgh Cancer Institute, discussed the RTOG 3504 trial, as well as the utility of immunotherapy agents in this landscape.
OncLive: Please provide an overview of this study.
At ASCO , we demonstrated that anti–PD-1 therapy as a monotherapy was better than standard of care chemotherapy. Demonstrating that head and neck cancer was an immune-responsive disease led to the natural application of anti–PD-1 therapy, such as nivolumab, into earlier stages of disease.
Now in the locally advanced setting, the RTOG 3504 trial aims to look at an intensification by adding immunotherapy to the standard of care chemoradiation, using cisplatin with intensity-modulated radiation therapy. Therefore, in a randomized trial, we hope to add nivolumab to chemoradiation and improve progression-free and overall survival.
At this stage, the RTOG 3504 is focused on a phase I safety evaluation. Adding nivolumab to chemoradiation either in the weekly setting at 40 mg/m2
or as a bolus cisplatin 100 mg/m2
every 21 days. There are 2 standards of care for adding cisplatin to radiation, so we needed to test the addition of nivolumab to both standard of care regimens for locally advanced head and neck cancer.
What is the significance of this trial?
In head and neck cancer, we have HPV-positive disease, which tends to do better, and HPV-negative disease, which really has not seen any improvements in survival despite intensification with multiple chemotherapies, or even better radiation techniques. So, what we’ve done in the RTOG 3504 trial is to ask whether adding an immunotherapy on top of concurrent chemoradiation—which is really the most efficacious therapy for locally advanced disease—improves survival for the intermediate and high-risk patients who have really not seen a benefit in survival. So, we can randomize nivolumab monotherapy versus chemotherapy in recurrent metastatic disease, but by applying it to earlier stages—such as the locally advanced setting—we have the potential to actually elevate the survival curve and cure more patients in the intermediate and high-risk setting, which have not seen benefits in some decades regarding survival.
Combining immunotherapy with radiation makes a lot of sense—according to preclinical models—but we have relatively little data from patients. Another complicating issue is that the dosing schedule, the fractionation schemes of radiation, are a little bit restrictive, so we have to use them in the approved and traditionally applied format. There is some data that suggests such a fraction scheme may not be the best partner with immunotherapy, but in the locally advanced setting we have a curative regimen and we are pretty uncomfortable moving away from that in a group that we are trying to cure more.