Expert Discusses Immunotherapy Advances in Head and Neck Cancer

Barbara Burtness, MD

Following the FDA approvals of pembrolizumab (Keytruda) and nivolumab (Opdivo) for patients with metastatic or recurrent head and neck squamous cell carcinoma, researchers are now focused on expanding on these immunotherapy successes.

Barbara Burtness, MD, hopes combination regimens will build on the response rates with single-agent immunotherapy.

“Regarding the responsiveness of immunotherapy versus the responsiveness of standard-of-care chemotherapy, platinum-based doublets with cetuximab have response rates of 40% and PD-1 inhibitors have response rates of 18%. For symptomatic patients, either a dual immunotherapy approach or a combination of chemotherapy with immunotherapy might be necessary to augment those response rates and help control the disease.”

OncLive: Can you start by giving an overview of your talk?

In an interview at the 2017 Onclive^® State of the Science Summit on Head and Neck Cancers, Burtness, a professor of Medicine at Yale Cancer Center, discussed her presentation on the current and emerging role of immunotherapy for patients with head and neck cancer.Burtness: Head and neck cancer has many of the qualities of other cancers that have done well with immunotherapy, which is to say that there is a subset of patients with head and neck cancer that have an inflamed phenotype. In head and neck cancer there are tumors that carry lymphocytes. Additionally, the ligand interacts with the PD-1 receptor and reduces the immune checkpoint phenotype.

There are many antigens in head and neck cancer because some are virally associated, creating viral antigens, and both HPV-positive and HPV-negative tend to have high mutational burdens. That means that there are new antigens that are expressed and these could be targets for immune effector cells if we could overturn the immune checkpoint.

We now have data that demonstrates the success of immune checkpoint inhibitors for patients with head and neck cancer. With pembrolizumab, there was a phase Ib trial and a confirmatory single-arm trial, both of which show response rates of 14% to 22% in previously treated head and neck cancer. They were both associated with long duration of response.

What are the next steps with pembrolizumab and nivolumab?

Subsequently, we saw the results of a randomized trial that studied patients with platinum-refractory disease, which is defined as either a recurrence that happens within 6 months of platinum in the definitive setting or they had progressed with metastatic recurrent disease. In this trial, the patients were randomized to nivolumab or to a standard of care—such as docetaxel, methotrexate, or cetuximab—of the investigators choice. The trial determined a survival advantage for the use of nivolumab over standard of care chemotherapy.Both nivolumab and pembrolizumab were approved for platinum-refractory disease. In my opinion, the most exciting area of research is to determine how to use immunotherapy for earlier stages of cancer. There is a confirmatory trial of pembrolizumab against the standard of care in platinum-refractory disease, which recently finished accrual. The results will hopefully be out next year. There are still some questions regarding whether or not immunotherapy has a role in the definitive setting or in frontline metastatic recurrent disease and if so how does it fit with standard of care and how do you pick a patient for immune therapy versus standard of care. I think the results of the current generation of studies will be very interesting.

In the setting of first-line metastatic recurrent disease, there are 2 trials that are attempting to combine immune checkpoint inhibitors to PD-1 pathways with agents that work specifically for that pathway. There was a randomized trial of nivolumab plus ipilimumab (Yervoy) versus nivolumab versus chemotherapy.

In a slightly different approach to the problem, there’s the trial of pembrolizumab combined with another immunotherapy versus chemotherapy and cetuximab, which is the standard of care in that setting, up against pembrolizumab alone. I think the attraction of the immune therapy only frontline approach would be the much milder adverse event profile, with respects to neutropenia, renal injury, and vomiting. Once you have the second immune therapy agent, the rate of immune-related adverse events will probably increase in head and neck.

Are there any ongoing trials in the space that you are excited about?

Regarding the responsiveness of immunotherapy versus the responsiveness of standard of care chemotherapy, platinum-based doublets with cetuximab have response rates of 40% and PD-1 inhibitors have response rates of 18%. For symptomatic patients, either a dual immunotherapy approach or a combination of chemotherapy with immunotherapy might be necessary to augment those response rates and help control the disease.At AACR this year, we saw some very interesting data from the CheckMate-141 study, where it appeared as if PD-L1 expression helped predict which patients will be most responsive and show more of a benefit. With that we were able to create a signature that demonstrated patients who were more likely to benefit from nivolumab compared to standard of care, where in a small subset of patients who [did not express] PD-L1 and did not have tumor-associated immune cells, it appeared as if they were less likely to benefit.

re there any other challenges that you would like to see addressed?

In pembrolizumab studies, there was an interest in looking at gene signatures using interferon response genes and if that signature is up, it appears that patients are more likely to benefit. Again, in the pembrolizumab trials, the PD-L1 expression in both tumor and tumor-infiltrating immune cells has appeared to be more impactful. A Pembrolizumab was approved in August and nivolumab was a couple of months later and we are routinely using those agents in patients with platinum-refractory disease who don’t have access to clinical trials. The majority of trials that we have now involve looking at novel uses of immunotherapy. I think that there are many patients who could benefit from these agents. We sometimes have patients who have progressed on immunotherapy and return to standard of care agents and seem to benefit from using them again. We also have phase I trials that use novel immunotherapy combinations.