Role of Immunotherapy Expanding in Head and Neck Cancer

Ezra Cohen, MD

Immunotherapy and novel multikinase inhibitors continue to play an important role for patients with head and neck cancer, particularly as ongoing clinical trials are further exploring these agents.

The field already has 2 immunotherapy approvals with PD-1 agents. Pembrolizumab (Keytruda) was granted an accelerated approval by the FDA in August 2016 for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma following progression on a platinum-based chemotherapy. Then in November 2016, the FDA approved nivolumab (Opdivo), another PD-1 inhibitor, for patients with metastatic or recurrent disease for a similar indication.

“We’ve come to learn that immunotherapy is effective in patients with head and neck cancer,” said Ezra Cohen, MD.

OncLive: Can you provide an overview of treatment options for patients with advanced head and neck cancer?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Head and Neck Squamous Cell Carcinoma and Thyroid Cancer, Cohen, professor of medicine, Division of Hematology/Oncology, associate director for Translational Science, Moores Cancer Center, University of California (UC), San Diego, discussed the role of immunotherapy, the potential of entrectinib, and the importance of multidisciplinary teams for the treatment of patients with head and neck cancer.Cohen: There are [immunotherapy] drugs and single agents for patients with platinum-refractory disease. In my talk, I discussed those data and the reason behind their approvals.

Can you discuss immunotherapy combinations in head and neck cancer?

The excitement that is yet to come is around combinations of immunotherapies and the integration of chemotherapy with radiation. Hopefully, that will have the ability to cure more patients.When we look at the most exciting combinations in head and neck cancer, it is important to understand what we know about the biology of the disease. For an anti—PD-1 drug to be effective, we know that an immune response has happened.

We have anti—PD-1/PD-L1 agents that are activating T cells, but when those T cells are at the tumor, they still may not be effective because they are suppressed by so many other things in that tumor microenvironment, such as Tregs (regulatory T cells), myeloid derived suppressor cells, macrophages, and fibroblasts.

What do you hope community oncologists will take away from this discussion regarding immunotherapy?

We are seeing that agents can affect other processes, for instance how STAT3 inhibitors affect myeloid-derived suppressor cells, Tregs, and natural killer cells, and an IDO inhibitor can affect both T cells and partially myeloid-derived suppressor cells. We are seeing a doubling or tripling of response rates, with many of those responses being complete responses. It is still in the early days, but these are very exciting data.The most important thing to take away regarding immunotherapy is that it is now the standard of care for patients with recurrent, metastatic, platinum-refractory disease.

Can you discuss the role of entrectinib in head and neck cancer?

Immunotherapy is moving into the first-line setting very rapidly. We are going to see data from phase III trials in late 2018 into 2019. It would not surprise me if immunotherapy augmented existing chemotherapy. In 2019 or 2020, we are going to begin to look at immunotherapy in the curative setting with the hope that we can cure more patients. The message would be: immunotherapy is here, but look out for more to come in the near future. Entrectinib is a drug that inhibits kinases at very low molecular level. It’s a specific and potent inhibitor of ROS1, ALK, and NTRK. We have come to understand that, for some cancers, the NTRK gene can fuse with other elements—usually transcription factors—and activate the cancer phenotype in multiple ways. That fusion is centrally controlled by the biology of that cancer cell and that tumor. We’ve seen that by inhibiting that, we can often see dramatic responses in patients.

We presented a case of a patient with anaplastic thyroid cancer who had failed multiple lines of therapy, including chemotherapy, radiation, and other types of targeted therapies that are approved for thyroid cancer. We discovered that the tumor had this NTRK3 fusion and, within 10 days, the patient went from being dependent to being out of the hospital.

What are the main challenges and unmet needs for patients with head and neck cancer?

The patient achieved a dramatic response that was maintained 6 months after he started the drug. This was a patient who would have died of this disease by now. This is not a unique case as we’re seeing this in other cancer types as well, such as salivary gland cancer, non—small cell lung cancer, and sarcomas. This dramatically tells us that we are in a different era in cancer therapy. We are in the age where we need to understand the tumor at a molecular level, find out what's driving it, and hit those drivers. When we do, we see dramatic effects. There are more than a few unmet needs in head and neck cancer. When we think about the different cancer types, we realize that it is important to understand and individualize therapy for the patients.

In broad terms, the challenge that remains for all head and neck cancers is the desire to cure the patient. In head and neck cancer, we are fortunate to be discussing cure with curative intent therapy, particularly for locally advanced squamous cell carcinoma, salivary gland cancer, and thyroid cancer.

There is a challenge to preserve the quality of life of the individual. For local events, such as squamous cell carcinoma in the HPV-positive area, we're curing more patients; however, we are also seeing more patients who are suffering the long-term morbidities of surgery, radiation, and chemotherapy.

Do you have any advice in terms of multidisciplinary teams or palliative care?

We're trying to cure patients at a higher rate. We're hopefully going to achieve that with immunotherapy and other new agents, but we need to realize that the function that comprises the organs of the head and neck, such as our ability to speak, swallow, and interact as humans, is so critical that the quality of life is almost as important as life itself in this disease. For head and neck cancer, data clearly state that patients do better when there is a multidisciplinary team in place. What does that mean exactly? It's not just having the list of names and their specialties, but it is having them interact at a multidisciplinary tumor board.

What do you think is particularly exciting about this State of the Science SummitTM?

Is there anything else you're working on right now or that you find particularly exciting in the field?

There is evidence to suggest that patients who are [treated] in a multidisciplinary tumor board have better outcomes. Having the right people in place who are dedicated to treating the patient in a comprehensive and collaborative way at the beginning is how we can achieve the best outcome, whether it is with surgery, radiation, chemotherapy, better nutrition, getting speech and swallow exercises, dentistry, or the many other healthcare disciplines in line.This program illustrates what we are trying to do in head and neck cancer and thyroid cancer. We are trying to bring different people together with different disciplines—each with their area of expertise. It’s important to begin a dialog to share ideas for how different specialties interact and learn from each other. We can review the field in a comprehensive way with people who are among the best in the world at what they do.What I find the most exciting in the field are clinical trials. At UC San Diego, we have a lot of clinical trials for patients with head and neck cancer. We have a very deep interest in immunotherapy and many of our studies are geared toward that.

One of the things that we will be seeing in the future is precision immunotherapy. That means understanding the tumor at a molecular level, what the mutations are that create antigens for the immune system, and understanding the individual’s immune system and what they are most likely to respond to. We can create personalized approaches that should be much more effective than what we have today.

Those approaches will be combined with other types of immunotherapies that stimulate T cells. The core of taking those big steps forward is going to be that the personalized or precision approach might be in personalized vaccines or cellular therapies that are specifically engineered for that specific tumor.