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State of the Science Summit on Head and Neck Squamous Cell Carcinoma and Thyroid Cancer

Michael Bouvet, MD, professor of surgery, University of California, San Diego, discusses the remaining challenges with thyroid cancer surgery.

The biggest challenge is to determine the right balance between treatment and observation, says Bouvet. It is also crucial that the initial operation on a large tumor is thorough in order to avoid a second operation and consequential risks.

Preoperative staging with ultrasound has really improved the accuracy of surgery for thyroid cancer, explains Bouvet.

Michael Bouvet, MD, professor of surgery, University of California, San Diego, discusses the remaining challenges with thyroid cancer surgery. 

Dr. Bouvet on Remaining Challenges With Thyroid Cancer Surgery

Joseph A. Califano, MD, professor of surgery, University of California, San Diego, discusses the future of surgery in head and neck cancer.

The newer targeted therapies combine well with surgery, says Califano. Surgery is the only way to see if a patient has a complete response following treatment with a systemic agent such as immunotherapy. Consequentially, surgeons can conduct minimally invasive surgery while clearing the disease, explains Califano.

In addition, advances in imaging technologies have increased the accuracy and efficiency of surgery for patients with head and neck cancer.

Joseph A. Califano, MD, professor of surgery, University of California, San Diego, discusses the future of surgery in head and neck cancer. 

Dr. Califano on the Future of Surgery in Head and Neck Cancer

Head and neck squamous cell carcinoma (HNSCC) consists of 2 biologically and clinically different diseases, according to Kathryn A. Gold, MD. The first of which is carcinogen induced, caused by tobacco or alcohol use, and the second being virally associated through the contraction of the human papilloma virus (HPV).

The recent rise in HPV has directly affected the increase in HNSCC cases, namely oropharyngeal cancer in men. Patients with HPV-positive present with a different set of prognostic factors and symptoms, says Gold, and should be treated with therapies that differ from those used in carcinogen-induced HNSCC.

 Can you provide an overview of your presentation on virally mediated head and neck cancer?

 State of the Science Summit™ on Advanced HNSCC and Thyroid Cancer, Gold, a medical oncologist and associate professor of medicine at University of California, San Diego Heath, discussed HPV status and prognosis of these patients, as well recognizing risk factors of virally-associated HNSCC. In an interview during the meeting, Gold emphasized the need for differentiated treatment, as well as the realistic opportunity to prevent cancer through vaccination.

 In the clinic, we are increasingly recognizing that more of our patients are coming in without the traditional risk factors that we think of for head and neck cancer. Traditionally, we think of head and neck cancer as being a disease of older men and those with tobacco or alcohol exposure. Some of our younger patients do not have any of those exposures. It is becoming increasingly recognized that HPV is the cause of their head and neck cancer.

How should we approach HPV-positive patients differently?

This seems to be very clinically important. These patients are younger and healthier than our HPV-negative patients and the treatment outcomes do tend to be different, as well.

We know that HPV-positive patients tend to have a better prognosis. If a patient who is HPV positive comes in with locally advanced disease, there is a good chance that I can cure their cancer. Right now, we are not using that as a factor to select treatment options, but we will in the future. As we learn more about this cancer, we may be able to dial back a little bit on the treatment for these patients and possibly spare them some of the long-term toxicities that we see with head and neck cancer therapy.

What are the clinical characteristics that are seen with this population?

Can you provide some insight into the treatment of HPV-related oropharyngeal cancer?

We now know that HPV is prognostic. For patients who come in with locally advanced disease, we typically treat them with chemoradiation—which are the vast majority of patients that I see in my clinic. Chemoradiation of HPV-negative cancer does not have great overall survival; it is only about 40% at 5 years. For HPV-positive cancer&mdash;especially nonsmokers&mdash;we cure about 85% of those patients so the prognosis is very different. Even for HPV-positive patients, smoking affects this rate. If a patient is HPV positive and they are a smoker, their outcome in a more intermediate category than those who have never smoked. 

The clinical characteristics that we see in someone coming in with an HPV-positive head and neck cancer, firstly, is that the primary site tends to be in the base of the tongue or tonsils, while HPV-negative disease is more likely to be found in the oral cavity, larynx, or hypopharynx. HPV-positive patients also tend to be younger than those who present with HPV-negative. They are usually male; it’s about a 3:1 ratio of men to women with HPV-positive head and neck cancer. Pathologically, these tumors are more likely to be differentiated, non-keratinizing carcinoma. 

Oropharyngeal cancer typically presents locally advanced, meaning with a large primary tumor—or more often, with lymph node metastases. The textbook treatment for these is to combine chemotherapy with radiation, specifically, intensity-modulated radiotherapy with high-dose cisplatin at 100 mg/m

 every 3 weeks. That is our typical treatment, and it leads to good outcomes; however, we also know that it is very hard to tolerate. It can leave people with lifelong swallowing difficulties, dry mouth, and neuropathy. Obviously, if that is the only way to cure the cancer, than most people would say that it is worth it. However, our goal is to cure them with less intensive therapy. 

What challenges have you observed with the HPV vaccination?

We are looking at newer approaches. Surgery, specifically robotic surgery, is being more frequently used for these patients. The idea is that we can clear out most of their disease and then perhaps they can get a lower radiation dose and spare chemotherapy afterwards. We are also looking at the possibility of using only radiation therapy. We know that chemotherapy is necessary for HPV-negative tumors; however, for HPV-positive disease, we may be able to get away with using less or no chemotherapy. There are a lot of clinical trials focusing on that right now.

I am a strong proponent of vaccination. I have 2 children, and I can tell you as soon as they are old enough I will be dragging them to the pediatrician’s office to get them their shot because this presents a very real opportunity to prevent cancer. It has gotten more press for preventing cervical cancer, but we also believe it will prevent most cases of oropharyngeal cancer related to HPV, as well.

The side effects of the vaccine are pretty mild. A sore arm is the thing complained of most often; however, if you look on the internet, you can see a lot of websites alleging other bad things will happen. The science hasn't really borne that out. Hopefully, the HPV vaccine will put me out of a job and force me to learn something else in 20 years.

Unfortunately, the uptake has been low. Less than 30% of eligible people across the country get the vaccination. More girls than boys get it, but boys need to be vaccinated, too. It protects them not only against oropharyngeal cancer, but against genital warts, and possibly penile and anal cancer. 

What would you like your main message to be about HPV-related head and neck cancer?

One of the reasons that this vaccine hasn't been taken up too much is that there is an association of HPV as a sexually transmitted disease. There is a fear that we are giving our children mixed messages by vaccinating them at a young age against a disease that is sexually transmitted. I can understand that complaint, but at the same time I would do everything that I can to protect my children from getting cancer, and I don't think the squeamishness about them one day becoming sexually active should factor into that. 

HNSCC is 2 entirely different diseases. Biologically and clinically, HPV-negative squamous cell carcinoma is a very different disease than HPV-positive squamous cell carcinoma. Therefore, clinical trials in the future need to differentiate between them. 

For HPV-negative disease, we need to focus on intensifying therapy and trying to get better outcomes. In the recurrent and metastatic setting, we need to focus on targeting things like CDK4/6 and other pathways that are possibly involved in cell cycle regulation. 

On the other hand, in the locally advanced setting of HPV-positive disease, we need to focus on de-intensifying therapy and trying to spare patients from toxicities. In the metastatic setting, the focus might be a bit different, as well. Immunotherapy might be even more important for HPV-positive disease. Although it is important for both groups, we may have different opportunities to target pathways, such as PI3K. There is also an opportunity to study therapeutic vaccines in this group.

The biggest thing moving forward is that we need to treat these cancers like the 2 entirely different diseases that they are, and not group them together just because, geographically, they occur in the same areas. 

Kathryn A. Gold, MD, discusses HPV status and prognosis, as well recognizing risk factors of virally-associated head and neck squamous cell carcinoma.

Expert Differentiates Carcinogen-Induced and Virally Associated HNSCC

As with other solid tumors, researchers are now exploring both BRAF/MEK inhibitor combinations and PD-1 therapy in the field of thyroid cancer for patients who are refractory to radioactive-iodine treatment, according to Gregory Daniels, MD, PhD, who adds that there is an increased emphasis on genetic testing to determine potential driver mutations in these patients.

For example, an ongoing phase II clinical trial is investigating the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) versus dabrafenib alone in patients with recurrent 

-mutated thyroid carcinoma (NCT01723202). This is a next step from other systemic agents, such as sorafenib (Nexavar) and lenvatinib (Lenvima), which are already FDA approved to treat patients with thyroid cancer.

The FDA approved lenvatinib in 2015 as a treatment for patients with progressive, radioactive iodine-refractory differentiated thyroid cancer based on initial progression-free survival results from SELECT, which showed that the drug reduced disease progression and significantly improve overall survival (OS) compared with placebo in patients older than 65 years old.

: Please provide an overview of your presentation on thyroid cancer.

What have been some recent advancements in the field?

Are there any clinical trials in this space that you are excited about?

 on Head and Neck Squamous Cell Carcinoma and Thyroid Cancer, Daniels, a clinical professor in the Department of Medicine at University of California, San Diego, discussed the current treatment landscape of thyroid cancer and the development of immunotherapy for patients with this disease.

 I discussed advanced thyroid cancer, meaning thyroid cancers that have become refractory—usually to radioactive iodine or other conventional therapies, such as surgery. Surgery remains to be the first choice of treatment. However, patients with advanced cancer see their cancer spread to the lungs, bone, or other organs. The main focus of my talk was the current role of medical oncology in the field of thyroid cancers after radioactive-iodine therapy.

Like other areas of oncology, thyroid cancer is now getting personalized therapies [targeted to the driver mutations], as well as immunotherapy with checkpoint inhibitors. The 2 FDA-approved medications in thyroid cancer, sorafenib and lenvatinib, are tyrosine kinase inhibitors (TKIs) and target VEGF 1/2/3. That's what is currently happening regarding the genetics for these patients.

When looking at a differentiated thyroid cancer—papillary thyroid cancer being the most common&mdash;that is refractory to radioactive-iodine therapy and need systemic treatments, the first thing we will do is sequence their somatic mutations in their tumor. That is not whole-genome sequencing, but it is looking at 200 or 300 targets. Thyroid cancer often has the MAP kinase pathway perturbed with a

We are attempting to utilize the drugs that we have in other tumor types, such as melanoma, by inhibiting 

 with either dabrafenib or vemurafenib (Zelboraf). These are not FDA approved in thyroid cancers, but are [being explored] in clinical trials. Dr Manisha Shah at The Ohio State University just completed a study demonstrating that combination therapy with both dabrafenib and trametinib has good activity in thyroid cancers with

Another area is the observation that MAP kinase activation appears to be associated with less differentiation in the cancers. There is a hypothesis that we can increase iodine uptake in cancers by inhibiting the MAP kinase pathway.

If drugs such as dabrafenib are approved by the FDA, what impact would they have on the treatment landscape? Would they be better used in combinations?

A study that is ongoing is utilizing a MEK inhibitor compared with placebo in patients who have received radioactive iodine. We are looking to give them another dose, but can we enhance the benefit of radioactive iodine by turning off this MAP kinase pathway? We hope to find the answer in that exciting trial.

In my opinion, we should use genetics to discover what is driving the mutation. The next thing that happens with these targeted therapies is resistance. We are beginning to understand these secondary pathways that are coming up. For example, 

 is activated at MAP kinase resistance when you start turning off BRAF. There are ongoing studies looking at those combinations. 

What advice do you have for oncologists who are treating patients with thyroid cancer?

As far as immunotherapy is concerned, we have pembrolizumab (Keytruda), nivolumab (Opdivo), and many other PD-1 inhibitors. These have good activity, but many times they cause stable disease for a period of time. That is also another opportunity for combination therapies that have been successful in melanoma, lung cancer, and other tumor types. That should be coming to thyroid cancer, as well. 

It is important to start with the genes. A patient with thyroid cancer who is looking at first-line options and is resistant to radioactive-iodine therapy should have a somatic gene panel done to figure out the driver mutation. Even though lenvatinib and sorafenib are first-line agents that are approved in this indication, they do not depend on the gene. However, you will be needing that information if they have toxicities from these agents and need to switch.

What should community oncologists take away from this presentation?

These drugs are not FDA approved in thyroid cancer, but we can use them off-label with sufficient justification. The clinical trials are showing us good activity and a good safety profile. I would advise physicians to go ahead and get sequencing upfront. 

The treatment paradigm of thyroid cancer continues to move forward. We have gotten out of the realm of cytotoxic chemotherapies that are now giving personalized treatments.

We also now have immunotherapies [in clinical trials]. We need to put more patients with thyroid cancer on clinical trials. I encourage patients and providers to think about that as they are looking at their options. We do have approved agents, but we need to do better and clinical trials are the way to improve.

Gregory Daniels, MD, PhD, discusses the current treatment landscape of thyroid cancer and the development of immunotherapy for patients with this disease.

Immunotherapy, New Targeted Approaches Explored in Thyroid Cancer

Gregory A. Daniels, MD, PhD, medical oncologist, associate professor of medicine, UC San Diego Health, discusses treatment options for patients with thyroid cancer.

The 2 FDA-approved agents for the treatment of patients with thyroid cancer are sorafenib (Nexavar) and lenvatinib (Lenvima). These are tyrosine kinase inhibitors that target VEGF1, VEGF2, and VEGF3, but these are not necessarily the driver mutations, says Daniels.

The hype of personalized medicine now is making its way into thyroid cancer, says Daniels, and a genetic-based approach to treatment may be in the future for this disease.

Dr. Daniels Discusses Treatment Options in Thyroid Cancer

Ezra Cohen, MD, associate director, Moores Cancer Center at the University of California, San Diego, discusses the role of entrectinib in treating patients with head and neck cancer.

gene will fuse with other elements, usually transcription factors, and can activate the cancer phenotype in multiple ways.

In a case of anaplastic thyroid cancer, the tumor had this 

fusion and within 10 days, the patient went from being dependent to being out of the hospital after being treated with entrectinib.

Ezra Cohen, MD, associate director, Moores Cancer Center at the University of California, San Diego, discusses the role of entrectinib in treating patients with head and neck cancer.
 

Dr. Cohen Discusses Entrectinib in Head and Neck Cancer

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.

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

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.

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 

. We have come to understand that, for some cancers, the 

 gene can fuse with other elements—usually transcription factors&mdash;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 

 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.

Ezra Cohen, MD, discusses the role of immunotherapy, the potential of entrectinib, and the importance of multidisciplinary teams for the treatment of patients with head and neck cancer.

State of the Science Summit on Head and Neck Squamous Cell Carcinoma and Thyroid Cancer | Conference