Ezra Cohen, MD, professor of medicine, UC San Diego Moores Cancer Center, discusses the challenges of treating patients with medullary thyroid cancer (MTC).

Cohen says there is a clear cohort of patients with MTC who have relatively indolent disease that doesn’t progress rapidly and therefore does not require treatment. However, for patients with progressive disease, physicians need to discuss treatment options and potential side effects, Cohen says. Additionally, it is important for all patients to undergo germline testing before treatment, since MTC can develop as a result of a hereditary syndrome Cohen says.

Once a therapy has been decided and started, physicians must follow the disease and manage the patients’ side effects. Unfortunately, all patients will end up progressing on their treatment. The biggest challenge in MTC, Cohen says, is that there is no third-line option following cabozantinib and vandetanib.

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Ezra Cohen, MD, professor of medicine, UC San Diego Moores Cancer Center, discusses the challenges of treating Medullary Thyroid Cancer (MTC).

Dr. Cohen Discusses the Challenges of Treating Medullary Thyroid Cancer

Ezra Cohen, MD, professor of medicine, UC San Diego Moores Cancer Center, discusses the rationale of the Active8 study.

This study is evaluating VTX-2337, a novel Toll-like receptor 8 (TLR8) agonist, for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). This study was conducted because TLR8 can activate immune effector cells, the agent can be administered with cetuximab, and it potentiates other cytotoxic chemotherapy agents. It was thought that the best setting for this agent would be in combination with a regimen that employed platinum and cetuximab.

In this phase II, randomized, double blind study, VTX-2337 was combined with the EXTREME regimen. The endpoint of the study was progression-free survival by immune RECIST criteria.

Cohen says it is intriguing that VTX-2337 does not appear to add any toxicity to the EXTREME regimen. For the first time ever with this trial, immunotherapy is being integrated into an active regimen in SCCHN.

Dr. Cohen on the Rationale of the Active8 Study in SCCHN

Ezra E. W. Cohen, MD, Associate Professor, Section of Hematology/Oncology, Department of Medicine, Co-Director, Head and Neck Cancer Program, Director, Hematology/Oncology Fellowship Program, University of Chicago Medical Center, discusses altering the dose size of cabozantinib in order to improve tolerability in medullary thyroid cancer (MTC).

The phase III EXAM trial administered 140 mg of base cabozantinib daily to patients with MTC, representing the maximum tolerated dosage as discovered in previous trials. Similar studies that are examining cabozantinib in various other types of cancer used lower doses effectively to treat patients. The effectiveness of this lower dose size raises the question of whether the dosage can be successfully reduced for MTC.

Cohen explains that approximately two thirds of patients on the EXAM trial required a dose reduction by either one or two levels. These lower dosages were better tolerated. If cabozantinib is approved, the message to physicians should be to start at the approved dose and liberally reduce as needed to provide optimal quality of life.

Ezra Cohen, MD, from the University of Chicago Medical Center, discusses the impact of cabozantinib's dose size on tolerability. 

Dr. Cohen on the Cabozantinib Dosage and Tolerability

Ezra E.W. Cohen, MD, Associate Professor, Section of Hematology/Oncology, Department of Medicine, Co-Director, Head and Neck Cancer Program, Director, Hematology/Oncology Fellowship Program, University of Chicago Medical Center, discusses an analysis of the phase III EXAM trial that examined the efficacy and pharmacokinetics of cabozantinib (XL184) for patients with advanced medullary thyroid cancer (MTC).

Cohen explains that one of the aspects of the study was to examine if the presence of mutations in the proto-oncogene 

 effected the activity of cabozantinib, an active inhibitor of the RET tyrosine kinase, which is theorized to be one of the main drivers in MTC. Regardless of the presence of 

 mutations all patients benefited from treatment with cabozantinib and only a slight difference was observed between those with or without a 

The pharmacokinetics of cabozantinib are fairly well understood; however, the impact of dose size and drug exposure on efficacy was further examined in the EXAM trial. Cohen explains that evidence from this study seems to suggest that exposure levels did not alter the efficacy of cabozantinib. Overall, this agent demonstrates very robust activity across multiple patient groups.

Ezra E.W. Cohen, MD, from the University of Chicago Medical Center, on the pharmacokinetics and efficacy of cabozantinib for medullary thyroid cancer. 

Dr. Ezra Cohen on the Pharmacokinetics of Cabozantinib

Ezra Cohen, MD, Associate Professor of Medicine, University of Chicago, discusses treating patients with medullary thyroid cancer (MTC) who do not have an available curative option and have progressive disease in need of therapeutic intervention.

Cohen believes that it is important to first assess the pace of progression for patients with MTC, before making a treatment decision. Determining the rate of progression, lesions, symptoms, and metastasis will help guide the therapy that is administered.

Cohen's first choice for progressive patients would be the multikinase inhibitor cabozantinib (XL184), if the FDA approves it. He believes the data from the phase III EXAM trial demonstrated a very strong response to this agent. Patients on the trial represented an aggressive and refractory population that experienced an 11.2-month increase in progression-free survival, compared to only 4 months in the placebo arm (HR 0.28, 95% CI 0.19-0.40, 

Other tyrosine kinase inhibitors have not achieved this degree of response for patients with MTC, in the past. As a result, Cohen describes these findings as very impressive.

Dr. Ezra Cohen, from the University of Chicago, Discusses Treating Medullary Thyroid Cancer

Dr. Cohen Discusses Treating Medullary Thyroid Cancer

Ezra Cohen, MD, Associate Professor of Medicine, University of Chicago, discusses the phase III EXAM trial that investigated the multikinase inhibitor cabozantinib (XL184) in patients with medullary thyroid carcinoma.

The trial enrolled 330 patients and randomized them 2:1 to receive either cabozantinib or placebo. For those receiving the active agent, the progression-free survival (PFS) was prolonged by 7.2 months, from 4 months in the placebo arm to 11.2 months in the investigational arm. Additionally, the overall response rate for the patients receiving cabozantinib was 28% compared to 0% in the placebo arm.

Various groups of patients were enrolled on the trial, including those who had previously received tyrosine kinase inhibitors, such as vandetanib or sunitinib. Cohen notes that the pretreated patients also demonstrated improvement over the placebo arm.

Cohen adds that he is optimistic that the positive results from the EXAM trial will lead to cabozantinib’s approval in the near future.

Dr. Ezra Cohen, from the University of Chicago, Discusses the Cabozantinib (XL184) EXAM Trial

Dr. Cohen Discusses the Cabozantinib EXAM Trial

Ezra Cohen, MD, Associate Professor of Medicine, University of Chicago, discusses the utility of inhibiting the mammalian target of rapamycin (mTOR) in head and neck cancer.

Cohen describes mTOR inhibition as being one of the more compelling targets in head and neck cancer. Drugs that inhibit mTOR, such as apamycin (sirolimus) and everolimus (Afinitor), are already approved for other indications and are currently being tested in head and neck cancer.

It remains difficult to determine how effective these therapies are as single agents, when given alone mTOR inhibition is most effective in the adjuvant setting and may help prevent recurrence. Adjuvant mTOR inhibition demonstrated efficacy in patients with minimal disease or no evidence of disease. Large or metastatic tumors, however, generally have multiple drivers and mTOR inhibition may not be as effective as a single agent.

Dr. Ezra Cohen, from University of Chicago, on mTOR Inhibition in Head and Neck Cancer

Dr. Cohen on mTOR Inhibition in Head and Neck Cancer

Ezra Cohen, MD, Associate Professor of Medicine, University of Chicago, discusses the next steps for head and neck cancer signaling pathways, specifically for patients that do not respond to the inhibition of the epidermal growth factor receptor (EGFR).

Cohen explains that every head and neck cancer expresses EGFR to some degree. The amount the tumor depends on the EGFR pathway for its survival varies from a complete reliance to none at all. If inhibiting EGFR is not effective another target may be active parallel or downstream from the pathway.

The mammalian target of rapamycin (mTOR) in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway seems to be a logical choice for inhibition in patients that do not respond to EGFR treatment. If this pathway is active it may be signaling independently from EGFR and would need to be targeted separately.

There are targeted agents that could aid in inhibiting these pathways but it is still unclear exactly which head and neck cancer patients will respond to PI3K/Akt/mTOR inhibitors. The next step is to take a closer look at the patients not responding to EGFR treatment and discover why and if another pathway is active.

Dr. Ezra Cohen from the University of Chicago Discusses Head and Neck Cancer Pathways

Ezra Cohen, MD

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