The Endocrine Society's 97th Annual Meeting & Expo:

Targeted Therapies in Medullary Thyroid Cancer

New approaches and outcomes to targeted therapies in medullary thyroid cancer were the subject of a talk by Ezra Cohen, MD, on March 8, 2015, at The Endocrine Society Annual Meeting in San Diego, California. Dr. Cohen is Professor of Medicine, University of California, San Diego.

Biology of Medullary Thyroid Cancer
Medullary thyroid cancer accounts for about 5% of thyroid cancers, and distant metastases carry a poor prognosis, with a median overall survival of approximately 2 years. Seventy-five percent of medullary thyroid cancer is sporadic, with approximately 65% of these sporadic cases mutated at the RET tyrosine kinase receptor. Medullary thyroid cancer is hereditary in 25% of cases, almost all being universally RET-mutated. “Medullary thyroid cancer is unique in many respects,” asserted Dr. Cohen. “It represents an excellent example of a cancer about which knowledge of its biology eventually led to effective therapy.”

Tyrosine Kinase Receptor (RET)
The tyrosine kinase receptor signals through multiple pathways to regulate survival, cell growth, and cell and tumor differentiation.

Typical Patient’s Journey
After initial diagnostic evaluation with a surgeon, internist, or endocrinologist, the patient typically undergoes locoregional therapy with a surgeon or radiation oncologist and germline mutation testing, with genetic counseling if necessary. Testing and counseling are usually with an endocrinologist. If the patient has refractory, recurrent, or metastatic disease, a medical oncologist will treat this. A radiation oncologist, surgeon, or interventionalist will treat a discrete lesion requiring palliation. Symptoms or thyroid management will be administered by an endocrinologist, palliative care specialist, or medical oncologist.

Recurrent Medullary Thyroid Cancer Treatment
Questions to consider at initial assessment:

  • Does the patient represent the proband of a hereditary medullary thyroid cancer syndrome? Perform germline testing to find out.
  • Is the patient potentially curable? If the patient has localized disease with a single metastatic focus, refer him or her to a surgeon, for external beam radiation therapy, or another ablative procedure.   
  • Does the patient require therapy?
  • Does the patient require nonmedical symptom palliation?
  • What is the extent of disease?

The National Comprehensive Care Network offers several management guidelines based on whether the metastatic medullary thyroid cancer is locoregional, asymptomatic, or symptomatic and/or progressive.

The American Thyroid Association recommends (grade E) that asymptomatic patients with small-volume metastatic disease that is stable to slowly progressive not receive systemic therapy. Any decision to undergo such treatment should be made only after a thorough discussion with the patient.

Therapy is ideally initiated in patients with good performance status, no to minimal symptoms, and evidence of disease progression within 6–12 months by x-ray or objective clinical observation, possibly carcinoembryonic antigen (CEA), and least likely, calcitonin.

Targeted Therapies
Phase 3 vandetanib (Caprelsa®) results were reported in 2012 (Wells et al, J Clin Oncol). At data cutoff (2009, median follow-up, 24 months), 37% of patients had progressed and 15% had died. The primary endpoint of progression-free survival prolongation with vandetanib was met (hazard ratio, 0.46, P < 0.001. A significantly higher objective response rate was observed for vandetanib vs placebo (45% vs 13%, P < 0.0001). In the open-label trial, 12 of 13 placebo nonresponders responded to vandetanib. A response in calcitonin was seen in 69% of vandetanib patients vs 3% for placebo (P < 0.0001). A CEA response was seen in 52% of vandetanib patients vs 2% for placebo (P < 0.0001). Time to worsening of pain was significantly delayed with vandetanib (P = 0.006). Common adverse events occurring in over 25% of patients were diarrhea, rash, nausea, hypertension, and headache. Dose reductions were required in 35% of vandetanib patients vs 3% for placebo.

Phase 3 results for cabozantinib (Cometriq®) were reported in two 2013 trials (Elisei et al, J Clin Oncol and Sherman et al, 2013 American Society Clinical Oncology Annual Meeting).

In the Elisei trial, cabozantinib resulted in a median progression-free survival of 11.2 months vs 4.0 months for placebo. A total of 47.3% of patients achieved a 1-year progression-free survival vs 7.2% for placebo. Target lesion regression was achieved in 94% of 180 patients vs 27% of patients taking placebo.

In the second trial, cabozantinib patients with an M918T RET mutation, (the predominant RET mutation in medullary thyroid cancer), experienced a 61-week median progression-free survival vs 36 weeks for those with other RET mutations. Cabozantinib patients with unknown RET status experienced a 48-week prolongation in progression-free survival vs 13 weeks for placebo.

In some patients with advanced medullary thyroid cancer who lacked a RET mutation, RAS mutations were uncovered. These patients experienced 47 weeks of prolonged median progression-free survival, vs 8 weeks for placebo.

Higher objective response rates were observed for cabozantinib across six mutations subgroups, and a 28% objective response rate was observed for all patients taking the drug.

Investigational Drugs for Advanced Medullary Thyroid Cancer

  • Everolimus
  • Anti-RET+ monoclonal antibodies
  • Anti-RET+ chimeric antigen receptor T-cells (CARs)
  • Anti-GFRA4 monoclonal antibodies
  • Anti-GFRA4 CARs
  • Yeast carcinoembryonic antigen (CEA) vaccine

Conclusions
With two approved drugs for advanced medullary thyroid cancer, patients now have effective options, though the decision to proceed with such treatment should be carefully considered. New therapies in development for RET inhibitor-refractory patients are fraught with barriers to their use, inasmuch as initial options are effective and no comprehensive molecular profiling exists for this relatively rare form of the disease.

“Despite medullary thyroid cancer being a relatively rare disease, the development of specific targeted therapy culminated in the approval of two drugs than can clearly prolong progression-free survival and improve symptoms,” reflected Dr. Cohen. “The challenge now is understanding how tumors become resistant to available therapies and developing new agents that are effective in highly refractory patients.”


March 13, 2015

 

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