Clinical trials performed at Penn Medicine under the aegis of the Abramson Cancer Center and the Penn Center for Head and Neck Cancer  were instrumental in the 2013 approval of the oral multi-kinase inhibitor sorafenib for the treatment of metastatic, radioiodine-refractory thyroid carcinoma.

Performed under the direction of lead investigator Marcia Brose, MD, PhD, these studies established sorafenib as a significant advance over chemotherapy in both response rate and progression-free survival (PFS) for patients with metastatic, iodine-refractory thyroid carcinoma.

In the Phase II study, all patients had progressive disease at baseline. Sorafenib was administered at a dose of 400 mg orally twice daily for a minimum of 16 weeks; dose adjustments were made as needed for toxicity. Study endpoints included best objective response rate and PFS. The overall clinical benefit rate for these patients (defined as partial response plus stable disease) was 77%. Median progression-free survival (PFS) was 79 weeks. No patient died before disease progression and no significant differences in PFS were observed between follicular and papillary subtypes.

Sorafenib Mechanism of Action

Sorafenib targets a number of factors that contribute to thyroid cancer, including:

  • B-type Raf kinase (BRAF) - A mitogen-activated protein known to play a key role in thyroid cancer, Raf is the kinase most efficiently inhibited by sorafenib. The oncogene BRAFV600E has been found in 29 to 69 percent of patients with papillary thyroid cancers, in whom it is associated with extrathyroidal extension and a poorer clinical prognosis.
  • Vascular endothelial growth factor (VEGF) - Overexpressed in thyroid tumors, VEGF contributes to angiogenesis. Inhibition of VEGF receptor signaling has been shown to inhibit growth of thyroid tumors in xenograft models.

On the basis of clear evidence of efficacy, the Phase II study was published early and Dr. Brose was invited to become the principal investigator for the international Phase III study, a double-blind, randomized study at Penn and elsewhere that compared sorafenib to placebo in locally advanced or metastatic patients with RAI-refractory DTC.

This trial subsequently demonstrated significantly extended progression-free survival (PFS) for patients taking sorafenib compared to placebo. The median PFS was 10.8 months among patients treated with sorafenib, compared to 5.8 months among patients receiving placebo.

In 2013, sorafenib was approved by the FDA for the first-line treatment of metastatic and RAI-refractory differentiated thyroid cancer.

Dr. Brose continues to investigate sorafenib and other new MKIs for patients with all types and stages of thyroid cancer. Her work has contributed to the FDA approval of the multi-kinase inhibitor cabozantinib (an inhibitor of MET, VEGFR2 and RET) for the treatment of advanced medullary thyroid cancer, and the completion of SELECT, a Phase 3 study of lenvatinib (another highly effective kinase inhibitor) for RAI-refractory DTC.

Case Study

Mr. K, a 37-year-old man, was referred to Penn Medicine by his internist after discovering a lump in his neck. His medical history was previously unremarkable. At Penn, a needle aspiration biopsy determined that the lump was a follicular carcinoma. Mr. K was scheduled for a thyroidectomy and bilateral central neck lymph node dissection. Of the 32 lymph nodes removed from Mr. K’s central and right lateral neck, 14 were positive for cancer. A subsequent total body PET scan revealed lesions in his left lung. Mr. K was diagnosed with metastatic iodine-non avid differentiated thyroid cancer. With an anticipated survival of approximately 8 months, Mr. K agreed to participate in the Phase II clinical trial of sorafenib in thyroid cancer at Penn. Within two months of initiating therapy at 400 mg bid, the progression of Mr. K’s disease stabilized; a marked decrease in thyroglobulin levels and CT-documented tumor burden in the lungs was noted (Fig 1). At 6 months, Mr. K experienced palmar erythema, which responded well to anti-inflammatory agents; he had no other significant adverse effects during treatment. At 27 months post-treatment, his disease was progression free and he was otherwise healthy.

Sorafenib treatment results, before and after

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Abramson Cancer Center
Perelman Center for Advanced Medicine
West Pavilion, 2nd Floor
3400 Civic Center Boulevard
Philadelphia, PA 19104

Otorhinolaryngology - Head and Neck Surgery
Perelman Center for Advanced Medicine
South Pavilion, 3rd Floor
3400 Civic Center Boulevard
Philadelphia, PA 19104

Published on: August 3, 2016

Penn Faculty Team

Marcia Brose, MD, PhD

Associate Professor of Medicine

Associate Professor of Otorhinolaryngology: Head and Neck Surgery at the Hospital of the University of Pennsylvania

Bert W. O'Malley, Jr., MD

Associate Vice President, Physician Network Development

Chair, Department of Otorhinolaryngology - Head and Neck Surgery

Co-Director, Head and Neck Cancer Center

Gabriel Tucker Professor of Otorhinolaryngology: Head and Neck Surgery

Professor of Otorhinolaryngology in Neurosurgery

Professor of Radiation Oncology

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