Clinical Briefing: Sorafenib for Differentiated Thyroid Cancer
March/April 2009
Researchers at Penn Medicine recently completed a phase II
trial of sorafenib (Nexavar®), a promising new agent for the
treatment ofmetastatic, iodine-refractory thyroid carcinoma. Led
by Marcia S. Brose, MD, PhD, the research team included members
of both the Abramson Cancer Center of the University of Pennsylvania
and the Center for Head and Neck Cancer at Penn.
The trial population included a spectrum of thyroid cancer
histologic subtypes, including differentiated, anaplastic,medullary
and nonmedullary cancers. All patients had progressive disease at
baseline. Sorafenib, an oral multi-kinase inhibitor currently approved
for the treatment of non-resectable hepatocellular carcinoma
and advanced renal cell carcinoma, was administered at a
dose of 400mg orally twice daily for aminimumof 16weeks. Dose
adjustments were made as needed for toxicity. Study endpoints included
best objective response rate and progression-free survival.
On the basis of findings fromthe first 30 trial participants, the
Penn team concluded that sorafenib represents a significant advance
over chemotherapy in both response rate and progression free
survival (PFS) for patients with metastatic, iodine-refractory
thyroid carcinoma. 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. Treatment related adverse eventswere predominantly of
grade 1 or 2, with the most common events including palmar-plantar
erythema, rash, fatigue, stomatitis/mucositis, weight loss, and
musculoskeletal pain. The trial reportwas published in the Journal
of Clinical Oncology in October 2008.1
REFERENCES
1. Gupta-Abramson V, Traxel AB, Nellore A, Puttaswamy K, Redlinger M, Ransone
K, Mandel SJ, Flaherty KT, Loevner LA, O’Dwyer PJ, Brose MS. Phase II
trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008; 26:4714-4719.
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
and kidney. Mr. K was diagnosed with metastatic iodine-nonavid
differentiated thyroid cancer. With an anticipated survival of approximately
eight months, Mr. K agreed to participate in the
Phase II clinical trial of sorafenib in thyroid cancer at Penn.
|
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.
|
|
Within two months of initiating therapy at 400 mg bid, the progression
of Mr. K’s disease stabilized; a marked decrease in both
thyroglobulin levels and CT-documented tumor burden was
noted. At six months, Mr. K experienced palmar erythema, which
responded well to anti-inflammatory agents; he had no other significant
adverse effects during treatment. Today, at 27 months
post-treatment, his disease remains progression-free and he is
otherwise healthy.
Decreased metabolic activity in two metastatic thyroid lesions in a patient
before and after sorafenib treatment.
|
|
Thyroid Cancer Clinical Research at the Abramson Cancer Center
Clinical research is a fundamental mission of the Abramson
Cancer Center of the University of Pennsylvania. To determine
whether a patient is eligible for one of the following trials, please
visit oncolink.upenn.org and click on “Cancer Clinical Trials
Matching” in the left-hand column.
Title: An International, Randomized, Double-Blinded, Phase 3
Efficacy Study of XL184 Versus Placebo in Subjects With
Unresectable, Locally Advanced, or Metastatic Medullary Thyroid
Cancer
Phase: III
Rationale: The purpose of this research study is to evaluate the
progression-free survival (PFS) with XL184 as compared with
placebo (an inactive substance) in subjects with unresectable, locally
advanced, or metastatic medullary thyroid cancer (MTC).
Subjects will be randomized to receive XL184 or placebo in a 2:1
ratio. XL184 is an investigational drug that inhibits VEGFR2,
MET and RET, kinases implicated in tumor formation, growth
and migration.
Title: A Phase 1/2 Dose Finding Study of an Experimental New
Drug CS7017, an Oral PPARã Agonist Taken by Mouth Twice
Daily in Combination With Paclitaxel Chemotherapy Administered
Every Three Weeks by Venous Infusion by Patients With
Anaplastic Thyroid Cancer
Phase: I / II
Rationale: The Phase I/II study will be conducted as an open
label, multiple center study of CS-7017, an experimental drug
and paclitaxel chemotherapy in subjects with advanced anaplastic
thyroid cancer. Biopsies will be obtained from patients with accessible
tumor at baseline, two-weeks after the first CS-7017 dosage
(prior to the start of combination therapy) and at the end of the
first study cycle (week 3 of combination therapy), in order to
evaluate the effects of the study drug alone and in combination
with the chemotherapy agent on the tumor. Treatment will continue
until disease progression or the development of intolerable
toxicities.
Our Team of Faculty
The treatment of cancer at Penn Medicine involves more
than 300 specialists and researchers collaborating under the
auspices of the Abramson Cancer Center of the University of
Pennsylvania, a national leader in cancer research, patient care,
training, community education, and outreach. At Penn, cancer
patients are managed by oncologists, surgeons and radiation
oncologists who specialize in the diagnosis and treatment of
specific cancers; aftercare is tailored to address the emotional
challenges facing cancer patients and their families––and all of
these elements take place in a setting devoted to basic, translational,
clinical and cancer control research.
Department of Otorhinolaryngology – Head and Neck Surgery
Marcia S. Brose, MD, PhD
Assistant Professor of Otorhinolaryngology
Director, Cancer Genetics Laboratory
Abramson Cancer Center
Division of Endocrinology
Susan J, Mandel, MD, MPH
Professor of Medicine
Access
Patient appointments are available at:
Hospital of the University of Pennsylvania
3 Ravdin, Suite F | 3400 Spruce Street
Philadelphia, PA 10104
To refer a patient and/or consult with a doctor:
Call 800.789.PENN (7366) or refer
a patient online.
|
