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ASCO: Sorafenib Slows Progression in Advanced Thyroid Cancer

ASCO: Sorafenib Slows Progression in Advanced Thyroid Cancer

Ball-and-stick model of sorafenib

At the 2013 meeting of the American Society of Clinical Oncology (ASCO), there were promising results for patients with metastatic differentiated thyroid cancer (DTC) refractory to standard treatment with radioactive iodine (RAI). Investigators from the international randomized phase III DECISION (Study of Sorafenib in Locally Advanced or Metastatic Patients With Radioactive Iodine Refractory Thyroid Cancer) trial found treatment with the multitargeted tyrosine kinase inhibitor (TKI) sorafenib (Nexavar), which inhibits tumor growth signaling and angiogenesis, delayed disease progression by 5 months in patients with metastatic DTC that had progressed on RAI therapy.

Sorafenib, an oral agent targeting VEGFR1–3, PDGFRB, BRAF, RET, and c-Kit, is approved by the US Food and Drug Administration (FDA) to treat advanced cancers of the kidney and liver. A news release in mid May from ASCO, describing the DECISION study and its results, noted that if sorafenib is approved by the FDA for treatment of RAI-refractory DTC, “[it] would become the first new active drug for this form of thyroid cancer in 40 years.”

At the ASCO meeting, DESCISION trial investigator Marcia S. Brose, MD, PhD, highlighted the study results (plenary abstract 4) and their potential for improving care in this patient population. Dr. Brose is assistant professor of otolaryngology and head and neck surgery and director of the Thyroid Cancer Therapeutics Program at the Abramson Cancer Center, University of Pennsylvania, Philadelphia. The study was completely funded by the University of Pennsylvania, with only the study drug provided by Onyx and Bayer.

Differentiated Thyroid Cancer: An Orphan Cancer

Dr. Brose explained that thyroid cancer is the most common type of endocrine cancer, with an estimated 60,000 new cases and 1,850 deaths from the disease in the United States in 2013. The three main subtypes of thyroid cancers are anaplastic, medullary, and differentiated, with differentiated cancers being most common. “The vast majority of these will be [DTC]—that accounts for over 80% [of cases]. The majority of patients diagnosed with [DTC] will be cured by standard treatment involving surgery [thyroidectomy] and radioactive iodine, to suppress thyroid stimulating hormone (TSH), which acts as a growth hormone for these tumors. However, between 5% and 15% of patients with [DTC] will develop resistance to radioactive iodine, and once this happens, the overall survival for these patients drops to 2.5 to 3.5 years, and…clinically significant in this patient population is that a continuous progression of their disease results in significant morbidity, with frequent bone, pulmonary, and brain complications,” she said. “Thus, radioactive iodine–refractory thyroid cancer represents an orphan cancer.”

Currently, she emphasized, “there are no treatment options for patients, and the standard of care has been palliative care, or more recently, referral to a clinical trial.”

Study Details and Enrollment Criteria

DECISION was carried out by oncologists at 89 cancer centers in the United States (at the University of Pennsylvania and the University Texas MD Anderson Cancer Center), Europe (at centers in the United Kingdom, Italy, France, Germany, Poland, the Netherlands, and Denmark), and Asia (at the University of Ulsan College of Medicine, Seoul, South Korea).

Conducted from October 2009 to July 2011, DECISION enrolled 417 patients who had locally advanced (4%) or metastatic (96%) RAI-resistant DTC (with at least one target lesion without RAI uptake, or progression following a treatment dose of RAI, or a cumulative lifetime RAI treatment dose ≥ 600 mCi) that had progressed (based on RECIST criteria) in the preceding 14 months, and had not received prior chemotherapy, targeted therapy, or thalidomide, since the trial was designed to assess the efficacy of sorafenib in the first-line setting. Patients also had to have adequate TSH suppression (with TSH levels < .5 mU/L), as part of the standard of care for patients with persistent metastatic thyroid disease. Enrolled patients were required not to be candidates for surgery or radiotherapy with curative intent; to have adequate bone marrow, liver, and renal function; and to have an ECOG (Eastern Cooperative Oncology Group) performance status of 0–2. Median patient age was 63 years, and 52% of patients were female. Independent tumor histology showed 57% papillary, 25% follicular, and 10% poorly differentiated disease.

Patients were randomized 1:1 to sorafenib at 400 mg bid (n = 207) or placebo (n = 210). The experimental and control groups “were well balanced with regard to gender, age, region [of disease] and performance status,” Dr. Brose said. Crossover from placebo to open-label sorafenib upon disease progression at the investigator’s discretion was allowed.

Regarding dosing on trial, Dr. Brose pointed out that “the dose-reduction scheme for adverse events was modified from prior studies to include a mean 75% dose rate…to allow us to increase the ability to manage adverse events while minimizing the decrease in active drug.” She reported that 64.3% of patients on the sorafenib arm required a dose reduction, compared with 9.1% of patients on placebo. Permanent discontinuation from the study occurred in 18.8% of patients in the sorafenib arm vs 3.8% of patients on placebo. The mean dose that patients received was 651 mg in the sorafenib arm vs 793 mg in the placebo arm, but mean treatment duration was about twice as long in the sorafenib arm vs the placebo arm (about 40 weeks vs about 20 weeks, respectively), Dr. Brose said.

The primary endpoint, progression-free survival (PFS), was assessed every 8 weeks by independent radiologic review using modified RECIST 1.0 criteria. Secondary endpoints included overall survival (OS), response rate (which included both complete responses and partial responses), and safety.

Clinical Outcomes

Median PFS was 10.8 months with sorafenib group vs 5.8 months with placebo (hazard ratio [HR] 0.58; P < .0001). This short PFS in the placebo group “reflects that, unlike radioiodine-sensitive disease that can be indolent, the patients that were enrolled on DECISION represent a group of patients with clearly progressing disease,” Dr. Brose noted.

The response rate (all partial responses, defined as tumor shrinkage of 30% or greater) in the sorafenib vs placebo arms was 12.2% and 0.5%, respectively (P < .0001). Tumor shrinkage of any degree was seen in 73% of patients on sorafenib vs 27% of patients on the placebo arm. An important point, Dr. Brose emphasized, is that “while tumor shrinkage may not always reach the 30% cutoff for partial response, the shrinkage observed was often sufficient to alleviate symptoms in the symptomatic patients.” In the sorafenib arm, 42% of patients had stable disease for 6 months or longer compared with 33% in the placebo arm (for a disease control rate of 54% with sorafenib vs 34% in the placebo arm; P < .0001). “The median duration of partial responses [with sorafenib] was 10.2 months, which is close to the median [PFS] in this study,” Dr. Brose commented. OS has not been reached in either arm. About 70% of patients on the placebo arm have crossed over to the sorafenib arm, Dr. Brose said.

Adverse Events

Adverse events (any grade) were generally manageable with over-the-counter medications and reflected some known toxicities of sorafenib; they included hand–foot skin reaction, diarrhea, alopecia, rash/desquamation, fatigue, weight loss, and hypertension. The most frequent serious adverse events reported in the double-blind period of the study included secondary malignancy, which was 4.3% in the sorafenib arm vs 1.9% in the placebo arm. “This difference is accounted for entirely by the incidence of squamous cell carcinoma of the skin, a known side effect of sorafenib and easily controlled,” Dr. Brose said. Two drug-related deaths, one in the sorafenib arm and one in the placebo arm, occurred during the double-blind period.

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