Sorafenib a Possible Option for Medullary Thyroid Carcinoma?

Roxanne Nelson, BSN, RN

April 19, 2016

Sorafenib (Nexavar, Bayer/Onyx) may be a good alternative for the treatment of advanced medullary thyroid cancer (MTC) when two agents approved for this carcinoma, vandetanib (Calpresa, AstraZeneca) and cabozantinib (Cometriq, Exelixis), are not available, according to a new Brazilian trial published in the March issue of Thyroid.

Both vandetanib and cabozantinib have improved the treatment of advanced MTC, but they are not universally obtainable. Sorafenib does not carry an official indication for MTC, but clinical trials in the United States have shown activity for this drug.

The Brazilian researchers therefore initiated a small study to see whether sorafenib could be used as an alternative therapy, since they do not have access to the other two agents.

Asked to comment, Saad Khan, MD, an assistant professor in the department of internal medicine at University of Texas Southwestern Medical Center, Dallas, told Medscape Medical News, "There are a good number of drugs available for treatment of medullary thyroid cancer that is advanced, and of the roughly 3000 patients diagnosed with MTC every year in the US, many of them do not require drugs like cabozantinib or vandetanib."

But "patients in the US with MTC who have progressed on or did not tolerate cabozantinib and vandetanib will often be offered sorafenib, even though it is not an official indication and the degree of benefit is unclear," he explained.

"In places where cabozantinib or vandetanib is not available, sorafenib is definitely worth trying," he added. "It is also reasonable to give as treatment after the other ones, as long as the side effects are tolerable."

However, another expert contacted by Medscape Medical News is not convinced and says that a phase 3 trial of sorafenib for the indication of MTC must first confirm the utility of sorafenib and validate the drug for use in this setting.

Evolving Treatment for MTC

MTC is a rare form of neuroendocrine cancer and accounts for only about 5% of all thyroid malignancies. In about a quarter of patients, MTC is hereditary and associated with an autosomal dominant syndrome denominated multiple endocrine neoplasia type 2 (MEN2).

The Brazilian authors, led by Luciana Audi de Castroneves, MD, of the endocrinology department, Instituto do Cancer do Estado de São Paulo, note that treatment of advanced MTC has historically consisted of surgical resection of the primary tumor and regional lymph nodes and cytotoxic chemotherapy for progressive and/or symptomatic metastatic disease.

But the development of antiangiogenic tyrosine kinase inhibitors (TKIs) such as vandetanib and cabozantinib are changing treatment of the disease.

Both drugs have been approved in the United States but are not currently available in the Brazilian public-health system.

Sorafenib is a kinase inhibitor with activity against RET, VEGFR 2 and 3, PDGFR, and RAF and has received approval in Brazil for the treatment of progressive, metastatic differentiated thyroid cancer.

In addition, note the authors, it has been investigated in MTC, with response rates ranging from 80% to 100% and progression-free survival from 10.5 to 17.9 months.

Based on those results, and the unavailability of the other TKIs, the authors initiated their small study.

However, they note also that a recent study found that the incidence of adverse effects related to sorafenib appears to be considerably higher in patients with differentiated thyroid cancer than in patients with renal-cell or hepatocellular cancer (for which sorafenib is also approved). These events frequently led to dose reductions and even discontinuation of the treatment.

Hence, a secondary end point of their small study was the assessment of the toxicity profile.

Brazilian Study Details

Dr de Castroneves and colleagues conducted a retrospective longitudinal study that included 13 patients with progressive metastatic MTC who were treated with sorafenib 400 mg twice daily between December 2011 and January 2015.

One patient was excluded due to a serious allergic skin reaction that erupted 1 week after beginning sorafenib therapy and was excluded from the final analysis.

Of the remaining 12, 10 patients had sporadic disease and two had hereditary disease. Three patients also had locally advanced disease in addition to distant metastatic disease.

The median duration of sorafenib treatment was 11 months, varying from 2 to 34 months, while the median follow-up period was 15.5 months, ranging from 2 to 40 months.

The researchers observed that 75% of patients achieved a durable clinical response (stable disease 6 months or more), which ranged from 7 to 24 months.

While the median progression-free survival for the entire cohort was 9 months, three patients with extensive and rapid progressive disease died within a 3-month period after the initiation of sorafenib therapy.

When these patients were excluded and classified as early deaths, the progression-free survival was 12 months.

They also noted clinical improvement of disease-related symptoms, such as diarrhea, flushing, and bone pain, in 40% of the patients.

The most common adverse events were skin toxicity, weight loss, and fatigue, and five patients (41.6%) required a dose reduction.

In addition, another patient discontinued treatment because of toxicity.

Three (25%) patients had elevation of thyrotropin serum levels and required a median increase of 33.5% in levothyroxine dosage.

Results Need Validation; Phase 3 Trial of Sorafenib in MTC Required

Charles J Schneider, MD, from the Helen F Graham Cancer Center and Research Institute, Christiana Care Health System, New Castle, Delaware, says this very small retrospective analysis of only 12 patients "at best hints at disease responsiveness to this agent, which may or may not be enough to justify a legitimate clinical trial, since two other antiangiogenic tyrosine kinase inhibitors are available for use on the international marketplace."

He pointed out that there were several problems with this study, including its retrospective design and small size.

"The exclusion of three patients with rapidly progressing disease who died within 3 months of starting treatment in the 'calculation' of progression-free survival make this particular statistic invalid," Dr Schneider said.

But in its favor, the investigators used accepted and rigorous measurement parameters to determine response criteria, lending validation to their conclusion that 83.3% of patients enjoyed stable disease status, with durable clinical benefit in 75% of patients, he explained.

"This observation, in conjunction with perhaps better tolerability of sorafenib compared with vandetanib and cabozantinib, could be used to move this drug into a prospective trial," Dr Schneider observed.

"But it does not justify the author's conclusion that 'sorafenib treatment could be considered when vandetanib and cabozantinib are not available or after failing these drugs.' "

"Needless to say, a phase 3 randomized trial of sorafenib compared with either placebo or one of the two FDA-approved drugs is necessary to confirm the utility of sorafenib and validate the drug for use in the standard setting," he concluded.

The authors have no relevant financial relationships.

Thyroid. 2016;26:414-419. Abstract

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