VANTETANIB FOR MEDULLARY THYROID CANCER

A study of 60 patients in France with advanced medullary thyroid cancer who were treated with the kinase inhibitor vandetanib (Caprelsa, AstraZeneca) outside of a clinical trial showed that the drug could be an option for some patients.

Specifically, after a median of 9.7 months of treatment and a median of 20 months of follow-up, 55% of the patients had stable disease and 20% had a partial response. Those treated with the agent also had a median progression-free survival of 16.1 months, which is similar to the efficacy of this drug seen in clinical trials.

The work "also confirms that adverse events are frequent and that most are manageable with dose reduction and symptomatic treatment," lead author Dr Cecile N Chougnet, from the department of nuclear medicine, Hôpital Saint Louis, in Paris, France, and colleagues write, in an article published in the April issue of Thyroid.

"The prescription is rather safe and efficient even outside a trial and for several years, but side effects must be managed carefully," Dr Chougnet told Medscape Medical News.

"Vandetanib is a therapeutic option when local treatment is not effective any more, for selected patients," she noted, adding that her work shows this drug can be given for several months to several years and "can provide real help to control disease in some cases."

Vandetanib's Real-World Efficacy and Safety 

Vandetanib was approved by the US Food and Drug Administration (FDA) in 2011, followed by the European Medicines Agency (EMA), based on the ZETAphase 3 clinical trial (J Clin Oncol 2012;30:134–141), Dr Chougnet and colleagues write.

Median progression-free survival was more than 30 months with vandetanib vs 19 months with placebo in that trial, and 45% of patients responded to the drug. The adverse events included hypertension, diarrhea, fatigue, and skin toxicities (rash, folliculitis, photosensitivity), as well as prolongation of the QT interval on ECG that could lead to torsades de pointes and sudden death.

About 2160 patients with medullary thyroid cancer have been treated with vandetanib in total, of whom 565 were treated in clinical trials, but little is known about the efficacy and safety of this drug in a real-world setting, the researchers stress.

They therefore analyzed data from 60 patients (39 men) with advanced medullary thyroid cancer who were not part of a clinical trial and were treated with vandetanib from August 2010 to February 2012, based on a temporary-use authorization, before the drug was available in France.

Four patients (7%) had unresectable, locally advanced cancer and 56 had had metastatic cancer that had spread to the mediastinal lymph nodes (78% of patients), bones (65%), liver (53%), lung (53%), and other areas.

The patients had a median age of 48 when they were diagnosed. When they began treatment with vandetanib at a median age of 58, most patients (85%) had ECOG grade 0 or 1 cancer and the rest had ECOG grade 2 or 3 cancer.

Most received an initial dose of vandetanib of 300 mg/day, but patients with higher-grade cancer received lower initial doses. The patients received vandetanib for 0.3 to 36 months.

A total of 78% of patients survived 1 year, and 60% survived 2 years. One patient had a complete response and the cancer progressed in 7 patients (12%).

Three-quarters of patients had adverse skin reactions (folliculitis/rash/dry skin, photosensitivity, and hand/foot skin reactions); 58% of patients had diarrhea; 52% had asthenia; and 10% had visual abnormalities. Moreover, 19 patients (32%) had prolonged QT interval on ECG.

At the end of the data collection, 25 patients had died after receiving vandetanib for a median of 12 months; 23 deaths were related to disease progression. One patient died from arrhythmia after 8 months of treatment with vandetanib.

A total of 33% of patients switched to a lower dose of the drug, and 27% of patients discontinued it.

"Importantly, [the study showed that vandetanib] does not demonstrate any unexpected toxicity," the researchers write. Clinicians need to closely monitor patients to manage symptoms and adverse events, adjust doses, and, if needed, discontinue treatment, they note.

For example, patients should be advised to avoid sun exposure, and they may require dietary advice or treatment for diarrhea, Dr Chougnet said. Most patients may be able to avoid QT prolongation on ECG if they maintain normal levels of serum electrolytes (potassium, calcium, and magnesium) and avoid taking other drugs that affect this.

Thus, overall, "vandetanib is an effective option for patients with advanced medullary thyroid cancer," Dr Chougnet and colleagues conclude. "Adverse events should be monitored carefully and should be minimized by educating both patients and care providers and by applying symptomatic treatment and dose reduction."

Dr Chougnet was on the AstraZeneca advisory board after the completion of the study. Disclosures for the coauthors are listed in the article. The TUTHYREF (thyroid tumor board in France) received research support from AstraZeneca. 

Thyroid. 2015; 25:386-391. Article