The indication for AstraZeneca's investigational medullary thyroid cancer drug vandetanib (proposed trade name Zictifa) should be limited to patients with progressive and/or symptomatic disease to reduce the population at risk of drug-induced toxicities, FDA's Oncologic Drugs Advisory Committee said at a Dec. 2 meeting.

Although the majority of the panelists favored a more limited indication than that proposed by AstraZeneca, they also hesitated to place restrictions on use of the drug, particularly in patients who may be at risk for serious complications once their thyroid tumors progress. Instead, treating oncologists and endocrinologists should be educated that the drug may not be appropriate for those with indolent disease or for whom other treatment modalities, such as surgery, may be a better option, committee members said.

Looking For The Optimal Dose

Believing that alternative doses or dosing regimens could potentially reduce the toxicity burden, the panel voted unanimously, 10-0, that AstraZeneca should be required to conduct post-marketing studies to establish an optimal dose. Several committee members concurred with the suggestion by FDA Office of Oncology Drug Products Director Richard Pazdur that such studies could be performed in other tumor types, with the results extrapolated to the rare disease setting of medullary thyroid cancer.

If details about post-marketing studies and a Risk Evaluation and Mitigation Strategy can be worked out in the next month, vandetanib would be on-track for approval by its Jan. 7, 2011 user fee date.

AstraZeneca is seeking an indication for treatment of unresectable, locally advanced or metastatic medullary thyroid cancer, a rare disease with approximately 2,000 new cases per year in the U.S. The 10-year survival rate is estimated at approximately 40%.

The thyroid cancer indication would be the first for vandetanib, which in 2009 was the subject of an NDA submission for non-small cell lung cancer. That NDA was withdrawn several months later, however, because the progression-free survival benefit was not considered clinically robust and there was no benefit on overall survival (Also see "AstraZeneca Takes Hint From Regulators In Pulling Zactima Applications" - Pink Sheet, 28 October, 2009.).

In briefing documents and at the advisory committee meeting, FDA reviewers did not quibble with the drug's efficacy in medullary thyroid cancer. The agency's primary analysis of the pivotal Phase III trial found a significant 65% reduction in risk of progression with vandetanib (Also see "Toxicity Of AstraZeneca's Vandetanib Expected Focus For FDA Advisory Committee" - Pink Sheet, 30 November, 2010.).

However, agency reviewers said the long natural history of medullary thyroid cancer and the considerable toxicity associated with vandetanib warranted consideration of whether the drug should be reserved only for those whose disease had progressed or become symptomatic.

QT Concerns Exacerbated In Thyroid Cancer Patients

The most concerning toxicity is the drug's ability to prolong the QT interval. In the pivotal trial, 8% of vandetanib-treated patients experienced grade 3-4 QTc prolongation reported by investigators as adverse events. A review of study electrocardiograms showed that more than 35% of patients experienced QTcF prolongation exceeding 60 msec.

FDA medical officer Katherine DeLorenzo, who presented the agency's safety review, said the risks from vandetanib-induced QT prolongation are exacerbated by other factors common to medullary thyroid cancer patients, including hypocalcemia, electrolyte imbalance caused by diarrhea, and bradycardia.

FDA also raised concerns about a host of other events reported in the 3,000-patient vandetanib safety database, including sudden death, Torsades de Pointes, interstitial lung disease, cerebrovascular events, Stevens-Johnson Syndrome and diarrhea.

"Vandetanib has considerable toxicity which in some instances mirrors or is worse than the symptoms of untreated medullary thyroid carcinoma," DeLorenzo said. "Most significantly, the risk of sudden death from QT prolongation needs to be brought to the forefront of discussion in a drug that could potentially be taken for many years in patients who have a propensity for electrolyte fluctuations from either disease symptoms or treatment side effects. The clinical significance of frequent and more common toxicities, such as rash and diarrhea, need to be considered in the face of the continuous use of the drug."

Though the committee was not asked to vote on the issue, six of 10 members generally favored limiting the indication to those patients with progressive and/or symptomatic disease.

"I would favor some language that's a little more restrictive than simply locally advanced or metastatic, but keep the language open so that the physician's hands aren't tied, but at the same time it's not just wide open," committee chairman Wyndham Wilson, National Cancer Institute, said. "I do think you could craft language that would include progression [or] symptomatic organ risk that's sufficiently broad that really does cover the waterfront of what an oncologist would keep in mind."

Committee member Ralph Freedman, University of Texas M.D. Anderson Cancer Center, said the main emphasis should be on use for disease that cannot be controlled by other modalities.

"I don't think if you put down progressive and symptomatic it will handcuff any doctor," said committee member Patrick Loehrer, Indiana University, adding that it would be "logical" to study vandetanib's use as adjuvant therapy following surgery.

Patient representative and temporary voting member Marilyn Eichner opposed the more restrictive indication. "I would not like to tie my doctor's hands in any way with the language. I think they have the knowledge of who to treat and who not to treat."

Similarly, committee member Mikkael Sekeres, Cleveland Clinic Taussig Cancer Institute, said he preferred AstraZeneca's proposed indication. "I think that oncologists would have the good sense to view this appropriately, and if you limit the language to symptomatic/progressive, you may not be treating patients who have what I would call impending doom," such as tumors that are close to encroaching on the airway or interfering with other vital functions.

A "Cautionary Note" On Toxicity

After the committee members expressed their views, Pazdur said FDA was not trying to hamstring physicians by limiting the indication but, rather, to instill a "cautionary note" in labeling about the compound's inherent toxicities.

"Off-label use is alive and well in oncology and people can use this drug in any way they can in the treatment of these patients," Pazdur said. "But it is more of our purpose of drawing attention to the toxicities of this drug. Especially when you have an oral therapy - many people equate oral therapy with benign therapies, and this obviously is not a benign therapy given the QT prolongation here. So it's really more of a cautionary note that we're interested in."

Several panelists cited the need for physician education about the types of patients for whom vandetanib therapy would be appropriate. Presumably, information on the appropriate patient population and necessary safety assessments, such as QT interval monitoring, would be part of a REMS.

AstraZeneca Medical Science Executive Director Peter Langmuir said the company is planning to work with FDA on a REMS with a Medication Guide and physician education component. However, the company has not submitted a REMS because FDA has not yet formally asked for one, a company spokesman said after the meeting.

Committee members uniformly agreed that AstraZeneca should be required to conduct post-marketing studies to explore whether lower doses or alternative dosing strategies are less toxic, but still efficacious, compared with the proposed 300 mg daily dose that was used in the Phase III clinical trial.

Given the small medullary thyroid cancer patient population, several committee members liked Pazdur's suggestion that AstraZeneca could potentially explore alternative dosing strategies in studies involving other cancer types. The company could measure the drug's impact on thyroid cancer biomarkers, such as calcitonin levels, in these other cancers and then extrapolate those data to the thyroid cancer setting.

-Sue Sutter (s.sutter@elsevier.com)

FDA Committee Backs AstraZeneca's Vandetanib For Narrower Population Of Thyroid Cancer Patients

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