FDA Explains Erlotinib Approval After ODAC Advised Against It
(I guess my question is why they held the ODAC in the 1st place if they were going to overide it no matter what)
Elsevier Global Medical News. 2010 Apr 21, E Mechcatie
Why did the Food and Drug Administration go against the advice of its own advisory panel to approve erlotinib tablets as a maintenance therapy for patients with locally advanced or metastatic non-small cell lung cancer?
Regulatory precedents, trial design, and lack of a comparative effectiveness standard all played a part in the unusual decision, according to Dr. Robert Justice, director of the Center for Drug Evaluation's Division of Oncology Drug Products.
The Oncologic Drugs Advisory Committee (ODAC) voted 12-1 against the FDA's giving a maintenance indication to erlotinib (Tarceva) at a meeting in December 2009. Members cited concerns about the modest effect in the study that manufacturer OSI Pharmaceuticals Inc. had submitted for approval, and the fact that only one study was available to support the new indication.
"After the December meeting there were extensive discussions within FDA regarding the application, and the ODAC's recommendation was carefully considered," Dr. Justice responded to an inquiry by this news organization following the approval announcement on April 19.
One issue was regulatory precedent, he said. The agency had approved bevacizumab (Avastin) in a regimen for nonsquamous non-small cell lung cancer (NSCLC) based on a 20% reduction in the risk of death, compared with chemotherapy alone. It had also accepted pemetrexed (Alimta) as a maintenance treatment for nonsquamous NSCLC "based on a 30% reduction in the risk of death compared to no maintenance therapy and a 21% reduction in the risk of death in patients with all types of NSCLC," noted Dr. Justice.
"The reduction in the risk of death with erlotinib maintenance treatment compared to no maintenance therapy was similar at 19%," he said.
The double-blind, international SATURN (Sequential Tarceva in Unresectable NSCLC) trial that formed the basis of the erlotinib application had randomized almost 900 patients with locally advanced or metastatic NSCLC that did not progress during first-line, platinum-based chemotherapy.
Median progression-free survival was 2.8 months in patients who were given erlotinib as maintenance therapy vs. 2.6 months in a placebo arm - a statistically significant difference that represented a 29% reduction in risk of progression. Overall survival, a secondary end point, reached a median of 12 months with erlotinib and 11 months with placebo - again, a statistically significant difference.
A second issue was trial design, Dr. Justice said. He cited general agreement "that the optimal trial design would have been erlotinib maintenance vs. erlotinib at progression of disease." Although OSI has agreed to do such a study as part of its postmarketing commitment, he suggested that "this may not reflect what will actually happen in practice."
In the SATURN trial, he noted, 259 patients (57%) of the placebo group received second-line treatments for NSCLC vs. 47% of the erlotinib group. Among those who received second-line treatments in the placebo group, 59% received an FDA-approved therapy: erlotinib or gefitinib (Iressa) at first progression in 14%, docetaxel (Taxotere) in 31%, and pemetrexed in 14%.
"Therefore the trial did test the value of maintenance therapy with erlotinib vs. treatment at progression with a second-line therapy in patients who chose to receive it and demonstrated a survival benefit," said Dr. Justice.
The absence of an FDA comparative effectiveness standard also played a role in the agency's decision, he added. "Once safety and effectiveness have been demonstrated, it is up to patients in consultation with their physicians to determine the treatment that is most appropriate for them," he said.
The new indication endorses erlotinib tablets for maintenance treatment of patients with locally advanced or metastatic NSCLC that has not progressed after four cycles of platinum-based, first-line chemotherapy. Erlotinib is also approved as a second-line treatment for locally advanced or metastatic NSCLC and, in combination with gemcitabine (Gemzar), as a first-line treatment of locally advanced, unresectable, or metastatic pancreatic cancer.
The approved dose of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, is 150 mg/day in NSCLC and 100 mg/day in pancreatic cancer. Rashlike events and diarrhea are the most common adverse events, experienced by more than 20% of NSCLC patients treated, according to the agency.
"We are delighted that lung cancer patients and their physicians will have the option of beginning Tarceva therapy in the first-line maintenance setting. We believe that Tarceva, as the only medicine approved in the maintenance setting" for the squamous and nonsquamous forms of NSCLC, "offers a valuable treatment option for these patients," said Colin Goddard, Ph.D., chief executive officer of OSI Pharmaceuticals in a statement on the company's Web site.
The company is committed, he added, to pursuing additional uses for erlotinib, "including as a first-line treatment for lung cancer patients with an activating EGFR mutation, as an adjuvant therapy in NSCLC, and in other tumor types such as ovarian cancer and hepatocellular carcinoma."
The European Medicines Agency announced on March 19 that it has issued a positive opinion on erlotinib as a maintenance treatment. The EMEA's positive opinion on extending the indication for erlotinib was expected to be endorsed by the European Commission within 45 days.
Jane Salodof MacNeil contributed to this report.
