SILVER SPRING, Maryland—The Oncologic Drugs Advisory Committee (ODAC) has essentially recommended that the US FDA grant accelerated approval to Iressa (gefitinib, AstraZeneca) for the oral treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) in patients who have previously received platinum-based chemotherapy regimens.
A senior FDA official said that a decision that data from the company’s pivotal phase II trial of Iressa are "reasonably likely to predict clinical benefit" in NSCLC would be "tantamount" to recommending accelerated approval. The 11-to-3 vote to that effect came despite discussion of two much larger phase III studies that failed to show improvement in response rate or survival with Iressa, compared with placebo, when used as first-line therapy in conjunction with standard chemotherapy regimens.
Iressa is the first of a new class of drugs called epidermal growth factor receptor-tyrosine kinase inhibitors to come before ODAC. It is a targeted molecule that attaches to the transmembrane receptors for epidermal growth factor. In doing so, the drug interrupts the receptor’s signal transduction pathway, which results in an inhibition of cancer cell proliferation and an increase in apoptosis.
Should FDA grant accelerated approval to Iressa, Astra-Zeneca will be obligated to carry out phase IV postmarket-ing studies to confirm the drug’s efficacy. A key point in the company presentation to ODAC was data that showed a significant improvement in symptoms. However, prior to their approval recommendation, ODAC advised FDA by a 9-to-5 vote that symptom improvement could not be adequately evaluated without a randomized, blinded study. Thus, FDA could order such a study as a condition of accelerated approval.
Addressing Efficacy
Much of the discussion at the meeting reflected on the unresolved issue within FDA about how to best address the efficacy of targeted drugs, whose mechanisms of action are quite unlike those of traditional cytotoxic drugs.
George Blackledge, MD, PhD, Astra-Zeneca’s vice president of oncology, addressed the issue immediately, quoting Larry Norton, MD, director of medical breast oncology, Memorial Sloan-Kettering Cancer Center: "We’ve said that these new therapies are dramatically unlike chemotherapy, but we’ve tried to develop them as if they were. Now we know they’re not, and Iressa has to be used following different paradigms."
