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.
SILVER SPRING, MarylandThe 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.
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."
Iressa was granted fast-track approval status by the FDA, which includes a "rolling submission" process in which a drug company submits certain data as it becomes available. AstraZeneca submitted a phase II trial conducted in the United States that evaluated 216 NSCLC patients as its pivotal studyIressa Dose Evaluation in Advanced Lung Cancer (IDEAL 2)and a supporting trial of 206 patients conducted in Europe and Japan (IDEAL 1). Both trials used the same design and methods to test the drug as third-line monotherapy for NSCLC.
The pivotal trial of 216 patients included 139 patients with tumors resistant or refractory to cisplatin (Platinol) and docetaxel (Taxotere) and considered to have no available therapy. For its analysis, the FDA accepted only the 139 resistant/refractory patients in the pivotal study. Fourteen (10.1%) of these patients had a partial response, according to the company, a figure that the FDA accepted in its data analysis.
However, prior to the ODAC meeting, the company submitted two phase III Iressa studiesIressa NSCLC Trials Assessing Combination Therapy, INTACT 1 and 2)each involving more than 1,000 patients. Both trials used the drug in conjunction with standard chemotherapy as first-line treatment. Neither found a significant improvement in response rates or survival.
That finding raised important questions within FDA about Iressa’s true clinical benefit. "The question is in the context of the two other trials," said Richard Pazdur, MD, director of FDA’s Division of Oncology Drug Products. "If we didn’t have these two trials, we probably wouldn’t even be here. We would already have approved the drug." But, he added, "we do have this data. We just can’t ignore it." Dr. Blackledge acknowledged that AstraZeneca was surprised by results from the two phase III trials, but argued they did not annul the pivotal study’s findings. "These trials were carried out in a different treatment setting and utilized combination chemotherapy rather than monotherapy," he said. "Therefore, the lack of survival benefit in first-line therapy does not negate the objective responses and symptom control in third-line monotherapy."
In its presentation, AstraZeneca emphasized the need for a third-line drug to treat NSCLC. "There is no effective treatment for patients following second-line therapy," said Ronald B. Natale, MD, medical director, Cedars-Sinai Comprehensive Cancer Center, Los Angeles, who spoke for the company. "In these patients, disease progression is inevitable. The best they can hope for is that disease-related symptoms will stabilize for a brief time with optimal supportive care."
In the pivotal study, patients were randomized to receive either 250 mg or 500 mg of Iressa daily. The two primary endpoints of the study were response rate and an improvement in disease-related symptoms. Patients served as their own controls. Dr. Natale noted that 22 of the 216 patients (10%) showed a partial response (tumor shrinkage of more than 50%), 16 of them within 4 weeks of beginning treatment and the remaining 6 within 16 weeks. The median duration of response was 7.4 months for the 250-mg arm and 5.8 months for the 500-mg group. Responses occurred regardless of prior therapy regimens, performance status, age, and sex. "The lack of relationship to the number of prior regimens and performance status is a remarkable observation that distinguishes this biologic agent from cytotoxics," he said.
Symptoms improved in 84 of the 216 patients, 43% in the 250-mg arm and 35% in the 500-mg arm but the difference was not statistically significant. "Iressa produces a 40% improvement rate in highly symptomatic patients with advanced NSCLC," Dr. Natale said. "The strong association of this outcome with radiographic response and its rapidity, magnitude, and weeks and weeks of stability and durability indicate that a placebo effect is very unlikely."
The symptoms that showed the most improvement were shortness of breath, coughing, ease of breathing, and tightness in the chest. Improvement occurred within 4 weeks in 86% of the patients. At 6 months, 65% remained improved.
The pivotal trial showed Iressa’s mild side effects, compared with cytotoxic drugs. Adverse events occurring in 15% or more of the 216 patients, in descending order of occurrence, were diarrhea, rash, asthenia, acne, nausea, anorexia, dyspnea, dry skin, increased cough, vomiting, and pain. These side effects were generally more common in patients receiving the higher dose. There were no significant adverse hematologic events.
Eight grade 3-4 adverse events occurred in the 250-mg group: two cases of asthenia (2) and one each of rectal bleeding, dyspnea, peripheral edema, scrotal edema, epistaxis, and thrombocytopenia. Grade 3-4 events in the 500-mg group were asthesia (1), decreased GI motility (1), dehydration (3), increased AST/SGOT (2), increased ALT/SGPT (2), and lung hemorrhage (1). There was one drug-related death, which resulted from the one case of lung hemorrhage.