NEWS

Despite Concerns, FDA Panel Backs EGFR Inhibitor

Renee Twombly

An advisory panel for the U.S. Food and Drug Administration for the first time has recommended accelerated approval of a selective epidermal growth factor receptor (EGFR) inhibitor to treat cancer.

But it was not a clean victory for the agent, ZD1839 (also known as gefitinib or Iressa®), a daily pill designed to shrink tumors without producing the toxic side effects of chemotherapy. The FDA had released a report that was critical of the drug shortly before its Oncologic Drugs Advisory Committee (ODAC) met in September, and during the hearing, the committee itself issued several votes that appeared to be contradictory.



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AstraZeneca’s Iressa was recommended for accelerated FDA approval in September.

 
The ODAC agreed with the FDA in a 9-5 vote that the phase II studies backing the drug application that tested ZD1839 in advanced non-small-cell lung cancer made it impossible to adequately analyze data on patients’ symptoms. Yet, following testimony from several lung cancer patients who said that their cancers had shrunk after using the drug, the committee voted 11-3 that ZD1839 probably did offer benefit to some patients, and so should be approved for third-line therapy.

When physicians have nothing else to offer patients dying from lung cancer, ZD1839 looks good despite problems with the studies, said long-time panel member, John Carpenter, M.D., an oncologist at the University of Alabama at Birmingham. "I was convinced that some people got better on this drug," he said. "Yet it’s hard to know what the real response is."

The final decision is, of course, up to the FDA, and although the agency often follows the lead of ODAC, no one can predict what it will do in this case.

"It’s the first EGFR inhibitor to get this far," said Carpenter, who voted for approval. "But I’d be surprised if it got full regulatory approval on this data."

Questions About Benefit

ZD1839 is a member of a new class of drugs that work by blocking the activation of the EGF receptor. Activation of EGFR, whether through binding of its ligands (EGF or TGF-{alpha}), mutation, or amplification, can stimulate cell proliferation and survival pathways. Because many solid tumors express EGFR, scientists had hoped that agents inhibiting receptor signaling would prove to be effective in the same way that the closely related drug Gleevec has revolutionized treatment of chronic myeloid leukemia. Another well-known EGFR inhibitor, Erbitux, encountered rough waters during its FDA review, and ZD1839 is the first to reach an ODAC hearing.

The data available for the FDA to evaluate were two small multicenter phase II studies (IDEAL 1 and 2) that tested ZD1839 as monotherapy in more than 400 U.S., European, and Japanese lung cancer patients who had already been given one or more rounds of chemotherapy. Both studies were sponsored by AstraZeneca, the manufacturer of ZD1839. Because there is no third-line therapy for advanced lung cancer, AstraZeneca applied for accelerated approval based on evidence of antitumor activity in patients who had received prior treatment with both platinum and taxane chemotherapy regimens.

Accelerated approval is intended to make promising products for life-threatening diseases available based on preliminary evidence using surrogate markers, but prior to formal studies demonstrating patient benefit. The drug had already passed the regulatory hurdle in Japan; in July, the country approved the use of ZD1839 for treatment of advanced, recurrent lung cancer.

Results of studies using ZD1839 were very encouraging, according to the researcher who led the study of U.S. patients. Mark Kris, M.D., chief of the Thoracic Service at Memorial Sloan-Kettering Cancer Center, New York, found that tumors in 10% of 216 patients shrank by one-half or more, and an additional 39% of patients had improvement in such symptoms as shortness of breath, cough, and chest discomfort. The majority of patients benefited from the drug within 10 days of starting the therapy and experienced minimal side effects, Kris said.

"This kind of improvement for refractory lung cancer is unheard of. It’s absolutely remarkable," said Kris. "There hasn’t been a new way to fight lung cancer in decades."

"You have to be a lung cancer doctor in a lung cancer clinic to appreciate what these patients go through," said Lawrence Einhorn, M.D., an Indiana University School of Medicine oncologist who has chaired panel sessions on ZD1839 at scientific conferences. "For a small minority of patients, Iressa melts tumors away, but for many patients, it offers hope instead of despair."

But in its critique, the FDA staff noted that the lack of a control group in the phase II trials made the symptom improvement results difficult to interpret, and the agency questioned whether a substantial number of patients had really failed to respond to the two different chemotherapy regimens.

And further clouding the hearing was news that in two large, well-designed phase III trials (known as INTACT), ZD1839 failed to improve the survival of about 2,000 lung cancer patients when it was combined with chemotherapy.

So the big question that ODAC wrestled with was whether using surrogate endpoint data, such as tumor shrinkage and symptom relief from an uncontrolled clinical trial, was enough to recommend accelerated approval for this biologic drug when phase III studies evaluating the effects of adding ZD1839 to chemotherapy failed to show survival benefit.

This conflicting data made the ODAC hearing unique, said Janet Dancey, M.D., a senior clinical investigator at the National Cancer Institute who has been following the development of EGFR inhibitors. "Uncontrolled data for phase II studies were presented at the same time that conflicting results from phase III studies were discussed. It was an unusual and difficult situation."

Richard Pazdur, M.D., director of the FDA’s Division of Oncology Drug Products, said during the meeting he was "floored" when results of the phase III studies became known. That situation prompted the FDA to bring the ZD1839 application before ODAC, instead of acting on it in-house. At the meeting, Pazdur said that such contradictory results are "like no other situation I know of in medical oncology."

Although AstraZeneca had hoped the phase III results would not derail the ODAC discussion, they were enough to prevent one committee member from endorsing ZD1839. "The company was doing damage control by backing away from negative first-line results by suggesting there is no link to their third-line findings," said University of Washington biostatistician Thomas Fleming, Ph.D. "We have to look at the totality of evidence, and I don’t think this meets what was intended for accelerated approval."

But Kris, who attended the ODAC meeting, said the third-line studies cannot be compared to the first-line research because patients in the phase III studies had never received any prior chemotherapy. Moreover, the FDA "was asking for phase III data from a phase II trial. The process is intended to take preliminary findings into account to fill an unmet need while more testing is done," he said. "They should absolutely approve this application."

Sorting out Future Directions

Researchers watching the progression of ZD1839 clinical trials are disappointed that the agent apparently does not work synergistically with chemotherapy, as had been expected. But many believe the agent still has the potential to help a small percentage of patients, and that the trick to proving its future success is determining who best can benefit.

Observers noted that many of the lung cancer patients who spoke glowingly about ZD1839 at the ODAC meeting were young women who had never smoked. "If that reflects the types of patients who benefit from ZD1839, it raises the question of whether the biology of their lung cancer is different—perhaps more sensitive to the agent," said Dancey.

Patients with advanced squamous cell cancer of the head and neck have also benefited in almost exactly the same proportion as in the lung cancer trials. A phase II clinical trial using the drug as monotherapy in 47 patients showed an overall tumor response of about 11%, and more than half of the patients showed some disease stabilization.

"It’s an interesting coincidence that the response rate we obtained was the same as in the lung cancer trial," said an investigator in the study, Everett Vokes, M.D., director of Hematology/Oncology at the University of Chicago. ZD1839 offers a response rate that "is as good as any currently available chemotherapy drug" for head and neck cancer, Vokes said. "Head and neck cancers overexpress EGFR receptors, so it is an especially relevant disease model," he said.

More research is needed to define the group of patients who have specific abnormalities in their tumor pathways that indicate who will benefit from the drug, Dancey said. "And we need scientists to give us an idea why it works—what the signaling pathways are that determine sensitivity and resistance to EGFR inhibitors," she added.

Einhorn suggested that the best use of ZD1839 will likely be found years after it is in use. "The optimal role for many drugs is often found after they have been approved," he said. "I’m sure that in 5 years we will know a lot more about the drug, and we all hope it won’t be used just for third-line therapy."



             
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