ODAC Votes to Approve Erlotinib (Tarceva) for New Indication

BETHESDA, MD—Erlotinib (Tarceva) received FDA approval almost a year ago for non-small-cell lung cancer. The drug's sponsor, OSI Pharmaceuticals, Inc., now sought approval for use in combination with gemcitabine for first-line treatment of locally advanced, unresectable, or metastatic pancreatic cancer. The Oncologic Drugs Advisory Committee voted overwhelmingly to recommend approval, primarily because this disease is almost invariably fatal. Pablo Cagnoni, MD, OSI's Vice President for Medical Affairs and Translational Research, told the committee that erlotinib is an orally available small molecule inhibitor of HER1/epidermal growth factor receptor (EGFR) tyrosine kinase (TK) and is a potent, selective EGFR-TK inhibitor. He explained its use in pancreatic cancer: “HER1/EGFR overexpression is common and is associated with a more aggressive form of the disease, resulting in poor prognosis. In addition, in preclinical models, HER1/EGFR inhibitors enhance gemcitabine-induced tumor apoptosis.” Malcolm Moore, MD, Professor of Medicine and Pharmacology at Princess Margaret Hospital in Toronto and Chair of the National Cancer Institute of Canada Clinical Trials Group Gastrointestinal Committee, said that in the United States and Canada, about 35,400 new cases of pancreatic cancer will be diagnosed in 2005, and 35,000 people will die of the disease. The five-year survival rate is only 4%. “Gemcitabine is the only approved treatment, and attempts to improve outcome in advanced disease have been unsuccessful. It is a dismal situation.” He described Study NCIC CTG PA.3, a randomized placebo-controlled trial, international in scope and led by the NCI of Canada and cosponsored by OSI, for which he was principal investigator. The 569 patients in the study had unresectable, locally advanced or metastatic adenocarcinoma of the pancreas. They were allowed to have had prior radiotherapy but not chemotherapy. Patients were randomized to (Arm 1) gemcitabine at 1,000 mg/m2 intravenously on a cyclic schedule plus erlotinib at 100 mg by mouth daily; or (Arm 2) the same dose of gemcitabine plus oral placebo once a day. The primary endpoint was overall survival, and the key secondary endpoints were progression-free survival, tumor response rate, quality of life, and tumor EGFR status. Gary M. Clark, PhD, OSI's Vice President for Biostatistics and Data Management, discussed clinical efficacy. The median survival for the gemcitabine-plus-erlotinib patients was 6.37 months, and the one-year survival rate was 23%. Patients in the gemcitabine-plus-placebo group survived for 5.95 months, and the one-year survival rate was 17%. This made the added survival time for erlotinib only two or three weeks. The overall tumor response rate was 8.6% for the erlotinib arm and 7.9% for the placebo arm. Progression-free survival time was 3.81 months for erlotinib and 3.55 months for placebo—again only a week or two. In summary, Dr. Clark said, “Tarceva treatment in combination with gemcitabine resulted in a statistically significant 23% improvement in overall survival and a 30% improvement in progression-free survival. There was no difference in response rates, but there was an improvement in the disease-control rate. We found no detrimental effect on global quality of life compared with placebo.” These were not glowing results, but even small gains count for something in metastatic pancreatic cancer. Karsten Witt, MD, OSI's Vice President for Drug Safety and Medical Writing, reviewed the safety data. He said that to date more than 18,000 patients have been treated with erlotinib, and no new adverse events have been discovered. On this study, 27 patients on the erlotinib arm withdrew because of toxicity, as did 13 patients on the placebo arm. The most common reasons for discontinuation were rash, lung infiltration, decrease in platelet count, and diarrhea. Other common adverse events were infection, weight loss, and stomatitis.Figure: Mace Rothenberg, MD, said that the study was well designed and of high quality and that “the clinical benefit was associated with modest or infrequent toxicities, primarily rash and diarrhea, and the magnitude of toxicity is substantially less than what has been observed when other cytotoxic agents have been added to gemcitabine. Tarceva is an oral, self-administered drug that does not place a burden on outpatient resources, nor does it inconvenience patients.”Grade 3 or 4 adverse events occurred in less than 5% of patients, but five patients on the erlotinib arm died, four of which were probably drug related. What the company described as serious adverse events (those requiring hospitalization and those that were life threatening or fatal) occurred in only 2% of patients, the most common of which were fever, pneumonia, and sepsis. Dr. Witt summarized the safety data by saying that treatment with erlotinib in combination with gemcitabine was tolerated by most patients, and hematologic toxicity was not increased by the addition of erlotinib to the regimen. Mace Rothenberg, MD, Professor of Medicine at Vanderbilt Ingram Cancer Center, told the members of ODAC that this was a well-designed, high-quality study. “The clinical benefit was associated with modest or infrequent toxicities, primarily rash and diarrhea, and the magnitude of toxicity is substantially less than what has been observed when other cytotoxic agents have been added to gemcitabine. “Tarceva is an oral, self-administered drug that does not place a burden on outpatient resources, nor does it inconvenience patients.” FDA & ODAC Discussion Adrian Senderowicz, MD, Medical Officer of the FDA Division of Oncology Drug Products, reviewed OSI's data and said he found nothing with which to disagree. He did, however, note that the agency does not generally like to grant approval to an agent that has been tested in only one study without independent substantiation. On the plus side, though, this study was multicentered, and no single investigator or site was disproportionately responsible for favorable effects. “There was consistency across study subjects—age, gender, disease state—and the multiple endpoints involving different events were positive,” he said. “Statistically it was very persuasive, and it would probably be unethical to repeat the trial.” The FDA had five questions for the committee: Is the survival effect statistically persuasive? Members voted unanimously that that it was. Is the size of the survival effect clinically important? Eleven members said it was, two did not think so. Is the risk-benefit ratio favorable? Again, the vote was 11 to 2 that it was. The fourth question engendered the most discussion. There was almost an hour of heated argument about whether evidence of efficacy from a single trial without independent confirmation is adequate for marketing approval. In other words, was the study statistically persuasive enough that it would be unethical to repeat it—or would the committee recommend a confirmatory trial prior to approval? Members of the committee agreed that there was only a small increase in survival with erlotinib over placebo, and the quality-of-life issues were difficult, if not impossible, to delineate and assess. The committee was divided about what the small increase in survival time might mean to patients and families, especially if the short time comes with a large price tag: no improvement in quality of life. In the end, it appeared that the members agreed to disagree about these value-laden issues, and the vote was called. Eleven members said that a confirmatory trial would not be ethical. Two members disagreed. When the question of approvability was put to the committee, 10 voted yes, and three voted no.

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