ODAC Says Gemzar Active in Ovarian Cancer, but Votes Against Recommending Approval Due to Poorly Designed Studies (2006)

GAITHERSBURG, MD—Even though gemcitabine (Gemzar) has obvious activity in advanced ovarian cancer, the pivotal clinical trial that its sponsor, Eli Lilly and Co., presented to the Oncologic Drugs Advisory Committee here at its most recent meeting was so poorly designed that the members voted overwhelmingly not to recommend approval for a new indication. Richard Gaynor, MD, Vice President of Global Oncology for Lilly Research Laboratories, told the committee that the supplemental new drug application was submitted on the basis of a 356-patient randomized Phase III trial that met its primary endpoint of statistically significant improvement in progression-free survival. “Gemcitabine is effective in combination with carboplatin for treatment of women with recurrent ovarian cancer that has relapsed at least six months following platinum-based therapy,” he said. It was noted at the outset of the meeting, and came up as a point of discussion throughout the afternoon, that the combination of gemcitabine and carboplatin had no effect on overall survival in this group of patients. Gemcitabine has been approved for advanced pancreatic cancer, in combination with cisplatin for advanced non-small cell lung cancer, and in combination with paclitaxel for first-line treatment of metastatic breast cancer. Ovarian cancer research pioneer Robert Ozols, MD, PhD, Senior Vice President for Medical Science at Fox Chase Cancer Center, explained that the current first-line treatment is debulking surgery followed by carboplatin and paclitaxel. Of the patients so treated, 75% will have a complete remission, but about 75% of those will ultimately have disease relapse and die in 18 to 24 months. And of patients treated with carboplatin-paclitaxel, 75% to 80% will have significant neurotoxicity, Dr. Ozols said. “Many women have such severe neuropathy that they can't button their clothes or write a check. They also have trouble walking. It's a permanent life-changing toxicity.” If a patient turns out to be resistant to platinum therapy, other treatment options are liposomal doxorubicin, topotecan, paclitaxel, and gemcitabine as single agents. The overall response rate is less than 22%, and time to progression is four months or less. Dr. Ozols described the ICON 4 trial, a study of combination therapy for platinum-sensitive disease conducted in England. Use of carboplatin, either as a single agent or in combination with gemcitabine increased both progression-free and overall survival, but the high percentage of neurotoxicity limits usefulness. A European cooperative group that specializes in gynecologic malignancies, AGO-OVAR (Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom), Dr. Ozols continued, found a gemcitabine-carboplatin regimen that was less neurotoxic in Phase I and II trials for recurrent ovarian cancer. These studies were the jumping-off point for the Lilly pivotal trial. Dr. Ozols defended progression-free survival (PFS) as the primary endpoint for ovarian cancer patients. “PFS in conjunction with other efficacy parameters—overall response rate, complete response, and quality of life—can be a measure of clinical benefit, especially if there is statistically significant improvement.” Trials Presented to ODAC Allen Melemed, MD, Associate Medical Director for Lilly, described three clinical trials, of which the JHQJ/OVAR 2.5 study was pivotal. It compared gemcitabine at 1,000 mg/m2 on Days 1 and 8 plus carboplatin at an area under the curve (AUC) of 4 on Day 1 every three weeks for six cycles with carboplatin at AUC 5 on Day 1 every three weeks for six cycles. The Phase III randomized trial was conducted in 12 countries with 105 investigators. The primary endpoint was progression-free survival, measured from randomization to progressive disease or death. Secondary endpoints were overall survival and response rate. Median progression-free survival times for the combination regimen were 8.6 and 5.8 months for carboplatin alone. Overall survival was 18 vs. 17.3 months. The overall response rate was 47.2% for the combination and 30.0% for carboplatin alone. Complete responses were seen in 14.6% of combination patients and 6.2% of carboplatin patients. “The primary endpoint [progression-free survival] significantly favors the combination of gemcitabine and carboplatin, and the overall and complete response rates were significantly improved in the combination arm,” Dr. Melemed said. “This demonstrates a clinically meaningful benefit for women with recurrent ovarian cancer.” Richard Gralla, MD, a past president of the Multinational Association of Supportive Care in Cancer, noted that there was a significant difference between the two arms of the study in neutropenia but only minor differences in other adverse events such as anemia, thrombocytopenia, nausea and vomiting, diarrhea, and constipation. The FDA Medical Officer said that for Phase III trials in second-line treatment, progression-free survival is not a good surrogate for survival—even when the improvement is significant. Nineteen patients in the combination arm discontinued the study because of adverse events, as did 17 patients in the carboplatin arm. According to Dr. Gralla, the majority who left the study probably did so because of drug-related toxicity. Five patients on each arm died during the study or within 30 days afterward. He concluded that gemcitabine-carboplatin is a safe and well tolerated regimen, and no new safety issues cropped up during JHQJ/OVAR 2.5. “Certain Grade 3 or 4 hematologic toxicities increased in the combination arm, but overall, there was a low incidence of neurotoxicity,” Dr. Gralla said. In terms of patient-reported outcomes, women who had a an objective response reported better symptom improvement, and global quality of life was about 30% better for patients on the combination arm, he added. Reservations from FDA Martin Cohen, MD, Medical Officer for the FDA Office of Oncology Drug Products in the Center for Drug Evaluation and Research, did not disagree with the sponsor's analysis of the study outcomes, but he said that the agency did have some questions and reservations: Although the study was randomized, it was not blinded; therefore, it was impossible to assess quality of life. Patients had been on a number of different prior and subsequent chemotherapy regimens (platinum plus paclitaxel, platinum plus docetaxel, platinum plus a non-taxane, and carboplatin only), which confounded the study results. Patients whose disease did not progress, patients with missing radiologic scans prior to progression, patients who died after an extended loss to follow-up, and patients who began a new treatment regimen prior to progression had to be dropped from the total number. Therefore the study did not have as many evaluable patients as claimed by the sponsor. Dr. Cohen summed up the safety conclusions by saying that the Grade 3 and 4 toxicity was primarily hematologic and was more frequent with the combination regimen, but there were no new safety concerns related to each drug. However—and this was the crux of the agency's concern: “Is a significant improvement in PFS and response rate, with no increase in overall survival, at the cost of some additional toxicity, an adequate basis for drug approval in this instance?” John R. Johnson, MD, Medical Team Leader in the same FDA office, added some questions of his own: Are there regimens that increase survival in recurrent ovarian cancer? The answer, he said, was yes: Paclitaxel and carboplatin, as demonstrated in a study of 802 patients, as well as pegylated liposomal doxorubicin, demonstrated in a study of 474 patients. Are there gemcitabine regimens, shown in randomized trials, that increase survival in this patient population? The FDA knows of none, Dr. Johnson said. Would a gemcitabine survival effect be likely if the clinical trial were expanded? Lilly's pivotal trial was not adequately powered for survival, and even if there were many more patients, it probably could not demonstrate survival. Is the 2.8-month improved progression-free survival an adequate basis for drug approval in this setting? This question, he said, was the one that ODAC would be asked to answer. In summary, Dr. Johnson said that for Phase III trials in second-line treatment, progression-free survival is not a good surrogate for survival—even when the improvement is significant. ODAC Concurs The main issue that members of ODAC discussed was whether the improvement in progression-free survival without a demonstrated survival advantage—and with the amount of toxicity found—is a sufficient basis for approval of this supplemental new drug application. FDA reminded the members that a paclitaxel-carboplatin combination does prolong survival in women with recurrent ovarian cancer, in addition to strong suggestive evidence that liposomal doxorubicin does the same. ODAC members spent remarkably little time discussing this trial. There was general agreement that because patients were evaluated differently with regard to disease progression (objective vs clinical vs radiologic measures), the outcome reflected investigator bias. Moreover, they agreed with FDA that progression-free survival is not a surrogate for survival and said that this was an extremely poorly designed study. For these reasons, they voted 9 to 2, with 1 abstention, not to recommend approval. Ways and Means Committee Criticize 2007 Budget Proposals For Health Secretary of the Treasury John W. Snow appeared before the House Committee on Ways and Means, but his appearance was so short that members were unable to ask critical questions. Following is a synopsis of a letter sent to Secretary Snow by Reps. Charles B. Rangel (D-NY), Pete Stark (D-CA), and Jim McDermott (D-WA). In addition to answering the questions, they asked for a copy of the health savings account (HSA) estimates prepared by the Administration. “Similar questions were submitted for the record by Rep. Stark, but your answers were largely nonresponsive and lacked detail,” the letter said. The representatives added that they expected more thoughtful analyses to the current questions: “It is hard to believe that the Administration would propose such dramatic, expensive changes without an inkling of understanding about how such policies would affect individuals, employers, and the system.” The questions/requests concerned coverage and participation estimates; the effect on prices and savings for individuals and employers; the effect on the price of medical services; the extent of employer, individual, and family contributions to health savings accounts; revenue effects of the estimated cost of $156 billion over 10 years; premium increases for traditional insurance; portability; market access; and consumer protection in the non-group market.