GAITHERSBURG, MarylandThe FDA's Oncologic Drugs Advisory Committee (ODAC) declined to recommend that the agency approve Gemzar (gemcitabine, Eli Lilly) in combination with carboplatin(Drug information on carboplatin) for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.
"We are disappointed in today's recommendation," said Richard Gaynor, MD, Lilly's vice president for cancer research. "We firmly believe that this trial demonstrated the clinical value of Gemzar and was positive relative to its primary endpoint, progression-free survival, as well as the additional endpoint of response rate." The company plans to discuss with FDA what is required to provide further data for approving the drug.
The committee's 9-to-2 vote, with one abstention, came after Lilly provided findings from three studiesa 356-patient pivotal trial and two small studies. Gemzar was initially approved in 1996 for the treatment of advanced pancreatic cancer and, subsequently, for use in combination with cisplatin(Drug information on cisplatin) for advanced non-small-cell lung cancer and in combination with paclitaxel(Drug information on paclitaxel) for the first-line treatment of metastatic breast cancer.
Lilly's pivotal study was an open-label, phase III trial conducted by three European cancer trial groups in 12 countries, not including the United States. Enrollees had advanced ovarian cancer not amenable to curative surgery or radiation therapy and had suffered a relapse 6 months or more after discontinuation of first-line platinum-containing therapy. The women were randomized, 178 each, to receive Gemzar plus carboplatin or carboplatin alone. The primary endpoint was progression-free survival (PFS); secondary endpoints were survival, response rate (RR) and duration, and quality of life. The trial was not conducted under an FDA investigational new drug (IND) application, and the agency did not review the study protocol.
The Gemzar patients showed a significant increase in PFS, compared with the carboplatin-only women (median 8.6 vs 5.8 months, P = .0039). However, the Gemzar arm failed to show a significant increase in overall survival (median 18.0 vs 17.3 months for carboplatin only, P = .8977). The overall RR was 47.2% with Gemzar vs 30.9% with carboplatin only (P = .0016); complete response rate was 14.6% vs 6.2% (P = .0092).
No significant difference was found in all serious adverse events between the two arms or in serious side effects related to the study drugs. Some hematologic grade 3-4 toxicities were increased in the Gemzar-treated patients, including anemia, neutropenia, and thrombocytopenia requiring increased red blood cell and platelet transfusions and increased use of granulocyte-stimulating factors and erythropoietic agents. Grade 3-4 nausea, vomiting, diarrhea, and constipation were also higher in the Gemzar arm, as was grade 3 neurotoxicity (1.1% vs 0.6%).
The key question FDA presented to ODAC was whether a significant improvement in PFS and RR without an increase in overall survival and with some additional toxicity provided an adequate basis for approving the Gemzar/carboplatin combination for the treatment of patients with advanced ovarian cancer who have relapsed at least 6 months after completion of platinum-based therapy. FDA noted in its report that the Gemzar combination does not satisfy an unmet need in ovarian cancer, since studies have shown prolonged survival in this setting with paclitaxel/platinum combinations. It also noted that the Gynecologic Intergroup has voted unanimously that "progression-free survival does not seem to be a good surrogate for survival" in this setting. The panel then voted 9-2 not to recommend Gemzar's approval for use in ovarian cancer.