ROCKVILLE, Md--In a surprise move, the FDA Oncologic Drugs Advisory Committee failed to recommend approval of Taxotere (docetaxel, Rhône-Poulenc Rorer) for commercial use.
ROCKVILLE, Md--In a surprise move, the FDA Oncologic Drugs AdvisoryCommittee failed to recommend approval of Taxotere (docetaxel,Rhône-Poulenc Rorer) for commercial use.
The drug was being considered for approval in patients with locallyadvanced or metastatic breast carcinoma in whom previous therapywith an anthracycline has failed, and patients with locally advancedor metastatic non-small-cell lung cancer (NSCLC) after failureof platinum-based therapy.
The panel characterized docetaxel as very efficacious, but notedthe drug's significant toxicity. In addition, the panel felt thatit was difficult to judge the net benefit of docetaxel based onlyon phase II trials and urged the company to begin phase III trials,including randomized trials of untreated lung cancer that wouldtest docetaxel against approved drugs.
Taxotere, which is derived from the needles of yew trees insteadof the tree bark, thus forestalling destruction of the trees,has a 40% to 70% response rate in clinical trials of previouslyuntreated metastatic breast cancer patients, the company saidin its presentation.
According to Jean-Pierre Bizzari, MD, of Rhône-Poulenc Rorer,of the 912 patients in phase I/II trials, 10% to 15% of untreatedbreast cancer patients had an unequivocal complete remission (meanduration, 10 months). The optimum dose was 100 mg/m² pertreatment cycle.
The major side effect was neutropenia. Other adverse effects includedleukopenia; anemia (rare); alopecia, which was almost universal;skin toxicity, which can be successfully controlled with corticosteroids;and fluid retention, which was the principal reason for discontinuation.
The cumulative effects of fluid retention can be managed by corticosteroidsand can be prevented to some extent by premedication with dexamethasone,Dr. Bizzari said.
Mark Kris, MD, Memorial-Sloan Kettering Cancer Center, and HowardBurris, MD, director of clinical research, Cancer Therapy andResearch Center, San Antonio, presented data on the use of docetaxelin NSCLC. Of 248 chemotherapy-naive patients in six separate studies,they found a 21% to 32% response rate, which lasted for 4 to 6months.
On average, the survival rate was 2 months longer than survivalafter treatment with etoposide (VePesid) and vinorelbine tartrate(Navelbine), both administered in conjunction with cisplatin (Platinol).In addition, they found that patients given Taxotere had a significantdiminution of disease-associated pain.
Dr. Burris said that there is no established second-line treatmentfor NSCLC after platinum-based therapy has failed. In the 88 patientsin his trial of Taxotere in platinum failures, 17% responded fora median of 7 months. One year after the first Taxotere dose,38% were alive.
Side effects included neutropenia in about 80% of patients, mildneurotoxicity, GI symptoms such as nausea and vomiting, skin toxicity,and alopecia.
In an interview with Oncology News International, Dr. Burris saidhe thought that the safety profile of Taxotere is much higherthan that suggested by the data presented by the company. "Inthe 1,600 patients who have ever received docetaxel in a clinicaltrial, the death rate as a result of drug toxicity was less than2%, but that didn't come across in the company's presentation,"he said.
Moreover, Dr. Burris said, during the course of the clinical trials,which have been going on since 1990, "we have learned howto manage the side effects, and thus now have a much lower incidenceof serious toxicity problems."
After the initial vote rejecting the recommendation to approvethe drug for use in breast cancer, several panel members proposedrecommending approval conditionally, pending results of phaseIII trials. These trials are comparing Taxotere with paclitaxel(Taxol) in breast cancer patients previously treated with doxorubicin,to determine time to disease progression, as well as quality oflife for the patients who respond. Due to a tie vote, this proposalwas not approved.
Because the two votes, looked at together, would send an equivocalmessage to FDA, a third vote was taken. Six voted against therecommendation to approve for breast cancer and two abstained.