The FDA's Oncology Drugs Advisory Committee on Wednesdayrecommended approval of Bristol-Myers Squibb's drug Taxol asa second-line treatment for metastatic breast cancer.

The committee specified that the drug is approvable in patientswho have failed to respond to first-line chemotherapy or haverelapsed within six months of adjuvant therapy. The paneladded that prior therapy should have included anthracyclinetreatment.

Taxol was approved by FDA as a second-line treatment forovarian cancer in December 1992. The approved dose is 135milligrams per square meter delivered by continuous infusionover 24 hours.

The committee based its decision on Wednesday primarily on alarge, randomized trial of 471 patients that compared 175mg/m2 to 135 mg/m2 Taxol infusion over three hours. Theoverall response rate was 29 percent with the 175 mg dose and22 percent with the 135 mg dose, p value=.108. The time todisease progression was about 4.2 months in the high-dosegroup and three months in the lower-dose group. The mostimportant adverse reaction was grade 4 neutropenia, whichoccurred more frequently in the high-dose group, as didperipheral neuropathy and mucositis.

Bristol-Myers (NYSE:BMY) also presented data from threePhase II trials, two conducted at Memorial Sloan Ketteringhospital and one at the University of Texas M.D. AndersonCancer Center.

In the first Memorial Sloan Kettering study, 25 patients whohad one prior chemotherapy regimen received either 200mg/m2 or 250 mg/m2 Taxol over a 24-hour infusion. Thosereceiving the 250-mg dose had a 52 percent response rate,including a 12 percent complete response rate. The mediantime to disease progression was 8.4 months. All patients hadgrade 4 neutropenia and the majority had infection.

Bristol-Myers reported that in the M.D. Anderson trial,granulocyte-macrophage colony stimulating factor (GM-CSF)was added to the Taxol regimen and reduced the incidence ofneutropenia and infection. A representative from the NationalCancer Institute also presented data from NCI's TreatmentReferral Center program. The center has 267 registered Taxolpatients who received either 175 mg/m2 or 135 mg/m2 by24-hour infusion every three weeks. Of 247 evaluable patients,the response rate was 22 percent.

An FDA staffer reviewing the Taxol data told the committeethat Bristol-Myer's study was "excellent," one of the only dose-response studies he has seen in cancer. He described thecompany's supplemental application for breast cancer as"precedent setting."

The agency noted that it expects several other new applicationsfor drugs to treat advanced metastatic breast cancer in the next12 months and requested that the committee address severalquestions that could be applicable to these submissions.

First, FDA said it "does not believe that an objective tumorresponse rate of 20-30 percent without showing patient benefitis sufficient as the basis for marketing approval," and thecommittee members concurred overall.

Committee member Kathleen Pritchard of the Toronto BayviewRegional Cancer Center added a proviso that a 20-30 percentresponse rate in patients who have had several chemotherapyregimens is different from such a response in patientsreceiving one adjuvant therapy. So a 20-30 percent response"may be sufficient for heavily pre-treated" patients, Pritchardsaid.

The committee also agreed with FDA's conclusion that aresponse rate of 20-30 percent "accompanied by sufficientevidence of relief of tumor-specific symptoms" may besufficient for approval. Members also said such a response ratecomplemented by "physical performance status or possibly byan increase in time to deterioration of physical performancestatus" also may be sufficient for approval.

Pritchard said the data presented to the committee Wednesdaywas "soft," adding that it looked at lack of deterioration ratherthan improvement. This gave committee members an "edgyfeeling" as to whether or not they were seeing somethingvaluable, she said.

The committee discussed the issue of dosage at length but didnot make a specific recommendation. Several membersemphasized that toxicity was significantly higher in the high-dose group. Chairman Charles Schiffer of the University ofMaryland Cancer Center said the non-statistically significantincrease in response rate and the one-month improvement intime to disease progression with the 175-mg dose must bebalanced with the greater neutropenia and neuropathy.

One committee member suggested that Taxol labeling forbreast cancer include a table showing the difference betweenthe two doses in response rate, time to disease progression,median survival, percent of patients with grade 4 neutropenia,febrile neutropenia and neuropathy. Such a table wouldaddress the issue of informed consent, letting patients knowabout the increased risk of toxicity with the higher dose, saidanother member.

-- Brenda Sandburg News Editor

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