Taxotere Gets FDA OK for Use in NSCLC

 BETHESDA, Md—As ONI went to press, the FDA acted on the recommen-dation of its Oncology Drugs Advisory Committtee (ODAC) to approve Taxotere for injection (docetaxel) for the treat-ment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) after failure of cisplatin-based chemotherapy. The panel voted 12 to 1 for approval and unanimously agreed that data presented by the company showed acceptable safety for Taxotere in NSCLC patients when given at a dose of 75 mg/m² over 1 hour every 3 weeks.

Taxotere is a product of Rhône-Poulenc Rorer (now Aventis Pharma, through the recent merger with Hoechst Marion Roussel, Inc.). The FDA previously granted Taxotere accelerated approval for the treatment of breast cancer in 1996 and gave it full approval for that use in 1998. Taxotere is currently approved for the treatment of breast, ovarian, and/or lung cancer in 93 countries, 44 of which have approved its use in lung cancer.

To support its application to expand Taxotere’s labeling in the United States to include NSCLC, Rhône-Poulenc Rorer presented data from two phase III multicenter, randomized, controlled studies. Survival was the primary endpoint in each study.

TAX 317 involved 204 patients treated at 36 centers in eight countries: 100 patients received best supportive care and 104 were treated with 100 mg/m² or 75 mg/m² of Taxotere. Patients who had already received a taxane were excluded.

In TAX 320, patients with prior taxane treatment were accepted. Researchers randomized 373 patients treated at 23 US sites to one of three groups: Taxotere 100 mg/m²; Taxotere 75 mg/m²; or a control arm in which patients received either vinorelbine (Navelbine) or ifosfamide (Ifex), with the choice left to the treating physicians.

Data from the two studies indicated that the 100 mg/m² dose was unacceptably toxic. Five deaths occurred among the first 49 patients enrolled in TAX 317, which led researchers to reduce the dose to 75 mg/m² in the second half of the study. Two of the deaths were attributed to the patient’s disease and the other three may have resulted from the drug, according to the sponsor. As a result, Rhône-Poulenc Rorer amended the dosage proposed in its supplemental new drug application to 75 mg/m².

Survival Results

In TAX 317, the 55 patients who received Taxotere 75 mg/m² had a median survival of 9.0 months with 1-year survival of 40% vs median survival of 4.6 months with 1-year survival of 16% in the best supportive care group. The company also provided the FDA an updated analysis (September 1999) that showed a 7.5 month median survival rate with 1-year survival of 37% in the drug group vs 4.6 month median survival with 1-year survival of 12% among controls.

Several ODAC members expressed concern about the small number of patients receiving Taxotere 75 mg/m² in the study. “My take on it is that the company was incredibly lucky to get a statistically significant survival benefit,” said panel member Richard M. Simon, DSc, chief of the NCI’s Biometric Research Branch.

Median survival among the 125 patients in TAX 320 who received Taxotere 75 mg/m² was 5.7 months with 1-year survival of 32% vs 5.6 months median survival and 19% one-year survival in the control group receiving vinorelbine or ifosfamide. The company’s updated analysis reported the same median survival as before in both groups, but with a 1-year survival of 30% in the drug group and 20% among controls. There was no statistical difference in survival between patients who had received earlier taxane treatment and those who had not.

Time to progression in TAX 317 was 12.3 weeks in the Taxotere arm vs 7.0 weeks among controls; the response rate was 5.5% in the drug patients. In TAX 320, the time to progression was 8.3 weeks for Taxotere patients and 7.6 weeks for controls, and the response rate was 4.8% vs 0.8% in controls.

Analgesic Use

In TAX 320, analgesic use was not significantly different between the Taxotere arm and the control group receiving other chemotherapy. In TAX 317, however, a difference was noted. “Taxotere provided significant clinical benefit over patients with best supportive care,” said Frances Shepherd, MD, of Princess Margaret Hospital, Toronto. “Tumor-related medication was significantly less in patients treated with Taxotere 75 mg/m².”

Treatment-related mortality was 1.8% among the Taxotere 75 mg/m² patients in TAX 317, and 3.3% for Taxotere vs 3.4% for controls in TAX 320.

In TAX 317, 18.2% of the Taxotere patients and 28.0% of the controls suffered grade 3-4 asthenia; in TAX 320, the trend was reversed, with 12.4% of patients in the Taxotere group experiencing grade 3-4 asthenia vs 10.9% in the control arm. In both studies, sensory neuropathy was less in the Taxotere group, 1.8% vs 3% in TAX 317 and 0.8% vs 3.4% in TAX 320.

ODAC members disagreed on whether TAX 320 confirmed the findings of TAX 317. Dr. Simon, for one, thought it did not. Kathy S. Albain, MD, of Loyola University Medical Center, disagreed. “If you look at the 1-year survival rates, they are very similar,” she said.

George W. Sledge, Jr., MD, of Indiana University School of Medicine, said that “essentially one trial is negative and one is positive. The 1-year analysis is essentially irrelevant and illogical. There is no reason to believe that a 1-year point is any different than a 6-month point or an 18-month point.”

Derek Raghavan, MD, PhD, of the University of Southern California, suggested that some of his panel colleagues were looking at trees and missing the forest. He noted that the two studies involved second-line treatment in a disease where first-line efforts obtain a low response rate and most patients die. “The company took on a tough target. I think it took a gamble, and, to their credit, it paid off,” he said.