ODAC Recommends Approval of Two New Taxol Indications

BETHESDA, Md--Bristol-Myers Squibb went 2-for-2 before the FDA’s Oncologic Drugs Advisory Committee (ODAC). The panel recommended that the FDA approve injectable Taxol (pacli-taxel), in combination with cisplatin (Platinol), for both the first-line treatment of ovarian cancer and for the treatment of non-small-cell lung cancer (NSCLC) in patients who are not candidates for potentially curative surgery and/or radiation therapy.

Taxol, a synthetic version of a compound found in the bark of the Pacific yew tree, first won FDA approval in December, 1992, for the second-line treatment of ovarian cancer. FDA has since approved the drug’s use for second-line breast cancer therapy and for the treatment of AIDS-related Kaposi’s sarcoma.

Ovarian Cancer Trial

Bristol-Myers Squibb presented as its pivotal study for the new ovarian cancer indication a phase III trial conducted by the Gynecologic Oncology Group, designated GOG-111, which was reported in the Jan. 4, 1996, issue of the New England Journal of Medicine.

The company also presented two recently completed phase III trials, GOG-132 and EORTC/Intergroup (a Canadian-European study coordinated by the European Organization for Research and Treatment of Cancer), as supporting studies in favor of Taxol’s first-line use in ovarian cancer.

The multicenter, randomized GOG-111 study involved 410 stage III and IV patients: 196 received 135 mg/m2 of Taxol over 24 hours plus cisplatin at 75 mg/m2 and 214 got cyclophosphamide at 750 mg/m2 plus cisplatin at 75 mg/m2.

The primary endpoint was time to progression. Median age was 59 in both arms. Stage III disease was diagnosed in 69% of the Taxol group and 63% of controls. Clinical response was based on 240 patients with measurable disease, 113 in the Taxol arm and 127 among the controls.

Better Overall Response Rate

The company’s analysis showed a 60% overall response rate--35% complete and 25% partial--among the Taxol-cisplatin patients versus a 50% overall response in the cyclophosphamide-cisplatin group, 25% complete and 25 partial. The FDA review put the overall response at 62% in the Taxol arm and at 48% in the control group.

The company and the FDA agreed on the median survival of 35.5 months for the Taxol patients and 24.2 for the controls. The sponsor reported a median progression-free survival of 16.6 months versus 13 months in favor of Taxol-treated patients; the FDA put the numbers at 15.7 months for the Taxol group versus 12.6 months for the cyclophosphamide arm.

"The results of this trial are overwhelming," said Stephen Williams, MD, director of the Indiana University Cancer Center, who spoke in favor of the application. "For the first time in more than 15 years, we’re seeing significant improvement in survival rates for patients with advanced ovarian cancer."

Bristol-Myers Squibb reported that hematologic events occurred more often among the Taxol recipients in GOG-111: 92% of Taxol patients had grade III or IV neutropenia versus 80%, a significant difference. Infections occurred in 21% of the Taxol group vs 15% of controls. Nausea and vomiting were the most common nonhematologic problems, occurring in about 10% of both groups.

Hypersensitivity reaction and peripheral neuropathy each occurred in 3% of Taxol patients, but no controls suffered either, a significant finding. Only 5% of the Taxol patients and 7% of the cyclophosphamide group discontinued treatment because of toxicity.

ODAC members addressed two questions posed by FDA staff: whether the GOG-111 study demonstrated the efficacy and safety of the Taxol-cisplatin combination in patients with advanced ovarian cancer and whether Taxol should be approved for use in combination with cisplatin for the first-line treatment of such patients. The panel voted "yes" unanimously to both questions.

Use in NSCLC

To support Taxol’s use in NSCLC, Bristol-Myers Squibb presented data from three randomized, prospective, multicenter clinical trials including more than 1,300 patients.

ECOG Study 165, involving 599 patients, compared three arms: low-dose Taxol (135 mg/m2, 24-hour infusion) plus cisplatin; high-dose Taxol (250 mg/m2, 24-hour infusion with G-CSF support) plus cisplatin; and cisplatin plus etoposide.

Study 103 compared 332 patients equally divided between standard-dose Taxol (175 mg/m2, 3-hour infusion) plus cisplatin vs cisplatin-teniposide, and study 208 compared 190 patients on Taxol-cisplatin vs 197 receiving cisplatin alone.

Data from the three phase III studies show that Taxol-cisplatin chemotherapy is generally well tolerated and effective, the company said, with consistently improved response rates, increased time to disease progression, symptom alleviation, and survival as good as or better than the standard first-line treatment.

"Taxol-based regimens represent an important advance in the treatment of NSCLC," said Paul A. Bunn, director of the University of Colorado Cancer Center, who spoke on behalf of the company.

The FDA generally agreed with the sponsor’s statistical analysis. "The Taxol combination arms in the three trials showed superior response rates compared to the control arms," the FDA concluded in its review of the data presented. "A significant increase in time to tumor progression was shown only in the high-dose Taxol-cisplatin arms in study 165. There was no statistically significant difference in overall survival between treatment arms in any of the studies."

Grade 4 neutropenia was a common toxicity, as were grades 3-4 alopecia, and diarrhea, arthralgia, and myalgia. "The Taxol combination arms were more toxic than the cisplatin-etoposide arm in study 165, and more toxic than a higher dose of cisplatin in study 208," the FDA noted. "In study 103, the teniposide-cisplatin arm had significantly more hematologic toxicities, while the Taxol-cisplatin arm had more arthralgia, myalgia, and neurosensory events."

The ODAC Vote

In addressing FDA staff questions, the panel agreed 7-to-1 that study 165 was an adequate and well-controlled trial that demonstrated the efficacy and safety of Taxol given as a 24-hour infusion at 135 mg/m2, followed by cisplatin, in the lung cancer patients treated.

The panel’s vote to recommend approval of Taxol in NSCLC patients who are not candidates for potentially curative surgery and/or radiation therapy passed 5-to-2, with one abstention.

The panel, however, did not recommend approval of the company’s request for Taxol’s use in these NSCLC patients as a 3-hour infusion at 175 mg/m2 in combination with cisplatin. The vote was five against and two in favor, with one abstention.

Panel member Richard L. Schilsky, MD, director of the University of Chicago Cancer Research Center, termed the decision "a very tough call."

Other ODAC News

In other action, ODAC recommended to the FDA that it approve Hoffmann-LaRoche’s new oral tumor-activated agent Xeloda (capecitabine) for the treatment of patients with advanced or metastatic breast cancer who have failed Taxol and an anthracycline-containing chemotherapy regimen.

The advisory panel also gave its okay to a new indication for Eli Lilly’s Gemzar (gemcitabine) as palliative treatment of locally advanced and metastatic non-small-cell lung cancer, both as a single agent or in combination with cisplatin.

Both these actions will be reviewed more fully in articles in next month’s Oncology News International, along with a decision by the FDA’s Biological Response Modifiers Advisory Committee to recommend approval of a new use for CellPro’s Ceprate SC System.