Cancer Medications : Tarceva

by National Cancer Institute

(Page 16 of 18)

Taxotere for Breast Cancer

On August 18, 2004, the FDA approved docetaxel for injection (Taxotere®, a trademark of Aventis Pharmaceuticals, Inc.) for use in combination with doxorubicin and cyclophosphamide for the adjuvant treatment of women with operable node-positive breast cancer.

Investigators enrolled 1491 women with node positive operable breast cancer in an international, multicenter, randomized trial (TAX316). Patients were stratified according to the number of positive axillary lymph nodes (1-3, 4+) and were randomly allocated to receive adjuvant treatment with either docetaxel 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclophosphamide 500 mg/m2 (FAC arm). Both regimens were given every 3 weeks for 6 cycles. After the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years.

The primary endpoint, disease free survival (DFS), included local and distant recurrences, contralateral breast cancer and deaths from any cause. At a median follow up of 55 months, results from a second interim analysis showed that the TAC regimen has significantly longer DFS than FAC, with an overall reduction in risk of relapse of 25.7% (hazard ratio= 0.74; 2-sided 95% CI= 0.60, 0.92, stratified log rank p = 0.0047). At the time of this interim analysis, based on 219 deaths, overall survival was longer for TAC than FAC (hazard ratio=0.69, 2-sided 95% CI=0.53, 0.90). There will be further analysis at the time survival data mature.

Women receiving TAC had an increase in anemia, grade > 3 neutropenia, stomatitis, amenorrhea, fever in absence of infection, hypersensitivity reactions, peripheral edema, neurosensory and skin events compared to those receiving FAC. The toxicity, while significant, did not cause a large number of patients to withdraw from treatment. As with other anthracycline/cyclophosphamide-containing regimens, long-term serious toxicity for the TAC regimen included leukemia (0.4%) and congestive heart failure (1.6%).

The approved dose of docetaxel for the adjuvant treatment of operable node-positive breast cancer is 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 cycles.

Taxotere for Gastric Cancer

On March 22, 2006, the FDA approved docetaxel (Taxotere® Injection Concentrate, made by Sanofi-Aventis) for use in combination with cisplatin and fluorouracil for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease.

This indication is based on the results of a multicenter, open-label, comparative clinical trial of 457 patients with locally advanced or metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for advanced disease. Patients were randomized to one of two arms.

TCF (docetaxel 75 mg/m² in combination with cisplatin 75 mg/m² on Day 1 and fluorouracil 750 mg/m²/day by continuous infusion for five days every three weeks), or

CF (cisplatin 100 mg/m² on Day 1 and fluorouracil 1000 mg/m²/day by continuous infusion for five days every four weeks). Four hundred and forty five patients were treated (TCF = 221, CF = 224)

Time-to-progression (TTP) was the trial's primary endpoint and was defined as time from randomization to disease progression or death from any cause within 12 weeks of the last evaluable tumor assessment or within 12 weeks of the first infusion of study drugs for patients with no evaluable tumor assessment after randomization.

The hazard ratio (HR) for TTP was 1.47 (CF/TCF, 95 percent CI: 1.19-1.83) with a significantly longer TTP (p=0.0004) in the TCF arm. The median TTP in the TCF arm was 5.6 months compared to 3.7 months in the CF arm.

Overall survival was significantly longer (p=0.02) in the TCF arm with a HR of 1.29 (95 percent CI: 1.04-1.61). The median survival was 9.2 months in the TCF arm and 8.6 months in the CF arm.

Compared to patients receiving CF, patients receiving TCF had more neutropenia, fever, infection, febrile neutropenia, neutropenic infection, allergic reactions, fluid retention or peripheral edema, neurosensory toxicity, dizziness, alopecia, rash, nail changes, diarrhea, esophagitis/dysphagia/odynophagia, gastrointestinal pain or cramping, and tearing than patients receiving CF.

Eighty-two percent of patients on the TCF arm had grade 3 or 4 neutropenia and 32 percent had febrile neutropenia or neutropenic infection. The most frequent causes for treatment discontinuation were GI toxicities, flu-like symptoms and neurosensory toxicity. Patients receiving CF had more thrombocytopenia, vomiting, anorexia, constipation, and altered hearing.

For gastric carcinoma, the recommended dose of Taxotere is 75 mg/m2 administered as a one-hour infusion, followed by cisplatin 75 mg/m2, as a one-to-three hour infusion (both on Day 1 only), followed by fluorouracil 750 mg/m2 per day given as a 24-hour continuous infusion for five days, starting at the end of cisplatin infusion. Treatment is repeated every three weeks.

Taxotere for Prostate Cancer

On May 19, 2004, the FDA approved docetaxel for injection (Taxotere®, made by Aventis Pharmaceuticals, Inc) for use in combination with prednisone for the treatment of metastatic, androgen-independent (hormone-refractory) prostate cancer.

Safety and efficacy were demonstrated in TAX327, a randomized, multicenter global clinical trial designed to evaluate chemotherapy with Taxotere and prednisone in the treatment of men with metastatic, hormone-refractory prostate cancer. One thousand and six patients were randomized to one of three treatment arms:

• mitoxantrone + prednisone (MTX + P),
• weekly Taxotere (TXT qw) + prednisone, or
• Taxotere once every three weeks (TXT q3w) + prednisone

The primary efficacy endpoint was survival. The treatment arm of TXT q3w + prednisone demonstrated a statistically significant survival advantage over MTX+P control (median survival 18.9 vs. 16.5 months, respectively, p = 0.0094). The TXT qw + prednisone arm did not demonstrate an advantage in overall survival over the control arm.

Adverse events included anemia, neutropenia, infection, nausea, vomiting, anorexia, and fatigue. Adverse events occurring more frequently with TXT q3w compared to MTX+P included allergic reactions, fluid retention, sensory neuropathy, alopecia, nail changes, diarrhea, and stomatitis.

The approved dose for this indication is 75 mg/m2 docetaxel given intravenously as a 1-hour infusion every 21 days on day 1 plus 5 mg oral prednisone twice daily for 10 cycles.

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