Sanofi-aventis announced that the US Food and Drug Administration (FDA) has accepted for filing and assigned priority review status to the supplemental new drug application (sNDA) for Taxotere (docetaxel) Injection Concentrate in combination with cisplatin and fluorouracil for the induction (neo-adjuvant) therapy of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) prior to chemoradiotherapy and surgery.
The FDA grants priority review to products that, if approved, would be a significant improvement compared to marketed products, including non-drug products in the treatment, diagnosis or prevention of a disease. The Prescription Drug User Fee Act (PDUFA) date for completion of review by the FDA of the Taxotere sNDA is slated for Fall 2007. Currently, Taxotere in combination with cisplatin and fluorouracil is approved for the induction therapy of inoperable advanced SCCHN. To date, Taxotere has received a total of seven indications in the US. If granted, this will be the eighth FDA approval for Taxotere in five different tumour types.
"We are very pleased that FDA has granted priority review to Taxotere as part of a sequential treatment program that also includes chemoradiotherapy and surgery for advanced head and neck cancer," said Dr. Nassir Habboubi, vice president of US Medical Affairs, Oncology, for sanofi-aventis. "We are hopeful that Taxotere may soon be available for many patients suffering from advanced head and neck cancer. Sanofi-aventis is committed to continuing the development of effective chemotherapeutics and seeking FDA review and approvals of treatments for patients with many types of cancer."
The FDA submission is based on results of TAX 324, a randomized, open-label, international phase III trial presented at the American Society of Clinical Oncology (ASCO) annual meeting in 2006 showing a Taxotere-based regimen, versus standard chemotherapy, improved overall survival as part of a sequential treatment plan for locally advanced SCCHN. All patients entering the study had stage III or IV cancer with no distant metastases. Patients in both treatment groups had tumours of the oral cavity, oropharynx, larynx or hypopharynx that could not be removed, tumours considered operable but unlikely to be cured with surgery, or tumours that could not be removed in order to preserve crucial organs.
Patients were treated every three weeks for three cycles with either Taxotere 75 mg/m2 plus cisplatin 100 mg/m2 and fluorouracil 1000 mg/m2 a day for four days (TPF) or intravenous cisplatin 100 mg/m2 followed by fluorouracil 1000 mg/m2 a day for five days (PF), the standard therapy. Both groups of patients were then given weekly chemotherapy (carboplatin) together with radiation therapy for seven weeks, followed by surgery for those patients identified as candidates. The primary endpoint of the study was to evaluate overall survival (OS); secondary endpoints included progression-free survival (PFS), response rates (RR), and toxicity.
Overall survival was significantly improved for patients treated with Taxotere based therapy compared to patients receiving just cisplatin and fluorouracil; the relative risk of death was 30% lower (HR 0.70; p=0.0058). Patients treated with the Taxotere based therapy had a longer median overall survival of 70.6 months vs. 30.1 months for patients receiving cisplatin and fluorouracil, which represents a 40 month absolute improvement in median OS for patients treated with TPF. At three years, 62% of patients who received TPF were alive compared with 48% of those receiving PF1.
"This randomized trial demonstrated that Taxotere-based induction chemotherapy followed by chemoradiotherapy and surgery improved overall survival and progression-free survival for patients with locally advanced squamous cell carcinoma of the head and neck," said TAX 324 clinical investigator Marshall Posner, MD, Medical Director of the Head and Neck Oncology Program at Dana-Farber Cancer Institute in Boston. "These results provide potential hope for these patients, in whom survival rates have been historically low. If approved, the addition of Taxotere to standard therapy would represent a clinically important treatment option."
In addition to improvements in overall survival and mortality, the TAX 324 trial showed that progression free survival (PFS) defined as either tumour progression, the length of time before the cancer progressed, or death, was significantly improved with Taxotere. The intent-to-treat population included 255 patients in the TPF arm and 246 patients in the PF arm. The risk reduction for disease progression or death was significantly reduced by 29% (HR 0.71; p=0.004) for patients treated with Taxotere plus cisplatin and fluorouracil compared to patients receiving just cisplatin and fluorouracil. Fifty-three percent of patients treated with the Taxotere regimen were alive without cancer progression at two years versus 42% of standard therapy patients. At three years, 49% of patients in the Taxotere group were alive without disease progression versus 37% of patients in the group without Taxotere treatment. Although not statistically significant, the overall response rate was also increased among patients treated with Taxotere: 72% of patients versus 64% of patients not treated with Taxotere (p=.07).
Overall, the incidence of grade 3/4 toxicity was 65% in the Taxotere arm (TPF) compared to 62% in the group receiving cisplatin and fluorouracil (PF). Patients treated with TPF had more grade 3/4 neutropenia (84% vs. 56%), febrile neutropenia (12% vs 7%), neutropenic infection (12% vs 8%), alopecia (4% vs 1%) and diarrhoea (7% vs. 3%) than those in the PF group. Patients in the PF group had more grade 3/4 stomatitis (27% vs. 21%), lethargy (10% vs. 5%), vomiting (10% vs. 8%) and altered hearing (3% vs. 1%). The incidence of other grade ¾ events was similar between the two groups: nausea 14%, anorexia 12% and constipation 1%.
Taxotere is currently approved in 5 different cancer types in Europe and the US.
In the United States and in Europe Taxotere is approved to treat patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. It is also approved in Europe in combination with doxorubicin for patients who have received prior cytotoxic therapy for this condition and in combination with capecitabine after failure of cytotoxic therapy which would have included anthracycline. In the adjuvant setting (post surgery) it is approved in the US and in Europe in combination with doxorubicin and cyclophosphamide (TAC regimen) for the treatment of patients with operable, node-positive breast cancer.
Finally, in Europe, Taxotere is approved in combination with trastuzumab for the treatment of patients with metastatic breast cancer- over expressing HER2 receptor.
In the US and in Europe, Taxotere, in combination with cisplatin, is approved for the treatment of patients with unresectable locally advanced or metastatic non-small cell lung cancer (NSCLC) who have not received prior chemotherapy, and it also is approved, as a single agent, for patients with unresectable locally advanced or metastatic NSCLC after failure of prior platinum-based chemotherapy.
Taxotere is approved for use in combination with prednisone as a treatment for androgen independent (hormone-refractory) metastatic prostate cancer in the US and in Europe.
The FDA and the Committee for Medicinal Products for Human Use (CHMP) of the European Agency for the Evaluation of Medicinal Products (EMEA) approved in March 2006, the use of Taxotere Injection Concentrate in combination with cisplatin and 5-fluorouracil for the treatment of patients with advanced stomach (gastric) cancer, including cancer of the gastro oesophageal (GE) junction, who have not received prior chemotherapy for advanced disease.
In October 2006, the European Medicines Agency (EMEA) and the FDA approved Taxotere (docetaxel) Injection Concentrate in combination with cisplatin and fluorouracil for the induction treatment of patients with inoperable locally advanced squamous cell carcinoma of the head and neck (SCCHN).