FDA Panel Votes Against Adding Doxil to Docetaxel for Advanced Breast Cancer

[Hopeful]

Elsevier Global Medical News. 2009 Jul 15, E Mechcatie


GAITHERSBURG, Md. (EGMN) - A Food and Drug Administration advisory panel unanimously agreed that the increased risks associated with adding the pegylated liposomal formulation of doxorubicin (Doxil) to docetaxel for treating advanced breast cancer outweighed any possible benefits of the combination therapy. The FDA's Oncologic Drugs Advisory Committee voted 13-0 on July 15 that the risk-benefit analysis of adding liposomal doxorubicin to docetaxel in this population was not favorable. It cited the marked toxicity associated with the combination treatment, a modest effect on time to progression with no evidence of improvement in overall survival, and questionable applicability to the United States population.
The panel was not asked to specifically recommend for or against approval. The FDA usually follows the advice of its advisory panels.
Centocor Ortho Biotech Products L.P., proposed that liposomal doxorubicin, administered intravenously, be approved in combination with the antimitotic agent docetaxel (Taxotere) for treating patients with locally advanced or metastatic breast cancer who have received prior anthracycline treatment.
Doxorubicin, an anthracycline with a favorable cardiac safety advantage, is approved for treating ovarian cancer and multiple myeloma, but not for breast cancer in the United States, according to the company. As a single agent, doxorubicin has been shown to be effective in treating breast cancer and is approved in the European Union as monotherapy in patients with metastatic breast cancer, in cases where cardiac risk is a concern.
For approval of this indication, Centocor submitted an open-label, randomized, controlled, phase III study comparing liposomal doxorubicin plus docetaxel with docetaxel alone in 751 women with locally advanced or metastatic breast cancer; nearly all had been treated previously with an anthracycline and an alkylating agent.
The median time to progression - the primary end point - was significantly longer (9.8 months) among those on the combination, compared to those on docetaxel alone (7.0 months). But median overall survival, a secondary end point, was 20.5 months in the combination group and 20.6 months in the monotherapy group.
Moreover, those on the combination experienced significantly more toxicities, with 61% developing hand-foot syndrome vs. 1% of those on monotherapy. In addition, 52% of those on the combination had stomatitis and 4% had pneumonia, compared with 14% and 1%, respectively, among those on docetaxel alone. One case of pneumonia in the combination arm was fatal.
These adverse events often resulted in delayed treatment and dose reductions, a concern raised by FDA reviewer Dr. Tatiana Prowell of the FDA's Division of Drug Oncology Products.
Only 4% of the study participants were in the United States - most were from Russia and Eastern Europe - and important disease characteristics that are used in the United States for treatment selection were unknown. ER/PR status was unknown in 32% of the patients, and HER-2/neu status was not known in half the patients.

Hopeful