Washington Editor

GAITHERSBURG, Md. - An FDA advisory panel on Monday voted against recommending a radiation sensitizer shown to nearly double median survival time in breast cancer patients with brain metastases.

In a 16-1 vote, the Oncologic Drugs Advisory Committee said Allos Therapeutics Inc.'s new drug application on RSR13 failed to demonstrate substantial evidence of efficacy in the breast cancer subset of patients. The FDA is not bound by ODAC's recommendation.

Following the meeting, Michael Hart, president and CEO of Allos, told reporters he was disappointed with the vote, but planned to move forward with RSR13. "This is an unfortunate day for breast cancer patients," he said.

Allos anticipates FDA action on or before June 4, its Prescription Drug User Fee Act III action date. RSR13 is a priority-review, fast-track product.

Allos, of Westminster, Colo., is requesting approval of RSR13 (efaproxiral) as an adjunct to whole-brain radiation therapy (WBRT) for the treatment of brain metastases that originated from breast cancer.

The firm's NDA is based on a 538-patient Phase III trial (called RT-009) that missed its survival endpoint, but improved the median survival time of breast cancer patients from 4.6 months in the control group to 8.7 months in the treatment arm. (See BioWorld Today, April 23, 2003, and Nov. 18, 2003.)

RT-009 enrolled patients suffering from brain metastases that had originated from non-small-cell lung cancer (56 percent), breast cancer (21 percent, or 115 patients) and other cancers (23 percent). The study was a randomized, multicenter, open-label trial designed to demonstrate the added benefit of RSR13 for the treatment of brain metastases.

At issue here is whether the FDA will approve a drug based on data from a subset of patients that was not prespecified. ODAC clearly voted against such a proposal.

According to the FDA, when the primary analysis in the overall study population is negative, subgroup analyses often are considered to be exploratory, not capable of providing a conclusive finding.

However, of the trial data, Silvana Martino, panel member and head of the breast cancer section of the John Wayne Cancer Institute at St. Johns Health Center in Santa Monica, Calif., said, "I have a feeling that something is going on here, but if we approve this for breast cancer, I'm concerned that physicians with good intentions will say, Well, if it works in population A, why wouldn't it work in population B, C and D.' I think we need to consider the consequences when we make this decision."

Donna Przepiorka, professor of medicine at the University of Tennessee in Memphis and panel chair, was the single vote in favor of the drug.

RSR13 is a synthetic small molecule designed to increase the release of oxygen from hemoglobin, which is important in treating hypoxia in connection with radiation treatments for tumors. It is designed to make radiation therapy more effective.

In RT-009, patients receiving RSR13 plus WBRT experienced a 17.6 percent improvement in median survival compared with patients receiving WBRT alone (5.26 months vs. 4.47 months; p=0.17; n=538). In the prospectively defined intent-to-treat group of patients with brain metastases only from breast cancer and NSCLC, patients receiving RSR13 had a 32.4 percent increase in median survival vs. control (5.91 vs. 4.47 months; p=0.12; n=414).

Meanwhile, in January, Allos initiated a Phase III trial using RSR13 as an adjunct to WBRT for the treatment of brain metastases from breast cancer. The randomized, open-label study will enroll about 360 patients at up to 50 North American cancer centers. Labeled ENRICH (Enhancing Whole-Brain Radiation Therapy In Patients with Breast Cancer and Hypoxic Brain Metastases), the trial is designed to compare the effect of WBRT with supplemental oxygen with or without RSR13 in women with brain metastases from breast cancer.

While panel members praised the firm for initiating another Phase III trial, others, including Martino, suggested that if ODAC recommended approval, Allos might end up dropping the trial.

On the contrary, in a previous discussion with BioWorld Today, Hart said the ENRICH data would be used for the European filing.

Allos officials were unclear as to when ENRICH would be fully enrolled, making the point that it took 29 months to enroll 115 patients in RT-009. Hart said 10 patients currently are enrolled.

Allos will hold a conference call Thursday to discuss its second-quarter financials.

Allos' stock (NASDAQ:ALTH) fell $2.09 Friday, or 45 percent, to close at $2.55 after FDA reviewers issued a negative opinion on the filing. The stock fell another 16 cents Monday to close at $2.39.