BETHESDA, Md--Three months after refusing to give its blessing to
Valstar (valrubicin), the Oncologic Drugs Advisory Committee (ODAC)
reheard Anthra Pharmaceuticals new drug application and
recommended that the FDA approve the new anthracycline for use in a
limited population of patients with carcinoma in situ (CIS) of the
The panel gave its backing to Valstar for intravesical use in
patients who are refractory to BCG immunotherapy and who have a
medical contraindication to cystectomy. It refused to endorse the
drugs use in BCG-refractory patients who are candidates for
cystectomy but who refuse to undergo the surgery. During its
presentation, the company had argued that after BCG failure, people
who refuse cystectomy and those who cannot undergo the surgery have
no effective drug treatment.
Last June, Anthra presented ODAC with combined data from two
nonran-domized, open-label phase II studies that involved a total of
90 patients. The trials were identical except for the study sites.
Patients were treated with 800 mg of Valstar weekly for 6 weeks in
Anthra claimed complete responses in 19 patients. The FDA staff
accepted only 7 of these in its analysis, which the company and its
ODAC members in June generally found Valstars toxicity
acceptable but questioned whether the trial data supported the
benefit claimed, because a number of people who didnt respond
also did not go on to cystectomy, with no apparent difference in
outcome. Several suggested that Anthra might have additional
information that would make its case more persuasive.
At the September ODAC meeting, both the company and FDA presented new
analyses of the combined studies, A9301 (35 patients) and A9302 (55
patients), that included additional data supplied by Anthra. The
company again listed 19 complete responders; the FDA classified 9
patients as complete responders and 7 more as potential complete
responders, for a response rate of 18%.
In the FDA analysis, three patients were listed as "potential
CR" because they had single lesions with negative or inadequate
baseline cytologies. Another four patients were considered potential
complete responders because they had only one follow-up biopsy
documenting complete response instead of the two sequential biopsies
designated by the protocol.
Barton Grossman, MD, deputy chairman of urology, M.D. Anderson Cancer
Center, said that Anthra asked him to do an independent analysis of
the two trials to determine if patient benefit was observed.
"After careful review of these data, I can honestly answer that
question in the affirmative," he told the panel. "These
patients are a highly refractory population. . . . A very
conservative definition of complete response was employed."
Anthra also contended that the 19 complete responders derived
clinical benefit from Valstar. It cited a longer time to cystectomy
in complete responders than in nonresponders. Also, the time to
disease recurrence after treatment with Valstar was longer for
complete responders than nonresponders, approximately 18 months vs 6
months, a significant difference in favor of the Valstar group, Dr.
The FDA generally agreed. "These data demonstrate that
intravesical treatment with Valstar produces durable complete
responses and delays time to cystectomy in patients with
BCG-refractory CIS of the urinary bladder," it told the
committee in a written document.
Committee members spent considerable time debating whether it was
wise to encourage people who fail BCG treatment to avoid cystectomy.
Speaking for the company, Paul Lange, MD, of the University of
Washington, maintained that, "there is a value in many patients
in trying to delay or avoid cystectomy."
Michael Droller, MD, of Mt. Sinai Medical Center, New York, also
presenting for Anthra, said: "I think the issues are, Do we have
an agent that has efficacy; can we apply that agent in a patient
population that is not at risk for immediate progression of disease
and in whom drug failure can be cured by cystectomy; and does the use
of the agent identify a group of patients who can then be urged to
undergo cystectomy at some point?"
In the end, the committee decided the study data failed to support
the wisdom of using Valstar as an alternative to cystectomy in
patients medically able to undergo the procedure but who refuse to do
so. It voted 9-to-2 with one abstention to approve Valstar only for
those patients in whom cystectomy is medically contraindicated.