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The FDA’s Oncologic Drug Advisory Committee Decides the Fate of Two Drugs for AIDS-Related Malignancies

‘Nowhere near bowled over’

On June 23rd, the FDA’s Oncologic Drug Advisory Committee held a hearing to determine the fate of Bristol Myers-Squibb’s supplemental new drug application for paclitaxol (Taxol) as second-line treatment for AIDS-related Kaposi’s sarcoma. Taxol is a popular, potent chemotherapeutic agent which had originally been approved by the FDA for use in breast cancer, and is also used off-label for ovarian cancer.

Bristol’s application included 85 patients with progressive KS from two Phase II studies: #174 conducted at the National Cancer Institute and #281 conducted at University of Southern California and Harvard. Because Bristol was seeking an indication for Taxol as second-line KS therapy (that is, patients who have failed or are intolerant to first-line treatment), the main focus was on the 59 patients (69%) who had received prior systemic therapy. The vast majority of the 59 patients were considered “poor prognosis” candidates for therapy because they had a median CD4 count of 16, other prior opportunistic infections (86%), and flu-like symptoms (54%) typical of abnormal activation of one’s B cells. Their KS involvement was pronounced: only 7% had KS limited to their skin, 42% also had oral involvement and 30% had KS in their lungs.

According to the FDA’s assessment, an overall response was documented in 35 of the 59 patients, 2 with a “complete response” and 33 with a “partial response.” The median time to the first response was 8.1 weeks (range 2.9-36.0 weeks, and the median time to progression for all 59 patients was 6.2 months (95% range: 4.6-8.7 months). Median survival for all patients (including the ones who had neither a complete nor a partial response to treatment) was 13.7 months. For those patients with prior systemic therapy, the median survival was 14.1 months, but of those, patients with pulmonary KS had a median survival of about half that time (7.4 months). Overall, 84% of patients developed secondary opportunistic infections during the treatment for KS. At the time of the analysis, over half of the total patients (forty-six of eighty-five) were dead.

Neutropenia (a dangerously low number of bacteria-fighting white blood cells) was the major toxicity associated with Taxol, with 100% of the patients in study 174 and 62% of those in study 281 developing grade 3 or 4 neutropenia. (Co-administration of G-CSF was more common in #281 than in #174.) Fever associated with neutropenia developed in 55% and 9% of the #174 and #281 patients, respectively. Other toxicities included, alopecia (hair loss) in 91% of patients, asthenia (weakness or loss of strength) in 84%, nausea/vomiting in 69%, diarrhea in 79%, arthralgia or myalgia (joint or muscle pain) in 64%, peripheral neuropathy in 58%, alterations in SGOT liver enzymes in 49%, and renal (kidney) toxicity in 24%. Even with such high rates of toxicity, only 7 (8%) patients discontinued Taxol due to adverse events.

After all these data were presented to the FDA’s Oncologic Drug Committee, a vote of 8 to 4 was rendered in favor of approving Taxol as second-line treatment for patients with KS. Bristol got its KS indication for Taxol, but the FDA stipulated that when used to treat KS in HIV-infected patients, Taxol must always be administered with G-CSF.

Two Taxol post-marketing studies generated by the AIDS Committee of the NCI’s Eastern Cooperative Oncology Group (ECOG) are soon to open: a Phase II study which will test the.pharmacological drug interactions of Taxol with all approved protease inhibitors, and a Phase III study of Taxol versus Doxil for first-line treatment of progressive KS. The endpoints for the Phase III study are efficacy, toxicity, and clinical benefit.

On the same day as the Taxol hearing, Ilex Pharmaceuticals presented its data on mitoguazone (MGBG) for the treatment of patients with HIV-related non-Hodgkin’s lymphoma (NHL) who have previously failed at least one “potentially curative” regimen. Currently, there are no approved drugs (or a standard of care) for patients with HIV-related lymphoma who have failed or are intolerant to standard, first-line chemotherapy.

The MGBG application included a total of 90 relapsed or refractory NHL patients who were enrolled in two open-label, single-arm Phase II studies. Of the 90 patients, 65 patients (72%) had more than 3 “poor prognostic” factors; only one patient had none.

According to Ilex, six patients achieved a “complete response” and 7 achieved a “partial response.” Median time-to-response was 53 days, and the median duration of response was 144+ days. Overall, time-to-tumor progression was 40 days, time-to-treatment failure was 30 days, and the median survival time was 84+ days. For the responders, time-to-tumor progression was 163+ days, time-to-treatment failure was 151 days, and the median survival time was 269 days.

After closely examining Ilex’s methods for assessing treatment responses, the FDA medical officer adjusted Ilex’s reported 14.4% overall response rate down to 6% due to either patient ineligibility, protocol violation or simple disbelief. Even at 14.4%, the Oncologic Drug Committee members were nowhere near bowled over by MGBG’s purported success rate, but when even that unimpressive response rate was whittled down to a single digit, they wanted nothing more to do with the drug-period! They promptly voted 0 to 12 against approving MGBG. Since the FDA usually follows its advisory committee’s decisions, it seems highly unlikely that MGBG will be approved.

While it may have been rational for the Committee to vote against approval of MGBG in light of the FDA’s data analysis, some activists and lookers-on are concerned that the FDA did not give Ilex adequate time to formally respond to the response rate discrepancy. So too, they are, while the Oncologic Drug Committee is honorably staffed with a phalanx of distinguished breast, prostate, lung and ovarian cancer doctors, representation of AIDS physicians is sorely lacking. And the differences between HIV-related and non-HIV lymphoma are striking. For the future review of new AIDS malignancy agents, the FDA must insure that its oncologic drug advisory committee has adequate representation of AIDS oncologists so that it may professionally, logically and sensibly advise.

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