BETHESDA, MdThe Biological Response Modifiers Advisory Committee has recommended that the FDA usher cancer therapy into a new era by approving IDEC Pharamceuticals Rituxan (rituximab) for patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkins lymphoma.
If the FDA agrees with the committees unanimous decision, Rituxan, also known as IDEC-C2B8, will become the first monoclonal antibody (MoAb) approved in the United States for therapeutic use in cancer.
Although monoclonal antibodies are used in a variety of in vivo diagnostic tests, including ones for prostate, ovarian, and colorectal cancer, only two have won FDA approval for therapeutic uses: OKT3, to counter transplant rejection, and ReoPro, directed against platelet reaggregation following angioplasty.
IDEC originally engineered the monoclonal antibody, and, since 1995, it has been developing Rituxan in a joint effort with Genentech Inc.
The drugs exact mechanism of action remains unknown. However, the binding of the monoclonal antibody to cancer cells apparently triggers complement-mediated cytotoxicity and appears to hasten apoptosis, or programmed cell death.
The company presented efficacy data from 203 previously treated patients who participated in two multicenter Rituxan trials: 102-02, a phase II trial involving 37 patients, and 102-05, the pivotal phase III study of 166 patients. In both studies, the treatment regimen consisted of 375 mg/m² of Rit-uxan given four times by intravenous infusion at weekly intervals.
The company also offered safety data derived from these two studies plus three others that included a total of 315 patients. The primary efficacy endpoint was an overall response rate of 35% to 40%. The secondary endpoints were a time to progression of eight months or greater and a response duration of six months or greater.
Results from the 203 patients in the two primary studies showed an overall response rate of 48% and a complete response rate of 6%. Median duration of remission had not yet been reached after nine months of observation.
In the 166-patient pivotal study, patients who failed to respond to their last chemotherapy (chemoresistant patients) showed a 34% response rate to Rituxan (15 of 44 patients). Patients who were chemosensitive (ie, those who responded to their last chemotherapy) had a 53% response rate (65 of 122).
Treatment also provided relief of such tumor-related symptoms as fever, night sweats, pain, and weight loss. These benefits occurred more often in patients with an objective clinical response, but were noted in some patients who had less than a 50% tumor reduction.
Toxicity Generally Mild
Researchers reported a high, albeit generally mild, toxicity level associated with Rituxan, about 93%. Most side effects were infusion related, and these usually resolved within two hours. Most of the adverse events were grade 1 or 2; only 32 of 315 patients suffered grade 3 or 4 effects, said IDEC senior vice president Antonio J. Grillo-López, MD.
According to the FDAs analysis, based on 282 patients, the most common adverse effects were fever (54%), chills (35%), nausea (23%), headache (18%), angioedema (13%), pruritus (13%), emesis (11%), bronchospasm (10%), hypotension (10%), thrombocytopenia (9%), abdominal pain, diarrhea, urticaria (8% each), and neutropenia, arthralgias, and myalgias (7% each).
In its analysis of 315 patients, the company reported a general B-cell depletion: 13% of patients had a decrease in immunoglobulins, and 29% suffered one or more infections in the year following treatment. In his analysis, FDA reviewer Bernard W. Parker, MD, generally concurred with IDECs safety and efficacy findings.
The committee members voted on two questions posed by the FDA staff. They first voted 12 to 0 that Rituxan is effective as a treatment for relapsed or refractory low-grade and follicular B-cell non-Hodgkins lymphoma.
I think the data are clear that this is effective, said Charles S. August, MD, of Miami Childrens Hospital. Most of the toxicity can be controlled with very simple therapy.
The panel also voted 12 to 0 that the risks of Rituxan are acceptable, given the efficacy data from the two studies. It does sound like the risk-benefit is definitely in favor of approving this medication, said acting chair Virginia C. Broudy, MD, of the University of Washington. Particularly attractive is the fact that it is not very myelosuppressive; the incidence of neutropenia and cytopenia was very low.