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Executive Summary

Chiron/Cetus' Proleukin (interleukin-2) was recommended for approval in treating metastatic renal cell carcinoma by FDA's Biological Response Modifiers Advisory Committee on Jan. 17. The committee, which recommended approval by a vote of 7-1 the second time around for Proleukin, had first reviewed IL-2 in July 1990. After considering the extent and duration of responses and adverse reactions resulting from Proleukin therapy, the committee unanimously recommended that the product be used in patients with metastatic renal cell cancer who are asymptomatic (performance status zero) or who are symptomatic but still ambulatory (performance status one). These are the indications being sought by Chiron. The PLA was filed in November 1988. Committee Acting Chairman Frederick Appelbaum, MD, Fred Hutchinson Cancer Research Center, recommended approval for Proleukin, but expressed the committee's concerns with the levels of toxicity displayed by the agent. "While [Proleukin] is not in any conventional and effective, I do think the individual patient should be given the benefit of the doubt in the benefit-risk ratio," Appelbaum commented. Committee member Ernest Borden, MD, Medical College of Wisconsin, dissented. "I remain unconvinced that [Proleukin] has changed the natural history in these patients and that these patients benefit," he said. "I'm concerned about two things. First, we have a relatively short duration of follow-up on these patients in terms of impacting the duration of their response -- the number who have been followed for one year or even two years is relatively small; secondly, there is a numerator of the non- responding patients who are clearly also alive." Presenting for the company, Richard Fisher, MD, Loyola University, Chicago, said individuals with metastatic renal cell cancer who are not treated have a median survival of six to 12 months. He noted that for the 255 patients in the seven Proleukin clinical trials, "the median survival is 16.1 months." Arthur Louie, MD, Cetus Oncology clinical research reported that in the nonresponder group, 14 patients were alive at two years; at two- and-one-half years, six patients were still alive; and at three years, two patients still survived. Committee member Borden was joined in his concern about Proleukin's utility by committee consultant John Rinehart, MD, Texas A&M University, who contended that the trial participants were an "extraordinary subset" of patients with renal cell carcinoma, since most were asymptomatic, all were ambulatory, and all were screened to avoid significant other renal, liver and heart disease. Committee member Michael Hawkins, MD, National Cancer Institute, countered that "the burden of proof is on someone else to show that this [product] isn't useful." Because company data indicated that Proleukin can cause severe adverse reactions and is less likely to invoke a response in symptomatic but ambulatory patients, Appelbaum insisted that "strong language needs to be put in the label insert [stating] that patients other than performance status zero have a...high chance of ending up intubated and suffering severe [and possibly] fatal toxicities." The committee unanimously adopted this recommendation. The committee also was asked to choose between the two dosage regimens and the two methods of dilution used in the clinical studies. Studies involved dosages of both 0.033 mg/kg and .04 mg/kg Proleukin, diluted in D5W (5% dextrose) alone, D5W plus 0.1% human serum albumin (HSA) and normal saline plus 5% HSA. Five of the seven trials used 0.033 mg/kg Proleukin and 159 of the 255 patients studied received Proleukin diluted in D5W, the committee unanimously agreed to recommend these dosage regimens. Committee member Paula Pitha-Rowe, PhD, Johns Hopkins Medical Center, remarked that there is "not enough data to make a scientific decision" on the best dosage or dilution method. The Proleukin PLA originally had sought approval for a continuous infusion regimen and an eight-hour regimen. However, the continuous infusion regimen was dropped following study results that showed that regimen to be inferior to Proleukin dosing every eight hours. The committee recommended that several issues discussed at the meeting be further explored in Phase IV studies. One of the recommendations for postmarketing studies concerned varying aggregates of IL-2. In preclinical trials, a monomeric IL- 2 was administered to sheep and rats that was found to be less effective but also less toxic than the polymeric Proleukin. The monomeric IL-2 also was found to be fully distributed in blood plasma, whereas Proleukin is only about 30% distributed in blood plasma. The differences found between varying dilution methods for Proleukin also should be explored further, the committee decided. Higher mortality was found among rats given Proleukin diluted in HSA, but human data were inconclusive. The committee also requested a Phase IV study aimed at better defining which patients of performance status one (symptomatic but ambulatory) are likely to benefit from Proleukin and who are more likely to suffer its toxic side effects. Committee members also expressed interest in learning about the role that nephrectomy plays in the efficacy of IL-2. Since all but 37 of the 255 patients in the trial database had nephrectomies before undergoing Proleukin treatment, the committee agreed that no conclusions could be drawn regarding the agent's efficacy in patients with their kidneys intact. Two patients who did not undergo nephrectomy responded partially to IL-2. At its July 30, 1990 meeting, the advisory committee determined that the efficacy data from the Proleukin trials were insufficient to support an approval recommendation ("The Pink Sheet" Aug. 6, 1990, p. 6). The committee recommended that a reanalysis of the clinical trial data be conducted to more clearly show efficacy and define the small subset of patients who might benefit from Proleukin. Representatives from Chiron and the National Cancer Institute made presentations to the committee of data from the seven trials of Proleukin treatment involving a total of 255 renal cell carcinoma patients. An additional 149 patients had been added to the trials since the data was presented at the July 1990 meeting. In the 255-patient database, an overall response rate of 15% was seen. The same overall response rate was observed in four "pivotal" studies presented at the July 1990 meeting. At that time, Cetus maintained that the response rate for IL-2 was as high as 20%. Study data then indicated a complete response rate between 2% and 5%. Cetus had calculated efficacy by focusing on the four pivotal studies. Of the 37 patients in the database of 255 who responded, nine were complete responders (4%) and 28 were partial responders (11%). The response rate was better in patients who were asymptomatic (18%). Projected duration of response is almost two years for all the responders and a year-and-a-half for partial responders. Although more patients were added to the trials, the incidence of treatment-related deaths remained the same at 4%. Cetus Oncology's Louie presented the results of the analysis conducted to determine which patients respond the best to Proleukin therapy. "When the entire 255-patient database is arrayed by response and performance status, we find that two- thirds of the patients began treatment [with] performance status of zero. This subset of 166 patients had an 18% response rate which included all of the complete responders [9] and 21 of the 28 partial responders," Louie said. "Seven partial responses were seen among the 80 performance status one patients for a 9% response." Louie noted that 15 of the 28 overall partial responders showed tumor size regression of 90% or more. Committee members agreed that such regression represented a major biologic response and might, in fact, represent complete responses that only appear partial due to scar tissue. Appelbaum asked Chiron how much a single cycle of IL-2 would cost. Cetus exec James Rurka said patients not requiring intensive care unit-support "would consume approximately $30,000 of healthcare costs, including $7,000 estimated cost for Proleukin." With ICU support, the cost is "approximately $45,000." The cost estimates are based on a study commissioned with SysteMetrics in January 1990.

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