Proleukin Wins ODAC Support For Use in Metastatic Melanoma

BETHESDA, Md—Proleukin (al-desleukin, Chiron) has won the backing of the Oncologic Drugs Advisory Committee (ODAC) for a new indication. The panel recommended that the FDA approve the recombinant human inter-leukin-2 as “indicated for the treatment of adult patients with metastatic melanoma.” The FDA approved Proleukin for use in renal cell carcinoma in 1992.

Durable Responses

“We believe that Proleukin can provide a durable response for some metastatic melanoma patients,” said Magnus Lundberg, president of Chiron Therapeutics and Chiron Vaccines. “This is particularly important when you consider that the median age for these patients is 42 years while average survival is unaffected by current treatments and aver-ages less than 1 year.”

Proleukin activates the immune system and induces the proliferation of natural killer and cytotoxic T cells, which recognize tumor-specific antigens on the surface of malignant cells and attack them. The drug’s precise mechanism of action remains unknown, however. Chiron sought the same dosage schedule for melanoma patients as the FDA previously had approved for renal cell carcinoma, 600,000 IU/kg.

The company presented data from eight open-label clinical trials to support the drug’s use in treating metastatic melanoma. The studies, conducted from 1985 through 1993, involved a total of 270 patients treated with a comparable dose and schedule of Proleukin. Sixty-nine percent of the patients had at least one site of visceral involvement.

The National Cancer Institute funded seven of the studies (four intramural and three extramural), and Chiron sponsored the eighth.

According to the company’s analysis of the data, 43 of the 270 patients (15.9%) responded to Proleukin, and 17 (6.3%) showed a complete response, which was defined as the total disappearance of tumors for two consecutive observations at least 28 days apart.

Twenty-two of the patients with a complete or partial response survived at least 4 years, and 59% of the complete responders had a survival rate of 5 years. The median duration of complete response has yet to be observed but is at least 40 months, compared with 5.9 months for patients exhibiting a partial response, the data showed.

Toxicity Data

Proleukin therapy was not an easy experience for patients. Episodes of capillary leak syndrome, neurologic toxicity, and sepsis were common, although reversible 1 to 4 days after treatment, said Lori Kunkel, MD, Chiron’s associate director for clinical development.

Twenty-two patients terminated treatment early because of adverse reactions, including cardiac events, respiratory problems, and sepsis.

Indeed, according to the FDA analysis of the eight-study data, 95% of the patients experienced grade 3 toxicity, and 35% had grade 4 toxicity. Infusion of Proleukin required that patients be hospitalized in an intensive care unit both during and after treatment.

Six of the 270 patients died of problems related to the drug. Using the Eastern Cooperative Oncology Group performance scale, in which 0 represents the best score, mortality was disproportionately higher in patients with ECOG scores of 1 or 2; only one of the six deaths occurred among the 211 patients with an ECOG performance status of 0.

Dr. Kunkel pointed out that advances in recent years have reduced the severity of Proleukin side effects in patients. For example, none of the deaths in the trials occurred during the 1990s, and no patient suffered significant sepsis after 1989 because of the introduction of prophylactic antibiotic treatments. The six deaths were all associated with sepsis prior to the use of prophylactic antibiotics.

“We feel Proleukin treatment in cases of metastatic melanoma has a favorable risk-benefit,” she said. “The toxicities, although severe, are predictable, manageable, and reversible, and this treatment provides the opportunity for durable responses in patients.”

The panel addressed a series of questions posed by the FDA staff. It agreed unanimously in two votes that Proleukin provided clinical benefit for patients with metastatic melanoma and should be approved for use in such patients. “The duration of the responses is very meaningful and clearly associated with clinical benefits,” said Robert Ozols, MD, PhD, senior vice president for medical science, Fox Chase Cancer Center. “The response rate is obviously low, but the duration is impressive.”

ODAC members also made clear, without a formal vote, that they opposed restricting the use of Proleukin to specific patient populations, such as those with an ECOG performance status of 0.

The committee voted 6 to 3, with one abstention, that the drug be granted standard approval. Had the ODAC recommended accelerated approval for Proleukin, Chiron would have had to gather considerably more safety and efficacy data once the FDA approved the drug’s use for metastatic melanoma.