ROCKVILLE, Md. _ The FDA's Oncologic DrugsAdvisory Committee (ODAC) voted nine-to-one (withone abstention) on Tuesday to recommend approval ofSchering-Plough Corp.'s alpha interferon 2b as anadjuvant to surgery for disease-free malignant melanomapatients at high risk of systemic recurrence.

If the FDA concurs, the drug, trade named Intron A, willadd a sixth indication to its label. It is currently approvedto treat hairy cell leukemia, AIDS-related Kaposi'ssarcoma, condylomata acuminata (genital warts), chronichepatitis NANB/C and chronic hepatitis B.

ODAC members concluded that Intron A improvesoverall survival and disease-free survival times inmelanoma patients, a benefit that outweighs the severeand even life-threatening flu-like symptoms experiencedby up to 80 percent of patients. Last year in the U.S.,34,000 new cases of malignant melanoma were reportedand it's estimated that the lifetime risk of developing thedisease will range from one in 75 to one in 90 by the endof this century.

ODAC based its recommendation on data from a single,multicenter Phase III clinical trial conducted by Madison,N.J.-based Schering-Plough. Early on in the deliberations,ODAC Chairman Paul Bunn, director of the University ofColorado Cancer Center in Denver, noted that ODACusually requires confirmatory studies for cancer drugsbecause the agents "are so toxic and often give a smallbenefit." But ODAC members repeatedly called IntronA's malignant melanoma results "compelling" onTuesday.

The single Phase III study, called EST 1684, enrolled 287patients at 29 centers (28 of which were in the U.S.).Patients were randomized to 52 weeks of treatment withIntron A or to 52 weeks of observation, the equivalent ofa control group in this disease setting. The trial took eightyears to complete, lasting from March 1985 to March1993.

Overall survival was the primary endpoint of the EST1684 trial, with a secondary endpoint of relapse-freesurvival. Although Intron A increased median overallsurvival times in the 143 patients who received it, thefinding fell slightly short of statistical significance,prompting FDA reviewers to deem it "borderlinesignificant." Intron A-treated patients survived a medianof 3.8 years as compared to 2.78 years for observationgroup (OBS) patients.

Secondary Endpoint Accepted As Primary Endpoint

However, Intron A had a strong impact on the importantsecondary endpoint of relapse-free survival. Intron A-treated patients enjoyed a median of 1.72 years of relapse-free survival vs. only 0.98 years for OBS patients."Relapse free survival is a thoroughly convincingendpoint," argued ODAC member Arlene Forastiere,associate professor of oncology at the Johns HopkinsOncology Center in Baltimore, Md. "I think we canaccept it as a primary endpoint."

When the trial data were broken down into subgroups bydisease severity, sicker patients appeared to do better withIntron A. Indeed, some ODAC members expressedconcern over results seen in a small subgroup of 31patients, known as "node-negative" patients, whosemelanoma was visible on the surface of the skin but hadnot yet spread to the lymph nodes. Intron A-treated node-negative patients did worse than their counterparts in theOBS group: eight out of 16 Intron A patients died whileonly 3 out of 15 OBS patients died.

But many ODAC members argued that retrospectivesubgroup analyses are inconclusive. "Subset analysis isan extremely dangerous business," cautioned ODACmember Robert Ozols, senior vice president of medicalscience at Fox Chase Cancer Center in Philadelphia. "Idon't think we can say what this means one or the otherin such a small group of patients."

Schering-Plough, concerned about the findings, originallyproposed labeling that excluded node-negative patientsfrom the melanoma indication. However, after six panelmembers voted against the restricted labeling, thecompany produced wording for a broader indication thatthey said had been their goal all along. Seven ODACmembers voted to recommend the FDA adopt the broaderlanguage, two opposed the move and two abstained.

Toxicities Deemed `Acceptable'

ODAC members ruled that Intron A's considerabletoxicities were acceptable in the setting of malignantmelanoma, a disease which is essentially untreatable forrelapsed patients. All 143 patients who received Intron Aexperienced at least one adverse event, with 66 percentexperiencing "severe" events and 14 percent experiencing"life-threatening" events.

Two patients died as a direct result of drug-relatedhepatotoxicity. The bulk of side effects involved a clusterof flu-like symptoms, such as fatigue, fever, myalgia,vomiting/nausea and headaches. Other side effectsreported included anorexia and depression.

Intron A was licensed by Schering-Plough from theCambridge, Mass.-based biotechnology Biogen Inc. in theearly 1980s. Worldwide sales of the drug totaled $426million in 1994, an undisclosed portion of which went toBiogen in the form of royalties. In 1993, Intron A salespeaked at $572 million, but a government-imposed pricecut and market contraction in Japan caused a 25 percentdrop in sales in 1994.

Although officially approved for only five indications inthe U.S., Intron A is approved for 16 indicationsworldwide. It is approved for the broadly definedtreatment of malignant melanoma, including metastaticmalignant melanoma, in France, Italy, Austria, Portugaland Finland. In Sweden, it has been approved as anadjuvant to surgery in melanoma patients, an indicationsimilar to that considered by ODAC on Tuesday.

Schering-Plough spokesman Steve Galpin told BioWorldthat Intron A is currently being tested in Phase III trials inthe U.S. as a treatment for a host of other diseases,including bladder cancer, chronic myelogenous leukemia,multiple myeloma, non-Hodgkin's lymphoma and renalcell carcinoma. n

-- Lisa Piercey Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.

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