October 7, 2009 — A longer-acting formulation of interferon was narrowly recommended for approval for use in malignant melanoma at a US Food and Drug Administration (FDA) advisory committee meeting.
The product, pegylated interferon alfa-2b (Pegintron, Schering-Plough), is administered subcutaneously once weekly by self-injection. The application for use in malignant melanoma suggested it could be used for 5 years.
The company said that this offers a more convenient administration schedule than the unpegylated formulation of the same product, Intron A, which is already approved for use in malignant melanoma. Intron A is administered by intravenous infusion for 5 days a week during the initial 4-week treatment period — which necessitates daily visits to a physician's office — followed by subcutaneous injections 3 times weekly for 48 weeks.
Pegintron is already marketed for use in the treatment of chronic hepatitis C in combination with ribavirin (Rebetol, Schering-Plough). However, the dose used for malignant melanoma is 2 times higher than that used for hepatitis.
Offers an Alternative
The FDA asked its Oncologic Drugs Advisory Committee to consider whether the new product offered sufficient benefit to warrant approval. The agency pointed out that the clinical trial of the product that was submitted with the application (EORTC 18991) showed a significant prolongation of relapse-free survival. "However, there was no effect on overall survival observed and substantial toxicity occurred with the treatment regimen administered in this study," it added.
At the dose used in this study, the product "can be toxic, likely decreasing the quality of life during drug administration," the agency pointed out.
"Potential benefits associated with delaying a relapse without a survival benefit would be to avoid the morbidity of surgical procedures for resection of recurrent disease and the possible psychological benefit of being tumor-free," according to the FDA.
"The primary question raised by this application is whether there is a favorable risk:benefit profile" for this product, the agency stated in its briefing documents.
The committee voted 6 to 4 in favor of recommending approval.
"This will provide an alternative that is at least more convenient for patients," said Michael Link, MD, head of oncology at Stanford University School of Medicine in California, according to a Reuters report of the meeting. Other experts suggested that having this formulation available would mean that patients who could not manage the daily visits for intravenous infusions for logistic reasons would have a chance to receive adjuvant interferon treatment.
Schering-Plough noted in documents filed for the meeting that the benefit for relapse-free survival with the standard product, Intron A, is well established, but added that individual trials have not consistently demonstrated a survival benefit. However, a meta-analysis, using individual patient data, of adjuvant interferon therapy trials in more than 6000 patients demonstrated a survival benefit that was statistically significant, with an absolute increase in 5-year survival of 2.8% (from 47.1% to 49.9%; P = .008).
Clinical Data From EORTC Trial
The clinical data to support the application comes from a trial conducted by the European Organization for the Research and Treatment of Cancer (EORTC), which has already been published and commented upon in medical journals.
The trial, known as EORTC 18991, was conducted in 1256 advanced malignant melanoma patients, and showed that Pegintron had a significant impact on relapse-free survival, increasing it to 34.8 months, compared with 25.5 months in the observational group (P = .01).
When the study was published in the Lancet (2008;372:117-126), an accompanying editorial (2008;372:89-90) noted that the median follow-up of 3.8 years was "too short for final conclusions," as reported by Medscape Oncology at the time. The significant improvement seen in recurrent-free survival could disappear after therapy ends, but then again, longer follow-up might show a significant overall survival advantage for those patients, which "would represent the real advance we've been awaiting for," the Lancet editorialists wrote.
More data from that trial, with details about the adverse effects and impact on quality of life, were reported earlier this year in the Journal of Clinical Oncology (2009;27:2916-2923), and an accompanying editorial (2009;27:2896-2897) questioned whether the toxicities are worth it, as reported by Medscape Oncology. That study showed that the toxicities encountered with the pegylated product were similar to those seen in other studies using standard interferon alpha in melanoma, and included fatigue, hepatotoxicity, and depression.
"These data are important and disappointing and do not support a conclusion that using pegylated interferon alfa-2b, at least with the schedule used in EORTC 18991, will either greatly improve the tolerability or significantly increase the feasible duration of treatment for adjuvant interferon in high-risk melanoma," the editorialists comment in the Journal of Clinical Oncology. However, they too remarked that the follow-up of this trial is still early, and that longer-term data may yet show improved outcomes, including an impact on overall survival.
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