YONDELIS FOR OVARIAN CANCER-TOO EXPENSIVE WITHOUT PROVEN BENEFIT IN OS-NOT APPROVED YET BY FDA

July 7, 2010 — Trabectedin (Yondelis) has been approved in Europe, Canada, and other regions of the world for use in platinum-sensitive recurrent ovarian cancer, but it is not available in the United States.

On the basis of the data from a pivotal phase 3 trial that resulted in its approval elsewhere, the drug was rejected last year by a US Food and Drug Administration (FDA) advisory committee (the vote was 14 to 1 against approval, as reported by Medscape Oncology at the time).

Some of the thinking behind this decision, and details from the pivotal trial, were published in the July 1 issue of the Journal of Clinical Oncology.

The fact that trabectedin has been rejected and approved in different countries on the basis of the same data "shows how confusing it can be to assess a new regimen in the recurrent-disease setting," writes Stephen Cannistra, MD, from the Beth Israel Deaconess Medical Center in Boston, Massachusetts, in an accompanying editorial. He was not on the FDA advisory committee for that hearing.

This is not the first time that regulatory authorities have reached opposing conclusions on the basis of the same data. However, in the recent case of bevacizumab (Avastin) for recurrent glioblastoma, the United States approved the drug and Europe rejected it, criticizing the American decision.

Trabectedin Trial Showed Survival Improvement

Trabectedin, which is based on a compound originally discovered in a sea squirt by PharmaMar, is now marketed by Zeltia and licensed to Johnson & Johnson in the United States.

The pivotal phase 3 trial that provided the data that led to regulatory approval was sponsored by the manufacturer and headed by Bradley Monk, MD, from the University of California at Irvine. The trial was conducted in 672 women with recurrent ovarian cancer who had failed first-line platinum-based chemotherapy. They were randomized to receive either pegylated liposomal doxorubicin (PLD) alone or in combination with trabectedin.

The results, now published, show that — for patients who were sensitive to platinum — there was a statistically significant improvement in progression-free survival, to 9.2 months for PLD plus trabectedin, compared with 7.5 months for PLD alone (P = .017), and in the overall response rate.

However, no improvement in progression-free survival or overall response rate was seen in platinum-resistant patients.

In addition, neutropenia and liver enzyme elevations were more common with trabectedin plus PLD than with PLD alone, although hand-foot syndrome and mucositis were less frequent.

Dr. Monk and colleagues conclude that trabectedin plus PLD improve progression-free survival and overall response rate over PLD alone, with acceptable tolerance in the second-line treatment of recurrent ovarian cancer.

In his editorial, Dr. Cannistra explains that there were several considerations that led to the FDA advisory committee rejecting the drug, including a "lack of an overall survival advantage and increased toxicity of the regimen compared with PLD alone."

Dr. Monk previously told Medscape Medical News that he was surprised that the committee "didn't recognize progression-free survival as a valuable indicator of tumor control in recurrent ovarian cancer," and said the concern over toxicity was "exaggerated," because most of the reported events were not clinically important.

Waiting for Overall Survival Data

An interim analysis presented at the FDA advisory committee showed that there was little difference in the median survival between the 2 groups (20.5 months for trabectedin plus PLD and 19.4 months for PLD alone).

"The FDA is appropriately waiting for mature overall survival data from this trial before reevaluating the regimen," Dr. Cannistra writes in his editorial.

The interim analysis presented at the meeting was conducted after 300 deaths (46% of trial participants), and it was estimated at that time (June 2009) that a final analysis would be possible in 18 to 24 months (i.e., January to June 2011).

If an overall survival advantage cannot be demonstrated with long-term follow-up, then what matters is that a patient did not live longer and "did not live better, despite receiving the more aggressive and complicated regimen," Dr. Cannistra writes in the editorial.

If an overall survival advantage does eventually emerge, then trabectedin plus PLD "may well represent an important option for patients with platinum-sensitive relapse who cannot tolerate platinum as a result of neuropathy or hypersensitivity," he notes.

"Even so, in patients with platinum-sensitive relapse who have no contraindications, platinum-based therapy should still be considered the treatment of choice because we do not yet know how PLD and trabectedin might compare with a regimen such as paclitaxel and carboplatin in that setting," he adds.

The combination of paclitaxel and a platinum compound was shown to produce an overall survival benefit in patients with relapsed but platinum-sensitive disease in the International Collaborative Ovarian Neoplasm-4 trial (Lancet. 2003;361:2099-2106). So far, this is the only trial to have demonstrated a statistically significant improvement in overall survival in recurrent ovarian cancer, Dr. Cannsitra points out.

Approached for comment, Maurie Markman, MD, professor of gynecologic medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston, who has an oncology videoblog on Medscape Medical News, said the phase 3 trial with trabectedin and PLD in recurrent ovarian cancer was "an important study."

"It is the first phase 3 trial to demonstrate the superiority of a nonplatinum-containing combination chemotherapy regimen, compared with a single nonplatinum agent, in recurrent (and potentially still platinum sensitive) ovarian cancer," Dr. Markman told Medscape Medical News.

"One can certainly imagine patients in whom [trabectedin plus PLD] would be quite useful. These include individuals with documented platinum hypersensitivity and women with preexisting (from previous chemotherapy) peripheral neuropathy," he added.

However, Dr. Markman agrees with the editorialist that the major unanswered issue is how this approach compares with a carboplatin-based combination in the same setting.

Dr. Monk reports receiving researcher funding from Johnson & Johnson and providing expert testimony to the FDA advisory committee meeting that reviewed trabectedin. Several coauthors have disclosed relevant financial relationships, and 2 are employees of companies (Johnson & Johnson, PharmaMar). Editorialist Dr. Cannistra has disclosed no relevant financial relationships. Dr. Markman reports serving as an advisor or consultant for Boehringer Ingelheim Pharmaceuticals, Genentech, MedImmune, Celgene, Ortho Biotech Products, and serving as a speaker or member of a speakers bureau for Eli Lilly and Company

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