July 23, 2009 —Trabectedin (Yondelis) for use in ovarian cancer was rejected by a US Food and Drug Administration (FDA) advisory committee last week. The application was filed by Ortho (a Johnson & Johnson company), which licensed the drug from Zeltia, and both companies said that they would work with the FDA to address concerns that were raised at the meeting.
The application was for the use of trabectedin in combination with Doxil (liposomal doxorubicin) in patients with relapsed ovarian cancer, and was based on data from a pivotal phase 3 trial conducted in 672 patients.
The trial compared the combination of trabectedin plus doxorubicin with doxorubicin alone. Results were presented last year at the European Society for Medical Oncology meeting, and were reported by Medscape Oncology at the time.
At last week's meeting, the Oncologic Drugs Advisory Committee (ODAC) said that the combination did not represent a favorable risk–benefit option (voting 14 to 1 against), according to press reports. The addition of trabectedin to doxorubicin increased progression-free survival by 6 weeks, but it also increased adverse effects, including adverse cardiac effects and liver enzyme increases.
Expressing surprise at some of the discussion that took place during the meeting, the lead investigator of the phase 3 trial, Bradley Monk, MD, FACOG, FACS, associate professor and director of research in the Division of Gynecologic Oncology at the University of California Irvine Medical Center, told Medscape Oncology: "I do feel that there are enough data to show that trabectedin is useful in recurrent ovarian cancer."
The FDA usually follows the advice of its advisory committees on whether to approve a new drug or drug combination, but not always. There have been cases in the past when the advisory committee voted against approval but the FDA decided to approve a treatment. In the field of recurrent ovarian cancer, this happened a few years ago for the combination of gemcitabine and carboplatin.
Trabectedin (marketed by Zeltia) was recently approved for use in ovarian cancer in the Philippines, and has been available in Europe for use in soft-tissue sarcoma since 2007.
Trabectedin was welcomed as an "important new option" for advanced sarcomas, and was the first new drug to be approved for this cancer in more than 30 years, as reported by Medscape Oncology . The drug was originally isolated from a sea sponge.
Question About the Ovarian Cancer Trial
In the FDA briefing document prepared for the meeting, the agency asked ODAC to consider whether progression-free survival was reliable as the primary end point, given that it was measured radiologically and there were wide variations in individual reader's assessments.
Progression-free survival was increased by 6 weeks — from 5.8 months for doxorubicin alone to 7.3 months for trabectedin plus doxorubicin (hazard ratio [HR], 0.79).
But the FDA pointed out that the combination showed more toxicities than doxorubicin alone (see table below), and questioned whether the 6-week increase in progression-free survival at a cost of additional toxicity was "sufficient benefit for approval."
Toxicities Reported in the 2 Groups
| Adverse Event | Trabectedin Plus Doxorubicin | Doxorubicin Alone |
| Grade 3–4 Neutropenia | 63% | 22% |
| Grade 3–4 Thrombocytopenia | 18% | 3% |
| Febrile Neutropenia | 8% | 2% |
| Raised Liver Enzyme Levels | 31% | 1% |
| Cardiac Adverse Events | 10% | 3% |
Other Measures Also Showed Benefit
The lead investigator of the trial queried these points in an interview with Medscape Oncology. Dr. Monk, who was present at the meeting, said: "I was surprised that the ODAC didn't recognize progression-free survival as a valuable indicator of tumor control in recurrent ovarian cancer, and I was disappointed that the FDA questioned the variability of CT [computed tomography] scan measurement when they mandated that this should be performed to measure [progression-free survival]."
Dr. Monk also said that even though the CT scans might be inaccurate, the other measures of progression-free survival used in the trial — investigator assessment, assessment by an independent oncologist, and measurement of CA125 levels — all pointed in the same direction, toward a statistically significant and clinically important prolongation of progression-free survival.
He also suggested that the concern over toxicity was "exaggerated," because most of the toxicities that were seen with the combination were laboratory based (e.g., raised liver enzyme levels and bone marrow suppression). Most of them were not clinically important and did not have a detrimental effect on quality of life, he said. In addition, the "cardiac events" were not life threatening and were mostly palpitations.
Dr. Monk also noted that the combination of trabectedin plus doxorubicin has a very low incidence of neuropathy and alopecia, in contrast to that encountered with taxanes and platinum-based products, which are commonly used in the treatment of ovarian cancer. These are 2 adverse effects that many women would be eager to avoid, he suggested, and he pointed out that the 1 vote in favor of approval at the meeting came from an ovarian cancer patient who had not been treated with the combination, but said she would like to have that option.
Another cancer patient who spoke at the meeting had been treated with trabectedin alone, and had responded to the drug after having failed to respond to several other agents. Dr. Monk said that she told the meeting that the toxicity she experienced with trabectedin was not excessive, and she found the drug easier to tolerate than gemcitabine (Gemzar), docetaxel (Taxotere), and sorafenib (Nevaxar).
"There is clearly an unmet medical need in recurrent ovarian cancer," Dr. Monk notes. The combination of trabectedin plus doxorubicin would be particularly useful in patients with platinum-sensitive recurrent ovarian cancer who are allergic to carboplatin, he said.
Wait for Final Overall Survival Analysis?
At the meeting, the committee discussed whether it should wait for the results of a final overall survival analysis before making a decision. These data should be forthcoming in about 18 to 24 months, after a planned 520 deaths have occurred.
An interim analysis, conducted after 300 deaths (46% of trial participants), showed little difference between the 2 groups, with median survival of 20.5 months for trabectedin plus doxorubicin and 19.4 months for doxorubicin alone (HR, 0.85).
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