By Ian Ingram
Trial stopped for futility, but 13-month OS improvement seen in patients with BRCA mutations.
Trabectedin (Yondelis) plus pegylated liposomal doxorubicin (PLD) failed to improve survival in a phase III trial of third-line ovarian cancer, but a survival advantage was seen in BRCA mutation carriers, a researcher reported here.
Overall survival (OS) was no different in the intent-to-treat population, but in the prespecified analysis of patients with germline BRCA mutations, OS was 34.2 months with the trabectedin combination compared with 20.9 months with PLD alone (HR 0.54, 95% CI 0.33-0.90), according to Bradley Monk, MD, of Arizona Oncology in Phoenix.
An even more pronounced 17-month OS advantage was seen in BRCA patients whose previous platinum-free interval was 6 to 12 months (HR 0.37, 95% CI 0.17-0.82), though Monk cautioned that this was a post-hoc analysis of just 60 patients.
In the first interim analysis of the OVC-3006 study, the hazard ratio for OS crossed the threshold of futility, and with higher rates of toxicity in the combination arm the independent data monitoring committee recommended discontinuing the trial.
“Trabectedin is a complicated anti-cancer cytotoxic medication,” Monk said during his presentation at the Society of Gynecologic Oncology (SGO) meeting.
The agent received FDA approval in 2015 for soft-tissue sarcoma. But in Europe and other parts of the world, it received regulatory approval for treating platinum-sensitive ovarian cancer years before this, based on findings from the OVA-301 trial.
In the U.S., however, the drug’s chances for an ovarian cancer indication were sunk by an Oncologic Drugs Advisory Committee, which voted against recommending approval of the agent 14 to 1 over concerns that the drug’s benefits were not outweighed by its toxicities.
Post-hoc analyses from OVA-301 had suggested that BRCA-mutant patients and those whose platinum-free interval was 6 to 12 months might benefit most from the drug, which formed the basis for the current study.
“Results of this phase III subanalysis are consistent with the previous observations in OVA-301,” said Monk, though he acknowledged that while the combination showed selective antitumor activity, it also added more toxicity — twice as many patients on the combination discontinued due to toxicity.
“Do you think this is the end of the road for trabectedin?” asked SGO session moderator Mark Shahin, MD, of Jefferson Health in Abington, Pennsylvania.
“Never give up — I think that’s what Muhammad Ali said. But no, I don’t,” Monk replied. “I don’t think we should be penalized because we enrolled all those non-BRCA patients. When you look at the BRCA cohort, I think that there’s an opportunity.”
He said that the major challenge based on the data presented was that patients were naive to PARP inhibitors, and suggested that a confirmatory trial would have to show the drug works after PARP inhibition.
“I’m just baffled,” Shahin told MedPage Today. “European patients with ovarian cancer cannot be that different than our American counterparts.”
He said that anecdotally, he’s enrolled patients on both trials and seen patients benefit on the drug.
“I’m partially frustrated because the number of active agents in the disease is limited,” said Shahin, adding that perhaps the agent would be best studied as a single agent in later-line recurrent disease. But he expressed concern over whether the sponsor would continue to pursue further trabectedin studies in ovarian cancer.
“I’d like to have it available,” he said.
While the drug is approved for sarcoma, Shahin said it’s not readily available in cancer centers and insurance companies would be likely to reject covering off-label use in ovarian cancer.
Study Details
OVC-3006 included 576 patients with epithelial ovarian, primary peritoneal, or fallopian tube cancer, which included 155 patients with germline BRCA mutations. Eligibility criteria included advanced or relapsed disease and no more than two prior lines of therapy. Patient characteristics were well balanced between the two arms of the trial. Most patients were white (89%), under 65 years of age (63%), and two-thirds had tumors with serous histology. Previous platinum-free interval was 6 to 12 months in 39% of patients, 12 to 24 months in 36% of patients, and greater than 24 months in 25% of patients.
OS in the intent-to-treat population was 23.2 months with the trabectedin combination versus 22.2 months with PLD alone (HR 0.93, 95% CI 0.73-1.18, P=0.5236). Progression-free survival was also no different.
There was a trend toward improved OS in the group of patients whose previous platinum-free interval was from 6 to 12 months (HR 0.69, 95% CI 0.48-1.01).
Treatment-emergent adverse events (AEs) occurred in nearly all patients, 99.0% with the combination versus 98.2% with PLD alone. Grade 3/4 AEs were higher with the trabectedin combination (85.0% vs 63.8%, respectively), as were serious AEs (41.3% vs 20.6%). In the combination arm, 32.5% discontinued treatment due to AEs compared with 16.3% of those on PLD alone. While deaths from treatment-emergent AEs were higher in the combination arm (3.5% vs 1.8%), none were considered drug related.
This article was published by Medpage Today.