Survival Outcomes for Trabectedin in Soft Tissue Sarcomas Discussed

epigenetic modulation

George Demetri, MD

Trabectedin has been in clinical development for nearly 20 years with a focus on leiomyosarcomas and liposarcomas for the past 12 in subtypes thought to be particularly sensitive. Numerous studies, many of them designed in the United States, have resulted in the approval of the drug in over 70 countries worldwide. Despite this, the drug was only recently approved in the United States on October 30, 2015.

According to George D. Demetri, MD, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute, an application for trabectedin was submitted to the FDA for patients with advanced soft tissue sarcoma who received prior chemotherapy in late 2014 and was granted a priority review. A decision deadline was then set for August 2015, though the approval came a few months later.

“Trabectedin is fascinating, partially because we still do not understand all of the things that it does. It is very multifunctional; it is derived from a sea squirt that grows in a colony. To protect itself since it can’t get away from things, it creates this chemical to thwart predators,” he said in an interview with Targeted Oncology. “This chemical is now synthetic and can be made in mass quantities. The reason our sarcoma community is interested in it is because with trabectedin, some patients get extremely good responses and durable stability of their disease, sometimes lasting 4 or 5 years. This is not trivial at all.”

The final analysis of the phase III data for trabectedin, presented recently at the 2015 European Cancer Congress, found that after a 21-month follow-up, the median progression-free survival (PFS) with trabectedin was 4.2 versus 1.5 months with dacarbazine (HR, 0.55; 95% CI, 0.44-0.70; P <.001). However, the median overall survival (OS) advantage, which was the primary outcome measure for the trial, was not statistically significant, at 13.7 months with trabectedin versus 13.1 months with dacarbazine (HR, 0.93; 95% CI, 0.75-1.15;P= .492).

Grade 3 adverse events found to be higher in the trabectedin arm included ALT levels (25% vs 1%), neutropenia (21% vs 11%), anemia (14% vs 11%), and increased AST levels (12% vs 0%). Sixteen percent of patients receiving trabectedin had grade 4 neutropenia compared with 10% in the dacarbazine group.

Approximately 70% of patients in each group went on to receive additional treatment, a fact that could have impacted OS data, said Demetri. Eighteen percent of patients in the trabectedin arm and 28% of patients in the dacarbazine arm received subsequent pazopanib (Votrient).

&ldquo;Interestingly, the study did not show that the trabectedin-controlled patients lived longer. There is probably a reason for that. The study began in 2011; however, in 2012, the FDA approved pazopanib so there was a new and effective therapy that patients could go on after they were part of the trabectedin study,&rdquo; he said.

&ldquo;This may have impacted OS results. In our study, patients once randomized to one of these drugs, either trabectedin or dacarbazine, did not have the option to cross over to the other arm if their disease progressed. Therefore, the patients who were on the dacarbazine arm truly needed another therapy quicker than the trabectedin-treated patients. That could have also easily confounded the OS results.&rdquo;

Demetri said he decided that the goal had to be overall survival (OS), knowing that it is a difficult endpoint.

&ldquo;Obviously, OS has an appeal; it is easy to measure, patients want to live longer, and we want to help patients live longer. The FDA really wanted us to test OS, likely because we have tested this drug for several years this way. When we were testing it in the 1990s, there was a lot more debate about the value of PFS.&rdquo;

He added that OS is a difficult endpoint as well because it measure not just what a medical professional is doing to the patient in a particular trial, but also what happens to the patient after a tumor progresses and after the patient comes off the study.

Demetria concluded his interview by saying that the study confirmed the safety data that has been looked at for the past 15 years with trabectedin.

&ldquo;The interesting thing about this drug is that it is a continuous infusion, an IV drip, which gives the patient small amounts of trabectedin over 24 hours. This is a tried and true way of delivering the trabectedin, and we already went through the learning curve of understanding that back in the early 1990s,&rdquo; he said.

&ldquo;Generally speaking, the patients tolerated both drugs as expected. With trabectedin, the side effects were very similar to dacarbazine, such as low blood count, possible risk of infection, anemia, and fatigue. These are standard side effects for chemotherapy. There is one unique side effect for trabectedin, which is that it can irritate the liver and the liver can release some enzymes into the blood stream about 5 to 10 days after trabectedin is given.&rdquo;