George D. Demetri, MD
The path of trabectedin (Yondelis), an investigational treatment for soft tissue sarcomas, has been an interesting one, said George D. Demetri, MD, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute.
The drug, which Demetri described as “extraordinarily powerful in the laboratory” 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 trabectedin in more than 70 countries worldwide. Despite this, data have not been of the quality required for an FDA approval in the United States thus far, said Demetri.
In late 2014, an application for trabectedin was submitted to the FDA for patients with advanced soft tissue sarcoma who received prior chemotherapy. The application was granted a priority review, with a decision deadline set for August 2015. However, with this date passed, the FDA decision is still unknown.
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
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).
In an interview with OncLive, Demetri expands on the challenges with OS as a primary outcome measure, the potential of trabectedin in soft tissue sarcomas, and the significance of the recent trial.
OncLive: What about trabectedin makes it interesting as a treatment for sarcoma?
: 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. 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 problem is, we do not know who those people are who are going to get the extraordinary benefit, who will get modest benefit, or who will get no benefit at all. That is why we designed this trial.
What have been the most significant findings from the trial?
We have seen a very sizable difference in terms of PFS for trabectedin over dacarbazine. As a clinically meaningful endpoint, PFS was validated by the last FDA-approved drug for soft tissue sarcoma, which was pazopanib. The important thing about that approval was that pazopanib did not have a survival benefit for patients who took it after all other chemotherapies had failed. That is an important consideration.
The FDA really learned about sarcomas in the process of evaluating pazopanib, and agreed with the experts in the sarcoma community that control of disease is a good thing for patients. Patients with sarcoma are very different than patients with other carcinomas. They can actually tolerate a great deal of disease burden in their body and still feel fairly well. However, if the disease burden gets just a little bit bigger, all of the systems can fail and the patient can die very quickly. Therefore, the important thing is to control the disease as much as possible, and hopefully keep people feeling well while their disease is managed.