In the past 12 months, two agents have been approved for soft tissue sarcoma, both of which have demonstrated impressive outcomes in patients with specific subtypes of the rare disease.
Trabectedin (Yondelis) was approved in October 2015 based on the phase III ET743-SAR-3007 trial for patients with liposarcoma and leiomyosarcoma who have previously received chemotherapy that included an anthracycline.
In the trial, patients receiving trabectedin had a statistically significant reduction in the risk of disease progression, with a median progression-free survival rate (PFS) of 4.2 months versus 1.5 months with dacarbazine (HR, 0.55; 95% CI, 0.44-0.70; P<.001). The 3-month PFS rates were 56% versus 34% for the two arms, respectively, and the 6-month PFS rates were 37% versus 14%.
The FDA also approved eribulin mesylate (Halaven) in January 2016 as a treatment for patients with advanced or unresectable liposarcoma following prior treatment with an anthracycline-based chemotherapy.
Among patients with liposarcoma in the phase III study which led to the approval, eribulin demonstrated a median overall survival of 15.6 months compared with 8.4 months with dacarbazine (HR, 0.51; 95% CI, 0.35-0.75). Median PFS with eribulin was 2.9 months versus 1.7 months with dacarbazine (HR, 0.52; 95% CI, 0.35-0.78).
Both agents have made an impact in the treatment of sarcoma, but there are still questions that remain, says Katherine Thornton, MD, co-clinical director, Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute.
In an interview withTargeted OncologyThornton discusses the use of the two agents both within and outside of their approved uses and explains how challenges in clinical trial design may have hindered broader approvals.
TARGETED ONCOLOGY:What impact has trabectedin had in sarcoma since its approval and what questions remain regarding the use of the agent?
Trabectedin was approved in 2015 for leiomyosarcoma and liposarcoma. It is a drug that we had a fair amount of experience with in the sarcoma world because it has been approved in many other countries, but could never really pass the muster in all-comer sarcomas with the FDA, so it never gained approval. It finally gained approval based on some disease-specific trials. It can be a very effective drug and I think it is well tolerated. When patients are responding to it, they can typically stay on it for a long period of time without having to stop due to toxicities.
We are now gaining more experience with this agent and it is being used more. It was approved with a 24-hour infusion and there were some earlier studies that looked at a 3-hour infusion, but I don’t think the question as to whether this was equivalent ever really got played out. This would be really great for the patients if a 3-hour infusion was equivalent, because that is one of the biggest limiting factors of the drug. Depending on the experience of the facility where they are being treated, some patients are needing to be admitted for their infusion, and there are some reimbursement problems that I’ve been hearing about in the community.
I also find that it is a very effective drug in synovial sarcoma, but I am not aware of any clinical trials that are trying to open it up to that specific subgroup. That would be a difficult trial to design, and since insurance companies are currently covering the drug in synovial sarcoma despite it not being approved, I don’t know if it would be necessary. Right now the way sarcomas are coded is really a universal code, so we haven’t been running into problems when I want to treat a patient with trabectedin with synovial sarcoma. I don’t know if that plays out in the community as well.
TARGETED ONCOLOGY:What role has eribulin played in sarcoma?
Eribulin is the newer kid on the block. It has a similar mechanism of action, but it only gained approval for liposarcoma. Primarily I believe that is because the comparator arm in the clinical trial was dacarbazine, which is an effective drug in leiomyosarcoma and it is a relatively ineffective drug in liposarcoma. The difference between the 2 arms was statistically significant in the liposarcoma patients and not in the leiomyosarcoma patients. But I think it actually is an effective drug in leiomyosarcoma. Fortunately for sarcoma-treatment providers, we are not getting too much pushback from insurance companies if patients don’t have the subtypes that the drugs are approved for. Whether that will change or not will remain to be seen.
TARGETED ONCOLOGY:Are most sarcoma trials designed to include all subtypes of sarcoma as opposed to a specific sarcoma and do you see that changing in the future?
Traditionally they have been and that is one of the biggest challenges in getting drugs approved. Sarcoma is essentially 100 different diseases and they can respond to therapies so dramatically differently from one another. There are sarcomas that are more indolent, and of course that will make your data look fantastic, and there are sarcomas that are more aggressive.
Up until really, the trabectedin study, most sarcoma trials were all comers. With trabectedin trying to get approval and go throughout the FDA pathway, they narrowed it down to the diseases that seem to respond best and ended up getting approval. I think people have picked up on that and there is a lot more in the way of disease-specific studies right now that we haven’t been seeing in the past.
I think they are harder trials to do and they are going to be smaller trials, but I think we can learn more from them at the end of the day. It will take a collaboration of multiple centers worldwide, but it can be done.