Siddharth Padia, MD, explaines TheraSphere’s unique mechanism of action and what its approval means in HCC and beyond.
Adult patients with hepatocellular carcinoma (HCC) gained a first-of-its-kind, radiotherapeutic cancer treatment option with the recent approval of TheraSphere Yttrium-90 (Y-90) Glass Microspheres.
On March 18, the FDA approved TheraSphere based on findings from the single-arm LEGACY trial, which examined 162 adult patients each with a single, unresectable HCC tumor measuring 1 to 8 cm. The treatment elicited an overall response rate of 72.2% (95% CI, 64.9%-78.5%) with 76.1% of patients having a duration of response at least 6 months.1,2
In an interview with OncLive®, Siddharth Padia, MD, a specialist in vascular and interventional radiology at the Ronald Regan UCLA Medical Center, in Los Angeles, California, explained TheraSphere’s unique mechanism of action and what its approval means in HCC and beyond.
Padia: The LEGACY trial was a multicenter trial of 3 sites looking at patients with HCC. Specifically, these were patients who were treatment naïve, who had a single tumor up to 8 cm in size, had [an ECOG] performance status of 0 or 1, and did not have extrahepatic disease. It was a relatively uniform population of patients with HCC, which lends credibility to sharing in a multicenter design.
Traditionally when we talk about local/regional therapies, such as Yttrium-90 [Y-90], chemoembolization, or external beam radiation, we usually look at 1 or 2 different efficacy parameters. Those might be objective response, time to tumor progression, progression-free survival, or overall survival. What often happens is that when 1 local/regional therapy succeeds in a specific efficacy parameter, it may fall short in a different efficacy parameter. For example, chemoembolization is often associated with a high rate of objective response. Unfortunately, its duration of response and time to tumor progression are not as optimistic.
We examined multiple parameters in the LEGACY trial. The primary objectives were objective response and duration of response. We also looked at overall survival. When we look at those 3 primary parameters, the results were overwhelmingly positive. For example, duration of response was greater than 6 months in the vast majority of patients, and the 3-year overall survival was approximately 87% in all comers. [TheraSphere] really fulfilled a high bar in terms of efficacy on multiple criteria.
TheraSphere is an intraarterial therapy used primarily for the treatment of patients with HCC. When we talk about intraarterial therapies for primary liver cancer, it’s key to note that HCC specifically receives its blood supply exclusively from the hepatic artery as opposed to the portal vein. One can utilize this in order to form treatment strategies for local/regional therapy because you can infuse something, whether that’s particles, chemotherapy, or radiation, via the hepatic artery into the tumor.
Traditionally, transarterial therapies have consisted of infusing particles or chemotherapy in addition to particles. The difference is that Y-90 radioembolization using TheraSphere is an infusion of microscopic glass beads that have a radioactive element inside of them, Y-90. Injecting these particles [into the tumor via a catheter in the artery] results in internal radiation to the tumor by what is essentially glass bead implantation inside the arterial flow.
What we saw in the LEGACY trial, as well as other trials, is that the safety profile is very good. The risk of grade 3 and grade 4 adverse effects is extraordinarily low. In the LEGACY trial it was well below 10%. The adverse effect rate was far lower than what is typically seen in trials of systemic chemotherapy. When done properly, this therapy does not compromise patients in terms of their hepatic function.
Patients with HCC invariably have underlying cirrhosis, so it’s paramount that any therapy, whether it’s local/regional or systemic, preserves their hepatic function and does not worsen their cirrhosis. If you don’t do that, you can worsen their survival regardless of tumor treatment. What the data from the LEGACY study and others have shown is that this [adverse effect] does not necessarily happen if [precautions are] appropriately taken and that patients’ underlying hepatic function can be relatively well preserved. In a [patient who is considered] well-compensated cirrhotic, they won’t necessarily have hepatic decompensation. This also allows them to receive future treatments should the need arise. For example, if someone develops extrahepatic disease, they are still eligible for systemic therapy down the line.
Prior to this approval, TheraSphere was held under a humanitarian device exemption, so it was not fully approved by the FDA; this is the first device approved by the FDA for the treatment of HCC. It allows this local/regional therapy to be considered essentially standard of care in the appropriate patient population. It also allows us to study this further in future clinical trials, whether it be as a solo therapy or in combination with systemic agents now that it has full FDA approval.
In the treatment of HCC, the LEGACY study’s results showed efficacy in a relatively early stage. I think we still need to do more studies looking at intermediate- and advanced-stage HCC, including those patients with vascular invasion. There have been several other single-arm trials that have shown very good efficacy in patients with portal vein tumor thrombus, including a recently published randomized trial called DOSISPHERE [NCT02582034]. We need to further explore this, especially in combination or in sequence with immune checkpoint inhibitors.
Outside of HCC, there are several potential applications in hepatic tumors, including cholangiocarcinoma, uveal melanoma, metastatic breast cancer, and sarcoma. Finally, there is an ongoing trial using TheraSphere in metastatic colorectal cancer to the liver in patients who have failed first-line systemic chemotherapy. The results of that will hopefully be out at the end of 2021.