EPOCH Trial Seeks to Establish the Role of TheraSphere Y-90 in Second-Line Metastatic CRC

Riad Salem MD

The safety and effectiveness of TheraSphere™ Yttrium-90 (Y-90) Glass Microspheres is under examination in patients with colorectal cancer with metastases in the liver who are scheduled to receive second-line chemotherapy as part of the ongoing EPOCH trial (NCT01483027).¹

“With EPOCH, we sought to investigate the role of Y-90 in the second-line setting. Y-90 does not have a role in the first-line setting for metastatic CRC, and it now has a decreasing role in the salvage setting, given the competitive landscape,” study investigator Riad Salem MD, said. “The second-line space was a prime area to see whether we could prolong progression-free survival [PFS], as well as hepatic PFS, and see whether we could either delay other types of treatments or add to standard-of-care treatment.”

In an interview with OncLive®, Salem, the vice chair for Image Guided Therapy, Department of Radiology; chief of Vascular and Interventional Radiology in the Department of Radiology; and professor of Radiology (Vascular and Interventional Radiology), Medicine (Hematology and Oncology), and Surgery (Organ Transplantation) at the Northwestern University Feinberg School of Medicine, discussed previous data with Y-90 in metastatic CRC, the potential role of this modality in the second-line setting, and future research directions.

OncLive®: To start, could you highlight efforts made to examine Y-90 in patients with metastatic CRC?

Salem: Historically, Y-90 has been used in the salvage setting [for patients with CRC] after [progression on] chemotherapy. Several phase 2 trials have looked at the safety and efficacy [of the agent], and those showed approximately response rates of 30% to 40% in the salvage setting, and a median overall survival [OS] of 12 to 14 months, depending on the amount of chemotherapy that [the patient] had been exposed to. Clearly, [we are seeing] that there has been more chemotherapy applied, given the new agents that have come out, and as such, a progressively longer delay in when Y-90 is initiated in this patient population. That OS has now dropped in the salvage setting.

Some level I studies were performed, including the SIRFLOX [NCT00724503] and the phase 3 FOXFIREGlobal [NCT01721954] studies, which looked at Y-90 in the first-line setting. Those studies did not find that adding Y-90 [to chemotherapy] in the first-line setting improved OS. As such, currently, Y-90 is reserved for the salvage setting, [for use] when no other options or clinical trials [are available for] patients who have liver-dominant disease and preserved liver function.

In terms of the design of these trials, were there any specific methods utilized?

In the salvage setting, most [studies] have [used] off-trial-type designs. A phase 1 trial [NCT00858429] [was done in patients with] metastatic disease to the liver, which includes CRC. That trial [utilized] a dose-escalation concept of Y-90, as well as a full dose of capecitabine, to see whether we could combine a radiosensitizer with standard-of-care therapy for metastatic disease. We were able to treat and get up to 170 Gy without any dose-limiting toxicities. As I mentioned before, [there have also been] the SIRFLOX and FOXFIREGlobal studies in the first-line setting that examined if Y-90 added to standard-of-care chemotherapy would improve OS. Again, those studies did not show an [improvement], and put to bed the idea that Y-90 would be [an option] to consider in that setting.

Those studies have led us to question whether [Y-90 would be beneficial in] the second-line setting. The first-line setting is a very competitive space; many agents work quite well and [improve OS]. However, once [a patient] progresses, the response rate drops, PFS drops, OS drops, and the number of agents available to use is reduced significantly. The question remains: What could we do in the second-line setting to improve the results of standard-of-care chemotherapies, prolong PFS, and provide patient benefit?

How is the EPOCH study serving to address that question? What were the inclusion/exclusion criteria?

[In terms of the] patient population we wanted to study, the first and most important characteristic was that they had to have progressed on first-line chemotherapy, with a regimen that included irinotecan or oxaliplatin. From there, it tends to be dealer's choice. We tend to switch and go to [the other option we did not use in] the second line. We wanted to have patients who were able to tolerate their first-line therapy, and therefore, would be good candidates for second-line chemotherapy.

We also wanted a patient population who had liver-dominant disease. What we did not want to do is have outcomes that were confounded by significant extrahepatic metastases. We wanted liver metastases only, although patients were allowed 1 or 2 small lesions that were deemed to be benign, or very slow-growing metastases.

Regarding the trial design, why were certain end points selected over others?

In terms of the end points, if we look at the guidelines for CRC, all the research suggests [utilizing] an imaging end point in the second-line setting. [As such, we chose] PFS, and we also added hepatic PFS as an end point to EPOCH. We wanted to see whether we could delay the progression of the disease by adding Y-90 to the standard-of-care second-line chemotherapy.

OS, in general, is not used as an end point in the second-line setting, because of the confounding effect of post-progression treatments. When a patient progresses, they crossover. They can crossover to Y-90, or they can crossover to other agents, and that is something we cannot control. It is not like patients receive a treatment and once they progress, they do not receive anything else. Because the landscape is so busy, and so active with so many treatments, patients then go on to a different clinical trial or a different treatment, and that is why OS is not the primary end point, but rather a secondary exploratory end point.

How do you foresee Y-90 potentially fitting into the treatment landscape for this population in the future?

All we know right now is that in the first-line setting, Y-90 does not have a role in CRC. We will wait to see what the results from the EPOCH trial show in terms of [the agent] playing a role in the second-line setting. In the third-line setting there is a minor role for Y-90, but the advent of immunotherapies in that space and other treatments has reduced the use of Y-90 in the salvage setting. However, right now, the salvage setting is where Y-90 sits in CRC. Again, we will see what the results from the EPOCH trial will show, and hopefully [we will see] a benefit.

What are some future research directions for Y-90?

It is an exciting time to continue to investigate the role of Y-90 in various cancers. Now that we have solidified the use of Y-90 in hepatocellular carcinoma, we are now [examining] Y-90 in colon cancer, brain tumors, and in prostate cancer. [Y-90] is a very effective method of delivering radiotherapy, [and] it allows [us to] provide a very focal, high radiotherapeutic dose to a small area of the body that we inject through the artery. We see very low adverse effect profile with a very high, ablative radiotherapy dose.

Now that the technical aspects have been resolved in their entirety, it is a very exciting time to be dealing with Y-90, and we look forward to working on other types of applications with [this approach]. Y-90 as a technology is very exciting given its versatility and its ability to be injected in multiple areas in the body with very high ablative radiotherapy.

Reference

1. Efficacy evaluation of TheraSphere following failed first line chemotherapy in metastatic colorectal cancer (EPOCH). ClinicalTrials.gov. Updated April 21, 2021. Accessed August 18, 2021. https://clinicaltrials.gov/ct2/show/NCT01483027

^{CAUTION: In the US, Therasphere is under and investigational device exemption for treatment of patients with metastatic colorectal cancer. The safety and effectiveness for this treatment has not been established.}