Tanios Bekaii-Saab, MD, discusses questions regarding regorafenib and TAS-102 in mCRC, compares the mechanisms of action and toxicities of both therapies, and shares his views on the optimal sequencing of the 2 agents.
Tanios Bekaii-Saab, MD
Tanios Bekaii-Saab, MD
Treatment options for patients with metastatic colorectal cancer (mCRC) have come a long way from what they once were, said Tanios Bekaii-Saab, MD.
“We used to run out of options,” said Bekaii-Saab, a professor of Medicine at Mayo Clinic. “Now patients go through 2 or 3 lines of therapy, depending on whether they have a mutation in RAS or not. We now have multiple options available to us, including regorafenib (Stivarga) and TAS-102 (Lonsurf).”
The FDA approved TAS-102 in September 2015 for the treatment of patients with mCRC who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, as well as an anti-VEGF biologic product and an anti-EGFR monoclonal antibody, if RAS wild-type.
The approval was based on the phase III RECOURSE trial, which demonstrated a median overall survival (OS) for patients with mCRC who received TAS-102 of 7.1 months compared with 5.3 months with placebo (HR, 0.68;P<.0001). The median progression-free survival (PFS) in the TAS-102 arm was 2 months versus 1.7 months with placebo (HR, 0.48;P<.0001).
Regorafenib was approved by the FDA in September 2012 for patients with mCRC, based on the randomized phase III CORRECT trial, which showed a significant improvement in OS in patients who received treatment with regorafenib.
Findings from the phase III CONCUR trial confirmed that regorafenib improves survival when compared with placebo in patients with pretreated mCRC, demonstrating a median OS of 8.8 months for patients who received regorafenib versus 6.3 months for patients who received placebo (HR, 0.55;P= .00016). Median PFS was 3.2 versus 1.7 months, with regorafenib and placebo, respectively (HR, 0.31;P<.0001).
Despite these successes, many questions still remain regarding regorafenib and TAS-102 in mCRC, according to Bekaii-Saab. In an interview withTargeted Oncology, he compared the mechanisms of action and toxicities of both therapies, and shared his views on the optimal sequencing of the 2 agents.
TARGETED ONCOLOGY:How do regorafenib and TAS-102 compare?
These are very different agents. Regorafenib is an agent that is essentially more of a biological multitargeted tyrosine kinase inhibitor. It hits multiple targets; it's what we call a “dirty drug.” It has too many targets.
TAS-102 is more of a traditional chemotherapy agent. It is oralas regorafenib is—but it is a cytotoxic agent. It has some properties that allow it to work even when patients are exposed to 5-FU (5-fluorouracil) and fail.
TARGETED ONCOLOGY:Is there an understanding of the optimal sequencing for the 2 agents?
These agents were tested in very similar settings, but they have never been compared head to head.
Regorafenib was compared with placebo in a large study and it showed superiority to placebo in all parameters. TAS-102 was also compared with placebo and also showed an improvement in all efficacy parameters.
We don't have any guidance. The little bit that we do have comes from the RECOURSE study, which is TAS-102 versus placebo, and about 20% of the patients were already exposed to regorafenib. Those patients seemed to do as well those who were not previously exposed to regorafenib. We know thatif you give regorafenib first—TAS-102 preserves its activity. Unfortunately, we don't have that data with regorafenib.
We also have some hints about where regorafenib work best. There is the CONCUR studywhich is an Asian study—looked at patients in which, of about 40% to 50% of them, did not have exposure to anti-VEGF or anti-EGFR therapies. What this study historically suggests compared with CORRECT—which was the initial regorafenib study—is that the deltas between regorafenib and placebo are bigger. This means that regorafenib seems to confirm a further benefit if moved up the line. The later we wait to introduce it, the less likely we are going to get the benefit.
With TAS-102, we have 2 hints. One comes from the RECOURSE study, which suggests that the patients who had less than 2 prior therapies didn't do as well as those who are more heavily treated. The TARA study, which is very similar to CONCUR and was done in an all-Asian population, showed very similar to what we saw in RECOURSE. This means that moving TAS-102 up the line didn't necessarily show a further benefit.
These may be hints that when thinking about sequencing, patients with good liver function tests and good performance status may be better off to receive regorafenib first. For those patients with bone marrow¬reserve issues, liver function abnormalities, and borderline performance status, you want to avoid TAS-102 because it is associated with significant neutropenia for those patients.
TARGETED ONCOLOGY:Is there a head-to-head trial between these 2 agents being planned?
I don’t think it is worth spending the money to compare these agents in a head-to-head trial. It has to be a clinical decision. They both seem to have similar activity. We would love all of our patients to be exposed to both agents whenever possible, because we know the more we expose our patients to multiple lines of therapy, the better their survival will be.
TARGETED ONCOLOGY:What challenges exist for using these drugs?
Their toxicities are very different. Regorafenib is mostly associated with hand-and-foot syndrome, fatigue, and hypertension. Those happen in the first 1 to 2 weeks. With regorafenib, patients need to come in every week in the first month to monitor these toxicities. The toxicities can be very tough, and that is why we need to keep an eye on them. Especially in patients who are, overall, very fatigued at this stage. They have gone through a lot of different treatments. It is very important to monitor this. The dose is not optimized, although there is a study that is investigating that. We will have the results of that study next year, so we should have, at least, a guide for the clinician.
For TAS-102, the toxicities are mostly hematological-related in the first month or 2. These toxicities occur fairly quickly. Neutropenia, anemia, and thrombocytopenia can occurmostly bone marrow toxicities. There are some gastrointestinal toxicities, but they seem to happen a little bit later.