Patients with metastatic colorectal cancer now have more treatment options than ever, explains Tanios Bekaii-Saab, M.D.
Recent advancements have drastically changed the treatment options for patients with metastatic colorectal cancer (mCRC), according to Tanios Bekaii-Saab, M.D.
“We used to run out of options,” said Bekaii-Saab, a professor of Medicine at Mayo Clinic. “Now patients go through two or three 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 Lonsurf 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 3 RECOURSE trial, which demonstrated a median overall survival (OS) for patients with mCRC who received Lonsurf of 7.1 months compared with 5.3 months with placebo. The median progression-free survival (PFS) in the Lonsurf arm was two months versus 1.7 months with placebo.
Stivarga was approved by the FDA in September 2012 for patients with mCRC, based on the randomized phase 3 CORRECT trial, which showed a significant improvement in OS in patients who received treatment with Stivarga.
Findings from the phase 3 CONCUR trial confirmed that Stivarga improves survival when compared with placebo in patients with pretreated mCRC, demonstrating a median OS of 8.8 months for patients who received Stivarga versus 6.3 months for patients who received placebo. Median PFS was 3.2 versus 1.7 months, with Stivarga and placebo, respectively.
How do Stivarga and Lonsurf compare?
Despite these successes, many questions still remain regarding Stivarga and Lonsurf in mCRC, according to Bekaii-Saab. In an interview with CURE, he compared the mechanisms of action and toxicities of both therapies, and shared his views on the optimal sequencing of the two agents.These are very different agents. Stivarga 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.
Is there an understanding of the optimal sequencing for the two agents?
Lonsurf is more of a traditional chemotherapy agent. It is oral — as Stivarga 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.These agents were tested in very similar settings, but they have never been compared head-to-head.
Stivarga was compared with placebo in a large study and it showed superiority to placebo in all parameters. Lonsurf 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 Lonsurf versus placebo, and about 20 percent of the patients were already exposed to Stivarga. Those patients seemed to do as well those who were not previously exposed to Stivarga. We know that — if you give Stivarga first — Lonsurf preserves its activity. Unfortunately, we don't have that data with Stivarga.
We also have some hints about where Stivarga work best. There is the CONCUR study — which is an Asian study — looked at patients in which, of about 40 percent to 50 percent 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 Stivarga study — is that the deltas between Stivarga and placebo are bigger. This means that Stivarga 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 Lonsurf, we have two hints. One comes from the RECOURSE study, which suggests that the patients who had less than two 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 Lonsurf up the line didn't necessarily show a further benefit.
Is there a head-to-head trial between these two agents being planned?
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 Stivarga first. For those patients with bone marrow—reserve issues, liver function abnormalities, and borderline performance status, you want to avoid Lonsurf because it is associated with significant neutropenia for those patients.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.
What challenges exist for using these drugs?
Their toxicities are very different. Stivarga is mostly associated with hand-and-foot syndrome, fatigue, and hypertension. Those happen in the first one to two weeks. With Stivarga, 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 Lonsurf, the toxicities are mostly hematological-related in the first month or two. These toxicities occur fairly quickly. Neutropenia, anemia and thrombocytopenia can occur—mostly bone marrow toxicities. There are some gastrointestinal toxicities, but they seem to happen a little bit later.
Therefore, these are the patients who mostly respond to treatment and are on for treatment for a prolonged period of time. They may develop cumulative toxicities that we typically see with cytotoxic agents, fatigue, diarrhea, and low-grade nausea. We need to understand a little bit more in terms of what happens to patients in the long term.