Expert Shares Significance of Approved Agents in CRC

Tanios Bekaii-Saab, MD

A sequencing strategy for 2 agents approved for the treatment of refractory colorectal cancer (CRC)—regorafenib (Stivarga) and TAS-102—would be effective for these patients, according to Tanios Bekaii-Saab, MD. Nevertheless, these agents have yet to be compared in a head-to-head clinical trial.

Phase III findings from 2 separate clinical trials, RECOURSE and CORRECT, demonstrate the efficacy of oral agent regorafenib and cytotoxic drug TAS-102 for patients with refractory CRC. These studies were done in succession to one another and shows similar efficacy data for both drugs, as well as equal toxicity profiles.

The current practice for use of these drugs is for patients to first receive regorafenib and upon progression to be given TAS-102. Bekaii-Saab, professor of medicine, Mayo Clinic, adds that these drugs would be given in reverse order in the treatment paradigm should a patient have liver function abnormalities or hand-foot syndrome. If a patient experiences significant bone marrow toxicities, they would be less likely to be given TAS-102 upfront.

OncLive: What are the current strategies for sequencing new agents for refractory CRC?

Can you compare and contrast the efficacy of regorafenib and TAS-102?

In an interview with OncLive, Bekaii-Saab discusses the use of both these drugs, as well as the potential role immunotherapy could have within CRC.Bekaii-Saab: The landscape of treating patients with metastatic colorectal cancer has expanded with multiple new agents being approved, specifically in the refractory setting. We have 2 agents that have recently made it the market. One is regorafenib, and then more recently TAS-102.Regorafenib is a biologic agent. It's a multi-kinase targeted therapy that targets VEGF and a number of other targets on the cancer cell. TAS-102 is a more traditional chemotheraputic agent that belongs to the overarching family of fluoropyrimidines. Both were looked at in studies that compared them to placebo in phase III studies in the refractory setting, so very similar settings. The one difference is that the TAS-102 study that came after the regorafenib study and included about 20% of patients who were previously exposed to regorafenib before they received TAS-102.

So they're different. Both have improved outcomes versus placebo in terms of magnitude of improvements. They've never been compared head-to-head, but historically at least they seem to be very similar.

Their toxicity profiles are a little different. Regorafenib has toxicities that are more specific for this mode of action, so hand and foot syndrome, diarrhea, hypertension. Those occur usually in the first 15 days, and the worst toxicity that you see with this agent happens about 3 to 4 weeks into the treatment. After that you figure out the correct dosing. Typically, patients that have those toxicities seem to clear up, although some have to discontinue the drug.

TAS-102 has more of the traditional chemotherapy toxicities such as neutropenia and fatigue. In terms of sequencing those agents, we have data for regorafenib followed by TAS-102 in the RECOURSE study. We don't have data on TAS-102 followed by regorafenib. From the practical standpoint right now, we use regorafenib first followed by TAS-102.

There are certain instances where we may consider one versus the other. For example, for patients with abnormal liver function tests, since those tend to increase with regorafenib, we tend to favor TAS-102. For patients with very limited performance status, perhaps TAS-102 would make more sense. Patients who have hematologic toxicities that have lingered after multiple chemotherapeutic regimens tend to favor regorafenib.

Should pembrolizumab (Keytruda) be approved by the FDA for patients with CRC and microsatellite instability, how could such an agent be incorporated into treatment?

Overall, in terms of the sequencing for the majority of the patients, our clinic at least tends to go naturally from regorafenib and then TAS-102 next.The microsatellite instability, or MSI group, is about 4% of all patients with stage IV cancer. For those patients, at least preliminarily, studies suggest that using therapies such as PD-1 inhibitors may induce significant responses that are both deep and durable. The question is, will these PD-1 inhibitors do better than chemotherapy or add any benefit to chemotherapy?

The studies that are looking at these agents now in a randomized fashion, are comparing them to chemotherapy or to essentially best supportive care, or chemotherapy in the refractory setting. There are two possible scenarios if the upfront studies suggest that PD-1 inhibitors hold promising results in a randomized fashion in the first-line. There is a good likelihood that we will take these PD-1 inhibitors to replace chemotherapy in the first-line in at least 4% of patients. There are also studies that are looking at them combined with chemotherapy, but these are not there yet.

On the other hand, if these studies don't seem to pan out and the studies in the refractory setting confirm the results that have been seen in single-arm studies, then the replacements will be in the refractory setting.