Tanios Bekaii-Saab, MD
Dosing strategies and novel treatment regimens are 2 of many areas being explored in the colorectal cancer (CRC) eld, while paying close attention to molecular subgroups, explained Tanios Bekaii-Saab, MD.
For example, Bekaii-Saab said that phase II results of the ReDOS dose-optimization study demonstrate that weekly dose escalation of 80/120/160 mg of regorafenib (Stivarga) is the favored treatment for patients with metastatic CRC (mCRC). Additionally, data need confirmation on moving the agent earlier in treatment, which may provide more benefit to patients, he said.
Moreover, the superiority of receiving regorafenib prior to cetuximab (Erbitux) versus cetuximab prior to regorafenib was shown in findings from the REVERCE study in patients with mCRC, he explained.
“They certainly need to be reproduced in a Western-patient population, but it was intriguing to see the same trends between CONCUR and REVERCE that moving regorafenib a little bit earlier may make a difference,” said Bekaii-Saab, a medical oncologist at Mayo Clinic.
Immunotherapy continues to be explored beyond the microsatellite instability–high (MSI-H) population, as well, though has proven to be more challenging to implement.
In an interview during the 2018 OncLive®
State of the Science Summit,™ Bekaii-Saab, who chaired the meeting, outlined clinical trials that have defined the current landscape of mCRC and what research is underway.
OncLive: What is currently being discussed in refractory mCRC?
: These patients go through first and second- line therapies, and sometimes through third-line therapy. The question becomes, “What do we do for patients beyond second-line therapy?” Previously, we had very few options, if any, for these patients. Now we have 2 oral options with regorafenib and TAS-102 (Lonsurf). These agents are different from each other. Regorafenib is a multikinase inhibitor; it’s a multitargeted agent. TAS-102 is a more traditional cytotoxic agent; it belongs to the family of fluoropyrimidines. It’s not 5-FU [5-fluorouracil] or capecitabine; it belongs to that family that seems to work when the others fail.
The knowledge we have about these 2 agents comes from separate studies that have never been compared in a head-to-head study. What we know about their activity primarily came from their comparison to best supportive care. [The agents] follow very similar pathways.
The RECOURSE study led to the approval of TAS-102, which looked at TAS-102 versus placebo. The study suggested a survival benefit; there was some progression-free survival (PFS) benefit. Toxicities with this agent are primarily gastrointestinal (GI) and hematologic events. We do see some early neutropenia in the first 4 weeks and some febrile neutropenia. About 4% of patients may need to be hospitalized.
On the other hand, regorafenib was approved based on the CORRECT trial [results], which randomized patients to regorafenib versus best supportive care and placebo. This study also showed a PFS benefit. The toxicities are a little bit different given the mechanism of action. We see a little bit more hand-foot syndrome in approximately 15% of patients; that can be quite significant. That’s something we don’t see with TAS-102. You also see some fatigue, very low nausea, diarrhea, and hypertension because of the VEGF activity.
In terms of toxicities, the differences between the 2 agents are primarily hand-foot syndrome, hypertension, and neutropenia. Fatigue is about the same. The GI toxicities are a little bit worse with TAS-102. The overall outcome seems to be very similar across the 2 studies. The next question is how to sequence these agents. We don’t have any randomized trials, so we have to rely on practical experience as well as whatever we can infer from the studies that were done.
The RECOURSE study included about 20% of patients who were previously exposed to regorafenib. This exposure to regorafenib did not seem to change the outcome. We don’t have data with TAS-102 followed by regorafenib.
There are also the CONCUR and TARA studies. CONCUR looked at regorafenib and TARA examined the use of TAS-102. Both studies had very similar designs as RECOURSE and CORRECT, but in Asian-only populations. Those studies examined patients with less exposure to pre-biologics because of lack of accessibility. In CONCUR and CORRECT, the delta value was much wider for regorafenib versus no treatment. On the other hand, TARA showed that earlier use of TAS-102 did not seem to change the delta value as much as in RECOURSE. There could be a hint that moving regorafenib up or not waiting until the end of the line to administer the agent may be more beneficial to patients.