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Advanced Colorectal Cancer

How Regorafenib and TAS-102 Fit into Current Practice

Carlson, Robert H.

doi: 10.1097/
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BARCELONA, Spain—Two new drugs for treatment of patients with metastatic colorectal cancer—regorafenib and TAS-102—are showing promise in clinical trials. Where do they fit in current practice and are they changing practice?

Tim Maughan, MD, Professor of Clinical Oncology of the of the Gray Institute for Radiation Oncology and Biology and Clinical Director of the CRUK/MRC Oxford Institute for Radiation Oncology at the University of Oxford, addressed these questions here at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer.

“There has been little movement forward in the last 10 years in effective therapies for colorectal cancer, and now we have two new agents that have shown enough activity to get them licensed in last-line treatment,” he said in his remarks as a Discussant during a session on colorectal cancer. “They show similar but only modest benefits in last-line, but with the promise that they may show something more further up in the disease pathway.”

The new agents give clinicians options for patients who remain fit for last-line therapy, he said, and give researchers opportunities to explore the drugs in other contexts.

“[Regorafenib and TAS-102] do not offer great overall survival benefits in colorectal cancer, but they are active options with overall survival comparable to that for current standard agents. They are a welcome addition.”

Differences Mainly in Safety Profiles

The differences between the two are mainly in safety, he said: Regorafenib is a multi-targeted kinase inhibitor with a broad spectrum of activity, and at the current dose levels a lot of dose modifications are being required.

“I have some concerns about the safety and need for dose modifications with regorafenib, but I think this is probably correctable with alternative schedules, which many clinicians are already using, but we need evidence on that.”

Show of Hands about Dose Modifications

Maughan asked for a show of hands in the audience from clinicians who prescribed regorafenib for patients with metastatic colorectal cancer, and then how many of them modified the dose from the start.

The majority indicated that they do modify the doses.

“If the majority use modification with regorafenib, the question then is what benefit does that give?” Maughan said. “We are using this agent in advanced patients and we are not sure we are getting the dose right.”

Maughan reviewed three regorafenib studies, as well as one for TAS-102:

  • The Phase III CORRECT trial by Axel Grothey et al (Lancet 2013;381:303-312);
  • The Phase III CONCUR trial by Shukui Qin et al reported earlier this year at the Gastrointestinal Cancers Symposium (Abstract 697);
  • The Phase IIIB CONSIGN safety trial underway by Bayer; and
  • The Phase III RECOURSE study of TAS-102 by Robert Mayer et al (NEJM 2015;372:1909-1919).

The critical difference between CORRECT and CONCUR, Maughan explained, was the number of patients who had previous biological therapy: 100 percent in CORRECT, but only about 60 percent in CONCUR—“That's going to be an important point,” he said.

Adverse Events

The rate of Grade 3 and higher adverse events was approximately the same in both regorafenib studies—55 percent for CONCUR and 54 percent for CORRECT.

But adverse events leading to a need for modification of the dose occurred in 67 percent of the CORRECT patients, 71 percent in CONCUR, and 74 percent in CONSIGN. And adverse events leading to a need for discontinuation occurred in 18, 14, and 25 percent, respectively.

TAS-102—Trifluridine and Tipiracil Mechanism of Action

“A major question is whether we have this drug schedule correct as we go into trials,” Maughan said.

He noted that regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer that has progressed after all standard therapies. “The CORRECT study provides evidence for a continuing role of targeted treatment after disease progression, with regorafenib offering a potential new line of therapy in this treatment-refractory population.”

He called TAS-102 a more conventional chemotherapy agent showing more typical chemotherapy-type toxicity—“and perhaps we're more used to managing that than the newer agents.”

Both TAS-102 and regorafenib result in greater benefit in RAS wild-type than RAS-mutant disease, he said. The overall survival hazard ratios reported for patients with KRAS wild-type tumors was 0.58 for TAS-102, which was similar to the 0.65 reported in the regorafenib trials.


For KRAS-mutant tumors the overall-survival hazard ratios were 0.8 for TAS-102 and 0.87 for regorafenib.

Questions to be Answered

Summing up, Maughan asked the following questions still to be determined:

  • Regorafenib showed very interesting activity in previously-treated patients in CONCUR—is there a role for earlier use?
  • Could TAS-102 be a new backbone for combination therapy?
  • What are the data on TAS-102 in combination with oxaliplatin or irinotecan?
  • Will there be biomarkers to guide patient selection for these drugs?

Howard Hochster: RECOURSE Trial

Earlier in the session, the RECOURSE trial was reviewed by Howard Hochster, MD, Professor of Medicine/Medical Oncology at Yale Cancer Center. He said improvements in both overall and progression-free survival were seen in patients with KRAS wild-type and KRAS-mutant tumors who received TAS-102 versus placebo. Similarly, the safety profile was favorable, with adverse events generally the same for RECOURSE patients with KRAS wild-type and KRAS-mutant tumors.

But KRAS status was not predictive of treatment outcome, he noted. While the effect on progression-free survival was the same for KRAS wild-type and KRAS-mutant groups, overall survival showed a more pronounced effect on wild-type.

In all RECOURSE patients, median overall survival with TAS-102 (534 patients) was 7.1 months versus 5.3 months for the 266 patients on placebo. In the KRAS wild-type subgroup taking TAS-102 (262 patients), overall survival was eight months, versus 6.5 months for the KRAS-mutant group (272 patients).

And in the placebo arms the overall survival times were 5.7 months for KRAS wild-type (131 patients) and 4.9 months for KRAS-mutant (136 patients).

Axel Grothey: CONCUR and CORRECT

Also in the session, Axel Grothey, MD, Professor of Oncology at the Mayo Clinic, reviewed the CONCUR and CORRECT trials, noting that CORRECT showed that regorafenib improves overall survival versus placebo in patients with previously treated metastatic colorectal cancer.

The CONCUR trial confirmed the overall survival benefit for regorafenib in Asian patients, he said; and adverse events were generally similar in the two trials and were consistent with the known safety profile of regorafenib.

In CORRECT, regorafenib was associated with a 23 percent reduction in the risk of death versus placebo, and in CONCUR, regorafenib was associated with a 45 percent reduction in the risk of death compared with placebo.

Eric Van Cutsem: CONSIGN

Finally, the CONSIGN trial was reviewed by Eric Van Cutsem, MD, PhD, Professor of Internal Medicine at the University of Leuven and Head of the Digestive Oncology Unit at University Hospital Gasthuisberg in Belgium.

The safety profile of regorafenib in CONSIGN was consistent with that reported in CORRECT, and progression-free survival in CONSIGN was similar across the wild-type and mutant subgroups, he said. “But the rate of dose reductions and treatment interruptions highlights the importance of optimal patient selection, management, and dose modification.”

FDA Approval Status

Both drugs are approved by the U.S. Food and Drug Administration: TAS-102, now with the brand name Lonsurf, was approved on Sept. 22 for use in patients with advanced colorectal cancer that no longer responds to other therapies; and regorafenib (Stivarga) has been approved since 2012 to treat colorectal cancer that has progressed and metastasized after treatment.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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