Robert J. Mayer, MD, discusses pivotal phase III results for TAS-102 in colorectal cancer.
Robert J. Mayer, MD
TAS-102 (tipiracil hydrochloride) demonstrated promise in patients with refractory metastatic colorectal cancer (mCRC) in the phase III RECOURSE study. In 800 patients, both progression-free survival (PFS) and overall survival (OS) were shown to improve with TAS-102 when compared with placebo, with a median PFS and OS of 2.0 months and 7.1 months, respectively, for the TAS-102 arm, compared with 1.7 months and 5.3 months, for the placebo arm. These findings, which were recently published in The New England Journal of Medicine, were particularly significant because the population was heavily pretreated.
The FDA is currently reviewing a new drug application for TAS-102, which was accepted in February 2015. A final decision is expected by December 2015. To further understand the findings and clinical implications of the RECOURSE trial, OncLive spoke with lead study author Robert J. Mayer, MD, faculty vice president for Academic Affairs at the Dana-Farber Cancer Institute.
OncLive: Can you discuss the RECOURSE trial and the significance of TAS-102?
Dr Mayer: The RECOURSE trial, which was recently published, is a global effort that involved 800 patients with heavily pretreated mCRC that was refractory to all previous types of therapy. The patients were randomized in a double-blinded manner to either receive the oral drug TAS-102 or placebo.
TAS-102 is a compound that is similar to fluoropyrimidines. However, fluoropyrimidines act by inhibiting an enzyme, which is necessary for cells to divide, whereas TAS-102 has trifluridine as its active component, which is actually incorporated into tumor DNA. It acts as an antimetabolite rather than an enzyme inhibitor. What makes TAS-102 particularly interesting is that along with the trifluridine, there is another compound that prevents the digestion of the trifluridine, therefore letting it remain in the circulation for a longer period of time. In the trial, those patients who were on TAS-102 had a highly significant prolongation in survival, PFS, and symptom-free survival. The drug was also well tolerated.
TAS-102 is interesting because, in this era where we focus so much on targeted forms of treatment, TAS-102 is an “old chestnut” of sorts. This is a molecule that was originally created more than 50 years ago and was really waiting for the right time for it to be properly used.
How will these findings impact patients?
The results of the trial are encouraging news for colon cancer patients. It will be very interesting to see if gradually, over the next few years, it will replace fluoropyrimidines in many of the roles fluoropyrimidines are used for, particularly in gastrointestinal cancers. TAS-102 has potential not just in CRC, but also in pancreatic cancer, stomach cancer, and esophageal cancer. This is very good and encouraging news, although it is still early.
I think there are some people who would say that the findings were not as significant because the survival benefit was only 2.5 months, but keep in mind that these were heavily pretreated patients. More than half of them had just been given a fluoropyrimidine as their most recent form of treatment and they benefited, which underscores how this molecule appears to be different than fluoropyrimidines and why it has so much potential to make a difference.
What is the ideal patient population for this treatment?
The benefit was seen across all different parameters that were assessed. That included men and women, younger and older, people from Japan, Europe, and the United States, and people with a KRAS-mutated tumor or a KRAS wild-type tumor. Every parameter that we looked at showed that TAS-102 was useful. In terms of eligibility, the only people that were treated in this trial were those who had exhausted every other therapy that was available. How much more or less the drug would be useful if given earlier in the course of the disease is something that we should examine. That examination will soon be underway.
What are the next steps in this research?
A drug that has become very important in the treatment of CRC is irinotecan, which is a topoisomerase inhibitor. It works in an entirely different way than fluoropyrimidine and is usually given with a regimen known as FOLFIRI, often as a second-line therapy. It will be very interesting to see whether FOLFIRI and irinotecan versus TAS-102 and irinotecan give equivalent, different, or more or less toxic outcomes. I think that would be an excellent next step. That type of study is under design. Something that is now just being completed is an early experience of adding irinotecan to TAS-102 and as soon as that is finished, we will be able to move to the next steps.