A Phase III, multinational clinical trial of the oral combination anti-cancer drug TAS-102 has found that it increased overall survival in patients with refractory metastatic colorectal cancer, with a tolerable toxicity profile.
TAS-102 combines trifluridine, a thymidine-based nucleic acid analogue, and tipiracil hydrochloride, a thymidine phosphorylase inhibitor that prevents rapid degradation of trifluridine. This allows adequate plasma levels of the trifluridine, the active agent, to be maintained for longer periods and at lower dosages.
Trifluridine was initially developed in the early 1960s, but the levels needed for activity proved too toxic for many patients. Testing was discontinued until about 15 years ago, when researchers in Japan introduced TAS-102 and began studying the combination drug at lower doses. In early clinical trials among Japanese patients, TAS-102 demonstrated efficacy and reduced toxicity.
The new trial, published in the New England Journal of Medicine (2015;372:1909-1919) was conducted by the RECOURSE Study Group, a multinational research effort, in hopes of replicating the findings in non-Japanese patients.
The investigators, led by Robert J. Mayer, MD, Faculty Vice President for Academic Affairs at Dana-Farber Cancer Institute and the Stephen B. Kay Family Professor of Medicine and Faculty Associate Dean for Admissions at Harvard Medical School, and a member of OT's Editorial Board, reported that median overall survival increased from 5.3 months in patients given a placebo to 7.1 months in those treated with TAS-102.
As described in the study, TAS-102 or placebo was randomly assigned to 800 patients in a 2:1 ratio, with a primary endpoint of overall survival. These were heavily pretreated, treatment-resistant, subjects including individuals with cancer refractory to fluorouracil, the researchers noted.
The hazard ratio for death in the TAS-102 group versus the placebo group was 0.68, while the most common adverse events were neutropenia in 38 percent of treated patients, and leukopenia, which occurred in 21 percent. Patients in the TAS-102 group were also more likely to experience more severe nausea and diarrhea, but there were no meaningful differences between the two groups in the development of serious liver or kidney problems, anorexia, stomatitis, hand-foot syndrome, or cardiac events.
Patients who received TAS-102 generally had more grade 3 or higher adverse events than those in the placebo group—69 versus 52 percent—and in 533 patients treated with TAS-102, 38 percent had neutropenia of grade 3 or higher, four percent developed febrile neutropenia, and one patient died from septic shock.
Grade 3 or higher anemia was also more common in TAS-102 subjects, at 18 percent compared with three percent in the placebo group. The incidence of Grade 3 or higher thrombocytopenia also occurred more often in the TAS-102 subjects.
The median period before wor-sening performance, on a scale of 5 to 0 (no symptoms) was 5.7 months with TAS-102 and 4.0 months with placebo.
Expanded Beyond Japanese Patients
“For us, our findings are very encouraging because the earlier studies primarily involved only Japanese patients,” Mayer said. “We have been able to extend testing and confirmed the Japanese findings in European, Australian, and U.S. patients.
“In addition, more than 90 percent of subjects had been refractory to fluoropyrimidines at some prior time and 50 percent of them were refractory when a fluoropyrimidine was part of their most recent treatment regimen.”
TAS-102 has already been granted Fast Track status and “rolling” FDA review, under which completed sections of a New Drug Application can be submitted to the agency instead of waiting for every section to be completed before an application can be sent for review (OT 11/25/14 issue).
The trial was funded by the manufacturer of TAS-102, Taiho Oncology, Inc.
Earlier trials in Japanese patients indicated that TAS-102 was effective in 28-day cycles of five days of treatment followed by a two-day rest period, each week, for two weeks, and then a 14-day rest period. A dose of 35 mg per square meter of body-surface area twice daily was recommended for further investigation on the basis of a Phase II double-blind, randomized, placebo-controlled trial conducted in 169 patients who had cancer refractory to fluorouracil and to both irinotecan and oxaliplatin.
Treatment in that study, published in 2012 in Lancet Oncology (2012;13:993-1001), showed that TAS-102 increased median overall survival to nine months versus 6.6 months in patients receiving placebo.
Also in 2012, Mayer and his colleagues presented data at the American Society of Clinical Oncology that found that Western patients responded to treatment in a similar fashion.
Individuals who had received at least two lines of chemotherapy including a fluoropyrimidine, irinotecan, and oxaliplatin received an initial TAS-102 dose level of 30 mg/m2 BID on days 1- 5 and on days 8-12 every four weeks. A second dose of 35 mg/m2, the maximum tolerable dose (MTD) in the Japanese patients was tested in 12 patients. No dose limiting toxicity (DLT) was found at the lower dose, while one DLT for grade 3 febrile neutropenia was reported at the 35 mg/m2 dose. The team reported that treated patients had the same MTD as the Japanese subjects, as well as a similar safety profile.
In an earlier study, published in 2008, a team led by Michael J. Overman, MD, Associate Professor in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, tested TAS-102 in 15 patients with solid tumors treated three times a day at 80 mg/m2 per day, and reported that two patients had dose-limiting fatigue and granulocytopenia, the primary toxicity with treatment, while seven had grade 3 or 4 granulocytopenia with the first course.
“I think this is a positive study for such patients with refractory colorectal disease, an area where we need more options,” Overman said in an interview for this article. “Based on the [new] data, my sense is that the FDA will approve TAS-102 and that it will be utilized by patients—but that is just a prediction. The results are pretty clear-cut. We see a lot of metastatic colorectal cancer, and this drug appears to fit that space.”
However he said that if and when TAS-102 receives FDA approval oncologists will still have to make a choice between options, and that is likely to hinge on its side effects.
For example, he noted, regorafenib, which received FDA approval in 2012 for use in patients with previously treated metastatic colorectal cancer, has different adverse events than TAS-102, and while the most common events reported in the Mayer et al study were neutropenia and leukopenia—symptoms that most patients may not be aware of—those most common with regorafenib are difficult for patients to ignore, such as mucositis, diarrhea, and fatigue.
“My experience with regorafenib is that there is a lot of toxicity, also including hand-foot syndrome,” Overman said. “With TAS-102 though, the side effects involve the bone marrow and are therefore not as evident.”
Another big question, he said, will be whether administering TAS-102 earlier might affect disease progression: “Given the difference in the nature of the respective side effects profiles of the two drugs and the similar survival benefits, I think oncologists are going to have to make a choice about which one to recommend should TAS-102 become available.”