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TAS-102 significantly improves OS in refractory colorectal cancer
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TAS-102, an oral agent composed of trifluridine and tipiracil hydrochloride, significantly prolonged OS in patients with refractory metastatic colorectal cancer, according to the results of a randomized, double blind, phase 3 trial.
“Trifluridine is the active cytotoxic component of TAS-102; its triphosphate form is incorporated into DNA, with such incorporation appearing to result in its anti-tumor effects,” Robert J. Mayer, MD, of the Dana-Farber Cancer Institute, and colleagues wrote. “Tipiracil hydrochloride is a potent inhibitor of thymidine phosphorylase and, when combined with trifluridine to form TAS-102, prevents the rapid degradation of the trifluridine, allowing for the maintenance of adequate plasma levels of the active drug.”
Robert J. Mayer
Preliminary trials conducted primarily in Japan demonstrated the safety and efficacy of TAS-102 (Taiho Pharmaceuticals) for refractory colorectal cancer and justified the initiation of a global phase 3 trial, according to study background.
The RECOURSE trial included 800 patients (median age, 63 years; range, 27-82) with biopsy-confirmed colon or rectum adenocarcinoma. All eligible participants underwent at least two prior standard chemotherapy regimens and had known KRAS tumor status.
Researchers randomly assigned patients 2:1 to TAS-102 (35 mg/m2) or placebo twice daily, 5 days a week for 2 weeks, followed by a 14-day rest period, in each 4-week cycle. Researchers stratified patients based on KRAS status (wild-type or mutant), period between first diagnosis and randomization (< 18 months vs. ≥ 18 months) and geographic location (Japan or the U.S., Europe and Australia).
OS served as the primary endpoint. Secondary endpoints included PFS, response rate and safety.
The safety analysis population included 798 patients who initiated treatment (TAS-102, n = 533; placebo, n = 265) and 760 patients were evaluable for tumor response.
Median OS was 7.1 months (95% CI, 6.5-7.8) in the TAS-102 cohort compared with 5.3 months (95% CI 4.6-6) in the placebo cohort. These data equated to a statistically significant reduction in the risk for death (HR = 0.68; 95% CI, 0.58-0.81).
The 1-year OS rates were 27% for TAS-102 and 18% for placebo. Researchers observed a TAS-102 OS benefit observed in all stratified subgroups.
Researchers identified time of first metastasis since diagnosis, ECOG performance status and number of metastatic sites as prognostic factors. However, the benefit of TAS-02 on survival persisted after adjusting for these factors (HR = 0.69; 95% CI, 0.58-0.81). TAS-102 efficacy also was observed in patients whose disease was refractory to fluorouracil.
Median PFS was 2 months (95% CI, 1.9-2.1) in the TAS-102 arm and 1.7 months (95% CI, 1.7-1.8) in the placebo arm. TAS-102 significantly reduced the risk for progression (HR = 0.48; 95% CI, 0.41-0.57).
Researchers observed disease control — defined as complete or partial response or stable disease achieved at least 6 weeks following randomization —in 44% of patients on the TAS-102 arm and 16% of the placebo arm (P < .001).
The median time to an ECOG performance status of 2 or higher was 5.7 months for TAS-102 and 4 months in the placebo group (HR = 0.66; 95% CI, 0.56-0.78).
More patients in the TAS-102 arm experienced grade 3 or worse adverse events (69% vs. 52%). The most commonly reported adverse events in the TAS-102 arm were neutropenia (38%) and leukopenia (21%), and one treatment-related death from septic shock occurred.
Participants assigned TAS-102 were also more likely to experience grade 3 or worse anemia (18% vs. 3%), thrombocytopenia (5% vs. < 1%), nausea (2% vs. 1%) and diarrhea (3% vs. < 1%). More patients assigned TAS-102 discontinued treatment due to adverse events (4% vs. 2%).
“In summary, TAS-102 was shown to have clinical activity in a large population of Japanese and Western patients with heavily pretreated metastatic colorectal cancer, including those whose disease was refractory to fluorouracil,” Mayer and colleagues concluded. “Such benefit was observed across the essentially all prespecified patient subgroups and was validated by the means of a multivariable analysis. TAS-102 was associated with few serious adverse events, with neutropenia being the most frequently observed adverse event.” – by Cameron Kelsall
Disclosure: The study was sponsored by Taiho Oncology-Taiho Pharmaceuticals. Mayer reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.
Perspective
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Leonard Saltz, MD
The results of the RECOURSE trial need to be interpreted in perspective. With a median OS benefit of less than 2 months, we would need to take a careful look at the overall value that use of TAS-102 in the salvage setting would bring to a patient with colorectal cancer. When considering value, we must look at the expected benefits, as well as the expected toxicities, including the potential financial toxicities. We can see from the trial that the incidence of neutropenia, fatigue and other toxicities is far from trivial, and that is in a population of patients who were medically fit enough to meet the eligibility criteria of a clinical trial. Toxicities would be expected to be higher in less fit patients, and clinical benefit would be expected to be lower. If we assume that this drug will be priced in the range of other recently approved antineoplastics, then the financial toxicity will be far from trivial, as well. All of these factors will figure into how this drug will or will not be incorporated into routine clinical practice.
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