TAS-102 (tipiracil hydrochloride) improved overall survival (OS) compared with placebo for patients with refractory metastatic colorectal cancer (CRC).
Robert J. Mayer, MD
TAS-102 (tipiracil hydrochloride) improved overall survival (OS) compared with placebo for patients with refractory metastatic colorectal cancer (CRC), according to results from the phase III RECOURSE study published inThe New England Journal of Medicine.
Based on these findings, FDA accepted a new drug application (NDA) for TAS-102 in February 2015. The agency is scheduled to make a final approval decision on the chemotherapy by December 19, 2015.
"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," the authors wrote. "Such benefit was observed across essentially all prespecified patient subgroups and was validated by means of a multivariate analysis."
In the phase III double-blind study, 800 patients with refractory mCRC were randomized in a 2:1 ratio to receive best supportive care plus TAS-102 (n = 534) or placebo (n = 266). TAS-102 was administered at 35 mg/m2twice daily with meals for 5 days, with 2 days of rest for 2 weeks followed by a 14-day rest period. The protocol allowed a maximum of 3 dose reductions of 5 mg/m2each. The primary endpoint of the study was OS, with secondary endpoints focused on progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR).
Outcomes Improved Across Subgroups
In the study, the median OS was 7.1 months with TAS-102 compared with 5.3 months with placebo (HR = 0.68; 95% CI, 0.58-0.81;P<.001). The median PFS with TAS-102 was 2.0 versus 1.7 months with placebo (HR = 0.48; 95% CI, 0.41-0.57;P<.001).
The 1-year OS rate with TAS-102 was 27% compared with 18% with placebo. This benefit was observed across all subgroups in the trial, including those with KRAS mutations and across all geographic regions.
The ORR was 1.6% with TAS-102, which consisted of a complete response in 1 patient. The ORR with placebo was 0.4% (P= .29). Stable disease at 6 weeks was achieved in 42.4% of patients treated with TAS-102. The DCR (partial response, complete response, and stable disease) was 44% with TAS-102 versus 16% with placebo (P<.001).
TAS-102 significantly delayed the worsening of disease for patients with mCRC. All patients were enrolled with an ECOG performance status (PS) of 1 (44%) or 0 (56%). The median time to worsening in PS was 5.7 months with TAS-102 compared with 4 months for placebo (HR = 0.66).
Adverse Events Illuminated
Grade 3/4 adverse events were more frequent with TAS-102 compared with placebo (69% vs 52%), including neutropenia in 38% of patients treated with the chemotherapy. Overall, febrile neutropenia occurred in 4% of patients, with 9% receiving G-CSF as a treatment.
The most frequently reported grade 3/4 adverse events of concern with TAS-102 versus placebo were anemia (18% vs 3%) and thrombocytopenia (5% vs <1%) in addition to nausea (2% vs 1%), vomiting (2% vs 1%), and diarrhea (3% vs <1%).
"Neutropenia was the most frequently observed clinically meaningful adverse event (grade 3 or 4), occurring in 38% of patients treated with TAS-102," the authors of the study wrote. "Grade 3 or 4 stomatitis, handfoot syndrome, and coronary spasm, which are associated with the use of fluoropyrimidines, were encountered in less than 1% of the patients treated with TAS-102."
Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer.NEJM. 2015;372:1909-1919.