TAS-102 Improves Survival in Phase III mCRC Trial

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Treatment with the investigational oral agent TAS-102 significantly improved overall survival (OS) in a phase III trial for patients with heavily pretreated metastatic colorectal cancer (mCRC), prompting Taiho Oncology, the company developing the drug, to prepare a New Drug Application (NDA) for submission to the FDA.

In the phase III trial, labeled RECOURSE, approximately 800 patients with mCRC were randomized to receive best supportive care with or without the novel nucleoside TAS-102. Patients in the trial had received a median of two prior therapies. The primary outcome measure was OS with secondary endpoints focused on progression-free survival (PFS) and safety. Full data from the study will be presented at the 2014 ESMO World Conference on GI Cancer in June.

"We are very pleased by the results from the phase III RECOURSE trial in refractory mCRC, which support TAS-102 as a potential new treatment option for this patient population," Fabio M. Benedetti, MD, senior vice president and chief medical officer at Taiho Oncology, said in a press release. "The Taiho Oncology team is preparing for the submission of the NDA and [marketing authorization application] MAA of TAS-102 in the United States and the European Union, respectively."

Prior to RECOURSE, TAS-102 demonstrated promising findings and a manageable safety profile in a randomized phase II study that was published in theLancet Oncologyin October 2012. This study randomized 169 patients with heavily pretreated mCRC in a 2:1 ratio to receive TAS-102 (n = 112) or placebo (n = 57). In both the phase II and III trials, TAS-102 was administered at 35 mg/m².

In the phase II study, the median OS was 9.0 months with TAS-102 compared with 6.6 months with placebo (HR = 0.56; 95% CI, 0.39-0.81;P= .0011). The median PFS was 2.0 months with TAS-102 compared with 1.0 month with placebo (HR = 0.41; 95% CI, 0.28-0.59;P< .0001).

In patients with wild-typeKRAStumors, the median OS with TAS-102 was 7.2 months compared with 7.0 months with placebo (P= .191). In patients withKRAS-mutant tumors, the median OS was 13.0 months with TAS-102 compared with 6.9 months for placebo (P= .0056).

Serious adverse events occurred in 19% of patients treated with TAS-102 compared with 9% of patients in the placebo arm. The most common grade 3/4 adverse events experienced with TAS-102 were neutropenia (50%), leucopenia (28%), and anemia (17%). Serious neutropenia and leucopenia did not occur in the placebo arm and grade 3/4 anemia occurred in 5% of patients receiving placebo.

TAS-102 is a novel nucleoside consisting of the cytotoxic agent trifluorothymidine (FTD) and the thymidine phosphorylase inhibitor tipiracil hydrochloride. Following the administration of treatment, FTD is phosphorylated into the DNA by thymidine kinase 1 (TK1), preventing the formation of new cancer cells.

An analysis of the prognostic qualities of TK1 in patients with mCRC treated with TAS-102 was explored in an analysis of the phase II data that were presented at the 2014 European Cancer Congress. This study looked specifically at 150 patients who underwent immunohistochemical analysis for TK1.

Overall, this study demonstrated a correlation between high-levels of TK1 expression and improved outcomes. In the TAS-102 arm, the median OS in TK1-high patients (n = 27) was 10.4 months versus 7.7 months in TK1-low patients (n = 72; HR = 0.51; 95% CI, 0.27—0.97). In the placebo arm, TK1-high patients (n = 13) had a median OS of 4.9 months compared with 7.2 months in TK1-low patients (n = 38). When applied to the entire population, the HR for OS in TK1-high patients was 0.14 (P= .0013). In TK1-low patients, the HR was 0.62 (P= .044).