Treatment with the oral nucleoside TAS-102 (tipiracil hydrochloride) demonstrated a significant improvement in overall survival compared with placebo for patients with refractory metastatic colorectal cancer.
Robert J. Mayer, MD
Treatment with the oral nucleoside TAS-102 (tipiracil hydrochloride) demonstrated a significant improvement in overall survival (OS) compared with placebo for patients with refractory metastatic colorectal cancer (CRC), according to results from the phase III RECOURSE study published in The New England Journal of Medicine.
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 progression-free survival (PFS) with TAS-102 was 2.0 versus 1.7 months with placebo (HR = 0.48; 95% CI, 0.41-0.57; P <.001).
Based on these findings, the 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.
“Metastatic colorectal cancer persists as one of the foremost common cancers among men and women,” lead study author Robert J. Mayer, MD, faculty vice president for Academic Affairs at the Dana-Farber Cancer Institute, said in a statement when the FDA accepted the NDA. “If approved, TAS-102 has the potential to become an important new treatment option for patients in the United States who are living with refractory metastatic colorectal cancer.”
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). The median age of patients was 63 years and the majority (60%-63%) received ≥4 prior lines of therapy. All patients had received prior fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab, and 52% had received an EGFR inhibitor. Approximately 20% of patients had received prior treatment with regorafenib.
TAS-102 was administered at 35 mg/m2 twice 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/m2 each. The primary endpoint of the study was OS, with secondary endpoints focused on PFS, overall response rate (ORR), and disease control rate (DCR).
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. Additionally, patients treated with prior regorafenib experienced responses to TAS-102, the authors wrote.
The ORR was 1.6% with TAS-102, which consisted of a complete response in 1 patient and partial responses. 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).
Dose delays were required for 53% of patients between the first and second cycles, overall 14% of patients in the TAS-102 arm required dose reductions and 4% of patients withdrew from the trial due to adverse events.
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, hand—foot 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."
TAS-102 consists of the cytotoxic agent trifluorothymidine (FTD) and the thymidine phosphorylase inhibitor tipiracil hydrochloride, which prevents FTD from degrading as a result of thymidine phosphorylase. Following the administration of treatment, FTD is phosphorylated into the DNA by thymidine kinase 1 (TK1), preventing the formation of new cancer cells.
On March 20, 2015, TAS-102 was approved in Japan, under the trade name Lonsurf. This approval was based on findings from a phase II study, with results from the RECOURSE study acting as supporting evidence.
Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. NEJM. 2015;372:1909-1919.