The FDA has granted a fast track designation to TAS-102 (tipiracil hydrochloride) as a treatment for patients with refractory metastatic colorectal cancer (mCRC), according to an announcement by Taiho Oncology, the company developing the drug in the United States.
Under the fast track designation, Taiho Oncology announced that it had initiated a rolling submission for a New Drug Application for TAS-102 to the FDA. The application for the oral nucleoside is based on promising findings from the phase III RECOURSE study. According to findings presenting at the 2014 ESMO Congress, treatment with TAS-102 reduced the risk of progression by 52% and extended survival by 32% when compared with placebo in patients with refractory mCRC.
"We are pleased that TAS-102 has been granted fast track designation," Fabio Benedetti, MD, senior vice president and chief medical officer at Taiho Oncology, said in a statement. "Patients with metastatic colorectal cancer, whose disease has progressed after treatment with standard therapies, have limited treatment options to manage their disease. We have initiated our rolling NDA submission to the FDA, and are committed to submitting the rest of the filing as efficiently as possible."
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.
In the RECOURSE 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). Patients had received at least two prior lines of treatment. TAS-102 was administered at 35 mg/m2 twice daily on days 1 to 5 and 8 to 12 of each 28-day cycle. The primary endpoint of the study was OS, with secondary endpoints focused on PFS, overall response rate (ORR), and disease control rate (DCR).
For patients treated with TAS-102, the median OS was 7.1 months compared with 5.3 months with placebo (HR = 0.68; P
<.0001). The median PFS in the TAS-102 arm was 2 months versus 1.7 months with placebo (HR = 0.48; P
<.0001). In patients with KRAS
wild-type mCRC, the hazard ratio for OS was 0.58. In those with KRAS
-mutated tumors, the HR for OS was 0.8. By geography, outcomes were similar for Western and Asian populations.
A statistically significant advantage in ORR was not demonstrated for TAS-102 in the study (1.6% vs 0.4%). However, when adding stable disease rates, the DCR was 44% versus 16.3% (P
<.0001), for TAS-102 and placebo, respectively. Additionally, time to worsening of performance status was significantly delayed with TAS-102 versus placebo (5.7 vs 4.0 months; HR = 0.66, P
< .0001). Post-study treatment was similar between arms.
The most frequently observed grade 3/4 adverse events in the TAS-102 arm compared with placebo were diarrhea (3% vs 0.4%), vomiting (2.1% vs 0.4%), nausea (1.9% vs 1.1%), fatigue (3.9% vs 5.7%) and stomatitis (0.4% vs 0%).
The most common grade 3/4 hematologic adverse events for TAS-102 and placebo were neutropenia (34.9% vs 0%), leukopenia (12.8% vs 0%), anemia (16.5% vs 2.6%), and thrombocytopenia (5.1% vs 0.4%). Febrile neutropenia was experienced by 3.8% of patients treated with TAS-102 compared with none in the placebo arm.
“TAS-102 is well tolerated, with a very mild safety profile. The most frequently observed side effect is hematologic, including anemia and neutropenia,” lead investigator Takayuki Yoshino, MD, a medical oncologist at National Cancer Center Hospital East, Chiba, Japan, said in an interview with OncLive when the data was initially presented. “There were very few increases in grade 3 or higher diarrhea, pyrexia, and vomiting, but these were generally manageable. This agent is very much tolerated for almost all patients.”