FDA Accepts NDA for TAS-102 in mCRC

The FDA has accepted a New Drug Application (NDA) for the oral nucleoside TAS-102 (tipiracil hydrochloride) as a treatment for patients with refractory metastatic colorectal cancer (mCRC), according to Taiho Oncology, the company developing the drug in the United States. The FDA will make a final approval decision on TAS-102 by December 19, 2015.

TAS-102 had previously been granted fast track designation from the FDA, and Taiho announced in December that it had completed its rolling NDA submission for the drug. The NDA is based on findings from the phase III RECOURSE study. According to results presented at the 2014 ESMO Congress, TAS-102 reduced the risk of progression by 52% and extended survival by 32% versus placebo in patients with refractory mCRC.

“If approved by the FDA, TAS-102 could become an important new treatment option for patients with metastatic colorectal cancer whose disease has progressed after treatment with standard therapies,” said Fabio Benedetti, MD, senior vice president and chief medical officer at Taiho Oncology.

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 overall survival (OS), with secondary endpoints focused on progression-free survival (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.

"The TAS-102 NDA submission represents a major milestone for the company as we seek FDA approval for our lead product candidate," said Benedetti.