FDA Approves TAS-102 for Metastatic Colorectal Cancer

Richard Pazdur, MD

The FDA approved the oral nucleoside TAS-102 (Lonsurf) for the treatment of patients with metastatic colorectal cancer (mCRC) who have previously received fluoropyrimidine-, oxaliplatin- , and irinotecan-based chemotherapy, an anti-VEGF biologic product, and an anti-EGFR monoclonal antibody, if RAS wild-type. The approval, which is based on the phase III RECOURSE trial, comes 2 months ahead of the FDA's scheduled action date.

In the RECOURSE study, the median overall survival (OS) for patients with mCRC who received TAS-102 was 7.1 months compared with 5.3 months with placebo (HR, 0.68; P <.0001). The median progression-free survival (PFS) in the TAS-102 arm was 2 months versus 1.7 months with placebo (HR, 0.48; P <.0001).

“The past decade has brought a new understanding around colorectal cancer, in how we can both detect and treat this often devastating disease,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “But there are many patients who still need additional options, and today’s approval is a testament to the FDA’s commitment to work with companies to develop new drugs in disease areas where unmet needs remain.”

The phase III double-blind RECOURSE study randomized 800 patients with refractory mCRC 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.

“In a pivotal clinical trial, Lonsurf demonstrated that it can extend overall survival, providing patients and their oncologists with a novel oral therapy,” RECOURSE principal investigator Robert J. Mayer, MD, faculty vice president for Academic Affairs at the Dana Farber Cancer Institute and professor of Medicine at Harvard Medical School, said in a statement.

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%).

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, based on findings from a phase II study.

Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. NEJM. 2015;372:1909-1919.