The approval was based on results from the phase 3 RECOURSE trial.
The FDA has approved the oral nucleoside Lonsurf (TAS-102) for the treatment of patients with advanced colorectal cancer (CRC) who have not responded to other treatments, based on results from the phase 3 RECOURSE trial.
In the RECOURSE study, the median overall survival (OS) for patients with refractory metasatic colorectal cancer (mCRC) who received Lonsurf was 7.1 months compared with 5.3 months with placebo. The median progression-free survival (PFS) in the Lonsurf arm was 2 months versus 1.7 months with placebo.
“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, 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.”
In the phase 3 double-blind RECOURSE study, 800 patients with refractory mCRC were randomized two-to-one to receive best supportive care plus Lonsurf (534 patients) or placebo (266 patients). The median age of patients was 63 years and the majority (60-63 percent) received at least four prior lines of therapy. All patients had received prior fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab, and 52 percent had received an EGFR inhibitor. Approximately 20 percent of patients had received prior treatment with regorafenib.
Lonsurf was administered at 35 mg/m2 twice daily with meals for five days, with two days of rest for two weeks followed by a 14-day rest period. The protocol allowed a maximum of three 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 one-year OS rate with Lonsurf was 27 percent compared with 18 percent 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 Lonsurf, the authors wrote.
The ORR was 1.6 percent with Lonsurf, which consisted of a complete response in 1 patient and partial responses. The ORR with placebo was 0.4 percent. Stable disease at six weeks was achieved in 42.4 percent of patients treated with Lonsurf. The DCR (partial response, complete response, and stable disease) was 44 percent with Lonsurf versus 16 percent with placebo (P <.001).
Lonsurf significantly delayed the worsening of disease for patients with mCRC. All patients were enrolled with an ECOG performance status of 1 (44 percent) or 0 (56 percent). The median time to worsening in performance status was 5.7 months with Lonsurf compared with four months for placebo.
Dose delays were required for 53 percent of patients between the first and second cycles, overall 14 percent of patients in the Lonsurf arm required dose reductions and 4 percent of patients withdrew from the trial due to adverse events.
Grade 3/4 adverse events were more frequent with Lonsurf compared with placebo (69 vs 52 percent), including neutropenia in 38 percent of patients treated with the chemotherapy. Overall, febrile neutropenia occurred in 4 percent of patients, with 9 percent receiving G-CSF as a treatment.
The most frequently reported grade 3/4 adverse events of concern with Lonsurf versus placebo were anemia (18 vs 3 percent) and thrombocytopenia (5 vs less than 1 percent) in addition to nausea (2 vs 1 percent), vomiting (2 vs 1), and diarrhea (3 vs less than 1 percent).
Lonsurf 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, preventing the formation of new cancer cells.
On March 20, Lonsurf was approved in Japan, based on findings from a phase 2 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.