TAS-102 Approved by FDA for Patients With Advanced Colorectal Cancer

Richard Pazdur, MD

Richard Pazdur, MD

The oral nucleoside TAS-102 (Lonsurf) received FDA approval today for the treatment of patients with advanced colorectal cancer (CRC) who are not responding to other treatments.

FDA’s approval was based on results from the phase III RECOURSE trial, which found that TAS-102 led to an improvement in both overall and progression-free survival for patients with metastatic CRC (mCRC) and significantly delayed worsening of their disease.

“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.”

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). 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).

Median OS for patients with refractory mCRC who received TAS-102 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).

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 one 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).

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%).

Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. NEJM. 2015;372:1909-1919.