TAS-102 (trifluridine and tipiracil; Lonsurf) improved overall survival (OS) compared with placebo in previously treated Asian patients with metastatic colorectal cancer (mCRC), according to findings from the phase III TERRA trial published in the Journal of Clinical Oncology.
Compared with placebo, the risk for death was significantly lower in the TAS-102 arm (HR, 0.79; 95% CI, 0.62-0.99; log-rank P
= .035) and median overall survival (OS) was significantly longer (7.8 months vs 7.1 months). The median survival follow-up time was 13.8 months in the experimental arm compared with 13.4 months for placebo.
“The TERRA trial showed a statistically significant prolongation of OS and [progression-free survival] in Asian patients with mCRC who might not have received targeted biologic therapy in their prior treatment, with a safety profile consistent with that in other trials,” corresponding author Jin Li, MD, Tongji University Affiliated Shanghai East Hospital, and coinvestigators wrote. “[TAS-102] can be an alternative treatment option for patients with mCRC who are refractory or intolerant to standard chemotherapies.”
From October 2013 to June 2015, investigators screened 516 patients with histologically or cytologically confirmed adenocarcinoma of the colon or rectum and known KRAS
status who were refractory or intolerant to two or more prior chemotherapy regimens. Ultimately, 406 patients from China, the Republic of Korea, and Thailand were enrolled in the randomized, double-blind, placebo-controlled phase III trial.
About two-thirds of patients in both groups had wild-type KRAS
. Forty-five percent of patients in the TAS-102 arm and 51% in the placebo arm had received prior targeted biologic therapy, including anti-VEGF therapy (19% vs 20%, respectively), anti-EGFR therapy (17% vs 19%), or a combination of both (9% vs 13%).
Patients were randomly assigned to twice-daily placebo or 35 mg/m2
of TAS-102 for 5 days a week, with 2 rest days, for 2 weeks, followed by a 14-day rest period in continuous 28-day treatment cycles until a discontinuation criterion was met. Survival follow-up could be extended until the target number of events (288 deaths) was reached.
There were 316 deaths recorded in the intent-to-treat population by the February 16, 2016, cutoff date for OS.
In the subgroup analysis by KRAS
status, the HR for death was 0.77 (95% CI, 0.57-1.04; log-rank P
= .083) for patients with wild-type KRAS
and 0.83 (95% CI 0.57-1.20; log-rank P
= .228) for patients with mutant KRAS
in the TAS-102 arm compared with the placebo.
The observed median OS times in the TAS-102 arm and placebo arm were similar among patients with wild-type KRAS (8.6 vs 7.4 months) and mutant KRAS
(7.0 vs 6.5 months).
HR for death was 0.91 (95% CI, 0.55-1.53) for patients with 2 prior chemotherapy regimens, 0.81 (95% CI, 0.52-1.26) for patients with 3 prior regimens, and 0.74 (95% CI, 0.54-1.03) among patients with ≥4 prior regimens (P
for interaction = .957). A prespecified subgroup analysis of OS showed a favorable trend for increased chemotherapy effect for TAS-102 for all parameters except age.
The mean number of treatment cycles was 3.5 in the TAS-102 arm and 2.2 in the placebo arm. Mean exposure time was 14.93 weeks in the experimental arm and 8.76 weeks in the placebo arm.
The median dose-intensity in the TAS-102 arm was 165.6 mg/m2
per week and 167.8 mg/m2 per week in the placebo group. The relative dosages were 98.2% and 100% in the TAS-102 and placebo groups, respectively.
The incidence of dose reduction was low in both treatment arms. Twenty-three patients (8.5%) in the TAS-102 arm and one patient (0.7%) in the placebo arm underwent at least 1 dose reduction.
Five patients in the experimental arm and 1 in the placebo arm died of treatment-emergent adverse events (TEAEs). However, no AEs leading to death were considered related to study medication in either treatment arm.
The incidence of treatment-emergent serious AEs was 23% in both groups. A total of 244 patients (90%) in the TAS-102 arm and 70 patients (51.9%) in the placebo arm experienced AEs related to the study drug. Roughly half (45.8%) of patients in the TAS-102 arm experienced study drug-related grade ≥3 AEs compared with 14 patients (10.4%) receiving placebo.
The most frequent AEs and laboratory abnormalities of grade ≥3 associated with TAS-102 were neutropenia (33.2%), leukopenia (20.7%), and anemia (17.7%). There was no febrile neutropenia reported.
The FDA approved TAS-102 in September 2015 for the treatment of patients with 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.