STOCKHOLM – The experimental cytotoxic agent TAS-102 significantly reduced the risk of death in a placebo-controlled phase II trial of patients with metastatic colorectal cancer refractory to current treatments.
Patients receiving oral TAS-102 plus best supportive care had a median overall survival of 9 months, compared with 6.6 months for placebo and best supportive care (hazard ratio, 0.56; P = .001).
TAS-102 also doubled median progression-free survival from 1 month to 2 months (HR, 0.41; P less than .0001), Dr. Yasutoshi Kuboki reported at the European Multidisciplinary Cancer Congress.
KRAS mutation testing revealed that TAS-102 offers a significant survival advantage for patients harboring a KRAS mutation, a biomarker of nonresponsiveness to the approved targeted agents cetuximab (Erbitux) and panitumumab (Vectibix).
KRAS mutation-positive patients treated with TAS-102 had a median overall survival of 13.0 months, compared with 6.9 months for placebo (HR, 0.44; P = .006,), and a progression-free survival of 2.8 months vs. 1.0 month (HR, 0.34; P less than .0001).
In the KRAS wild-type subset, median overall survival was similar at 7.2 months with TAS-102 and 7.0 months with placebo (HR, 0.70; P = .19), although time to disease progression increased from 1.0 to 1.9 months with TAS-102 (HR, 0.47; P = .0004).
Dr. Kuboki said a phase III trial is needed to confirm the promising results, but that "TAS-102 is the first cytotoxic agent to prolong survival in patients with metastatic colorectal cancer refractory to conventional cytotoxic agents."
Invited discussant Dr. Eric van Cutsem, of the University of Leuven, Belgium, said, "It’s less sexy, less fashionable to talk about cytotoxics in colorectal cancer because we have the impression we’ve seen it all," but the study is important nonetheless and the outcome "very impressive."
"It’s a phase II study, but if we could see similar numbers in a phase III study with hazard rates of 0.56, then we could say we have a new drug," he said.
Dr. van Cutsem pointed out that the hazard ratios observed with TAS-102 in the phase II study are similar to those reported in submission approvals for cetuximab and panitumumab in advanced, chemotherapy-refractory colorectal cancer.
TAS-102 is a novel agent that combines trifluorothymidine and thymidine phosphorylase inhibitor at a molar ratio of 1 to 0.5, explained Dr. Kuboki, with the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo.
Researchers at 10 Japanese centers recruited 172 patients with refractory metastatic colorectal cancer after at least two lines of chemotherapy containing fluoropyrimidine, irinotecan, and oxaliplatin. Prior treatment also included cetuximab in two-thirds and bevacizumab (Avastin) in at least three-fourths of the population.
Patients were randomized double-blind 2:1 to best supportive care plus placebo or TAS-102 70 mg/m2 twice daily on days 1-5 and days 8-12 every 4 weeks.
Among 169 evaluable patients, the disease control rate was 43.8% with TAS-102 vs. 10.5% with placebo, Dr. Kuboki said at the meeting, which was a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.
Treatment with TAS-102 was well tolerated in the heavily pretreated cohort, and there were no treatment-related deaths. Neutropenia was the main side effect (17.6%), but there was no neutropenic sepsis, he said.
Taiho Pharmaceutical Co. sponsored the study. Dr. Kuboki and his coauthors reported no conflicts of interest.