Improved OS, PFS Demonstrated by TAS-102, Regardless of KRAS Status

Howard S. Hochster, MD

TAS-102 demonstrated similar improvements in overall survival (OS) and progression-free survival (PFS) in patients with KRAS wild-type and mutated metastatic colorectal cancer (CRC) as the full group of patients treated in the phase III RECOURSE trial, according to findings presented at the 2015 World Congress on GI Cancer.¹

In the cohort of patients with KRAS mutated tumors, patients treated with TAS-102 (n = 272) had an improved OS compared with placebo (n = 135), median 6.5 versus 4.9 months, respectively (HR = 0.80; 95% CI 0.63, 1.02; P = .0712). PFS was also improved with TAS-102 compared with placebo, with a median of 1.9 versus 1.8 months, respectively (HR = 0.49; 95% CI 0.39, 0.61; P <.0001).

“As in the overall RECOURSE study group, TAS-102 was associated with significantly improved overall and progression-free survival compared with placebo in patients with KRAS wild-type and mutant tumors, along with a favorable safety profile,” said Howard S. Hochster, MD, professor of Medicine (Medical Oncology) and associate director for Clinical Sciences, Yale Cancer Center. “The survival benefit in patients with KRAS mutant tumors showed borderline statistical significance.”

RECOURSE evaluated the efficacy and safety of TAS-102 in 800 patients with metastatic colorectal cancer who were refractory to, or intolerant of, standard therapies. Patients were required to have undergone ≥2 prior lines of standard chemotherapy and patients with KRAS wild-type tumors must have had prior anti-EGFR treatment.

The primary results from RECOURSE have been previously reported in The New England Journal of Medicine.² That trial showed a significant improvement in OS of median 7.1 months in 534 TAS-102 patients compared with 5.3 months with placebo (HR = 0.68; 95% CI, 0.58-0.81; P <.001) and PFS of median 2.0 versus 1.7 months (HR = 0.48; 95% CI, 0.41-0.57; P <.001).

For the World GI analysis, KRAS wild-type tumors were identified in 394 (49.3%) patients; of these 63.7% were male, and the mean age was 62.0 years. KRAS mutated tumors were seen in 406 (50.8%) patients, with a mean age of 61.1 years and 59.1% were male. KRAS status was well-balanced across the treatment groups.

Of the 534 patients treated with TAS-102, KRAS wild-type was seen in 260 patients (48.7%) and mutated in 274 patients (51.3%). In all, 266 patients were given placebo of which 273 (51.3%) and 132 (49.6%) patients had tumors that were KRAS wild-type and mutated, respectively.

Researchers reported that patients with KRAS wild-type tumors demonstrated a median OS of 8.0 months in patients treated with TAS-102 compared with 5.7 months in patients receiving placebo (HR = 0.58; 95% CI 0.45, 0.74; P < .0001). PFS was a median 2.1 months for patients treated with TAS-102 versus 1.7 months in the placebo group (HR = 0.48; 95% CI 0.38, 0.60; P < .0001).

In the study, 116 (14.5%) patients were found to have BRAF wild-type and 8 (1.0%) patients were found to have BRAF mutant tumors. BRAF status, especially BRAF mutations, was identified in too few patients to allow meaningful analysis.

Researchers reported no overall differences in incidence of adverse events (AEs), ≥ Grade 3 AEs, or serious AEs across patient subgroups based on KRAS status. No significant differences were seen according to mutational status regarding the safety profile that accompanied treatment with TAS-102.

Patients receiving TAS-102 with KRAS mutant tumors had a higher incidence (≥5%) compared to patients with KRAS wild type, respectively, of diarrhea (35.2% vs 28.5%), asthenia (21.6% vs 14.6%), and decreased appetite (43.2% vs 34.6%), whereas patients with KRAS wild-type tumors had a higher incidence of decreased neutrophil (30.4% versus 25.3%) and white blood cell count (31.5% versus 23.4%).

“TAS-102 is a thymidine analog and actually quite an old molecule that showed early anti-tumor activity but was not pursued due to a short half life,” according to Hochster, who explained that modifications to TAS-102 lengthened the half-life considerably; the current molecule is an antineoplastic thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil hydrochloride. TAS-102 is incorporated in DNA but its mechanism of action differs from that of fluorouracil (5-FU). Based on preclinical data, cells that are resistant to 5-FU can be responsive to TAS-102.

TAS-102 received an FDA fast track designation in the refractory setting in October 2014. Earlier this year, the FDA accepted a new drug application for the drug, placing a final approval decision for December 19, 2015.

Reference

1. Hochster H, Hager S, Pipas JM, et al. KRAS and BRAF gene subgroup analysis in the Phase 3 RECOURSE trial of TAS-102 versus placebo in patients with metastatic colorectal cancer. Ann Oncol. 2015;26 (suppl 4; O-010).
2. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-1919.

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