Background
Phase III randomized double-blind placebo-controlled trial. 800 patients with metastatic colorectal cancer who had received ≥2 prior lines of standard therapy (including fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and anti-EGFR if RAS wild-type). ECOG PS 0–1. Global trial (Japan, Europe, USA). Evaluated TAS-102 (trifluridine/tipiracil) — an oral combination of thymidine-based nucleoside analogue and thymidine phosphorylase inhibitor — as a late-line option in heavily pretreated mCRC.
Interventions and follow up
Arm A: TAS-102 35 mg/m² PO bid on days 1–5 and 8–12 of each 28-day cycle + best supportive care until disease progression or unacceptable toxicity
Arm B: Placebo + best supportive care
Primary endpoint: Overall survival (OS)
mFollow up: 11.3 month
Arm B: Placebo + best supportive care
Primary endpoint: Overall survival (OS)
mFollow up: 11.3 month
Results
mOS: 7.1 vs 5.3 months, HR 0.68 (95% CI 0.58–0.81), P<.001
mPFS: 2.0 vs 1.7 months, HR 0.48 (95% CI 0.41–0.57), P<.001
DCR: 44% vs 16%, P<.001
ORR: 1.6% vs 0.4%
mPFS: 2.0 vs 1.7 months, HR 0.48 (95% CI 0.41–0.57), P<.001
DCR: 44% vs 16%, P<.001
ORR: 1.6% vs 0.4%
Adverse events
Hematologic (grade ≥3): Neutropenia 38% (most common), anaemia 18%, thrombocytopenia 5%, febrile neutropenia 4%; G-CSF use in 13%
GI: Nausea any grade 48% vs 24%
Other: No grade ≥3 hand-foot skin reaction (differentiating from regorafenib); dose reductions in 14%; treatment discontinuation 3% vs 1%
GI: Nausea any grade 48% vs 24%
Other: No grade ≥3 hand-foot skin reaction (differentiating from regorafenib); dose reductions in 14%; treatment discontinuation 3% vs 1%
Conclusions
TAS-102 produced a statistically significant OS benefit vs placebo in heavily pretreated mCRC (mOS 7.1 vs 5.3 months, HR 0.68, P<.001), with a manageable predominantly hematologic toxicity profile. Disease control was achieved in 44% vs 16% with placebo. TAS-102 became the first oral fluoropyrimidine analogue approved specifically for chemotherapy-refractory mCRC.
Key Limitations
Key Limitations: Modest absolute OS benefit (∼1.8 months); near-zero ORR (<2%) limiting utility for patients needing tumor response. PFS advantage is small in absolute terms (0.3 months). Subsequent SUNLIGHT trial showed that adding bevacizumab to TAS-102 nearly doubles mOS to 10.6 months (vs 7.5 months for TAS-102 alone), suggesting TAS-102 monotherapy has largely been supplanted. No predictive biomarker identified. Grade ≥3 neutropenia (38%) requires monitoring.
Clinical Context
RECOURSE established TAS-102 as FDA-approved (September 2015) for refractory mCRC. In the SUNLIGHT era (2023), TAS-102 + bevacizumab is now the preferred regimen based on superior OS, and TAS-102 monotherapy is generally reserved for patients with a contraindication to bevacizumab. Indirect comparisons and the SUNLIGHT data favor TAS-102 + bev over regorafenib. ESMO-MCBS score: 2 (monotherapy); 4 (combination with bevacizumab per SUNLIGHT).
References
References: Mayer RJ et al, NEJM 2015 (primary analysis)