Clinical trialPhase 3Colorectal cancer

Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer

N Engl J Med · 2023492 patients (246 in each group)

Prager GW, Taieb J, Fakih M, et al. N Engl J Med. 2023. 388:1657-1667

Study type: Clinical trial
Study name: SUNLIGHT
Phase: Phase 3
Design: Randomised phase 3 trial (1:1 randomisation); EudraCT number: 2020-001976-14
Sample size: 492 patients (246 in each group)
Source: N Engl J Med · 2023
Trial registration: NCT04737187

In plain words

This study was for patients whose bowel (colorectal) cancer had spread to other organs and had grown again after two lines of chemotherapy. Adding the drug bevacizumab (which blocks the tumour's blood vessel growth) to trifluridine-tipiracil tablets helped patients live about 3 months longer on average (10.8 versus 7.5 months) and more than doubled the time the disease was kept under control. Patients also kept their ability to carry out their daily activities for longer. Common side effects were low white blood cells, nausea and anaemia, which should be followed with regular blood tests.

Key results

10.8 months vs 7.5 months

Median overall survival

HR for death 0.61 (95% CI 0.49 to 0.77); P<0.001

5.6 months vs 2.4 months

Median progression-free survival

HR for progression or death 0.44 (95% CI 0.36 to 0.54); P<0.001

9.3 months vs 6.3 months

Median time to worsening of ECOG performance status to 2 or more

HR 0.54 (95% CI 0.43 to 0.67)

Drugs in this study:Bevacizumab (Avastin)

Dose and schedule cards

Trifluridine/tipiracil + bevacizumab (SUNLIGHT)

Disease previously treated with a fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF agent (optional) and, if RAS wild-type, an anti-EGFR agent; in SUNLIGHT, a maximum of 2 prior regimens and ECOG 0–1Cycle length: Every 28 daysOn the page “Colorectal cancer” · Metastatic colorectal cancer: later lines, regardless of biomarkers

Drug	Dose	Route	Schedule
Trifluridine/tipiracil	35 mg/m² twice daily (maximum 80 mg per dose; based on the trifluridine component)	Oral, with food	Days 1–5 and 8–12
Bevacizumab	5 mg/kg	IV	Days 1 and 15

Cycle length: Every 28 days
Duration: Until disease progression or unacceptable toxicity

Doses from the FDA label for trifluridine/tipiracil (SUNLIGHT section); evidence: SUNLIGHT.

Complete blood count before each cycle and on day 15; start a cycle only with neutrophils ≥1500 and platelets ≥75,000/µL; after febrile neutropenia or severe toxicity, reduce by 5 mg/m² per dose (up to 3 times). Creatinine clearance 15 to 29 mL/min → 20 mg/m² twice daily.

On the page “Colorectal cancer” · Metastatic colorectal cancer: later lines, regardless of biomarkers

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Trifluridine-tipiracil + bevacizumab (combination group)

Trifluridine/tipiracil (FTD-TPI) 35 mg/m² per dose, orally twice daily (within 1 hour after breakfast and dinner), days 1 to 5 and 8 to 12 + bevacizumab 5 mg/kg IV on days 1 and 15; 28-day cycles; until disease progression or unacceptable toxicity.

2Trifluridine-tipiracil alone

Trifluridine/tipiracil 35 mg/m² per dose, orally twice daily, days 1 to 5 and 8 to 12; 28-day cycles; until disease progression or unacceptable toxicity.

Source of the regimen details: ClinicalTrials.gov NCT04737187 (arm descriptions) and the FDA label for trifluridine/tipiracil (LONSURF; SUNLIGHT section)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with unresectable adenocarcinoma of the colon or rectum (known RAS status) who had received no more than two prior chemotherapy regimens for advanced disease and had progression on or intolerance to the last regimen. According to the FDA label, prior treatments included a fluoropyrimidine, irinotecan, oxaliplatin, an anti-VEGF agent (optional) and, in RAS wild-type disease, an anti-EGFR agent. Other criteria: ECOG 0 or 1, life expectancy of at least 12 weeks; exclusion criteria included uncontrolled hypertension (≥150/100), an arterial thromboembolic event in the past 6 months, ascites requiring drainage in the past 4 weeks and symptomatic brain metastases.

Endpoints

Primary outcome: overall survival.

Secondary outcomes: progression-free survival and safety, including time to worsening of ECOG performance status from 0 or 1 to 2 or more.

Safety and side effects

The most common adverse events in both groups were neutropenia, nausea and anaemia, and no treatment-related deaths were reported (abstract). According to the FDA label (SUNLIGHT section): grade 3 or 4 neutrophil decrease in 52% of the combination group versus 39% of the monotherapy group; grade 3 or 4 hypertension in 6% versus 1.2%; grade 3 or 4 fatigue in 5% versus 8%. In the combination group, serious adverse events occurred in 25%, fatal adverse events in 1.2% (rectal fistula, intestinal perforation and atrial fibrillation, each 0.4%) and permanent discontinuation due to an adverse event in 13% of patients.

Clinical significance and place in guidelines

SUNLIGHT made trifluridine-tipiracil plus bevacizumab the standard treatment for refractory metastatic colorectal cancer, and the FDA approved the combination in 2023. The ESMO metastatic colorectal cancer guideline (2026) considers this combination the standard approach in refractory disease and lists regorafenib or fruquintinib as later options.

Limitations

Open-label design (no placebo); only patients with no more than two prior chemotherapy regimens and good performance status (ECOG 0 or 1) were enrolled; the absolute gain in median overall survival is about 3 months. Subgroup results (for example by prior bevacizumab) are in the full text.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.