Lonsurf with Bevacizumab in Metastatic Colorectal Cancer
For patients with metastatic colorectal cancer who have progressed through standard therapies (fluoropyrimidine, oxaliplatin, irinotecan, anti-VEGF, and if RAS wild-type, anti-EGFR therapy), trifluridine/tipiracil (Lonsurf) combined with bevacizumab is the preferred treatment over trifluridine/tipiracil monotherapy, based on significant overall survival and progression-free survival benefits demonstrated in the phase III SUNLIGHT trial. 1
Evidence for the Combination in Later-Line Treatment
The combination of trifluridine/tipiracil with bevacizumab has established efficacy in the refractory metastatic colorectal cancer setting:
Survival Benefits from SUNLIGHT Trial
- Overall survival improved from 7.5 months with trifluridine/tipiracil alone to 10.8 months with the bevacizumab combination (HR 0.61; 95% CI 0.49-0.77; P<.001) 1
- Progression-free survival increased from 2.4 months to 5.6 months with the combination (HR 0.44; 95% CI 0.36-0.54; P<.001) 1
- Nearly all patients in SUNLIGHT had received prior fluoropyrimidine, irinotecan, and oxaliplatin; 72% had received prior anti-VEGF therapy; and 93.7% of RAS wild-type patients had received prior anti-EGFR therapy 1
Real-World Evidence
- A retrospective study of 57 patients with refractory metastatic colorectal cancer demonstrated improved median overall survival with trifluridine/tipiracil plus bevacizumab versus monotherapy (14.4 vs 4.5 months; P<.001) 1
- Another retrospective study reported improved overall survival and time to treatment discontinuation for the combination compared with either trifluridine/tipiracil alone or regorafenib 1
FDA-Approved Indication and Dosing
The FDA-approved indication for Lonsurf with bevacizumab is for adult patients with metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy 2
Recommended Dosing Regimen
- Trifluridine/tipiracil: 35 mg/m² (up to maximum 80 mg per dose) orally twice daily with food on Days 1-5 and Days 8-12 of each 28-day cycle 2
- Bevacizumab: administered per standard bevacizumab prescribing information 2
- Round dose to nearest 5 mg increment 2
- Instruct patients to swallow tablets whole and not to retake vomited or missed doses 2
Guideline Recommendations
NCCN Guidelines (2024)
- The NCCN panel designates the bevacizumab combination as preferred over trifluridine/tipiracil alone for patients whose disease has progressed through standard therapies 1
- The combination can be given before or after regorafenib or fruquintinib; no data inform the best order of these therapies 1
- Real-world data show better patient adherence to trifluridine/tipiracil compared with regorafenib 1
- The 144 patients in RECOURSE who had prior regorafenib exposure obtained similar overall survival benefit from trifluridine/tipiracil (HR 0.69; 95% CI 0.45-1.05) as the 656 patients who did not (HR 0.69; 95% CI 0.57-0.83) 1
Chinese Society of Clinical Oncology Guidelines (2025)
- A global randomized phase III study demonstrated that the combination of trifluridine/tipiracil and bevacizumab significantly prolonged overall survival and progression-free survival compared to trifluridine/tipiracil monotherapy 1
- The combination is recommended for patients with metastatic colorectal cancer who previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and who previously received or are not suitable for anti-VEGF and anti-EGFR treatment (if RAS wild-type) 1
Safety Profile and Toxicity Management
Common Adverse Events
- The most common adverse events with the combination are neutropenia, nausea, and anemia 1
- No treatment-related deaths occurred in the SUNLIGHT trial 1
- Grade ≥3 treatment-emergent adverse events occurred in 72.4% of patients in SUNLIGHT 3
Hematologic Toxicity Management
- Median time to resolution of grade ≥3 hematologic adverse events/neutropenia to grade ≤2 was 8 days 3
- Granulocyte colony-stimulating factor was used in 30.6% of patients in pooled analysis 3
- Obtain complete blood cell counts prior to and on Day 15 of each cycle 2
Dose Modifications for Adverse Reactions
Withhold trifluridine/tipiracil for: 2
- Absolute neutrophil count less than 500/mm³ or febrile neutropenia
- Platelets less than 50,000/mm³
- Grade 3 or 4 non-hematologic adverse reactions
After recovery, reduce dose by 5 mg/m²/dose from previous dose if: 2
- Febrile neutropenia occurs
- Uncomplicated Grade 4 neutropenia (recovered to ≥1,500/mm³) or thrombocytopenia (recovered to ≥75,000/mm³) results in more than 1 week delay in start of next cycle
- Non-hematologic Grade 3 or 4 adverse reaction occurs (except Grade 3 nausea/vomiting controlled by antiemetics or Grade 3 diarrhea responsive to antidiarrheals)
Maximum of 3 dose reductions permitted; permanently discontinue if unable to tolerate 20 mg/m² twice daily 2
Special Populations
Severe Renal Impairment
- In patients with severe renal impairment (creatinine clearance 15-29 mL/min), reduce starting dose to 20 mg/m² orally twice daily on Days 1-5 and Days 8-12 of each 28-day cycle 2
Vulnerable Patients
- Grade ≥3 treatment-related adverse events were more frequent in patients aged ≥75 years and those with ECOG performance status of 0 versus 1 or 2 3
- However, the combination showed a consistent and manageable safety profile across age groups and performance status levels 3
Important Clinical Caveats
Not Recommended in First-Line Setting
- The NCCN panel does not currently recommend trifluridine/tipiracil with or without bevacizumab as first-line therapy for metastatic colorectal cancer 1
- This recommendation is based on concerns about hematologic and financial toxicities compared with capecitabine, despite similar overall survival and progression-free survival results in the phase III SOLSTICE and phase II TASCO1 first-line studies 1
Sequencing with Other Agents
- The combination can be administered before or after regorafenib or fruquintinib 1
- No data definitively inform the optimal sequencing of these third-line agents 1
- Patient adherence data favor trifluridine/tipiracil over regorafenib 1