In a Danish phase II study reported in The Lancet Oncology, Per Pfeiffer, MD, PhD, and colleagues found that the addition of bevacizumab to trifluridine/tipiracil, also known as TAS-102, significantly improved progression-free survival among patients with chemorefractory metastatic colorectal cancer.

Per Pfeiffer, MD, PhD

Study Details

In the open-label multicenter trial, 93 patients with colorectal cancer who were refractory to or intolerant of treatment with fluoropyrimidines, irinotecan, oxaliplatin, and cetuximab or panitumumab (only for RAS wild-type disease) were randomly assigned between August 2017 and October 2018 to receive oral trifluridine/tipiracil at 35 mg/m² twice daily on days 1 to 5 and 8 to 12 every 28 days alone (n = 47) or trifluridine/tipiracil plus bevacizumab at 5 mg/kg on days 1 and 15 (n = 46) until disease progression or unacceptable toxicity. Previous therapy with bevacizumab, aflibercept, ramucirumab, or regorafenib was permitted. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population.

Progression-Free Survival

On the clinical cut-off date in February 2019, median follow-up was 10.0 months. Median progression-free survival was 4.6 months in the combination group vs 2.6 months in the trifluridine/tipiracil group (hazard ratio [HR] = 0.45, P = .0015). The difference remained significant when analysis was adjusted for the stratification factors of study center and RAS mutation status (HR = 0.47, P = .0015).

Median overall survival was 9.4 months vs 6.7 months (HR = 0.55, P = .028; HR = 0.58, P = .048, after adjustment for stratification factors). Disease control rates (one partial response was observed in the combination group) were 67% vs 51% (P = .14).

Adverse Events

The most common treatment-related grade ≥ 3 adverse event in the combination group was neutropenia (67% vs 38%); the most common treatment-related grade ≥ 3 nonhematologic adverse event was diarrhea (9% vs 0%). Serious adverse events occurred in 41% vs 45% of patients. No treatment-related deaths were observed.

The investigators concluded, “In patients with chemorefractory metastatic colorectal cancer, [trifluridine/tipiracil] plus bevacizumab, as compared with [trifluridine/tipiracil] monotherapy, was associated with a significant and clinically relevant improvement in progression-free survival with tolerable toxicity. The combination of [trifluridine/tipiracil] plus bevacizumab could be a new treatment option for patients with refractory metastatic colorectal cancer and could be a practice-changing development.”

Dr. Pfeiffer, of the Department of Oncology, Odense University Hospital, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Servier. For full disclosures of the study authors, visit thelancet.com.