Frontline Trifluridine and Tipiracil Plus Bevacizumab Matches Efficacy of Capecitabine-Bevacizumab Combo in Metastatic Colon Cancer

The findings, according to a third-party expert, suggest there’s no benefit to the use of trifluridine and tipiracil alone in earlier lines of therapy for the treatment of colon cancer.

There were no substantial efficacy or toxicity differences between the use of trifluridine and tipiracil (Lonsurf) combined with bevacizumab (Avastin) and capecitabine (Xeloda) plus bevacizumab in the treatment of patients with unresectable metastatic colorectal cancer ineligible for intensive treatment, according to data from the phase 3 SOLSTICE study (NCT03869892).

The hazard ratio for progression-free survival (PFS) with bevacizumab plus trifluridine-tipiracil vs capecitabine was 0.87 (95% CI, 0.75-1.02; P = .0464), which failed to meet the predetermined significance level (P = .021). Median PFS, as assessed by the investigators, was 9.4 months (95% CI, 9.1-10.9) vs 9.3 months (95% CI, 8.9-9.8) in the trifluridine-tipiracil and capecitabine groups, respectively.

The probability of PFS was estimated as 71% at 6 months in both the trifluridine-tipiracil (95% CI, 66%-75%) and capecitabine (95% CI, 66%-75%) groups. The PFS probability was 39% (95% CI, 34–43) vs 31% (95% CI 66–75) at 12 months and 19% (95% CI, 15–24) vs 13% (95% CI, 9–17) at 18 months in the trifluridine-tipiracil and capecitabine groups, respectively.

“To our knowledge, this study is the first phase 3 trial to evaluate the efficacy and safety of trifluridine-tipiracil plus bevacizumab as first-line therapy in patients with unresectable metastatic colorectal cancer and explore treatment in this population who are not candidates for intensive full-dose doublet or triplet chemotherapy,” the investigators wrote.

The overall response rate was 36% (95% CI, 31%-41%) in the trifluridine-tipiracil group and 42% (37%-46%) in the capecitabine group, which was deemed a non-significant difference (P = .0924). There was also no significant difference in the investigator-assessed disease control rates, which were 86% (95% CI, 83%-90%) and 85% (95% CI, 81%-88%), respectively (P = .6256).

A prespecified sensitivity analysis by blinded independent central review largely correlated the results of the primary analysis. Median PFS was found to be 10.6 months (95% CI, 9.3-11.1) in the trifluridine-tipiracil group vs 9.3 months (95% CI, 9.1-10.2) in the capecitabine group (HR 0.85; 95% CI, 0.72-1.00), with 287 events in the former and 299 events in the latter.

For the study, investigators randomly assigned 856 patients, a slim majority (54%) of whom were male, to receive trifluridine-tipiracil (n = 426) or capecitabine (n = 430) plus bevacizumab between March 21, 2019, and Sept. 14, 2020. The median age of this intention-to-treat population was 73 years (range 22–93; interquartile range [IQR] 65-80).

Most patients in both groups had an ECOG performance status of 1 (58% and 58%), a Charlson Comorbidity Index score of 0 (58% and 56%) and left-sided disease (70% and 70%).

There were also no substantial differences in patient quality of life.

Patients assigned to the experimental group received oral trifluridine-tipiracil at 35 mg/m² twice daily on days 1-5 and 8-12 of each 28-day cycle, as well as intravenous bevacizumab at 5 mg/kg on days 1 and 15.

Patients in the control group received oral capecitabine at a starting dose of either 1000 mg/m² or 1250 mg/m² twice daily on days 1-14 of each 21-day cycle, plus intravenous bevacizumab at 7.5 mg/kg on day 1. If patients received the lower dose, their dosage could be increased to 1250 mg/m² in subsequent cycles. No lower dose of trifluridine-tipiracil was deployed.

The most common grade 3 and higher treatment-emergent adverse events (TEAEs) were neutropenia, affecting 52% of patients in the experimental group vs 1% in the control group; decreased neutrophil count, affecting 18% vs less than 1%; anemia, affecting 14% vs 4%; and hand-foot syndrome, affecting 0 vs 15%. Nine deaths were treatment related, 5 in the experimental group and 4 in the control group.

These findings, according to an expert unaffiliated with this study, confirm that there’s limited benefit to single-agent trifluridine and tipiracil in the frontline setting.

“This study, along with the TRUSTY study, suggests no benefit to trifluridine-tipiracil in earlier lines of therapy,” said Tanios Bekaii-Saab, MD, a professor of medicine, senior associate consultant of hematology and oncology, and co-leader of the Gastrointestinal Cancer Program at the Mayo Clinic Cancer Center in Scottsdale, Arizona, in an conversation with CancerNetwork®. “The good news is that a recent study, SUNLIGHT [NCT04737187], suggests further benefit from trifluridine-tipiracil when bevacizumab is added in the refractory setting vs trifluridine-tipiracil alone. This continues to consolidate the role of trifluridine-tipiracil, along with regorafenib [Stivarga] and possibly fruquintinib, pending regulatory approval, in patients who fail at least 2 lines of therapy.”


André T, Falcone A, Shparyk Y, et al. Trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy (SOLSTICE): a randomised, open-label phase 3 study. Lancet Gastroenterol Hepatol. Published online December 2, 2022. doi:10.1016/S2468-1253(22)00334-X

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