Trifluridine/Tipiracil Plus Bevacizumab Provides Potential First-Line Alternative to Bevacizumab/Capecitabine in mCRC

Thierry André, MD

Although the addition of trifluridine/tipiracil (TAS-102; Lonsurf) to bevacizumab (Avastin) in the first line did not produce superior survival benefit vs standard capecitabine (Xeloda) and bevacizumab, similar efficacy results between both arms indicate that the regimen may still be a viable treatment for patients with unresectable metastatic colorectal cancer (mCRC) who are ineligible for intensive chemotherapy, according to Thierry André, MD.

At the 2023 ASCO Annual Meeting, analysis of the key secondary end point of overall survival (OS) was presented. Patients with unresectable mCRC treated with trifluridine/tipiracil plus bevacizumab experienced a median OS of 19.74 months (95% CI, 18.04-22.40) vs 18.59 months (95% CI, 16.82-21.39) when treated with capecitabine and bevacizumab (HR, 1.06; 90% CI, 0.90-1.25). Following adjustment for prognostic factors, a significant treatment effect with the experimental regimen was still not observed.

“The study [indicates] that trifluridine/tipiracil plus bevacizumab [should be] the standard of care [SOC] in the [third] line, but not in the first line. [However], it's important to also have [this regimen as a] possible [first-line alternative],” André, a professor of medical oncology at Sorbonne University and a senior physician and head of the Department of Medical Oncology at the Saint Antoine Hospital in Paris, France, said.

In an interview with OncLive^®, André discussed the investigation of trifluridine/tipiracil plus bevacizumab in patients with mCRC, including how its use as a SOC in the third line supported its investigation in the first-line setting, the regimen’s efficacy and safety in the SOLSTICE trial, and the importance of this combination for patients in this space despite negative trial results.

OncLive: What was the rationale for investigating the addition of trifluridine/tipiracil to bevacizumab in the first line for patients with mCRC?

André: The rationale of this study was the fact that trifluridine/tipiracil is now a well-known [fluoropyrimidine-based combination]. We had data [for this regimen] in the third line, but we didn't have data in the first line. [This study was] testing the combination of trifluridine/tipiracil plus bevacizumab in first line after a phase 2, randomized [study] with some hope that trifluridine/tipiracil plus bevacizumab would be superior to capecitabine (Xeloda) and bevacizumab. This was the rationale to begin the study.

The [regimen] is [comprised of] a fluoropyrimidine plus bevacizumab, and it's a well-known combination. It's clear that it's a good combination. Bevacizumab increases the effect of the fluoropyrimidine in [patients with] metastatic colorectal [cancer].

What survival data were presented from the phase 3 SOLSTICE trial at this year’s meeting?

We presented OS data [from the study] between [patients treated with] trifluridine/tipiracil plus bevacizumab [vs] bevacizumab and capecitabine. This population [was not eligible for intensive doublet or triplet chemotherapy] for different reasons, [including] age, comorbidities, [patient preference], and performance status. Results [show] that [the median] OS is around the same in both arms [at] about 19 months, with a hazard ratio of 1.06. PFS was [also similar] between the trifluridine/tipiracil plus bevacizumab vs bevacizumab and capecitabine [arms]. It was 9.4 months in the [experimental] arm and 9.3 months for the bevacizumab and capecitabine arm, and the hazard ratio [for PFS] was in favor of the trifluridine/tipiracil plus bevacizumab [regimen] at 0.87. [These data were] published in the past. [Ultimately, these survival rates] are similar between the 2 combinations.

Were any new safety findings observed in this analysis? What should be known about the differences in toxicity between these regimens?

There were no new [safety] data. [These regimens have] 2 different [primary] toxicities. For trifluridine/tipiracil plus bevacizumab it's neutropenia, and for capecitabine/bevacizumab it’s hand-foot syndrome. Diarrhea is possible with both. [The] schedules are [also] different because bevacizumab is [administered] every 3 weeks in the capecitabine schedule, [vs] every 2 weeks in the trifluridine/tipiracil arm.

Although trifluridine/tipiracil plus bevacizumab failed to produce superior PFS and OS vs capecitabine/bevacizumab, what might be some of the benefits of having this combination regimen in the first-line treatment armamentarium?

It [didn't show] a benefit, [but] it [could still be] a new option [for patients experiencing] toxicity with capecitabine plus bevacizumab, like hand-foot syndrome. [It’s important to note that trifluridine/tipiracil has no labeling] in the first line. [However, this regimen is] not a new [addition to the armamentarium], because it's [common], especially in Europe, to use trifluridine/tipiracil in the first line. In some cases, it's an opportunity [to provide a feasible therapeutic alternative] if capecitabine/bevacizumab is not well tolerated.

What are the clinical implications of this research?

It was important for us to know if trifluridine/tipiracil plus bevacizumab is better than a [different] fluoropyrimidine in the first line. [This] is not the case, but it was necessary to [conduct] the trial to demonstrate these facts.

The fact that [the experimental regimen] has the same efficacy in the first line compared with capecitabine and bevacizumab, [as well as] the fact that trifluridine/tipiracil plus bevacizumab increased PFS and OS in the third line, [confirms] that it is better to use trifluridine/tipiracil plus bevacizumab in the [third] line. After [investigators] presented [initial data from the trial, the results] [were] published in the New England Journal of Medicine.

[Overall, this result is] important, but it doesn’t change [current practice] or strategies in colorectal cancer.

What main message from this presentation would you like to impart to colleagues?

Trifluridine/tipiracil is an important drug in mCRC. It is the SOC with bevacizumab in the third line. It works in the first line, but without benefit compared with capecitabine and bevacizumab. For this reason, is better to [use] a fluoropyrimidine like 5-fluorouracil or capecitabine plus bevacizumab in the first line, and to reserve the combination of trifluridine/tipiracil plus bevacizumab for the third line.

Reference

Andre T, Falcone A, Shparyk YV, et al. Overall survival results for trifluridine/tipiracil plus bevacizumab vs capecitabine plus bevacizumab: results from the phase 3 SOLSTICE study. J Clin Oncol. 2023;41(suppl 16):3512. doi:10.1200/JCO.2023.41.16_suppl.3512