Real-world data support FTD/TPI plus bevacizumab for mCRC

A combination regimen comprising trifluridine/tipiracil (FTD/TPI) and bevacizumab demonstrates favourable efficacy and safety in individuals with metastatic colorectal cancer (mCRC) in the real-world BeTAS study presented at ASCO GI 2025.

“The objective of [this] study is to evaluate the effectiveness and safety of [this combination] in patients with refractory mCRC who have progressed after ≥2 lines of treatment in routine clinical practice,” said the investigators from the Galician Research Group on Digestive Tumors, led by Dr Nieves Martinez Lago from the Complexo Hospitalario Universitario de Ferrol in Spain.

In this retrospective study, Lago and colleagues evaluated 210 patients with mCRC who were refractory or intolerant to standard therapies. They received treatment with the FTD/TPI and bevacizumab combination between July 2019 and December 2023. The median age of participants was 66 years, nearly two-thirds were men, and 86.2 percent had ECOG PS 0–1.

About 34 percent of tumours were located in the rectum, 31.9 percent were left-sided and 22.9 percent right-sided. Fifty-three percent of participants had the RAS mutation, 90.5 percent had received prior anti-VEGF therapy, and 81.2 percent had liver metastases. About three-quarters received three lines of the experimental regimen and 24.8 percent had ≥3 metastatic locations.

Based on the Tabernero prognostic classification, 53.3 percent of the patients had a poor prognosis, while the rest had good (26.7 percent) or best (20 percent) prognosis.

After a median four cycles, the overall survival (OS) was 11.1 months, progression-free survival was 4.3 months, overall response rate 4.6 percent, and disease control rate 50.2 percent. [ASCO GI 2025, abstract 204]

The most common grade 3–4 toxicity reported was neutropenia (32.9 percent), followed by asthenia (8.6 percent), diarrhoea (5.2 percent), and anaemia (4.8 percent).

According to Lago, about half of the patients with neutropenia managed their toxicity with granulocyte-colony stimulating factor (G-CSF), 11.5 percent reduced their dose, and 9.5 percent did both. There were no treatment-related deaths reported.

“Our [study] confirms the efficacy and safety of FTD/TPI plus bevacizumab in routine clinical practice, even in a population with poor prognosis and an extensive history of previous treatments,” said Lago.

Black patients

In a separate analysis, the combination regimen appears to fare better than FTD/TPI only among Black patients with mCRC. “Black patients have a higher incidence of CRC and shorter survival as compared with White patients. Yet, Black patients are underrepresented in clinical trials of novel therapies,” noted the researchers, led by Dr Maliha Nusrat from the Memorial Sloan Kettering Cancer Center, New York, New York, US.

Nusrat and her team conducted a retrospective analysis using the ConcertAI real-world electronic medical record database (n=639; median age 60 years, 50 percent men). Of these, 551 were on FTD/TPI only while the remaining 88 were administered the combo regimen. In the combination arm, 60 percent had ECOG PS 0–1 and 90.9 percent received >2 regimens following mCRC diagnosis prior to index treatment. [ASCO GI 2025, abstract 81]

The combo regimen significantly prolonged real-world OS as opposed to FTD/TPI only (median 10.8 vs 6.2 months). This translated to a reduction in the risk of death by 55 percent in the adjusted Cox model (hazard ratio [HR], 0.45, 95 percent confidence interval [CI], 0.33–0.63; p<0.001).

These findings mirror those observed in the SUNLIGHT trial (median 10.8 vs 7.5 months; HR, 0.61, 95 percent CI, 0.49–0.77; p<0.001). [N Engl J Med 2023;388:1657-1667]

The results also favoured the combination therapy over FTD/TPI only in terms of real-world time to discontinuation (median 3.8 vs 2.4 months; HR, 0.515; p<0.001).

Of note, there was a nonsignificant trend towards longer real-world OS with the combo therapy vs FTD/TPI only in a subgroup of patients who had lower baseline neutrophil count (n=25; median 17.3 vs 7.2 months; p=0.733).

According to the researchers, they analysed this subgroup due to the inherently lower neutrophil count in Black patients. Of those who received FTD/TPI in this patient subset, 4 percent had documented use of G-CSF between the initial therapy and the next line of treatment. Among those who received the combination regimen, about 15 percent had documented use of G-CSF.

“This real-world study fulfils the critical need to confirm the effectiveness of FTD/TPI plus bevacizumab in Black patients with mCRC who were underrepresented in the phase III trial and showed real-world OS comparable to that seen in the overall population of SUNLIGHT,” said Nusrat and colleagues.

Despite missing data and potential misreporting or misclassification, they pointed out that this study reflects outcomes of patients who were primarily treated within community oncology practices in the US, thus reflecting the benefit of the combo regimen outside of the selected circumstances of a clinical trial.

The US FDA has given the nod for FTD/TPI monotherapy in 2015 for mCRC patients who have received prior chemotherapy, anti-VEGF biological therapy, and, in RAS wild-type cases, anti-EGFR therapy. [https://www.esmo.org/oncology-news/archive/fda-approves-new-oral-medication-to-treat-patients-with-metastatic-colorectal-cancer, accessed 27 February 2025]

Clinical treatment guidelines have recommended the FTD/TPI plus bevacizumab combination regimen since early 2021, but the US FDA green light was given in 2023 for the same indication. [https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-trifluridine-and-tipiracil-bevacizumab-previously-treated-metastatic-colorectal-cancer, accessed 27 February 2025]