Trifluridine–Tipiracil and Bevacizumab Improves Survival in Metastatic Pretreated Colorectal Cancer

1. The median overall survival was 10.8 months in the combination group (FTD–TPI + bevacizumab) and 7.5 months in the FTD–TPI alone group, with HR 0.61.

2. The most common adverse events in both groups included neutropenia, nausea, and anemia.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Trifluridine-tipiracil (cytotoxic nucleic acid analogue) is commonly used for refractory disease in patients with metastatic colorectal cancer. Adding a VEGF inhibitor (inhibition of angiogenesis) such as bevacizumab to such patients is thought to be an effective strategy. This phase 3 study continued to build on previous studies that investigated a combination of trifluridine-tipiracil (FTD-TPI) and bevacizumab. The primary end point was overall survival (OS) and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), quality of life (QoL), and safety. The median OS was 10.8 months in the combination group and 7.5 months in the FTD–TPI group, with HR 0.61. Median PFS was 5.6 months in the combination group and 2.4 months in the FTD–TPI group, and an HR of 0.44. ORR was seen in 6.1% of the combination group, and in 1.2% of the FTD–TPI group. Differences in adverse events between arms included hypertension (10.2% in the combination group vs 2.0% in the FTD–TPI group), nausea (37.0% vs 27.2%), and neutropenia (62.2% vs 51.2%). The median time to worsening ECOG from 0-1 to 2+ was 9.3 months in the combination group and 6.3 months in the FTD–TPI group with HR 0.54. The strengths of this paper included its randomized two-arm methodology and large sample size, and the limitations included short follow-up time. Overall the combination of FTD–TPI plus bevacizumab showed improved efficacy compared to FTD–TPI alone in patients with resistant metastatic colorectal cancer.

Click to read the study in NEJM

Click to read an accompanying editorial in NEJM

Relevant Reading: Combination of TAS-102 and bevacizumab as third-line treatment for metastatic colorectal cancer: TAS-CC3 study

In-Depth [randomized controlled trial]: This randomized, international, phase 3 trial investigated the combination of trifluridine-tipiracil alone (246 patients) vs trifluridine-tipiracil and bevacizumab (246) in patients with histologically confirmed advanced unresectable adenocarcinoma of the colon or rectum who have progressed on past treatments. 69% of patients have RAS mutations. The median duration of treatment was 5.0 months in the combination group by 2.1 months in the FTD-TPI group with median dose intensities being around 88% and 90% respectively. By the end of the study, 13.0% of patients in the combination group and 1.6% of patients in the FTD-TPI group were continuing to receive treatment. The median OS was 10.8 months (95%CI, 9.4 to 11.8) in the combination group and 7.5 months (95%CI, 6.3 to 8.6) in the FTD–TPI group, with HR 0.61 (95%CI, 0.49 to 0.77, p<0.001).  6-month OS was 77% in the combination group and 61% in the FTD–TPI group, with 12-month OS 43% and 30%, respectively. Median PFS was 5.6 months (95%CI, 4.5 to 5.9) in the combination group and 2.4 months (95%CI, 2.1 to 3.2) in the FTD–TPI group, with HR 0.44 (95%CI, 0.36 to 0.54, p<0.001). The superiority of FTD–TPI plus bevacizumab was observed in all subgroups examined. ORR was seen in 6.1% of the combination group (95%CI, 3.5 to 9.9), and in 1.2% of the FTD–TPI group (95%CI, 0.3 to 3.5). With regards to safety, adverse events (grade ≥3) occurred in 72.4% of the combination group and 69.5% of the FTD–TPI group, with the most common adverse events being neutropenia, nausea, and anemia. Differences in adverse events between arms included hypertension (10.2% in the combination group vs 2.0% in the FTD–TPI group), nausea (37.0% vs 27.2%), and neutropenia (62.2% vs 51.2%). Median time to worsening ECOG from 0-1 to 2+ was 9.3 months (95%CI, 8.3 to 10.6) in the combination group and 6.3 months (95%CI, 5.6 to 7.2) in the FTD–TPI group with HR 0.54 (95%CI, 0.43 to 0.67). Overall the combination of FTD–TPI plus bevacizumab showed improved efficacy compared to FTD–TPI alone in patients with resistant metastatic colorectal cancer.

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