FDA Grants Priority Review to Trifluridine/Tipiracil Plus Bevacizumab in mCRC

The FDA plans to conduct a speedy review of an approval application for trifluridine plus tipiracil and bevacizumab for the treatment of metastatic colorectal cancer.

The FDA has granted priority review to a supplemental new drug application (sNDA) for trifluridine (FTD) plus tipiracil (TPI; Lonsurf) in combination with bevacizumab (Avastin) for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, an anti-EGFR therapy, or if they are RAS wild-type.1

The sNDA is backed by data from the phase 3 SUNLIGHT clinical trial (NCT0437187), which showed that the trifluridine/tipiracil plus bevacizumab achieved a statistically significant and clinically meaningful improvement in overall survival (OS) and progression-free survival (PFS) vs trifluridine/tipiracil alone in patients with refractory mCRC after they developed disease progression or intolerance on 2 prior chemotherapy regimens. The FDA has set a Prescription Drug User Fee Act (PDUFA) action date of August 13, 2023, for the sNDA.

SUNLIGHT is an open-label, randomized study in which 492 patients with histologically confirmed mCRC who had been previously treated with fluoropyrimidine, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody (not necessarily bevacizumab), and/or an anti-EGFR monoclonal antibody in those patients whose tumor harbored a RAS mutation were evaluated on treatment with trifluridine/tipiracil plus bevacizumab. The population had a median age in the trifluridine/tipiracil plus bevacizumab arm of 62 years (range, 20-84) and 64 years (range, 24-90) in the control arm.2

Patients in the study were randomly assigned 1:1 to receive either 35 mg/m2 of FTD/TPI twice daily on days 1 through 5 and 8 through 12 of a 28-day cycle, and 5 mg/kg of bevacizumab on days 1 and 15 (n = 246) vs FTD/TPI alone (n = 246). These patients were evaluated for the coprimary end points of OS and PFS, as well as the secondary end points of disease control rate (DCR), and safety.

[Colon cancer. Cancer attacking cell. Colon disease concept. 3d illustration] Image Credit: ©  [Crystal light] - [stock.adobe.com]

Image Credit: © Crystal light [stock.adobe.co]

Results presented by Josep Tabernero, MD, PhD at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium 2023 showed that the median OS was 10.8 months in the experimental arm vs 7.5 months in the control arm (HR, 0.61; 95% CI, 0.49-0.77; P < .001). At 6 months, the OS rate was 77% vs 61%, respectively. At the 12-month timepoint, the OS rate was 43% vs 30%, respectively.

Trifluridine/tipiracil plus bevacizumab demonstrated a median PFS of 5.6 months compared with 2.4 months in the control arm (HR, 0.44; 95% CI, 0.36-0.54; P < .001). The 6-month PFS rate was 43% vs 16%, respectively, and the 12-month PFS rate was 16% vs 1%, respectively.

In terms of responses, it was reported that the combination of trifluridine, tipiracil, and bevacizumab achieved a superior overall response rate (ORR) vs the control. The absolute gain for ORR was 5.4% (P = .004), and the absolute gain for DCR was 29.6% (P < .001).

The number of adverse events (AEs) were similar between the 2 treatment arms. Severe AEs occurred in 72% of the experimental arm vs 70% of the control arm. Thirteen percent of patients in each arm experienced AEs leading to withdrawal from the study. Dose reductions occurred in 16% of the experimental arm vs 12% of the control arm, and there was a higher percent of dose delays (70%) in the experimental arm vs the control (53%).

Treatment-emergent AEs were comparable in the 2 treatment arms, however, the experimental arm has a higher incidence of that hypertension (10% v 2%), nausea (37% v 27%), and neutropenia (62% v 51%).


1. U.S. Food and Drug Administration accepts for priority review taiho oncology's supplemental new drug application for the use of trifluridine/tipiracil (LONSURF®) in combination with bevacizumab for refractory metastatic colorectal Cancer (mCRC). News release. Taiho Oncology, Inc. April 18, 2023. Accessed April 18, 2023. https://prn.to/3MVXjP5

2. Tabernero J, Prager GW, Fakih M, et al. Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: The phase 3 randomized SUNLIGHT study. J Clin Oncol. 2023;41(suppl 4):4. doi:10.1200/JCO.2023.41.3_suppl.4

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