Trifluridine/Tipiracil Receives FDA Approval in Metastatic CRC

The approval was based on results from the phase 3 SUNLIGHT study (NCT04737187), in which patients were randomly assigned 1:1 to either FTD-TPI and bevacizumab or FTD-TPI alone.

The FDA has approved trifluridine/tipiracil (FTD-TPI; Lonsurf) in combination with bevacizumab (Avastin) for patients with metastatic colorectal cancer who were previously treated with several chemotherapy-based regimens including fluoropyrimidine, oxaliplatin, and irinotecan; and a VEGF inhibitor., according to a press release from the agency.¹ The indication also includes patients with RAS wild-type disease who were treated with a prior EGFR inhibitor.

The approval was based on results from the phase 3 SUNLIGHT study (NCT04737187), in which patients were randomly assigned 1:1 to either FTD-TPI and bevacizumab or FTD-TPI alone.² A total of 246 patients were assigned to each group. Investigators reported that time from first metastasis to randomization lasting 18 months or more was observed in 57.5% of patients, as well as 30.7% in those with RAS wild-type disease.

“We have at least 2 reasonable options for 80% of the patients who have no targets, so [FTD-TPI plus] bevacizumab, is now a standard instead of [FTD-TPI alone], or regorafenib [Stivarga] with a dose optimization strategy,” Tanios S. Bekaii-Saab, MD, FACP, professor of medicine in the Division of Hematology/Oncology, Department of Internal Medicine at the Mayo Clinic in Phoenix, Arizona, said in an interview with CancerNetwork^®.

In the combination group, the median follow-up was 14.2 months vs 13.6 months in the FTD-TPI group. In the combination group, the median OS was 10.8 months (95% CI, 9.4-11.8) vs 7.5 months (95% CI, 6.3-8.6) in the FTD-TPI group (hazard ratio [HR], 0.61; 95% CI, 0.49-0.77; P <.001).

Investigators conducted a sensitivity analysis, and included patients who did not meet the relevant prespecified medical and therapeutic criteria and had a median OS of 10.8 months (95% CI, 9.6-12.1) in the combination group vs 7.2 months (95% CI, 6.3-8.5) in the FTD-TPI group (HR, 0.59; 95% CI, 0.47-0.74).

In the combination group, the 6-month OS was 77% vs 61% in the FTD-TPI group; at 12 months the OS rate was 43% and 30%, respectively.

Additionally, the median PFS was 5.6 months (95% CI, 4.5-5.9) in the combination group and 2.4 months (95% CI, 2.1-3.2) in the FTD-TPI group (HR, 0.44; 95% CI, 0.36-0.54; P <.001). The 6-month PFS rate was 43% in the combination group and 16% in the FTD-TPI group, and at 12 months it was 16% and 1%, respectively.

Patients in both cohorts were given FTD-TPI orally twice daily beginning at 35 mg/m² on days 1 to 5 and days 8 to 12 every 28 days, and bevacizumab at 5 mg/kg was given intravenously on days 1 and 15 in the experimental cohort.

The primary end point was overall survival (OS) and secondary end points were investigator-assessed progression-free survival (PFS), objective response rate (ORR), and disease control via RECIST v1.1.

A total of 92.1% of patients received 2 prior regimens, however, 4.5% in the FTD-TPI plus bevacizumab group and 6.1% in the FTD-TPI alone group only had 1 first-line triplet regimen, and 2.6% had 3 or more regimens for metastatic disease.

Patients underwent treatment for a median duration of 5.0 months in the combination group vs 2.1 months in the FTD-TPI group. Of note, the median dose intensity of FTD-TPI in the experimental arm was 88.3% and bevacizumab was 87.6%, while in the FTD-TPI alone group, it was 90.4%. At the time of data cutoff, 13.0% of patients in the combination group and 1.6% in the FTD-TPI group were still receiving treatment. A total of 6 patients discontinued treatment.

A total of 6.1% (95% CI, 3.5%-9.9%) of patients in the combination group experienced an objective response and 15 patients had a partial response (PR). Additionally, 1.2% (95% CI, 0.3%-3.5%) of patients in the FTD-TPI group had an objective response, 1 patient had a complete response, and 2 had PRs.

In either group, 98.0% of patients had an adverse effect (AE). Severe AEs of grade 3 or higher occurred in 72.4% of patients in the combination group and 69.5% in the FTD-TPI group. The most common grade 3/4 AEs included neutropenia (43.1% vs 32.1%), neutrophil count decrease (8.9% vs 5.3%), anemia (6.1% vs 11.0%), and hypertension (5.7% vs 1.2%) between the combination and FTD-TPI groups, respectively.

AEs attributed to FTD-TPI were observed in 89.8% of those in the combination group and 81.3% in the FTD-TPI group, with 48.4% having bevacizumab-related AEs. Investigators did not report any treatment-related deaths.

Discontinuation of treatment due to AEs occurred in 12.6% in both groups. AEs related to treatment occurred in 2.4% of patients in the combination group and 2.0% in the FTD-TPI group. A total of 16.3% of patients had dose reductions in the combination group vs 12.2% in the FTD-TPI group, with dose delays occurring in 69.5% vs 53.3%, respectively.

References

1. FDA approves trifluridine and tipiracil with bevacizumab for previously treated metastatic colorectal cancer. News release. FDA. August 2, 2023. Accessed August 2, 2023. https://bit.ly/3DEWtjV
2. Prager GW, Taieb J, Fakih M, et al. Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med. 2023;388(18):1657-1667. doi:10.1056/NEJMoa2214963