FDA Approves Trifluridine/Tipiracil Plus Bevacizumab in Previously Treated Metastatic Colorectal Cancer

The FDA has approved trifluridine and tipiracil (Lonsurf) plus bevacizumab (Avastin) for patients with metastatic colorectal cancer (mCRC) who were previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; a VEGF inhibitor; and an EGFR inhibitor, if they have RAS wild-type disease.^1,2

The regulatory decision is supported by data from the phase 3 SUNLIGHT trial (NCT04737187), in which the combination significantly improved overall survival (OS) and progression-free survival (PFS) vs trifluridine/tipiracil alone in this population.³

The addition of bevacizumab to trifluridine/tipiracil resulted in a a median OFS of 10.8 months (95% CI, 9.4-11.8) vs 7.5 months (95% CI, 6.3-8.6) with trifluridine/tipiracil alone, translating to a 39% reduction in the risk of death (HR, 0.61; 95% CI, 0.49-0.77; 1-sided P < .001).

Moreover, the median PFS in the investigative arm was 5.6 months (95% CI, 4.5-5.9) vs 2.4 months (95% CI, 2.1-3.2) in the control arm, translating to a 56% reduction in the risk of disease progression or death (HR, 0.44; 95% CI, 0.35-0.54; 1-sided P < .001).

Trifluridine and tipiracil plus bevacizumab has been approved for patients with metastatic colorectal cancer who were previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; a VEGF inhibitor; and an EGFR inhibitor, if they have RAS wild-type disease.

Credit: mi_viri - stock.adobe.com

The supplemental new drug application seeking the approval of the regimen was granted priority review by the regulatory agency in April 2023.⁴

“The poor prognosis for patients with previously treated, late-stage mCRC has been an ongoing challenge in the oncology community, which has driven our pursuit of a potential new treatment option,” Volker Wacheck, MD, PhD, vice president of clinical development at Taiho Oncology, Inc., stated in a previously received press release.⁴ “We believe the combination of trifluridine/tipiracil plus bevacizumab may represent a significant advance in the treatment of refractory disease..."

The open-label, international randomized, phase 3 SUNLIGHT study enrolled patients with histologically confirmed mCRC with an who had received no more than 2 previous treatments for advanced disease, including a fluoropyrimidine, irinotecan, and oxaliplatin.² Prior treatment with a VEGF inhibitor was optional, but prior EGFR inhibition was required for those with RAS wild-type disease.

To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1. They could not have symptomatic brain metastases, ascites in need of drainage in the past 4 weeks, uncontrolled hypertension, a wound that has not healed, or a deep venous thromboembolic event within the 4 weeks before study treatment.

Study participants were randomly assigned 1:1 to receive trifluridine/tipiracil at a twice daily dose of 35 mg/m2 on days 1 to 5 and 8 to 12 every 28 days with (n = 246) or without (n = 246) bevacizumab, which was given at 5 mg/kg on days 1 and 15 every 2 weeks of every 4-week cycle. Treatment continued until progressive disease or intolerable toxicity.

Key stratification factors included geographic region (North America, European Union, or rest of the world), time since diagnosis of metastatic disease (less than 18 months vs 18 months or longer), and RAS mutational status (wild-type vs mutation).

The primary end point of the study was OS in the full analysis set. Secondary end points included PFS, disease control rate, objective response rate, safety, and quality of life.

The median age of the 492 patients who underwent randomization was 63 years. Approximately half (52%) of patients were male, and the majority (88%) were White. Regarding ECOG performance status, 46% had a status of 0 and 54% had a status of 1. Seventy-three percent of patients had a primary disesae site of the colon, and 27% had disease in the rectum. Notably, 71% of patients had RAS-mutated disease.

In terms of prior treatment, 92% of patients received 2 prior lines for advanced disease. All patients previously received fluoropyrimidine, 99.8% had prior irinotecan, and 98% received prior oxaliplatin. Moreover, 76% had prior exposure to VEGF treatment, and 94% of the 142 patients with RAS wild-type disease had a prior EGFR inhibitor.

Of the patients who received trifluridine and tipiraci plus bevacizumab, 39% were exposed to treatment for at least 6 months and 14% were exposed for at least 1 year.

Twenty-five percent of patients experienced serious toxicities with the regimen, the most common of which being intestinal obstruction (2.8%) and COVID-19 (2%). Moreover, 1.2% of patients experienced adverse effects (AEs) that proved to be fatal; these included rectal fistula (0.4%), bowel perforation (0.4%), and atrial fibrillation (0.4%).

Dose reductions and interruptions were required by 7% and 11% of patients, respectively. Thirteen percent of patients experienced toxicities that resulted in permanent discontinuation of treatment. The AE that led to permanent discontinuation in at least 2% of patients was fatigue.

The most common AEs experienced by at least 20% of patients included neutropenia, anemia, thrombocytopenia, fatigue, nausea, increased aspartate aminotransferase, increased alanine aminotransferase, increased alkaline phosphatase, decreased sodium, diarrhea, abdominal pain, and decreased appetite.

References

1. FDA approves trifluridine and tipiracil with bevacizumab for previously treated metastatic colorectal cancer. FDA. August 2, 2023. Accessed August 2, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-trifluridine-and-tipiracil-bevacizumab-previously-treated-metastatic-colorectal-cancer
2. Trifluridine/tipiracil (Lonsurf). Prescribing information. Taiho Oncology, Inc; August 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/207981s012lbl.pdf
3. 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
4. US 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 August 2, 2023. https://www.taihooncology.com/us/news/2023-04-18_toi_snda_acceptance_lonsurf_combo/