FDA Grants Priority Review to TAS-102 Plus Bevacizumab for Refractory mCRC

The FDA has accepted for priority review the supplemental new drug application (sNDA) seeking the approval of trifluridine/tipiracil (TAS-102; Lonsurf) as a single agent or in combination with bevacizumab (Avastin) for use in adult patients with metastatic colorectal cancer (mCRC) who previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; a VEGF inhibitor; and an EGFR inhibitor, if they have RAS wild-type disease.¹

The submission is supported by findings from the phase 3 SUNLIGHT trial (NCT04737187), in which the combination regimen improved overall survival (OS) and progression-free survival (PFS) vs TAS-102 alone in patients with refractory mCRC whose disease progressed or became intolerant to 2 previous chemotherapy regimens.²

Specifically, the median OS with TAS-102 and bevacizumab was 10.8 months vs 7.5 months with TAS-102 monotherapy, translating to a 39% reduction in the risk of death in this population (HR, 0.61; 95% CI, 0.49-0.77; P < .001). The combination also reduced the risk of disease progression or death by 56% vs the monotherapy, with a median PFS of 5.6 months and 2.4 months, respectively (HR, 0.44; 95% CI, 0.36-0.54; P < .001).

Under the Prescription Drug User Fee Act, the regulatory agency is slated to decide on the sNDA by August 13, 2023.¹

“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 press release.¹ “We believe the combination of trifluridine/tipiracil plus bevacizumab may represent a significant advance in the treatment of refractory disease, and we look forward to working with the FDA as it considers the application.”

The open-label, randomized, phase 3 SUNLIGHT study enrolled patients with histologically confirmed mCRC who had known RAS mutational status and an ECOG performance status of 0 or 1.² Patients must have received 2 previous regimens that must have included a fluoropyrimidine, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody, and/or an anti-EGFR monoclonal antibody for those with RAS wild-type disease. They also must have had disease progression or intolerance.

Study participants were randomly assigned 1:1 to receive TAS-102 at a twice daily dose of 35 mg/m² on days 1 to 5 and 8 to 12 every 28 days plus bevacizumab at 5 mg/kg on days 1 and 15 every 28 days or TAS-102 alone at the same dose and schedule.

Key stratification factors comprised geographic region (North America, European Union, or rest of the world), time since diagnosis of first metastasis (<18 vs ≥18 months), and RAS mutational status (wild-type vs mutation).

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

The median age across the arms was 63 years (range, 20-90), with more than half of patients in the investigative and control arms under 65 years (59% vs 52%). Moreover, most patients had left primary tumor localization (75% vs 69%), previous treatment with a VEGF inhibitor (76% vs 76%), previous treatment with bevacizumab (72% vs 72%), and an ECOG performance status of 1 (52% vs 57%).

Most patients were from the European Union (64% in both arms), followed by the rest of the world (33% in both), and North America (3% in both). For more than half of patients (58% vs 57%), it had been 18 or more months from their diagnosis of their first metastasis to randomization. Most patients (70% vs 69%) had RAS-mutated disease and the remainder (31% vs 31%) had wild-type disease.

Additional data presented at the 2023 Gastrointestinal Cancers Symposium showed that the 6-month OS rate with TAS-102 and bevacizumab was 77% vs 61% with TAS-102 alone; at 12 months, these rates were 43% and 30%, respectively. The 6-month PFS rate in the investigative arm was 43% vs 16% in the control arm; the 12-months PFS rates were 16% and 1%, respectively.

TAS-102 plus bevacizumab (n = 222) induced an ORR of 6.3% vs 0.9% with TAS-102 alone (n = 215) in patients evaluable for tumor response (difference, 5.4%; P = .004). The DCR achieved with the combination regimen was 76.6% vs 47.0% with the monotherapy (difference, 29.6%; P < .001).

The median time to deterioration in global health status was 8.5 months (range, 0.1-17.6) in the TAS-102/bevacizumab arm vs 4.7 months (range, 0.03-14.3) in the TAS-102–alone arm (HR, 0.50; 95% CI, 0.38-0.65; P < .001). Moreover, the time to worsening to an ECOG performance status of 2 or higher in the investigative and control arms was 9.2 months (range, 0.03-18.0) and 6.3 months (range, 0.03-16.1), respectively (HR, 0.54; 95% CI, 0.43-0.67; P < .001).

Regarding safety, any-grade adverse effects (AEs) were experienced by 98% of those who received TAS-102 and bevacizumab (n = 246) and 98% of those who received TAS-102 alone. Toxicities related to TAS-102 occurred in 90% and 81% of patients in the investigative and control arms, respectively; AEs linked with bevacizumab were observed in 48% of patients.

Grade 3 or higher AEs occurred in 72% of those who received the combination vs 70% of those who were administered the monotherapy. Serious toxicities were observed in 25% of those in the combination arm and 31% of those in the monotherapy arm.

The most common grade 3 or 4 treatment-emergent AEs occurring in 20% or more of participants in the combination and monotherapy arms, respectively, included neutropenia (43% vs 32%), nausea (2% vs 2%), anemia (6% vs 11%), asthenia (4% vs 4%), fatigue (1% vs 4%), diarrhea (1% vs 2%), and decreased appetite (1% vs 1%). One case of febrile neutropenia was reported with the combination vs 6 cases with TAS-102 alone.

Dose reductions were required by 16% of those who received TAS-102 and bevacizumab vs 12% of those given TAS-102 alone; delays occurred in 70% and 53% of patients, respectively. Thirteen percent of patients in both arms experienced toxicities that resulted in study withdrawal. No treatment-related deaths occurred.

“All of the efficacy parameters such as PFS, time to deterioration in global health status, and time to deterioration to an ECOG performance status of 2 or more were favorable for the combination arm [and were] statistically significant,” lead study author, Josep Tabernero, MD, PhD, said in an interview with OncLive^®. “[Bevacizumab plus TAS-102] also led to an increase in ORR and DCR. [Moreover,] the safety profile was very manageable.”

References

1. 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 April 18, 2023. https://www.taihooncology.com/us/news/
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