Trifluridine-tipiracil

A phase III double-blind study (RECOURSE [NCT01607957]) randomly assigned 800 patients with stage IV colorectal cancer whose cancer had been refractory to two previous therapies. Patients were required to have received 5-FU, oxaliplatin, irinotecan, bevacizumab and, if the patients had KRAS wild-type cancer, cetuximab or panitumumab. Patients were randomly assigned in a 2:1 ratio to receive best supportive care plus trifluridine-tipiracil (n = 534) or placebo (n = 266). The median age of patients was 63 years, and most patients (60%–63%) received four or more previous lines of therapy. All patients had formerly received a fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab, and 52% of them had received an EGFR inhibitor. Approximately 20% of the patients had received previous treatment with regorafenib.[53][Level of evidence A1]

A phase III double-blind study (RECOURSE [NCT01607957]) randomly assigned 800 patients with stage IV colorectal cancer whose cancer had been refractory to two previous therapies. Patients were required to have received 5-FU, oxaliplatin, irinotecan, bevacizumab and, if the patients had KRAS wild-type cancer, cetuximab or panitumumab. Patients were randomly assigned in a 2:1 ratio to receive best supportive care plus trifluridine-tipiracil (n = 534) or placebo (n = 266). The median age of patients was 63 years, and most patients (60%–63%) received four or more previous lines of therapy. All patients had formerly received a fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab, and 52% of them had received an EGFR inhibitor. Approximately 20% of the patients had received previous treatment with regorafenib.[53][Level of evidence A1]

Trifluridine-tipiracil was administered at 35 mg/m2 twice daily with meals for 5 days, with 2 days of rest for 2 weeks, followed by a 14-day rest period.

A phase III double-blind study (RECOURSE [NCT01607957]) randomly assigned 800 patients with stage IV colorectal cancer whose cancer had been refractory to two previous therapies. Patients were required to have received 5-FU, oxaliplatin, irinotecan, bevacizumab and, if the patients had KRAS wild-type cancer, cetuximab or panitumumab. Patients were randomly assigned in a 2:1 ratio to receive best supportive care plus trifluridine-tipiracil (n = 534) or placebo (n = 266). The median age of patients was 63 years, and most patients (60%–63%) received four or more previous lines of therapy. All patients had formerly received a fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab, and 52% of them had received an EGFR inhibitor. Approximately 20% of the patients had received previous treatment with regorafenib.[53][Level of evidence A1]

The primary end point of the study was OS. The median OS for patients with metastatic colorectal cancer who received trifluridine-tipiracil was 7.1 months compared with 5.3 months for those who received a placebo (HR, 0.68; P < .0001).

A phase III double-blind study (RECOURSE [NCT01607957]) randomly assigned 800 patients with stage IV colorectal cancer whose cancer had been refractory to two previous therapies. Patients were required to have received 5-FU, oxaliplatin, irinotecan, bevacizumab and, if the patients had KRAS wild-type cancer, cetuximab or panitumumab. Patients were randomly assigned in a 2:1 ratio to receive best supportive care plus trifluridine-tipiracil (n = 534) or placebo (n = 266). The median age of patients was 63 years, and most patients (60%–63%) received four or more previous lines of therapy. All patients had formerly received a fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab, and 52% of them had received an EGFR inhibitor. Approximately 20% of the patients had received previous treatment with regorafenib.[53][Level of evidence A1]

The median PFS in the trifluridine-tipiracil arm was 2 months versus 1.7 months with a placebo (HR, 0.48; P < .0001).

A phase III double-blind study (RECOURSE [NCT01607957]) randomly assigned 800 patients with stage IV colorectal cancer whose cancer had been refractory to two previous therapies. Patients were required to have received 5-FU, oxaliplatin, irinotecan, bevacizumab and, if the patients had KRAS wild-type cancer, cetuximab or panitumumab. Patients were randomly assigned in a 2:1 ratio to receive best supportive care plus trifluridine-tipiracil (n = 534) or placebo (n = 266). The median age of patients was 63 years, and most patients (60%–63%) received four or more previous lines of therapy. All patients had formerly received a fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab, and 52% of them had received an EGFR inhibitor. Approximately 20% of the patients had received previous treatment with regorafenib.[53][Level of evidence A1]

Secondary end points focused on PFS, overall response rate, and disease control rate.

A phase III double-blind study (RECOURSE [NCT01607957]) randomly assigned 800 patients with stage IV colorectal cancer whose cancer had been refractory to two previous therapies. Patients were required to have received 5-FU, oxaliplatin, irinotecan, bevacizumab and, if the patients had KRAS wild-type cancer, cetuximab or panitumumab. Patients were randomly assigned in a 2:1 ratio to receive best supportive care plus trifluridine-tipiracil (n = 534) or placebo (n = 266). The median age of patients was 63 years, and most patients (60%–63%) received four or more previous lines of therapy. All patients had formerly received a fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab, and 52% of them had received an EGFR inhibitor. Approximately 20% of the patients had received previous treatment with regorafenib.[53][Level of evidence A1]

The overall response rate was 1.6% with trifluridine-tipiracil, which consisted of a complete response in one patient and partial responses in other patients. The overall response rate with a placebo was 0.4% (P = .29).

A phase III, international, multi-institutional trial (SUNLIGHT [NCT04737187]) included 492 patients with stage IV colorectal cancer whose cancer was refractory to up to two prior chemotherapy regimens. Patients were required to have received 5-FU, oxaliplatin, irinotecan, an anti-VEGF monoclonal antibody, or an anti-EGFR monoclonal antibody (for patients with RAS wild-type disease). Patients were randomly assigned 1:1 to receive either trifluridine-tipiracil monotherapy (n = 246) or trifluridine-tipiracil combined with bevacizumab (n = 246). The median patient age was 62 years for the combination arm, and 64 years for the monotherapy arm, and most patients (93% and 91%, respectively) had received two prior lines of therapy. More than 98% of patients in both arms had received 5-FU, irinotecan, and oxaliplatin, and more than 93% of patients with RAS wild-type variants in both arms had received anti-EGFR monoclonal antibody therapy. The median follow-up was 14.2 months. Trifluridine-tipiracil was given at 35 mg/m2 twice daily on days 1 to 5 and 8 to 12 of a 28-day cycle. Bevacizumab was given on days 1 and 15 of each cycle at 5 mg/kg. The primary end point of the study was OS.[54]

A phase III, international, multi-institutional trial (SUNLIGHT [NCT04737187]) included 492 patients with stage IV colorectal cancer whose cancer was refractory to up to two prior chemotherapy regimens. Patients were required to have received 5-FU, oxaliplatin, irinotecan, an anti-VEGF monoclonal antibody, or an anti-EGFR monoclonal antibody (for patients with RAS wild-type disease). Patients were randomly assigned 1:1 to receive either trifluridine-tipiracil monotherapy (n = 246) or trifluridine-tipiracil combined with bevacizumab (n = 246). The median patient age was 62 years for the combination arm, and 64 years for the monotherapy arm, and most patients (93% and 91%, respectively) had received two prior lines of therapy. More than 98% of patients in both arms had received 5-FU, irinotecan, and oxaliplatin, and more than 93% of patients with RAS wild-type variants in both arms had received anti-EGFR monoclonal antibody therapy. The median follow-up was 14.2 months. Trifluridine-tipiracil was given at 35 mg/m2 twice daily on days 1 to 5 and 8 to 12 of a 28-day cycle. Bevacizumab was given on days 1 and 15 of each cycle at 5 mg/kg. The primary end point of the study was OS.[54]

The median OS was 10.8 months for patients who received trifluridine-tipiracil and bevacizumab and 7.5 months for patients who received trifluridine-tipiracil monotherapy (HR, 0.61; 95% CI, 0.49–0.77; P < .001).[54][Level of evidence A1]

A phase III, international, multi-institutional trial (SUNLIGHT [NCT04737187]) included 492 patients with stage IV colorectal cancer whose cancer was refractory to up to two prior chemotherapy regimens. Patients were required to have received 5-FU, oxaliplatin, irinotecan, an anti-VEGF monoclonal antibody, or an anti-EGFR monoclonal antibody (for patients with RAS wild-type disease). Patients were randomly assigned 1:1 to receive either trifluridine-tipiracil monotherapy (n = 246) or trifluridine-tipiracil combined with bevacizumab (n = 246). The median patient age was 62 years for the combination arm, and 64 years for the monotherapy arm, and most patients (93% and 91%, respectively) had received two prior lines of therapy. More than 98% of patients in both arms had received 5-FU, irinotecan, and oxaliplatin, and more than 93% of patients with RAS wild-type variants in both arms had received anti-EGFR monoclonal antibody therapy. The median follow-up was 14.2 months. Trifluridine-tipiracil was given at 35 mg/m2 twice daily on days 1 to 5 and 8 to 12 of a 28-day cycle. Bevacizumab was given on days 1 and 15 of each cycle at 5 mg/kg. The primary end point of the study was OS.[54]

OS was significant across subgroups, including patients with RAS variants and wild-type variants, patients with microsatellite instability-high (MSI-H) and microsatellite stability cancers, and both for patients previously treated with bevacizumab and bevacizumab-naïve patients.

A phase III, international, multi-institutional trial (SUNLIGHT [NCT04737187]) included 492 patients with stage IV colorectal cancer whose cancer was refractory to up to two prior chemotherapy regimens. Patients were required to have received 5-FU, oxaliplatin, irinotecan, an anti-VEGF monoclonal antibody, or an anti-EGFR monoclonal antibody (for patients with RAS wild-type disease). Patients were randomly assigned 1:1 to receive either trifluridine-tipiracil monotherapy (n = 246) or trifluridine-tipiracil combined with bevacizumab (n = 246). The median patient age was 62 years for the combination arm, and 64 years for the monotherapy arm, and most patients (93% and 91%, respectively) had received two prior lines of therapy. More than 98% of patients in both arms had received 5-FU, irinotecan, and oxaliplatin, and more than 93% of patients with RAS wild-type variants in both arms had received anti-EGFR monoclonal antibody therapy. The median follow-up was 14.2 months. Trifluridine-tipiracil was given at 35 mg/m2 twice daily on days 1 to 5 and 8 to 12 of a 28-day cycle. Bevacizumab was given on days 1 and 15 of each cycle at 5 mg/kg. The primary end point of the study was OS.[54]

The median PFS was 5.6 months in the combination arm and 2.4 months in the trifluridine-tipiracil monotherapy arm (HR, 0.44; 95% CI, 0.36–0.54; P < .001).

A phase III, international, multi-institutional trial (SUNLIGHT [NCT04737187]) included 492 patients with stage IV colorectal cancer whose cancer was refractory to up to two prior chemotherapy regimens. Patients were required to have received 5-FU, oxaliplatin, irinotecan, an anti-VEGF monoclonal antibody, or an anti-EGFR monoclonal antibody (for patients with RAS wild-type disease). Patients were randomly assigned 1:1 to receive either trifluridine-tipiracil monotherapy (n = 246) or trifluridine-tipiracil combined with bevacizumab (n = 246). The median patient age was 62 years for the combination arm, and 64 years for the monotherapy arm, and most patients (93% and 91%, respectively) had received two prior lines of therapy. More than 98% of patients in both arms had received 5-FU, irinotecan, and oxaliplatin, and more than 93% of patients with RAS wild-type variants in both arms had received anti-EGFR monoclonal antibody therapy. The median follow-up was 14.2 months. Trifluridine-tipiracil was given at 35 mg/m2 twice daily on days 1 to 5 and 8 to 12 of a 28-day cycle. Bevacizumab was given on days 1 and 15 of each cycle at 5 mg/kg. The primary end point of the study was OS.[54]

Secondary end points focused on PFS, overall response rate, and safety.

A phase III, international, multi-institutional trial (SUNLIGHT [NCT04737187]) included 492 patients with stage IV colorectal cancer whose cancer was refractory to up to two prior chemotherapy regimens. Patients were required to have received 5-FU, oxaliplatin, irinotecan, an anti-VEGF monoclonal antibody, or an anti-EGFR monoclonal antibody (for patients with RAS wild-type disease). Patients were randomly assigned 1:1 to receive either trifluridine-tipiracil monotherapy (n = 246) or trifluridine-tipiracil combined with bevacizumab (n = 246). The median patient age was 62 years for the combination arm, and 64 years for the monotherapy arm, and most patients (93% and 91%, respectively) had received two prior lines of therapy. More than 98% of patients in both arms had received 5-FU, irinotecan, and oxaliplatin, and more than 93% of patients with RAS wild-type variants in both arms had received anti-EGFR monoclonal antibody therapy. The median follow-up was 14.2 months. Trifluridine-tipiracil was given at 35 mg/m2 twice daily on days 1 to 5 and 8 to 12 of a 28-day cycle. Bevacizumab was given on days 1 and 15 of each cycle at 5 mg/kg. The primary end point of the study was OS.[54]

The overall response rate was 6.1% for the combination arm and 1.2% for the monotherapy arm.

A phase III, international, multi-institutional trial (SUNLIGHT [NCT04737187]) included 492 patients with stage IV colorectal cancer whose cancer was refractory to up to two prior chemotherapy regimens. Patients were required to have received 5-FU, oxaliplatin, irinotecan, an anti-VEGF monoclonal antibody, or an anti-EGFR monoclonal antibody (for patients with RAS wild-type disease). Patients were randomly assigned 1:1 to receive either trifluridine-tipiracil monotherapy (n = 246) or trifluridine-tipiracil combined with bevacizumab (n = 246). The median patient age was 62 years for the combination arm, and 64 years for the monotherapy arm, and most patients (93% and 91%, respectively) had received two prior lines of therapy. More than 98% of patients in both arms had received 5-FU, irinotecan, and oxaliplatin, and more than 93% of patients with RAS wild-type variants in both arms had received anti-EGFR monoclonal antibody therapy. The median follow-up was 14.2 months. Trifluridine-tipiracil was given at 35 mg/m2 twice daily on days 1 to 5 and 8 to 12 of a 28-day cycle. Bevacizumab was given on days 1 and 15 of each cycle at 5 mg/kg. The primary end point of the study was OS.[54]

Adverse events leading to therapy discontinuation were observed in 12.6% of patients in both arms. Dose reductions occurred in 16.3% of patients in the combination group and 12.2% of patients in the trifluridine-tipiracil monotherapy group. The most common adverse event was neutropenia, with grade 3 or 4 neutropenia observed in 43% of patients in the combination arm and 32% of patients in the monotherapy arm.