Pooled safety analysis from phase III studies of trifluridine/tipiracil in patients with metastatic gastric or gastroesophageal junction cancer and metastatic colorectal cancer

Abstract

Background: Trifluridine/tipiracil (FTD/TPI) showed clinical benefit, including improved survival and manageable safety in previously treated patients with metastatic colorectal (mCRC) or gastric/gastroesophageal junction (mGC/GEJC) cancer in the phase III RECOURSE and TAGS trials, respectively. A pooled analysis was conducted to further characterize FTD/TPI safety, including management of haematologic toxicities and use in patients with renal or hepatic impairment.

Patients and methods: Adults with ≥2 prior regimens for advanced mGC/GEJC or mCRC were randomized (2 : 1) to FTD/TPI [35 mg/m² twice daily days 1-5 and 8-12 (28-day cycle); same dosage in both trials] or placebo plus best supportive care. Adverse events (AEs) were summarized in the safety population (patients who received ≥1 dose) and analysed by renal/hepatic function.

Results: TAGS and RECOURSE included 335 and 533 FTD/TPI-treated and 168 and 265 placebo-treated patients, respectively. Overall safety of FTD/TPI was similar in TAGS and RECOURSE. Haematologic (neutropenia, anaemia) and gastrointestinal (nausea, diarrhoea) AEs were most commonly observed. Laboratory-assessed grade 3-4 neutropenia occurred in 37% (TAGS)/38% (RECOURSE) of FTD/TPI-treated patients (median onset: 29 days/55 days), and 96% (TAGS)/97% (RECOURSE) of cases resolved regardless of renal/hepatic function. Supportive medications for neutropenia were received by 17% (TAGS) and 9% (RECOURSE); febrile neutropenia was reported in 2% and 4%, respectively. Overall grade ≥3 AEs were more frequent in patients with moderate renal impairment [81% (TAGS); 85% (RECOURSE)] versus normal renal function (74%; 67%); anaemia and neutropenia were more common in patients with renal impairment. FTD/TPI safety (including haematologic AEs) was consistent across patients with normal and mildly impaired hepatic function.

Conclusions: These results support FTD/TPI as a well-tolerated treatment in patients with mGC/GEJC or mCRC, with a consistent safety profile. Safety was largely similar in patients with normal or mildly impaired renal/hepatic function; however, patients with renal impairment should be monitored for haematologic toxicities.

Keywords: metastatic colorectal cancer; metastatic gastric cancer; neutropenia; renal impairment; safety; trifluridine/tipiracil.

Figure 1

Most common AEs of any cause in (A) TAGS and (B) RECOURSE. Haematologic AEs reported as combined preferred terms. All other AEs reported as preferred terms. AE, adverse event; FTD/TPI, trifluridine/tipiracil.

Figure 2

Time to onset and time to resolution of grade 3-4 chemotherapy-induced neutropenia in FTD/TPI-treated patients. (A) Median time to onset (range) is shown with the number of patients in each subpopulation with events. Time to onset was defined as days to first grade 3-4 neutropenia laboratory value that worsened from baseline by at least one grade. (B) Median time to resolution (range) is shown with the number of patients who recovered/number of patients with events for each subpopulation. Time to resolution was defined as recovery from first grade 3-4 neutropenia laboratory value that worsened from baseline by at least one grade; patients who recovered had at least one measurement recorded after the nadir that was grade <2 or the baseline grade or lower. All haematology measurements were carried out within 24 h before the start of study treatment from cycle 2 onwards and within 7 days before day 1 of cycle 1 or day 15 of cycle 1. In TAGS, two patients were not included in the analysis by renal function due to missing baseline data, and two patients were not included in the analysis by hepatic function due to moderate hepatic impairment at baseline. In RECOURSE, two patients were not included in the analysis by renal function due to missing baseline data; for the analysis by hepatic function, one patient was not included due to moderate hepatic impairment at baseline, and three patients were not included due to missing data at baseline. Renal function subgroups were defined as follows: normal renal function [creatinine clearance (CrCl) ≥90 ml/min], mild renal impairment (CrCl 60-89 ml/min), and moderate renal impairment (CrCl 30-59 ml/min). Hepatic function subgroups were defined as follows: normal hepatic function (total bilirubin and AST ≤ ULN) and mild impairment (total bilirubin between ULN and 1.5× ULN or AST > ULN). AST, aspartate transaminase; CrCl, creatinine clearance; FTD/TPI, trifluridine/tipiracil; HF, hepatic function; HI, hepatic impairment; RF, renal function; RI, renal impairment; ULN, upper limit of normal.

Figure 3

Incidences of haematologic AEs in FTD/TPI-treated patients by (A) renal function and (B) hepatic function. Haematologic AEs were reported as combined preferred terms. Renal function subgroups were defined as follows: normal renal function [creatinine clearance (CrCl) ≥90 ml/min], mild renal impairment (CrCl 60-89 ml/min), and moderate renal impairment (CrCl 30-59 ml/min). Hepatic function subgroups were defined as follows: normal hepatic function (total bilirubin and AST ≤ ULN) and mild impairment (total bilirubin between ULN and 1.5× ULN or AST > ULN). AE, adverse event; AST, aspartate transaminase; CrCl, creatinine clearance; FTD/TPI, trifluridine/tipiracil; HF, hepatic function; HI, hepatic impairment; RF, renal function; RI, renal impairment; ULN, upper limit of normal.