Trifluridine/tipiracil versus placebo for third or later lines of treatment in metastatic gastric cancer: an exploratory subgroup analysis from the TAGS study

Abstract

Background: Metastatic gastric cancer and cancer of the esophagogastric junction (GC/EGJ) is an aggressive disease with poor prognosis. In the TAGS study, trifluridine/tipiracil (FTD/TPI) improved overall survival (OS) compared with placebo in heavily pre-treated patients. This unplanned, exploratory subgroup analysis of the TAGS study aimed to clarify outcomes when FTD/TPI was used as third-line (3L) treatment and fourth-or later-line (4Lþ) treatment. Patients and methods: Patients were divided into a 3L group (126 and 64 in FTD/TPI and placebo arms, respectively) and 4Lþ group (211 and 106 in FTD/TPI and placebo arms, respectively). Endpoints included OS, progression-free survival (PFS), time to Eastern Cooperative Oncology Group performance status (ECOG PS) deterioration to !2, and safety. Results: Baseline characteristics were generally well balanced between FTD/TPI and placebo for 3L and 4Lþ treatment. Median OS (mOS) for FTD/TPI versus placebo was: 6.8 versus 3.2 months {hazard ratio (HR) [95% confidence interval (CI)] ¼ 0.68 (0.47-0.97), P ¼ 0.0318} in the 3L group; and 5.2 versus 3.7 months [0.73 (0.55-0.95), P ¼ 0.0192] in the 4Lþ group. Median PFS for FTD/TPI versus placebo was 3.1 versus 1.9 months [0.54 (0.38-0.77), P ¼ 0.0004] in the 3L group; and 1.9 versus 1.8 months [0.57 (0.44-0.74), P < 0.0001] in the 4Lþ group. Time to deterioration of ECOG PS to !2 for FTD/TPI versus placebo was 4.8 versus 2.0 months [HR (95% CI) ¼ 0.60 (0.42-0.86), P ¼ 0.0049] in the 3L group; and 4.0 versus 2.5 months [0.75 (0.57-0.98), P ¼ 0.0329] in the 4Lþ group. The safety of FTD/TPI was consistent in all subgroups. Conclusions: This analysis confirms the efficacy and safety of FTD/TPI in patients with GC/EGJ in third and later lines with a survival benefit that seems slightly superior in 3L treatment. When FTD/TPI is taken in 3L as recommended in the international guidelines, physicians can expect to provide patients with an mOS of 6.8 months.

Recent Trends and Advancements in the Diagnosis and Management of Gastric Cancer

“…A phase III trial “TAGS” [ 180 ] demonstrated an impressively prolonged mOS in the TAS-102 subgroup vs. placebo in AGC patients in the second-line and beyond setting. Furthermore, a subgroup analysis of the TAGS study investigated the efficacy of this treatment in patients using it as a third-line and fourth-line treatment and found statistically significant improvements in mOS and mPFS compared to placebo [ 181 ]. These promising results led to the approval of TAS-102 (trifluridine/tipiracil) as a third-line treatment option in AGC [ 182 ].…”

European-Australasian consensus on the management of advanced gastric and gastro-oesophageal junction cancer: current practice and new directions

“… 45 A subsequent post-hoc analysis by line of therapy (third or fourth line) showed numerically greater OS in third-line patients compared to fourth-line patients (median OS 6.8 versus 5.2 months, respectively), with similar corresponding OS HR: 0.68 ( p = 0.0318) compared with OS HR: 0.73 ( p = 0.0192). 46 The most frequent adverse events ⩾grade 3 were neutropenia (34%) and anaemia (19%) with trifluridine/tipiracil and abdominal pain (9%) and general deterioration of physical health (9%) with placebo. 44 The commonest lower grade (1–2) non-haematologic toxicity in the trifluridine/tipiracil arm included nausea (34%), reduced appetite (26%), vomiting (21%), diarrhoea (20%) and fatigue (20%), compared with 29%, 24%, 18%, 13% and 15% with placebo, respectively, highlighting the common frequency of disease symptoms in this disease in this setting.…”

“…45 A subsequent post-hoc analysis by line of therapy (third or fourth line) showed numerically greater OS in third-line patients compared to fourth-line patients (median OS 6.8 versus 5.2 months, respectively), with similar corresponding OS HR: 0.68 (p = 0.0318) compared with OS HR: 0.73 (p = 0.0192). 46 The most N Pavlakis, G Tincknell et al…”

The evolving strategies for the management of patients with metastatic gastric cancer: A narrative review and expert opinion

“…Further analyses reported a numerically higher efficacy of trifluridine/tipiracil in third line compared to the fourth one. The survival benefit in third line materializes in a median OS of 6.8 months (6.0 months for patients with peritoneal metastases), a median PFS of 3.1 months and in a median time to deterioration to a PS score ≥ 2 of 2.8 months ( 44 ). Taking in consideration that the fourth line is difficult to reach by mGC patients, these results confirm the key essential role of trifluridine/tipiracil in third-line setting and further support the updated guidelines for the use of the drug in patients with mGC ( 13 ).…”