Trifluridine/tipiracil in patients with metastatic gastroesophageal junction cancer: a subgroup analysis from the phase 3 TAGS study

Background Patients with advanced gastroesophageal junction cancer (GEJC) have poor survival outcomes, and GEJC-specific data from trials evaluating agents in gastric cancers (GCs) as a whole are lacking. Trifluridine/tipiracil (FTD/TPI) was approved for previously treated metastatic GC or GEJC (mGC/mGEJC) based on results of the phase 3 TAGS trial. Subgroup analyses by primary tumor type (GC or GEJC) in TAGS are reported here. Methods Pa tients with mGC/mGEJC treated with  ≥ 2 prior chemotherapy regimens were randomized (2:1) to receive FTD/TPI or placebo, plus best supportive care. A pre-planned sub-analysis was performed to evaluate efficacy and safety outcomes by primary tumor type (GEJC or GC). Results Of 507 randomized patients, 145 (29%) had GEJC and 360 (71%) had GC as the primary disease site. Baseline characteristics were generally similar between the GEJC and GC subgroups, except that more patients in the GEJC subgroup had received  ≥ 3 prior regimens (72 vs. 59% in the GC subgroup). Survival benefit with FTD/TPI was observed in both subgroups. The overall survival hazard ratio for FTD/TPI vs placebo was 0.75 (95% CI 0.50–1.11) and 0.67 (95% CI 0.52–0.87) in the GEJC and GC subgroups, respectively. Grade ≥ 3 adverse events of any cause were reported in 75 (77%) and 192 (81%) FTD/TPI-treated patients in the GEJC and GC subgroups, respectively. No new safety concerns were noted with FTD/TPI. Conclusion As in patients with GC, FTD/TPI showed an efficacy benefit in patients with GEJC in the TAGS trial, along with demonstrating a manageable safety profile. Supplementary Information The online version contains supplementary material available at 10.1007/s10120-021-01156-x.


Introduction
Gastroesophageal junction cancer (GEJC), though often grouped under gastric cancer (GC) in clinical trial and registries, has distinct clinical features, risk factors, and diagnosis and treatment challenges [1]. The incidence of GEJC has been increasing over several decades, doubling in the United States from 16% in 1973 to 32% in 2013 [2,3]. GEJC is often diagnosed at a relatively late stage when the disease has become unresectable, and patients with advanced/metastatic GEJC generally require multiple lines of therapy, as recurrence is common [4].
In a real-world analysis of over 3000 patients with advanced GC/GEJC (43% with GEJC); median OS with first-line therapy, composed primarily of chemotherapy combinations, was 10.7 months and declined with each subsequent line of therapy (7.6-2.8 months) [5]. Additional real-world data suggest that patients with GEJC may have reduced landmark survival rates compared with GC at 6 (20 vs. 30%) and 12 months (11 vs. 16%) [6].
Trifluridine/tipiracil (FTD/TPI) is an oral therapy comprising the thymidine analog trifluridine and tipiracil, which prevents trifluridine degradation [7]. FTD/TPI received approval in the United States, Europe, and Japan for previously treated metastatic GC/GEJC based on OS benefit observed in the phase 3 TAGS (TAS-102 Gastric Study; NCT02500043) [8,9]. Here, we present data from a preplanned subgroup analysis that was conducted to evaluate the efficacy and safety of FTD/TPI in patients with GEJC.

Materials and methods
TAGS, a global phase 3 randomized placebo-controlled clinical trial, enrolled patients with non-resectable metastatic GC/GEJC who had received at least two previous chemotherapy regimens and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. GEJ involvement was documented by endoscopic, radiologic, surgical, or pathology report.
Patients were randomized (2:1) to receive FTD/TPI 35 mg/m 2 or placebo, both twice daily with best supportive care, on days 1-5 and 8-12 of each 28-day treatment cycle. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), time to deterioration (TTD) of ECOG PS to ≥ 2, safety, and tolerability. The protocol was approved by the institutional review board/ independent ethics committee at each participating site. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent. Additional details about the conduct of this study have been reported previously [6].
Although pre-planned, the subgroup analyses described in this report were not powered for statistical significance and are not intended to be used to compare results between primary tumor locations with GEJC vs GC involvement. Hazard ratios (HRs) and associated 95% confidence intervals (CIs) for time-to-event endpoints were based on a stratified Cox proportional hazards model; median values were Kaplan-Meier estimates.

Results
Of 507 patients enrolled in the TAGS trial, 145 (29%) and 360 (71%) had a sole primary tumor location of GEJ or GC, respectively (2 patients had both gastric and GEJC tumors and were excluded from this analysis). Although baseline patient characteristics in these two subgroups were generally similar, there were some notable differences (Table 1). A higher proportion of patients in the GEJC than the GC subgroup were male (85 vs. 68%), were White (83 vs. 65%), had an ECOG PS of 1 (70 vs. 59%), or were more heavily pretreated (72 vs. 59% completing ≥ 3 prior regimens). Within both subgroups, baseline characteristics were generally similar between the treatment groups, with some exceptions in the GEJC subgroup. In this subgroup, patients randomized to FTD/TPI versus placebo were more heavily pretreated (74 vs. 66% had received ≥ 3 prior regimens), and a smaller proportion had undergone prior gastrectomy (40 vs. 55%).
At data cutoff (31 March 2018), ≥ 94% of patients in both treatment arms in each tumor-type subgroup had discontinued treatment (Supplementary Table). The most common reason for discontinuation in both the GEJC and GC subgroups was disease progression (78% of GEJC and 72% of GC in FTD/TPI-treated arm; GEJC of 87% and 86% of GC in placebo-treated arm).

Discussion
This subgroup analysis of the TAGS trial provides detailed efficacy and safety data in patients with metastatic GEJC treated with FTD/TPI. The analysis demonstrated efficacy benefits with FTD/TPI in both the GEJC and GC subgroups.
In multivariate Cox regression analyses of OS in TAGS, which included stratification factors and primary tumor site, primary tumor site (gastric or GEJ) was not identified as being prognostic or predictive of OS with FTD/ TPI treatment (P interaction = 0.29). In the current analysis, median OS with FTD/TPI was marginally lower in the GEJC (4.8 months) than the GC subgroup (6.0 months), although OS was similar with placebo in both subgroups (3.5 and 3.6 months). This could be attributed to patients in the GEJC subgroup overall being more heavily pretreated overall (72 vs. 58% of patients in the GC subgroup having received ≥ 3 previous lines of therapy), as well as differences in the proportion of patients receiving ≥ 3 prior lines treatment between FTD/TPI-treated (74%) and placebo-treated patients (66%) within the GEJC subgroup.
To date, data in GEJC subgroups in trials of other anticancer agents have been limited to mostly HRs of survival, with few studies reporting survival data. The KEYNOTE-059 study, one of the few with survival data, reported similar median OS in the GEJC and GC respectively) each indicated a marginally greater death risk reduction with the investigational regimen in the GEJC subgroup than in the GC subgroup [11][12][13]. In contrast, earlier trials testing non-immune-related agents showed  [14]. Possible mechanism for why GEJC does better or worse than GC is difficult based on the current evidence base. Many earlier trials were not stratified for the two anatomical sites, thus, making safe comparative conclusions difficult. There are differences in molecular characteristics between GEJC and GC as identified in the Cancer Genome Atlas (TGCA) which may explain differences in responsiveness to cancer [14]. As discussed, studies testing the emerging immune checkpoint inhibitors may demonstrate a clearer difference in survival outcomes predicated on the molecular differences of the two anatomical sites [15].
In the current sub-analysis, no new safety concerns were noted with FTD/TPI in the GEJC subgroup, and the incidence of grade ≥ 3 hematologic AEs appeared to be lower than in the FTD/TPI-treated GC subgroup. Comparable safety data have not been reported by these subgroups in trials of other agents, including those mentioned above.
The main limitation of the current analyses was that although they were pre-planned, they were not powered for statistical significance. This precluded a robust evaluation of the efficacy and safety of FTD/TPI in the GEJC or GC subgroups.

Conclusion
In summary, the results of this analysis indicate that FTD/ TPI is an effective treatment option with a manageable safety profile in patients with metastatic GEJC, similar to what was observed in GC. FTD/TPI resulted in an efficacy benefit in the GEJC subgroup despite patients in the FTD/TPI group being more heavily pretreated than in the placebo group.  (7) 1 (< 1) 6 (5) 1 (1) Dyspnea 12 (12) 5 (5) 5 (11) 1 (2) 12 (5) 1 (< 1) 12 (10) 5 (4) General physical health deterioration 9 (9) 8 (8) 4 (9) 4 (9) 14 (6) 14 (6) 12 (10) 10 (8) Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.