Gastric Cancer (2021) 24:970–977 https://doi.org/10.1007/s10120-021-01156-x SHORT COMMUNICATION Trifluridine/tipiracil in patients with metastatic gastroesophageal junction cancer: a subgroup analysis from the phase 3 TAGS study Wasat Mansoor1 · Hendrik‑Tobias Arkenau2 · Maria Alsina3 · Kohei Shitara4 · Peter Thuss‑Patience5 · Sinead Cuffe6 · Mikhail Dvorkin7 · David Park8 · Takayuki Ando9 · Marc Van Den Eynde10 · Giordano D. Beretta11 · Alberto Zaniboni12 · Toshihiko Doi4 · Josep Tabernero13 · David H. Ilson14 · Lukas Makris15 · Karim A. Benhadji16 · Eric Van Cutsem17 Received: 10 November 2020 / Accepted: 6 January 2021 / Published online: 13 March 2021 © The Author(s) 2021 Abstract 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 Patients 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 sub- groups. 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. Keywords Trifluridine/tipiracil · Gastroesophageal junction cancer · TAGS · Phase 3 · Subgroup analysis Introduction has been increasing over several decades, doubling in the United States from 16% in 1973 to 32% in 2013 [2, 3]. GEJC Gastroesophageal junction cancer (GEJC), though often is often diagnosed at a relatively late stage when the disease grouped under gastric cancer (GC) in clinical trial and reg- has become unresectable, and patients with advanced/meta- istries, has distinct clinical features, risk factors, and diag- static GEJC generally require multiple lines of therapy, as nosis and treatment challenges [1]. The incidence of GEJC recurrence is common [4]. In a real-world analysis of over 3000 patients with advanced GC/GEJC (43% with GEJC); median OS with This study was sponsored by Taiho Oncology, Inc., and Taiho first-line therapy, composed primarily of chemotherapy Pharmaceutical Co., Ltd. combinations, was 10.7 months and declined with each Supplementary Information The online version contains subsequent line of therapy (7.6–2.8 months) [5]. Additional supplementary material available at https​://doi.org/10.1007/s1012​ real-world data suggest that patients with GEJC may have 0-021-01156​-x. reduced landmark survival rates compared with GC at 6 (20 vs. 30%) and 12 months (11 vs. 16%) [6]. * Wasat Mansoor was.mansoor@nhs.net Trifluridine/tipiracil (FTD/TPI) is an oral therapy com- prising the thymidine analog trifluridine and tipiracil, which Extended author information available on the last page of the article 13 Vol:.(1234567890) Trifluridine/tipiracil in patients with metastatic gastroesophageal junction cancer: a… 971 prevents trifluridine degradation [7]. FTD/TPI received generally similar between the treatment groups, with some approval in the United States, Europe, and Japan for pre- exceptions in the GEJC subgroup. In this subgroup, patients viously treated metastatic GC/GEJC based on OS benefit randomized to FTD/TPI versus placebo were more heavily observed in the phase 3 TAGS (TAS-102 Gastric Study; pretreated (74 vs. 66% had received ≥ 3 prior regimens), and NCT02500043) [8, 9]. Here, we present data from a pre- a smaller proportion had undergone prior gastrectomy (40 planned subgroup analysis that was conducted to evaluate vs. 55%). the efficacy and safety of FTD/TPI in patients with GEJC. At data cutoff (31 March 2018), ≥ 94% of patients in both treatment arms in each tumor-type subgroup had discontin- ued treatment (Supplementary Table). The most common Materials and methods reason for discontinuation in both the GEJC and GC sub- groups was disease progression (78% of GEJC and 72% of TAGS, a global phase 3 randomized placebo-controlled clin- GC in FTD/TPI-treated arm; GEJC of 87% and 86% of GC ical trial, enrolled patients with non-resectable metastatic in placebo-treated arm). GC/GEJC who had received at least two previous chemo- In both the GEJC and GC subgroups, efficacy outcomes therapy regimens and had an Eastern Cooperative Oncol- were improved with FTD/TPI compared with placebo ogy Group performance status (ECOG PS) of 0 or 1. GEJ (Fig. 1). In the GEJC subgroup, OS and PFS HRs were 0.75 involvement was documented by endoscopic, radiologic, (95% CI 0.50–1.11) and 0.60 (95% CI 0.41–0.88), respec- surgical, or pathology report. tively. In the GC subgroup, OS and PFS HRs were 0.67 (95% Patients were randomized (2:1) to receive FTD/TPI CI 0.52–0.87) and 0.59 (95% CI 0.46–0.75). Median OS 35 mg/m2 or placebo, both twice daily with best support- in the FTD/TPI group was numerically lower in the GEJC ive care, on days 1–5 and 8–12 of each 28-day treatment than the GC subgroup (4.8 vs. 6.0 months). The HR for cycle. The primary endpoint was OS; secondary endpoints TTD of ECOG PS to ≥ 2 for FTD/TPI vs placebo was 0.68 included progression-free survival (PFS), time to deterio- (95% CI 0.46–1.01) in the GEJC subgroup and 0.71 (95% ration (TTD) of ECOG PS to ≥ 2, safety, and tolerability. CI 0.55–0.91) in the GC subgroup (Fig. 2). The protocol was approved by the institutional review board/ Grade ≥ 3 adverse events (AEs) of any cause with FTD/ independent ethics committee at each participating site. The TPI were reported in 75 (77%) and 192 (81%) patients in study was conducted in accordance with the Declaration of the GEJC and GC subgroups, respectively (Table 2). The Helsinki and Good Clinical Practice guidelines. All patients most frequently reported grade ≥ 3 AEs with FTD/TPI in provided written informed consent. Additional details about the GEJC group were neutropenia (25%) and anemia (13%); the conduct of this study have been reported previously [6]. incidences of these AEs in the GC subgroup were 38 and Although pre-planned, the subgroup analyses described 21%, respectively. In the GEJC subgroup, dosing modifica- in this report were not powered for statistical significance tions and discontinuations due to AEs of any cause with and are not intended to be used to compare results between FTD/TPI were 41 (42%) and 7 (7%), respectively, and in primary tumor locations with GEJC vs GC involvement. the GC subgroup, were 107 (45%) and 29 (12%). Treatment- Hazard ratios (HRs) and associated 95% confidence inter- related deaths were reported in 1 (< 1%) FTD/TPI-treated vals (CIs) for time-to-event endpoints were based on a strati- patient (attributed to cardiopulmonary arrest) and 1 (1%) fied Cox proportional hazards model; median values were placebo-treated patient (attributed to toxic hepatitis), both Kaplan–Meier estimates. in the GC subgroup. Results Discussion Of 507 patients enrolled in the TAGS trial, 145 (29%) and This subgroup analysis of the TAGS trial provides detailed 360 (71%) had a sole primary tumor location of GEJ or GC, efficacy and safety data in patients with metastatic GEJC respectively (2 patients had both gastric and GEJC tumors treated with FTD/TPI. The analysis demonstrated efficacy and were excluded from this analysis). Although baseline benefits with FTD/TPI in both the GEJC and GC subgroups. patient characteristics in these two subgroups were gener- In multivariate Cox regression analyses of OS in TAGS, ally similar, there were some notable differences (Table 1). which included stratification factors and primary tumor A higher proportion of patients in the GEJC than the GC site, primary tumor site (gastric or GEJ) was not identi- subgroup were male (85 vs. 68%), were White (83 vs. fied as being prognostic or predictive of OS with FTD/ 65%), had an ECOG PS of 1 (70 vs. 59%), or were more TPI treatment (Pinteraction = 0.29). In the current analysis, heavily pretreated (72 vs. 59% completing ≥ 3 prior regi- median OS with FTD/TPI was marginally lower in the mens). Within both subgroups, baseline characteristics were GEJC (4.8 months) than the GC subgroup (6.0 months), 13 972 W. Mansoor et al. Table 1  Baseline clinical and GEJCa GCa disease characteristics FTD/TPI Placebo FTD/TPI Placebo (n = 98) (n = 47) (n = 239) (n = 121) Age, years Mean 61 62 63.4 61.9 Median (range) 62.0 (24–89) 62.0 (42–80) 64 (27–86) 63 (32–82) Sex, n (%) Male 83 (85) 40 (85) 169 (71) 76 (63) Race, n (%) White 83 (85) 37 (79) 161 (67) 74 (61) Asian 6 (6) 4 (9) 45 (19) 25 (21) Black 0 0 1 (< 1) 2 (2) Not collected 8 (8) 4 (9) 30 (13) 20 (17) Other 1 (1) 2 (4) 2 (1) 0 ECOG PS, n (%) 0 28 (29) 15 (32) 95 (40) 53 (44) 1 70 (71) 32 (68) 144 (60) 68 (56) Geographic region, n (%) Japan 6 (6) 4 (9) 40 (17) 23 (19) USA 13 (13) 3 (6) 8 (3) 2 (2) EU 79 (81) 40 (85) 191 (80) 96 (79) Previous gastrectomy, n (%) Yes 39 (40) 26 (55) 108 (45) 156 (40) No 59 (60) 21 (45) 131 (55 73 (60) Prior radiotherapy, n (%) Yes 36 (37) 17 (36) 35 (15) 9 (7) No 62 (63) 30 (64) 204 (85) 112 (93) Number of metastatic sites, n (%) 1–2 50 (52) 25 (53) 105 (44) 47 (39) ≥3 48 (49) 22 (47) 134 (56) 74 (61) Number of prior regimens, n (%) 2 25 (26) 16 (34) 101 (42) 47 (39) 3 41 (42) 15 (32) 93 (39) 45 (37) ≥4 32 (33) 16 (34) 45 (19) 29 (24) EU Europe, FTD/TPI trifluridine/tipiracil, GEJC gastroesophageal junction cancer, GC gastric cancer, USA United States of America a Two patients had both gastric and GEJC tumors and were excluded from this analysis although OS was similar with placebo in both subgroups subgroups (5.7 months [95% CI 4.2–8.4) and 5.6 months (3.5 and 3.6 months). This could be attributed to patients in [3.8–7.2]) in the GC subgroups with pembrolizumab [10]. the GEJC subgroup overall being more heavily pretreated OS HRs for the GEJC and GC subgroups reported in other overall (72 vs. 58% of patients in the GC subgroup having phase 3 studies, such as KEYNOTE-061 (pembrolizumab received ≥ 3 previous lines of therapy), as well as differences vs paclitaxel; 0.61 [0.41–0.90] and 0.94 [0.71–1.23] for in the proportion of patients receiving ≥ 3 prior lines treat- GEJC and GC), ATT​RAC​TION-2 (nivolumab vs placebo; ment between FTD/TPI-treated (74%) and placebo-treated 0.44 [0.20–0.97] and 0.69 [0.55–0.87], respectively) and patients (66%) within the GEJC subgroup. RAINBOW (ramucirumab plus paclitaxel vs placebo To date, data in GEJC subgroups in trials of other plus paclitaxel; 0.52 [0.35–0.78] and 0.90 [0.70–1.10], anticancer agents have been limited to mostly HRs of respectively) each indicated a marginally greater death risk survival, with few studies reporting survival data. The reduction with the investigational regimen in the GEJC KEYNOTE-059 study, one of the few with survival subgroup than in the GC subgroup [11–13]. In contrast, data, reported similar median OS in the GEJC and GC earlier trials testing non-immune-related agents showed 13 Trifluridine/tipiracil in patients with metastatic gastroesophageal junction cancer: a… 973 Fig. 1  Efficacy outcomes in the GEJC and GC subgroups. a OS in the Eastern Cooperative Oncology Group performance status, GEJC: gas- GEJC subgroup. b OS in the GC subgroup. c PFS in the GEJC sub- troesophageal junction cancer, GC: gastric cancer, HR: hazard ratio, group. d PFS in the GC subgroup. CI: confidence interval, ECOG PS: PFS: progression-free survival, OS: overall survival trends towards better survival outcomes in the GC sub- inhibitors may demonstrate a clearer difference in survival group. For example, the ToGA trial in which the location outcomes predicated on the molecular differences of the of the primary cancer was stratified for reported OS HRs two anatomical sites [15]. for GEJC and GC for chemotherapy/ trastuzumab versus In the current sub-analysis, no new safety concerns were chemotherapy as 0.67 (95% CI 0.42–1.08) vs. 0.76 (95% noted with FTD/TPI in the GEJC subgroup, and the inci- CI 0.60–0.96), respectively [14]. Possible mechanism for dence of grade ≥ 3 hematologic AEs appeared to be lower why GEJC does better or worse than GC is difficult based than in the FTD/TPI-treated GC subgroup. Comparable on the current evidence base. Many earlier trials were not safety data have not been reported by these subgroups in stratified for the two anatomical sites, thus, making safe trials of other agents, including those mentioned above. comparative conclusions difficult. There are differences in The main limitation of the current analyses was that molecular characteristics between GEJC and GC as iden- although they were pre-planned, they were not powered for tified in the Cancer Genome Atlas (TGCA) which may statistical significance. This precluded a robust evaluation explain differences in responsiveness to cancer [14]. As of the efficacy and safety of FTD/TPI in the GEJC or GC discussed, studies testing the emerging immune checkpoint subgroups. 13 974 W. Mansoor et al. Fig. 2  Time to deterioration in the GEJC and GC subgroups. a Eastern Cooperative Oncology Group performance status, GEJC: gas- TTD of ECOG PS to ≥ 2 in the GEJC subgroup. b TTD of ECOG troesophageal junction cancer, GC: gastric cancer, HR: hazard ratio, PS to ≥ 2 in the GC subgroup. CIL: confidence interval, ECOG PS: TTD: time to deterioration 13 Trifluridine/tipiracil in patients with metastatic gastroesophageal junction cancer: a… 975 Table 2  Adverse events GEJC GC a a FTD/TPI (n = 97) Placebo (n = 46) FTD/TPI (n = 238)a Placebo (n = 120)a Any grade Grade ≥ 3 Any grade Grade ≥ 3 Any grade Grade ≥ 3 Any grade Grade ≥ 3 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Any AE of any cause 96 (99) 75 (77) 44 (96) 27 (59) 230 (97) 192 (81) 111 (93) 69 (58) Any treatment-related AE 73 (75) 40 (41) 23 (50) 2 (4) 198 (83) 136 (57) 71 (59) 19 (16) Action taken due to AEs of any cause Dosing modification (dosing delay or 52 (54) 41 (42) 11 (24) 9 (20) 143 (60) 107 (45) 25 (21) 19 (16) dose reduction) Treatment discontinuation 9 (9) 7 (7) 5 (11) 3 (7) 34 (14) 29 (12) 23 (20) 18 (15) AEs of any cause in ≥ 10% of patients Hematologic AEs Neutropeniab 41 (42) 24 (25) 0 0 135 (57) 90 (38) 7 (6) 0 Anemiac 36 (37) 13 (13) 6 (13) 2 (4) 114 (48) 51 (21) 25 (21) 10 (8) Leukopeniad 16 (17) 1 (1) 0 0 62 (26) 30 (13) 3 (3) 0 Thrombocytopeniae 12 (12) 1 (1) 0 0 48 (20) 10 (4) 8 (7) 0 Gastrointestinal AEs Nausea 43 (44) 5 (5) 13 (28) 1 (2) 81 (34) 5 (2) 40 (33) 4 (3) Vomiting 26 (27) 4 (4) 11 (24) 0 57 (24) 8 (3) 22 (18) 3 (3) Diarrhea 22 (23) 2 (2) 6 (13) 1 (2) 54 (23) 7 (3) 17 (14) 2 (2) Abdominal pain 19 (20) 4 (4) 10 (22) 7 (15) 36 (15) 10 (4) 21 (18) 8 (7) Ascites 4 (4) 1 (1) 0 0 15 (6) 11 (5) 16 (13) 11 (9) Constipation 27 (28) 3 (3) 12 (26) 2 (4) 18 (8) 1 (< 1) 13 (11) 2 (2) Dysphagia 15 (15) 5 (5) 4 (9) 3 (7) 5 (2) 2 (1) 3 (3) 1 (1) Other AEs Decreased appetite 28 (29) 5 (5) 15 (33) 2 (4) 87 (37) 24 (10) 36 (30) 9 (8) Fatigue 35 (36) 10 (10) 11 (24) 0 54 (23) 13 (6) 23 (19) 10 (8) Asthenia 18 (19) 4 (4) 8 (17) 1 (2) 47 (20) 12 (5) 32 (27) 10 (8) Back pain 8 (8) 1 (1) 5 (11) 3 (7) 17 (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) AE adverse event, FTD/TPI trifluridine/tipiracil, GEJC gastroesophageal junction cancer, GC gastric cancer a As treated population b Neutropenia and/or decreased neutrophil count c Anemia and/or decreased hemoglobin level d Leukopenia and/or decreased white blood cell count e Thrombocytopenia and/or decreased platelet count Conclusion Acknowledgements We thank the patients and families who made this trial possible and the clinical study teams who were involved in this trial, as well as the data and safety monitoring board members. 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Benhadji16 · Eric Van Cutsem17 1 5 The Christie NHS Foundation Trust, Manchester, UK Charité-Universitätsmedizin Berlin, Medizinische Klinik 2 M.S. Hämatologie, Onkologie Und Tumorimmunologie, Sarah Cannon Research Institute, Cancer Institute, University Berlin, Germany College London, London, UK 6 3 St. James’s Hospital, Dublin, Republic of Ireland Vall D, Institute of Oncology (VHIO), Hebron University 7 Hospital, Universitat Autònoma de Barcelona, Barcelona, Omsk Regional Clinical Centre of Oncology, Omsk, Spain Russian Federation 4 8 National Cancer Center Hospital East, Chiba, Japan St. Jude Crosson Cancer Institute/St, Joseph Heritage Healthcare, Fullerton, CA, USA 13 Trifluridine/tipiracil in patients with metastatic gastroesophageal junction cancer: a… 977 9 14 University of Toyama, Toyama, Japan Memorial Sloan Kettering Cancer Center, New York, NY, 10 USA UCL Cliniques Universitaires Saint-Luc, Brussels, Belgium 15 11 Stathmi, Inc, New Hope, PA, USA Humanitas Gavazzeni, Bergamo, Italy 16 12 Taiho Oncology, Inc, Princeton, NJ, USA Fondazione Poliambulanza–Istituto Ospedaliero, Brescia, 17 Italy University Hospitals Gasthuisberg Leuven and KU Leuven, 13 Leuven, Belgium Institute of Oncology (VHIO), Vall D’Hebron University Hospital, UVic-UCC, IOB-Quiron, Barcelona, Spain 13