Research JAMA Oncology | Original Investigation Efficacy and Safety of Trifluridine/Tipiracil Treatment in Patients With Metastatic Gastric Cancer Who Had Undergone Gastrectomy Subgroup Analyses of a Randomized Clinical Trial David H. Ilson, MD, PhD; Josep Tabernero, MD, PhD; Aliaksandr Prokharau, MD; Hendrik-Tobias Arkenau, MD, PhD; Michele Ghidini, MD, PhD; Kazumasa Fujitani, MD; Eric Van Cutsem, MD, PhD; Peter Thuss-Patience, MD; Giordano D. Beretta, MD; Wasat Mansoor, PhD; Edvard Zhavrid, MD; Maria Alsina, MD; Ben George, MD; Daniel Catenacci, MD; Sandra McGuigan, MD; Lukas Makris, PhD; Toshihiko Doi, MD; Kohei Shitara, MD Supplemental content IMPORTANCE Trifluridine/tipiracil (FTD/TPI) treatment has shown clinical benefit in patients with pretreated metastatic gastric cancer or gastroesophageal junction cancer (mGC/GEJC). Patients who have undergone gastrectomy constitute a significant proportion of patients with mGC/GEJC. OBJECTIVE To assess the efficacy and safety of FTD/TPI among patients with previously treated mGC/GEJC who had or had not undergone gastrectomy. DESIGN, SETTING, AND PARTICIPANTS This preplanned subgroup analysis of TAGS (TAS-102 Gastric Study), a phase 3, randomized, placebo-controlled, clinical trial included patients with mGC/GEJC who had received at least 2 previous chemotherapy regimens, and was conducted at 110 academic hospitals in 17 countries in Europe, Asia, and North America, with enrollment between February 24, 2016, and January 5, 2018; the data cutoff was March 31, 2018. INTERVENTIONS Patients were randomized 2:1 to receive oral FTD/TPI 35 mg/m2 twice daily or placebo twice daily with best supportive care on days 1 through 5 and days 8 through 12 of each 28-day treatment cycle. MAIN OUTCOMES AND MEASURES The primary end point was overall survival. This subgroup analysis was conducted to examine potential trends and was not powered for statistical significance. Efficacy and safety end points were evaluated in the subgroups. RESULTS Of 507 randomized patients (369 [72.8%] male; mean [SD] age, 62.5 [10.5] years), 221 (43.6%) had undergone gastrectomy (147 randomized to FTD/TPI and 74 to placebo) and 286 (56.4%) had not undergone gastrectomy (190 randomized to FTD/TPI and 96 to placebo). In the gastrectomy subgroup, the overall survival hazard ratio (HR) in the FTD/TPI group vs placebo group was 0.57 (95% CI, 0.41-0.79), and the progression-free survival HR was 0.48 (95% CI, 0.35-0.65). In the no gastrectomy subgroup, the overall survival HR in the FTD/TPI group vs placebo group was 0.80 (95% CI, 0.60-1.06), and the progression-free survival HR was 0.65 (95% CI, 0.49-0.85). Among FTD/TPI-treated patients, grade 3 or higher adverse events of any cause occurred in 122 of 145 patients (84.1%) in the gastrectomy subgroup and 145 of 190 (76.3%) in the no gastrectomy subgroup: 64 (44.1%) in the gastrectomy subgroup and 50 (26.3%) in the no gastrectomy subgroup had grade 3 or higher neutropenia, 31 (21.4%) in the gastrectomy subgroup and 33 (17.4%) in the no gastrectomy subgroup had grade 3 or higher anemia, and 21 (14.5%) in the gastrectomy subgroup and 10 (5.3%) in the no gastrectomy subgroup hD grade 3 or higher leukopenia. In the gastrectomy subgroup, 94 (64.8%) had dosing modifications because of adverse events vs 101 (53.2%) in the no gastrectomy subgroup; 15 (10.3%) in the gastrectomy group and 28 (14.7%) in the no gastrectomy group discontinued treatment because of adverse events. Treatment exposure was similar between groups. Author Affiliations: Author CONCLUSIONS AND RELEVANCE The FTD/TPI treatment was tolerable and provided efficacy affiliations are listed at the end of this benefits among patients with pretreated mGC/GEJC regardless of previous gastrectomy. article. Corresponding Author: David H. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02500043 Ilson, MD, PhD, Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E 66th St, Breast JAMA Oncol. 2020;6(1):e193531. doi:10.1001/jamaoncol.2019.3531 and Imaging Center 1031, New York, Published online October 10, 2019. NY 10065 (ilsond@mskcc.org). (Reprinted) 1/10 Downloaded From: https://jamanetwork.com/ on 01/30/2023 Research Original Investigation Efficacy and Safety of Trifluridine/Tipiracil in Patients With Metastatic Gastric Cancer and Gastrectomy S urvival outcomes are poor for patients with metastatic gastric cancer or gastroesophageal junction cancer (mGC/ Key Points GEJC), with a median survival time of 3 to 5 months with- Question Is trifluridine/tipiracil treatment safe and effective for out chemotherapy.1,2 Chemotherapy extends median overall the subpopulation of patients with previously treated metastatic survival (OS) by nearly 7 months,2,3 but ultimately the dis- gastric or gastroesophageal junction cancer who have undergone ease becomes refractory to chemotherapy, and all patients ex- gastrectomy? perience disease progression after first-line treatment.4-6 Du- Findings In this subgroup analysis of a randomized clinical trial, ration of response to second-line treatment is short,4-6 and trifluridine/tipiracil treatment improved overall survival and there are few options for third- and later-line therapy. progression-free survival compared with placebo among patients Nearly half of all patients with mGC/GEJC have undergone with previously treated metastatic gastric or gastroesophageal gastrectomy.7-11 Patients who have undergone gastrectomy tend junction cancer and who had or had not undergone gastrectomy. to be a more compromised patient subpopulation than those who No new safety concerns were reported, and hematologic toxic effects were more frequent among the subgroup who had have not undergone gastrectomy because the malnutrition as- undergone gastrectomy but were treated using dosing sociated with gastrectomy can delay recovery and potentially ren- modifications. der these patients more susceptible to adverse events (AEs). In addition, many patients who have undergone gastrectomy Meaning Trifluridine/tipiracil is a safe and effective treatment option for patients with pretreated metastatic gastric or have received adjuvant chemotherapy or radiotherapy.12-14 Being gastroesophageal junction cancer regardless of previous heavily pretreated, these patients have poorer chemotherapy gastrectomy. tolerance.15,16 However, studies13,16-23 that have evaluated the safety and efficacy of oral chemotherapy in this subpopulation have primarily involved adjuvant therapy, and few studies7,10,15 ducted at 110 academic hospitals in 17 countries in Europe, Asia, have examined patients with metastatic disease. and North America between February 24, 2016, and January Trifluridine/tipiracil (FTD/TPI), also known by the investiga- 5, 2018; the data cutoff was March 31, 2018.8 Eligible patients tional drug name TAS-102, is an oral therapy comprising the thy- had mGC/GEJC, had an Eastern Cooperative Oncology Group midine analogue trifluridine and the thymidine phosphorylase (ECOG) performance status of 0 or 1, had received at least 2 inhibitor tipiracil, which inhibits trifluridine degradation.24,25 In treatment regimens for advanced disease, and were refrac- 2015, FTD/TPI was approved for the treatment of refractory meta- tory to or were unable to tolerate the most recent therapy. Pa- static colorectal cancer at a dosage of 35 mg/m2 twice daily.26,27 tients were randomized (2:1) to receive either oral FTD/TPI 35 In a phase 2 Japanese study (EPOC1201),28 FTD/TPI showed mg/m2 twice daily plus best supportive care or placebo twice activity and tolerability among patients with previously treated daily plus best supportive care administered on days 1 through mGC/GEJC. Although the sample sizes were small, no differ- 5 and days 8 through 12 of each 28-day treatment cycle. Treat- ences were observed in the pharmacokinetics of either FTD or ment continued until disease progression, intolerability, pa- TPI at the approved dose between patients who had or had not tient withdrawal, or completion of the primary end point analy- undergone gastrectomy.28 sis, whichever occurred first. Before patient enrollment, the Based on these phase 2 results,28 FTD/TPI was evaluated in protocol was approved by the institutional review board or in- a global, randomized, double-blind, placebo-controlled phase dependent ethnics committee at each participating site8 3 clinical trial (TAS-102 Gastric Study [TAGS]) of 507 patients with (eTable 1 in Supplement 2). The study was conducted in ac- mGC/GEJC after disease progression following at least 2 standard cordance with the Declaration of Helsinki30 and Good Clini- chemotherapy regimens.8,29 Compared with placebo, FTD/TPI cal Practice guidelines, as specified by the International Con- significantly improved OS, the primary end point (hazard ratio ference on Harmonization.31 All patients provided written [HR], 0.69; 95% CI, 0.56-0.85; P < .001) and progression-free sur- informed consent. vival (PFS) (HR, 0.57; 95% CI, 0.47-0.70; P < .001).8 In the FTD/ The primary objective of the study was OS; secondary ob- TPI group, grade 3 or higher AEs occurred in 80% of patients and jectives included PFS, safety, and tolerability. Other end points were most frequently hematologic (neutropenia in 34% of pa- were time to deterioration of ECOG performance status to 2 tients and anemia in 19%); 13% discontinued treatment because or more, objective response rate, and disease control rate. of AEs. These findings supported the approval of FTD/TPI in the United States in 2019 for patients with mGC/GEJC previously Gastrectomy Subgroup Analysis treated with at least 2 lines of chemotherapy.27 We present the In this preplanned subgroup analysis, the efficacy and safety results of a preplanned subgroup analysis in the phase 3 TAGS of FTD/TPI vs placebo were evaluated among patients who had trial evaluating FTD/TPI treatment in patients with mGC/GEJC or had not undergone gastrectomy. All patients included in the who had or had not undergone gastrectomy. intention-to-treat assessment of the TAGS study were in- cluded in the efficacy assessments, and all patients who re- ceived 1 or more doses of study drug (as-treated population) were included in the safety assessments. Although planned, Methods these subanalyses were not powered for statistical signifi- Study, Design, and Participants cance, and no formal comparisons of efficacy and safety were This study was a subgroup analysis of the TAGS trial, a global, made between the gastrectomy and no gastrectomy randomized, placebo-controlled phase 3 clinical trial con- subgroups. 2/10 JAMA Oncology January 2020 Volume 6, Number 1 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ on 01/30/2023 Efficacy and Safety of Trifluridine/Tipiracil in Patients With Metastatic Gastric Cancer and Gastrectomy Original Investigation Research Statistical Analysis not undergone gastrectomy (eTable 2 in Supplement 2), al- For the overall study, 384 events were targeted to allow the de- though the proportions of some measures differed by more tection of an HR for death of 0.70, with 90% power at a 1-sided than 10% between the gastrectomy vs no gastrectomy sub- type I error of 0.025. Detailed statistical considerations for the groups. These measures that differed between the gastrec- phase 3 trial have been reported previously.8 tomy and no gastrectomy subgroups were: at least 3 sites of Detailed end point definitions are presented in the trial pro- metastatic disease (94 of 221 [42.5%] vs 186 of 286 [65.0%]), tocol in Supplement 1 and the eMethods in Supplement 2. For previous radiotherapy (57 of 221 [25.8%] vs 40 of 286 [14.0%]), the time-to-event end points, HRs with associated 95% CIs but and at least 3 previous regimens (166 of 221 [75.1%] vs 151 of not P values are presented for the subgroup analyses based on 286 [52.8%]). In addition, in the gastrectomy subgroup, a higher a stratified Cox proportional hazards model, along with Kaplan- proportion of patients in the FTD/TPI group had received ra- Meier estimates of the medians and specific time points. In the diotherapy (44 of 147 patients; 29.9%) compared with the pla- overall study analysis, previous gastrectomy was included as cebo group (13 of 74 patients; 17.6%), but in the no gastrec- a factor in a prespecified multivariate subgroup analysis for the tomy subgroup, the corresponding proportions of patients were primary end point of OS. All the subgroups used for the mul- similar in each treatment group (gastrectomy subgroup: 27 of tivariate analysis were prespecified, but a multiplicity com- 190 patients [14.2%] vs no gastrectomy subgroup: 13 of 96 parison adjustment method was not used because of the num- [13.5%]). More patients in the gastrectomy subgroup re- ber of subgroups. Subgroup analyses were conducted to ceived 1 to 2 neoadjuvant or adjuvant treatment regimens examine potential trends or estimations and not for inferen- (116 of 221 [52.5%]) than those in the no gastrectomy sub- tial purposes. The incidence of AEs was presented by sub- group (4 of 286 [1.4%]), but similar proportions of patients in group; events of interest (such as hematologic toxic events) the 2 subgroups had received at least 3 treatment regimens for were compared in patients treated with FTD/TPI in the 2 sub- metastatic cancer (gastrectomy subgroup: 113 of 221 patients groups using estimated relative risk (RR) and associated 95% [51.1%] vs no gastrectomy subgroup: 147 of 286 patients CIs. All statistical analyses were conducted using SAS statis- [51.4%]). tical software, version 9.4 (SAS Institute Inc). Efficacy As previously reported, FTD/TPI significantly improved OS and PFS compared with placebo in the overall patient population.8 Results In the OS subgroup analyses, FTD/TPI was more efficacious Patient Disposition and Demographics than placebo across most prespecified subgroups, including Between February 24, 2016, and January 5, 2018, 507 pa- patients who had undergone gastrectomy (Figure 2).8 tients (369 [72.8%] male; mean [SD] age, 62.5 [10.5] years) were Overall survival and PFS were improved with FTD/TPI enrolled and randomized (intent-to-treat population), with 337 treatment in patients in both gastrectomy subgroups (Figure 3 patients randomized to the FTD/TPI group and 170 to the pla- and Table 1). Among patients who had undergone gastrec- cebo group. A total of 503 patients received at least 1 study drug tomy, in the FTD/TPI vs placebo groups, the OS HR was 0.57 dose (as-treated population).8 (95% CI, 0.41-0.79), and the PFS HR was 0.48 (95% CI, 0.35- Previous gastrectomy had been performed in 147 of 337 pa- 0.65) (Figure 3A and C). Among patients who had not under- tients (43.6%) in the FTD/TPI group and 74 of 170 patients gone gastrectomy, in the FTD/TPI vs placebo groups, the OS (43.5%) in the placebo group. Of the 221 patients with previ- HR was 0.80 (95% CI, 0.60-1.06), and the PFS HR was 0.65 (95% ous gastrectomy, 153 (69.2%) had undergone total resection CI, 0.49-0.85) (Figure 3B and D). Additional efficacy data are and 56 (25.3%) had undergone partial resection; resection sta- provided in Table 1. tus was unknown for 12 patients (5.4%). Patient disposition was In both gastrectomy subgroups, ECOG performance sta- similar between patients who had or had not undergone gas- tus was maintained longer with FTD/TPI treatment com- trectomy. At the data cutoff of March 31, 2018, among FTD/ pared with placebo (eFigure in Supplement 2). For the me- TPI-treated patients, 137 of 145 patients (94.5%) who had un- dian time to deterioration of ECOG performance status to 2 or dergone gastrectomy and 179 of 190 patients (94.2%) who had higher in the FTD/TPI group vs placebo group, the HR was 0.63 not undergone gastrectomy had discontinued treatment (95% CI, 0.46-0.87) in the gastrectomy subgroup and 0.74 (95% (Figure 1). Among placebo-treated patients, 73 (100%) who had CI, 0.56-0.98) in the no gastrectomy subgroup. undergone gastrectomy and 92 of 95 patients (96.8%) who had not undergone gastrectomy had discontinued treatment. Dis- Safety ease progression was the most common reason among pa- The overall frequencies of any-cause AEs at grade 3 or higher tients treated with FTD/TPI who discontinued (107 of 137 pa- with FTD/TPI treatment were similar among patients in the gas- tients [78.1%] in the gastrectomy subgroup and 139 of 179 trectomy subgroup (84.1% [122 of 145]) and those in the no gas- [77.6%] in the no gastrectomy subgroup) and among patients trectomy subgroup (76.3% [145 of 190]) (Table 2). Among pa- treated with placebo who discontinued (62 of 73 [84.9%] in the tients who received FTD/TPI treatment, the incidence of gastrectomy subgroup and 83 of 92 [90.2%] in the no gastrec- hematologic AEs was higher among patients in the gastrec- tomy subgroup). tomy subgroup than among those in the no gastrectomy sub- Patient baseline demographics and disease characteris- group. Grade 3 or higher neutropenia was reported in 64 of 145 tics were generally similar between patients who had or had patients (44.1%) in the gastrectomy subgroup and 50 of 190 jamaoncology.com (Reprinted) JAMA Oncology January 2020 Volume 6, Number 1 3/10 Downloaded From: https://jamanetwork.com/ on 01/30/2023 Research Original Investigation Efficacy and Safety of Trifluridine/Tipiracil in Patients With Metastatic Gastric Cancer and Gastrectomy Figure 1. Patient Enrollment Flowchart 625 Patients assessed for eligibility 118 Screened, not randomized 111 Screen failures 1 Withdrew consent 1 Protocol violation 1 Death 4 Other 507 Patients randomized 221 Patients with prior gastrectomy 286 Patients without prior gastrectomy 147 Assigned to 74 Assigned to 190 Assigned to 96 Assigned to trifluridine/tipiracil placebo trifluridine/tipiracil placebo 2 Not treated 1 Not treated 1 Not treated 1 Death 1 Withdrew consent 1 Withdrew consent 1 Protocol violation 145 Received 73 Received 190 Received 95 Received trifluridine/tipiracil placebo trifluridine/tipiracil placebo 137 Discontinued 73 Discontinued 179 Discontinued 92 Discontinued 107 Disease 62 Disease 139 Disease 83 Disease progression progression progression progression 12 Adverse events 8 Adverse events 21 Adverse events 3 Adverse events 8 Withdrew 3 Withdrew 6 Withdrew 1 Withdrew consent consent consent consent 6 Physician’s 5 Physician’s 3 Physician’s decision decision decision 3 Deaths 8 Deaths 2 Deaths 1 Protocol violation 8 Continued treatment 0 Continued treatment 11 Continued treatment 3 Continued treatment Figure 2. Subgroup Analysis of Overall Survival Among Patients Who Had or Had Not Undergone Gastrectomy Trifluridine/ Placebo, Tipiracil Treatment, No. of Events/ Hazard Ratio Favors Trifluridine/ Favors Placebo Subgroup No. of Events/No. of Patients No. of Patients (95% CI) Tipiracil Treatment Treatment Previous gastrectomy Yes 102/147 64/74 0.57 (0.41-0.79) No 142/190 76/96 0.80 (0.60-1.06) All Patients 244/337 140/170 0.69 (0.56-0.85) 0.1 1 3 Hazard Ratio (95% CI) Prespecified multivariate subgroup analysis of overall survival in the TAGS metastatic gastric cancer (TAGS): a randomized, double-blind, (TAS-102 Gastric Study) trial based on previous gastrectomy. This figure is placebo-controlled, phase 3 trial. Lancet Oncol 2018;19:1437-1448; permission adapted with permission of Elsevier Science and Technology Journals, from conveyed through Copyright Clearance Center, Inc. Shitara K et al. Trifluridine/tipiracil vs placebo in patients with heavily pretreated patients (26.3%) in the no gastrectomy subgroup, grade 3 or in the no gastrectomy subgroup were considered to be treat- higher anemia in 31 (21.4%) in the gastrectomy subgroup and ment related: 1 patient treated with FTD/TPI (0.5%) died of car- 33 (17.4%) in the no gastrectomy subgroup, and grade 3 or diopulmonary arrest, and 1 patient who received placebo (1.1%) higher leukopenia in 21 (14.5%) in the gastrectomy subgroup died of toxic hepatitis. and 10 (5.3%) in the no gastrectomy subgroup. Incidence of Among patients treated with FTD/TPI, dose modifica- grade 3 or higher fatigue incidence was greater in the no gas- tions (delays or reductions) because of any-cause AEs oc- trectomy subgroup (20 of 190 patients [10.5%]) compared with curred in 94 of 145 patients (64.8%) in the gastrectomy sub- the gastrectomy subgroup (3 of 145 patients [2.1%]). Two deaths group and 101 of 190 (53.2%) in the no gastrectomy subgroup 4/10 JAMA Oncology January 2020 Volume 6, Number 1 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ on 01/30/2023 Efficacy and Safety of Trifluridine/Tipiracil in Patients With Metastatic Gastric Cancer and Gastrectomy Original Investigation Research Figure 3. Overall Survival and Progression-Free Survival Among Patients Who Had or Had Not Undergone Gastrectomy A Overall survival among patients with gastrectomy 100 Trifluridine/tipiracil Overall Survival, % 80 Placebo 60 HR, 0.57 (95% CI, 0.41-0.79) 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Time, mo No. at risk Trifluridine 147 144 125 103 90 70 59 48 32 27 22 16 12 9 8 7 6 5 5 5 3 3 3 3 1 0 /tipiracil Placebo 74 71 58 42 27 22 14 12 10 8 6 4 3 2 2 2 1 1 0 0 0 0 0 0 0 0 B Overall survival among patients without gastrectomy 100 HR, 0.80 (95% CI, 0.60-1.06) Overall Survival, % 80 60 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Time, mo No. at risk Trifluridine 190 184 157 137 111 91 65 54 48 39 29 24 19 13 8 4 3 2 2 2 1 1 1 0 0 0 /tipiracil Placebo 96 87 73 59 44 38 33 28 24 21 11 8 7 7 5 3 1 1 0 0 0 0 0 0 0 0 C Progression-free survival among patients with gastrectomy 100 HR, 0.48 (95% CI, 0.35-0.65) 80 Progression-free Survival, % 60 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time, mo No. at risk Trifluridine 147 139 75 54 31 26 17 14 10 9 5 4 3 2 0 /tipiracil Placebo 74 67 15 5 3 3 1 0 0 0 0 0 0 0 0 D Progression-free survival among patients without gastrectomy 100 HR, 0.65 (95% CI, 0.49-0.85) 80 Progression-free Survival, % 60 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time, mo No. at risk Trifluridine 190 175 79 68 41 34 20 18 10 9 7 5 1 0 0 /tipiracil Placebo 96 78 26 16 9 8 7 5 2 2 1 1 1 1 0 HR indicates hazard ratio. jamaoncology.com (Reprinted) JAMA Oncology January 2020 Volume 6, Number 1 5/10 Downloaded From: https://jamanetwork.com/ on 01/30/2023 Research Original Investigation Efficacy and Safety of Trifluridine/Tipiracil in Patients With Metastatic Gastric Cancer and Gastrectomy Table 1. Overall Survival and Progression-Free Survival Among Patients Who Had or Had Not Undergone Gastrectomya Gastrectomy Subgroup No Gastrectomy Subgroup Trifluridine/ Tipiracil Placebo Trifluridine/Tipiracil End Point (n = 147) (n = 74) HR (95% CI) (n = 190) Placebo (n = 96) HR (95% CI) Overall survival, median 6.0 (4.6-7.0) 3.4 (2.7-3.8) 0.57 (0.41-0.79) 5.6 (4.6-6.2) 3.8 (3.1-5.9) 0.80 (0.60-1.06) (95% CI), mob Rate (95% CI), % 6 mo 50 (41-58) 24 (15-35) NA 44 (37-52) 39 (30-49) NA 12 mo 20 (12-28) 9 (3-19) NA 22 (16-30) 16 (8-26) NA Progression-free survival, 2.2 (1.9-3.0) 1.8 (1.7-1.9) 0.48 (0.35-0.65) 1.9 (1.9-2.1) 1.8 (1.7-1.9) 0.65 (0.49-0.85) median (95% CI), mob Rate (95% CI), % 4 mo 24 (17-32) 5 (1-12) NA 29 (22-36) 10 (5-17) NA 6 mo 13 (8-20) 3 (1-10) NA 16 (10-22) 9 (4-16) NA Abbreviations: HR, hazard ratio; NA, not applicable. a Kaplan-Meier estimates in the intent-to-treat population. b 95% CIs were calculated using the methods of Brookmeyer and Crowley.41 (Table 2). The higher frequency of dose modifications in the Patients who have undergone gastrectomy constitute a sig- gastrectomy subgroup was primarily because of hematologic nificant proportion (approximately 40%) of patients with mGC/ AEs (38.6% [56 of 145] in the gastrectomy subgroup vs 28.4% GEJC who receive second- or third-line treatment.7,8,10,11 These [54 of 190] in the no gastrectomy subgroup). In the gastrec- patients tend to be more compromised nutritionally and more tomy subgroup, 33 of 145 patients (22.7%) received support- heavily pretreated; therefore, they may be less able to toler- ive treatment for neutropenia (30 patients [20.7%] received ate chemotherapy.13,15,16 In addition, sarcopenia is highly preva- granulocyte colony-stimulating factor) compared with 25 lent among patients who have undergone gastrectomy and is (13.2%) in the no gastrectomy subgroup (24 patients [12.6%] associated with toxic events and complications.32-35 In a phase received granulocyte colony-stimulating factor) (eTable 3 in 3 study (REGATTA),15 patients with advanced GC who had un- Supplement 2). The higher incidence of hematologic AEs was dergone gastrectomy in addition to chemotherapy did not ex- not associated with higher treatment discontinuation rates in perience survival benefit compared with patients who re- the gastrectomy subgroup: 15 of 145 patients (10.3%) in the gas- ceived chemotherapy alone. Among patients who had trectomy subgroup discontinued treatment because of AEs of undergone gastrectomy, chemotherapy compliance was lower any cause compared with 28 of 190 (14.7%) in the no gastrec- (they received fewer chemotherapy cycles) and the incidence tomy subgroup. The higher treatment discontinuation rate be- of severe AEs was higher than in patients who had not under- cause of AEs in the no gastrectomy subgroup was partly at- gone gastrectomy.15 In previous studies, gastrectomy was tributable to a higher incidence of gastrointestinal AEs shown to be associated with higher incidence of AEs in pa- associated with treatment discontinuation (10 patients [5.3%] tients who received adjuvant chemotherapy.16,36 In 1 report, in the no gastrectomy subgroup vs 5 [3.4%] in the gastrec- AEs in patients receiving adjuvant chemotherapy were more tomy subgroup). frequent among patients who underwent total gastrectomy Exposure to FTD/TPI was similar in the gastrectomy and than among those who underwent subtotal gastrectomy,16 and no gastrectomy subgroups. Mean (SD) dose intensity was 145 in another report, patients who underwent gastrectomy and (28) mg/m2 per week for patients in the gastrectomy sub- received the fluorouracil prodrug S-1 had higher incidences of group and 151 (25) mg/m2 per week for patients in the no gas- adverse reactions than did those receiving S-1 for unresect- trectomy subgroup (eTable 4 in Supplement 2). Mean (SD) treat- able GC.36 It is unclear whether these increased incidences of ment duration was 12.7 (11.8) and 11.6 (11.2) weeks in the AEs were associated with gastrectomy-induced changes in respective groups. Pharmacokinetic parameters for FTD/TPI pharmacokinetic exposure. Although a number of studies21-23 were not examined in this study. have shown that gastrectomy does not significantly alter the absorption and pharmacokinetics of oral adjuvant chemo- therapy, in at least 1 study, high fluorouracil plasma concen- trations were observed in patients who had undergone gas- Discussion trectomy and received adjuvant S-1.20 The pharmacokinetics The results of this subgroup analysis of the phase 3 TAGS study and distribution of fluoropyrimidines can also be affected by indicate that FTD/TPI was efficacious for patients with previ- the loss of lean body mass,37,38 which may be more common ously treated mGC/GEJC regardless of whether they had un- in patients who have undergone gastrectomy.32,39 This find- dergone gastrectomy. To our knowledge, this analysis repre- ing suggests that gastrectomy may be associated with higher sents the most detailed evaluation of the safety and efficacy drug exposures and, consequently, more frequent AEs.20 To- of an oral chemotherapeutic agent for mGC/GEJC among pa- gether, these studies indicate that the safety of chemo- tients who had undergone gastrectomy. therapy may need to be carefully monitored in patients who 6/10 JAMA Oncology January 2020 Volume 6, Number 1 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ on 01/30/2023 Efficacy and Safety of Trifluridine/Tipiracil in Patients With Metastatic Gastric Cancer and Gastrectomy Original Investigation Research Table 2. AEs Among Patients Who Had or Had Not Undergone Gastrectomya Patients, No. (%) Gastrectomy Subgroup No Gastrectomy Subgroup Trifluridine/Tipiracil (n = 145) Placebo (n = 73) Trifluridine/Tipiracil (n = 190) Placebo (n = 95) Variable Any Grade Grade ≥3 Any Grade Grade ≥3 Any Grade Grade ≥3b Any Grade Grade ≥3b Any AE 143 (98.6) 122 (84.1) 69 (94.5) 44 (60.3) 183 (96.3) 145 (76.3) 88 (92.6) 53 (55.8) Treatment-related AE 128 (88.3) 93 (64.1) 38 (52.1) 7 (9.6) 143 (75.3) 83 (43.7) 57 (60.0) 15 (15.8) Action taken because of AE of any cause Dose modification: 94 (64.8) 75 (51.7) 15 (20.5) 13 (17.8) 101 (53.2) 73 (38.4) 22 (23.2) 16 (16.8) delay or dose Treatment 15 (10.3) 12 (8.3) 12 (16.4) 8 (11.0) 28 (14.7) 24 (12.6) 16 (16.8) 13 (13.7) discontinuation AEs of any cause in ≥10% of patients Hematologic Neutropeniac 87 (60.0) 64 (44.1) 1 (1.4) 0 89 (46.8) 50 (26.3) 6 (6.3) 0 Anemiad 77 (53.1) 31 (21.4) 8 (11.0) 3 (4.1) 73 (38.4) 33 (17.4) 24 (25.3) 10 (10.5) Leukopeniae 40 (27.6) 21 (14.5) 1 (1.4) 0 38 (20.0) 10 (5.3) 2 (2.1) 0 Thrombocytopeniaf 30 (20.7) 7 (4.8) 1 (1.4) 0 30 (15.8) 4 (2.1) 7 (7.4) 0 Gastrointestinal Nausea 57 (39.3) 4 (2.8) 26 (35.6) 3 (4.1) 67 (35.3) 6 (3.2) 27 (28.4) 2 (2.1) Diarrhea 43 (29.7) 5 (3.4) 13 (17.8) 3 (4.1) 33 (17.4) 4 (2.1) 11 (11.6) 0 Vomiting 36 (24.8) 5 (3.4) 12 (16.4) 1 (1.4) 47 (24.7) 7 (3.7) 22 (23.2) 2 (2.1) Abdominal pain 26 (17.9) 5 (3.4) 16 (21.9) 7 (9.6) 29 (15.3) 9 (4.7) 15 (15.8) 8 (8.4) Constipation 17 (11.7) 1 (0.7) 12 (16.4) 2 (2.7) 28 (14.7) 3 (1.6) 13 (13.7) 2 (2.1) Ascites 5 (3.4) 3 (2.1) 4 (5.5) 3 (4.1) 14 (7.4) 9 (4.7) 12 (12.6) 8 (8.4) Upper abdominal pain 5 (3.4) 0 5 (6.8) 0 17 (8.9) 1 (0.5) 10 (10.5) 2 (2.1) Other Decreased appetite 50 (34.5) 11 (7.6) 23 (31.5) 5 (6.8) 65 (34.2) 18 (9.5) 29 (30.5) 6 (6.3) Fatigue 36 (24.8) 3 (2.1) 16 (21.9) 4 (5.5) 53 (27.9) 20 (10.5) 19 (20.0) 6 (6.3) Asthenia 30 (20.7) 3 (2.1) 19 (26.0) 5 (6.8) 35 (18.4) 13 (6.8) 21 (22.1) 6 (6.3) Back pain 15 (10.3) 1 (0.7) 4 (5.5) 1 (1.4) 10 (5.3) 1 (0.5) 7 (7.4) 3 (3.2) Dyspnea 12 (8.3) 2 (1.4) 9 (12.3) 3 (4.1) 12 (6.3) 4 (2.1) 8 (8.4) 3 (3.2) General physical 10 (6.9) 10 (6.9) 7 (9.6) 6 (8.2) 13 (6.8) 12 (6.3) 10 (10.5) 9 (9.5) health deterioration Malaise 5 (3.4) 0 8 (11.0) 1 (1.4) 4 (2.1) 0 1 (1.1) 0 c Abbreviation: AE, adverse event. Neutropenia and/or decreased neutrophil count. a d As-treated population. Anemia and/or decreased hemoglobin level. b e Grade 5 AEs were reported in 1 patient (0.5%) (cardiopulmonary arrest) in the Leukopenia and/or decreased white blood cell count. trifluridine/tipiracil group and 1 patient (1.1%) (toxic hepatitis) in the placebo f Thrombocytopenia and/or decreased platelet count. group. undergo gastrectomy. However, most of these data were de- ramucirumab plus paclitaxel in the context of second-line rived from studies of adjuvant therapy, and data on chemo- therapy did not improve OS compared with placebo plus pa- therapeutic agents for metastatic disease in the gastrectomy clitaxel in the gastrectomy subgroup (HR, 0.94 [95% CI, 0.70- subpopulation are limited. 1.26]), even though OS benefit was seen in the overall Among the few studies7,10,11,40 that have reported data on population.11 None of these studies reported safety data for the patients with mGC/GEJC who had undergone gastrectomy, the gastrectomy subpopulation.7,10,11,40 analyses were limited in scope, and in trials that met their In our detailed subgroup analysis of the TAGS study, pa- primary end point, the efficacy data reported for these tients who had undergone partial or total gastrectomy expe- subgroups appeared to be conflicting. In the phase 3 rienced improvement in OS after receiving FTD/TPI treat- ATTRACTION-2 trial,10 which evaluated nivolumab as third- ment. Patients who had not undergone gastrectomy also had line treatment in mGC, nivolumab improved OS compared with improved OS after receiving treatment with FTD/TPI, but this placebo in subgroups of patients who had (HR, 0.61 [95% CI, benefit was more pronounced in the gastrectomy subgroup in 0.47-0.80]) or had not undergone gastrectomy (HR, 0.69 [95% these analyses, the reasons for which remain unclear. In pre- CI, 0.49-0.98]).10 However, in the phase 3 RAINBOW trial,11 viously reported multivariate Cox regression analyses that in- jamaoncology.com (Reprinted) JAMA Oncology January 2020 Volume 6, Number 1 7/10 Downloaded From: https://jamanetwork.com/ on 01/30/2023 Research Original Investigation Efficacy and Safety of Trifluridine/Tipiracil in Patients With Metastatic Gastric Cancer and Gastrectomy cluded all prespecified factors, previous gastrectomy was not TPI who had undergone gastrectomy and that AEs were effec- identified as a factor associated with OS after FTD/TPI tively managed using dose modifications and concomitant treatment.8 The PFS benefits associated with FTD/TPI were medications. To our knowledge, this was the first safety analy- seen in both the gastrectomy and no gastrectomy subgroups. sis of a chemotherapeutic agent used for mGC/GEJC in the sub- In addition, FTD/TPI treatment prolonged the time to dete- population of patients who had undergone gastrectomy. rioration of ECOG performance status vs placebo in both the gastrectomy subgroups. Limitations The overall safety profile of FTD/TPI was similar among The main limitations of this study lie in the nature of these patients who had or had not undergone gastrectomy, with simi- analyses; although preplanned, they were not powered for sta- lar frequencies of grade 3 or higher AEs in both subgroups. The tistical significance. This circumstance precluded a robust main difference between the subgroups was a higher inci- evaluation of the safety and efficacy of FTD/TPI in the sub- dence of hematologic AEs (neutropenia and leukopenia) among groups of patients who had or had not undergone gastrec- patients who had undergone gastrectomy. These patients had tomy. The lack of pharmacokinetic exposure data in this study received more neoadjuvant or adjuvant therapy and radio- also limited the analysis. Although no differences in the phar- therapy compared with those who had not undergone gas- macokinetics of FTD or TPI were found between patients who trectomy, which may provide a partial explanation for the in- had or who had not undergone gastrectomy in the phase 2 creased myelosuppression observed. However, a preliminary EPOC1201 study, these earlier results were derived from small analysis showed no differences in hematologic AEs between numbers of patients.28 patients who received or did not receive irradiation in the 2 gas- trectomy subgroups, although patient numbers were too small to draw definitive conclusions (eResults in Supplement 2). Al- though nutritional status was not assessed in this trial, other Conclusions studies13,14 have shown that malnutrition and hypoalbumin- This subgroup analysis of the phase 3 TAGS trial showed emia associated with gastrectomy may be associated with in- that FTD/TPI was an effective treatment option that may creased incidence of hematologic AEs, including neutrope- improve survival outcomes and help maintain ECOG perfor- nia, among patients with mGC/GEJC. Unlike the REGATTA mance status among patients with previously treated mGC trial,15 treatment exposure (dose intensity and treatment du- or mGEJC regardless of whether they had undergone gas- ration) in the TAGS trial was similar in the gastrectomy and no trectomy. The benefits of FTD/TPI were especially notewor- gastrectomy subgroups and was unlikely to account for any ob- thy in the subpopulation of patients who had undergone served differences in safety profiles between the subgroups. gastrectomy, who tended to be more heavily pretreated and However, because the pharmacokinetics of FTD/TPI were not were less tolerant of therapy. The overall safety profile of assessed in the TAGS trial, differences in the pharmacoki- the drug, including the incidence of severe AEs, was similar netic exposure of FTD/TPI between patients who had or had among patients who had or had not undergone gastrectomy. not undergone gastrectomy cannot be ruled out. Hemato- No new safety concerns were reported in patients who had logic AEs were associated with more frequent dose modifica- undergone gastrectomy. Hematologic AEs associated with tions among patients treated with FTD/TPI in the gastrec- FTD/TPI in the gastrectomy subgroup were managed effec- tomy subgroup and were managed with supportive treatment; tively with dose modifications and had no detectable asso- they were not associated with increased permanent treat- ciation with treatment discontinuation rates. These results ment discontinuation rates: 10.3% of patients discontinued support the use of FTD/TPI among patients who have treatment because of AEs compared with 14.7% in the no gas- undergone gastrectomy, particularly in the context of the trectomy subgroup. Together, these results indicate that there recent approval of FTD/TPI for patients with previously were no new safety concerns in patients treated with FTD/ treated mGC/GEJC.27 ARTICLE INFORMATION London, London, United Kingdom (Arkenau); (George); Department of Medicine, University of Accepted for Publication: June 22, 2019. Department of Oncology, Azienda Ospedaliera di Chicago, Chicago, Illinois (Catenacci); Medical Cremona, Cremona, Italy (Ghidini); Department of Affairs Division, Taiho Oncology Inc, Princeton, Published Online: October 10, 2019. Surgery, Osaka General Medical Center, Osaka, New Jersey (McGuigan); Stathmi Inc, New Hope, doi:10.1001/jamaoncol.2019.3531 Japan (Fujitani); Digestive Oncology, University Pennsylvania (Makris); Department of Open Access: This is an open access article Hospitals Gasthuisberg Leuven, KU Leuven, Gastrointestinal Oncology, National Cancer Center distributed under the terms of the CC-BY-NC-ND Leuven, Belgium (Van Cutsem); Department of Hospital East, Chiba, Japan (Doi, Shitara). License. © 2019 Ilson DH et al. JAMA Oncology. Hematology, Oncology, and Tumor Immunology, Author Contributions: Dr Ilson had full access to all Author Affiliations: Department of Medicine, Charité–Universitätsmedizin Berlin, Berlin, of the data in the study and takes responsibility for Memorial Sloan Kettering Cancer Center, New York, Germany (Thuss-Patience); Department of the integrity of the data and the accuracy of the New York (Ilson); Department of Medical Oncology, Oncology, Humanitas Gavazzeni, Bergamo, Italy data analysis. Vall d’Hebron Institute of Oncology, Vall d’Hebron (Beretta); Department of Medical Oncology, The Concept and design: Ilson, Tabernero, Arkenau, University Hospital, Universitat Autònoma de Christie NHS Foundation Trust, Manchester, Van Cutsem, Makris, Doi, Shitara. Barcelona, Barcelona, Spain (Tabernero, Alsina); United Kingdom (Mansoor); Department of Acquisition, analysis, or interpretation of data: All Department of Oncology, Minsk City Clinical Chemotherapy, Alexandrov National Cancer Centre authors. Oncology Dispensary, Minsk, Belarus (Prokharau); of Belarus, Minsk, Belarus (Zhavrid); Division of Drafting of the manuscript: Ilson, Tabernero, Drug Development Unit, Sarah Cannon Research Hematology and Oncology, Department of Ghidini, Thuss-Patience, Mansoor, Catenacci, Institute, Cancer Institute, University College Medicine, Medical College of Wisconsin, Milwaukee Makris, Shitara. 8/10 JAMA Oncology January 2020 Volume 6, Number 1 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ on 01/30/2023 Efficacy and Safety of Trifluridine/Tipiracil in Patients With Metastatic Gastric Cancer and Gastrectomy Original Investigation Research Critical revision of the manuscript for important Company, Roche/Genentech, Eli Lilly & Company, 3. Wagner AD, Syn NL, Moehler M, et al. intellectual content: Ilson, Tabernero, Prokharau, Merck & Company Inc, and Taiho Pharmaceutical; Chemotherapy for advanced gastric cancer. Arkenau, Fujitani, Van Cutsem, Thuss-Patience, participating in the speakers’ bureau for Foundation Cochrane Database Syst Rev. 2017;8:CD004064. Beretta, Mansoor, Zhavrid, Alsina, George, Medicine and Guardant Health; and receiving doi:10.1002/14651858.CD004064.pub4 Catenacci, McGuigan, Makris, Doi, Shitara. honoraria from Amgen Inc, Bristol-Myers Squibb 4. Chrom P, Stec R, Szczylik C. Second-line Statistical analysis: Makris. Company, Foundation Medicine, Genmab A/S, treatment of advanced gastric cancer: current Obtained funding: Zhavrid. Roche/Genentech, Gritstone Oncology, Guardant options and future perspectives. Anticancer Res. Administrative, technical, or material support: Health, Five Prime Therapeutics, Eli Lilly & 2015;35(9):4575-4583. Tabernero, Arkenau, Van Cutsem, Thuss-Patience, Company, Merck & Company Inc, NantWorks, Mansoor, Catenacci, McGuigan. OncoPlex Diagnostics, and Taiho Pharmaceutical. 5. Zheng Y, Zhu XQ, Ren XG. Third-line Supervision: Ghidini, Beretta, Alsina, George, Doi, Dr McGuigan reported being employed at Taiho chemotherapy in advanced gastric cancer: Shitara. Oncology. Dr Makris reported being a paid a systematic review and meta-analysis. Medicine statistical consultant at Taiho Oncology. Dr Doi (Baltimore). 2017;96(24):e6884. doi:10.1097/MD. Conflict of Interest Disclosures: Dr Ilson reported 0000000000006884 receiving grants and advisory role support from reported having a consulting or advisory role at Amgen Inc, Astellas, AstraZeneca, Bayer AG, Amgen Inc, Chugai Pharma, Daiichi Sankyo, Kyowa 6. Choi IS, Choi M, Lee JH, et al. Treatment patterns Bristol-Myers Squibb, Eli Lilly & Company, Merck & Hakko Kirin, Eli Lilly & Company Japan, Merck Sharp and outcomes in patients with metastatic gastric Company Inc, Pieris Pharmaceuticals, F and Dohme Corporation, Sumitomo Dainippon cancer receiving third-line chemotherapy: Hoffman-LaRoche Limited, and Taiho Oncology Pharma, and Taiho Pharmaceutical and receiving a population-based outcomes study. PLoS One. outside the submitted work. Dr Tabernero reported research funding from Abbvie, Astellas, Boehringer 2018;13(6):e0198544. doi:10.1371/journal.pone. receiving advisory role support from Array Ingelheim, Bristol-Myers Squibb, Celgene, Chugai 0198544 Biopharma, AstraZeneca, Bayer AG, Biocartis, Pharma, Daiichi Sankyo, Janssen, Kyowa Hakko 7. Shitara K, Özgüroğlu M, Bang YJ, et al; Boehringer Ingelheim, Chugai Pharma, Foundation Kirin, Eli Lilly & Company Japan, Merck Serono, KEYNOTE-061 investigators. Pembrolizumab Medicine, Genentech Inc, Genmab A/S, F Merck Sharp and Dohme Corporation, Novartis, versus paclitaxel for previously treated, advanced Hoffman-LaRoche Limited, HalioDX SAS, Pfizer, Quintiles, Sumitomo Group, Taiho gastric or gastro-oesophageal junction cancer Halozyme, Imugene Limited, Inflection Biosciences, Pharmaceutical, and Takeda. Dr Shitara reported (KEYNOTE-061): a randomised, open-label, Ipsen Pharma, Eli Lilly & Company, Merck Sharp and having a consulting or advisory role at Astellas, controlled, phase 3 trial. Lancet. 2018;392(10142): Dohme Corporation, Menarini Group, Merck Bristol-Myers Squibb, Eli Lilly & Company, Ono 123-133. doi:10.1016/S0140-6736(18)31257-1 Serono, Merrimack, Merus, Molecular Partners, Pharmaceutical, Pfizer, and Takeda; receiving honoraria from Abbvie, Novartis, and Yakult 8. Shitara K, Doi T, Dvorkin M, et al. Novartis, Peptomyc, Pfizer, Pharmacyclics, Trifluridine/tipiracil versus placebo in patients with ProteoDesign SL, Rafael Pharmaceuticals, Roche Pharmaceutical; and reported receiving research funding from Chugai Pharma, Daiichi Sankyo, Eli heavily pretreated metastatic gastric cancer Diagnostics, Sanofi, Seattle Genetics, Servier, (TAGS): a randomised, double-blind, Symphogen, Taiho Pharmaceutical, and VCN Lilly & Company, Merck Sharp and Dohme Corporation, Ono Pharmaceutical, Sumitomo placebo-controlled, phase 3 trial. Lancet Oncol. Biosciences outside the submitted work. Dr Van 2018;19(11):1437-1448. doi:10.1016/S1470-2045(18) Cutsem reported receiving grants and personal fees Dainippon Pharma, and Taiho Pharmaceutical. No other conflicts are reported. 30739-3 from Servier during the conduct of the study; receiving grants from Amgen Inc, Bayer AG, Funding/Support: This study was funded by Taiho 9. Orditura M, Galizia G, Sforza V, et al. Treatment Boehringer Ingelheim, Bristol-Myers Squibb Oncology Inc and Taiho Pharmaceutical Company of gastric cancer. World J Gastroenterol. 2014;20(7): Company, Celgene, Ipsen, Eli Lilly & Company, Limited. 1635-1649. doi:10.3748/wjg.v20.i7.1635 Merck Sharp and Dohme Corporation, Merck KGaA, Role of the Funder/Sponsor: Taiho Oncology Inc 10. Kang YK, Boku N, Satoh T, et al. Nivolumab in Novartis AG, and Roche; and receiving personal and Taiho Pharmaceutical Company Limited patients with advanced gastric or fees from Astellas, AstraZeneca, Bayer AG, participated in the design and the conduct of the gastro-oesophageal junction cancer refractory to, Bristol-Myers Squibb, Celgene, Eli Lilly & Company, study and in data collection and analysis. Dr or intolerant of, at least two previous chemotherapy Merck Sharp and Dohme Corporation, Merck KGaA, McGuigan, an employee of Taiho Oncology Inc, and regimens (ONO-4538-12, ATTRACTION-2): Novartis, and Roche outside the submitted work. Dr Dr Makris, a paid consultant of Taiho Oncology Inc, a randomised, double-blind, placebo-controlled, Thuss-Patience reported receiving nonfinancial were authors of this manuscript. phase 3 trial. Lancet. 2017;390(10111):2461-2471. support from Roche; receiving personal fees and doi:10.1016/S0140-6736(17)31827-5 nonfinancial support from Bristol-Myers Squibb Meeting Presentation: These results were presented in part as of an oral presentation at the 11. Wilke H, Muro K, Van Cutsem E, et al; RAINBOW Company; and receiving personal fees from Eli Lilly Study Group. Ramucirumab plus paclitaxel versus & Company, Merck Darmstadt, Merck Sharp and 2019 Gastrointestinal Cancers Symposium; January 17, 2019; San Francisco, California. placebo plus paclitaxel in patients with previously Dohme Corporation, Nordic, and Pfizer outside the treated advanced gastric or gastro-oesophageal submitted work. Dr Beretta reported receiving Additional Contributions: We thank the patients junction adenocarcinoma (RAINBOW): grants from Taiho Pharmaceutical during the and families who made this trial possible, the a double-blind, randomised phase 3 trial. Lancet conduct of the study. Dr Alsina reported receiving clinical study teams who were involved in this trial, Oncol. 2014;15(11):1224-1235. doi:10.1016/S1470-2045 personal fees and consultancy support from Servier and the data and safety monitoring board (14)70420-6 and Bristol-Myers Squibb; personal fees from members. The board members received financial Amgen, Eli Lilly & Company, Merck Sharp & Dohme compensation through paid honoraria. Medical 12. Santarpia L, Contaldo F, Pasanisi F. Nutritional Corporation, and Roche/Genentech; travel, writing and editorial assistance were provided by screening and early treatment of malnutrition in accommodations, and expenses from Amgen Inc, Vasupradha Vethantham, PhD, Wendy Sacks, PhD, cancer patients. J Cachexia Sarcopenia Muscle. Eli Lilly & Company, and Roche/Genentech; and and Lilly Ostrovsky, MS, at Scientific Connexions 2011;2(1):27-35. doi:10.1007/s13539-011-0022-x participating in the speakers’ bureau for Amgen Inc, and funded by Taiho Oncology Inc. 13. Seo SH, Kim SE, Kang YK, et al. Association of Bristol-Myers Squibb Company, Eli Lilly & Company, Data Sharing Statement: Supplement 3. nutritional status-related indices and Merck Sharp and Dohme Corporation, Roche/ chemotherapy-induced adverse events in gastric Genentech, and Servier. Dr George reported having REFERENCES cancer patients. 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