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Real-world Treatment Patterns and Clinical Outcomes Across Lines of Therapy in Patients With Advanced/Metastatic Gastric or Gastroesophageal Junction Cancer

Open AccessPublished:September 24, 2019DOI:https://doi.org/10.1016/j.clcc.2019.09.001

      Abstract

      Background

      First-line (1L) and second-line (2L) therapies for advanced/metastatic gastric cancer (GC) and gastroesophageal junction cancer (GEJC) have modest efficacy, and therapeutic options in subsequent lines are limited as disease progresses. We assessed real-world treatment patterns and outcomes for advanced/metastatic GC/GEJC.

      Patients and Methods

      Adult patients diagnosed with advanced/metastatic GC/GEJC between January 1, 2011 and April 30, 2018 were identified using the Flatiron Health database. Median overall survival (OS) from start of each line of therapy until death was estimated by the Kaplan-Meier method. Duration of therapy (DoT) was time from start date until end date of each line.

      Results

      We identified 3291 patients with advanced/metastatic GC/GEJC adenocarcinoma. At diagnosis, the median age was 68 years, 60% were white, 53% had initial stage IV disease, and 57% had GC. Of these 3291 patients, most (75%) received at least 1 therapy; 32% received 2L, 14% received third-line (3L) therapy, and 6% received at least 4 lines of therapy (4L+). The median OS from start of 1L was 10.7 months (2L, 7.6 months; 3L, 6.1 months; 4L+, 2.8 months). The median DoT in 1L was 2.2 months (2L, 2.1 months; 3L, 1.7 months; 4L+, 3.0 months). Use of targeted and immunotherapies generally increased progressively with each subsequent line of therapy.

      Conclusion

      One-quarter of patients with advanced/metastatic GC/GEJC remained untreated, and only approximately one-half of patients receiving 1L therapy received subsequent treatment. In all lines of therapy, OS was generally poor and DoT was short. More effective treatment options are needed across all lines of therapy for this highly burdensome disease.

      Keywords

      Introduction

      Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide, and is responsible for approximately 26,240 new cases and 10,800 deaths annually in the United States (US).
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      For unresectable advanced/metastatic GC or gastroesophageal junction cancer (GEJC), the National Comprehensive Cancer Network
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      Clinical practice guidelines in oncology: Gastric cancer. Version 2.2018.
      recommends first-line (1L) treatment with fluoropyrimidine- (fluorouracil or capecitabine) and platinum-based (cisplatin or oxaliplatin) regimens, with the addition of trastuzumab for patients who have human epidermal growth factor receptor 2 (HER2)-positive tumors. Despite these treatment options, prognosis for patients with advanced/metastatic GC/GEJC remains poor; the median overall survival (OS) in recent trials of 1L chemotherapy for advanced GC was 8.8 to 12.2 months.
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      Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.
      Second-line (2L) therapy typically consists of chemotherapy with paclitaxel, docetaxel, irinotecan, ramucirumab (either with or without paclitaxel), or a combination of fluorouracil and irinotecan (if not previously used in 1L).
      National Comprehensive Cancer Network
      Clinical practice guidelines in oncology: Gastric cancer. Version 2.2018.
      Similar to 1L treatments, available therapies provide only modest improvements in survival, with several clinical trials of 2L chemotherapy reporting a median OS of 4.0 to 5.3 months.
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      Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone.
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      Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO).
      The combination of ramucirumab with paclitaxel in the 2L setting, following disease progression with chemotherapy, has demonstrated improved outcomes in patients with GC/GEJC, with median OS of 9.6 months reported,
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      RAINBOW Study Group
      Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial.
      and received US Food and Drug Administration (FDA) approval in this setting in November 2014.
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      FDA approval summary: ramucirumab for gastric cancer.
      Once patients progress to the third-line (3L) setting, the programmed death 1 (PD-1) inhibitor pembrolizumab is approved for patients with GC/GEJC whose tumors express PD-L1, based on observations from the KEYNOTE-059 trial of durable overall response rate (13.3%; duration of response ranged from 2.8 to 19.4 months) in this patient subgroup.
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      FDA approval summary: pembrolizumab for recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma expressing PD-L1.
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      Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial.
      In September 2017, pembrolizumab received FDA approval for treatment of patients with microsatellite instability-high or mismatch repair deficient solid tumors (including GC/GEJC) that have progressed following prior treatment and who have no satisfactory alternative treatment options.
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      Other than the addition of immuno-oncology (I-O) therapies, the same treatment options as in 2L are generally available as disease progresses, and selection is typically based on performance status and previous treatment regimens.
      National Comprehensive Cancer Network
      Clinical practice guidelines in oncology: Gastric cancer. Version 2.2018.
      Data are currently lacking that inform on real-world treatment patterns by line of therapy (LoT) in patients with advanced/metastatic GC/GEJC in routine US clinical practice. The objective of this study was to investigate treatment patterns and outcomes in routine clinical practice for patients with advanced/metastatic GC/GEJC in the US across all LoTs, especially for later LoTs where limited information exists within treatment guidelines.

      Patients and Methods

      Data Source and Patient Selection

      This retrospective, observational study used patient-level data from Flatiron Health’s electronic health record (EHR) oncology database,
      Flatiron Health
      Flatiron Health electronic health record database.
      representing over 2000 clinicians covering over 1.5 million patients in the United States; demographics are generally similar to those of the Surveillance, Epidemiology, and End Results (SEER) program.
      • Howlader N.
      • Noone A.M.
      • Krapcho M.
      • et al.
      SEER cancer statistics review, 1975-2014.
      The Flatiron GC/GEJC cohort used for this analysis includes all patients with a recorded diagnosis of advanced or metastatic disease (as indicated by de-identified patient-level unstructured data collected via technology-enabled chart abstraction from physician notes and other documents, in addition to structured data). Structured data include demographics, diagnosis codes (International Classification of Diseases, 9th Revision [ICD-9]/International Classification of Diseases, 10th Revision [ICD-10]), laboratory visits, medications, and Eastern Cooperative Oncology Group (ECOG) performance status (PS). Unstructured data include date of initial diagnosis, stage at initial diagnosis, primary tumor characteristics, biomarker testing, and limited information on surgeries.
      Patients with a diagnosis of advanced/metastatic GC/GEJC between January 1, 2011 and April 30, 2018 were identified; the index date was the date of diagnosis. Patients were eligible for this study if they were ≥ 18 years of age and had a histologically confirmed diagnosis of adenocarcinoma GC/GEJC; eligibility criteria and patient attrition are presented in Figure 1. Eligible patients were followed until death, loss to follow-up, or when the study period ended, whichever occurred first. Informed consent was waived as this is a non-interventional study, and the anonymized data in the Flatiron database are protected against breach of confidentiality.
      Figure thumbnail gr1
      Figure 1Patient Identification and Attrition
      Abbreviations: EC = esophageal cancer; GC = gastric cancer; GEJC = gastroesophageal junction cancer. aMedical Data Were Defined as Clinical Data in the Patient Record From Outpatient Physician Office Visits, Non-facility Visits, Laboratory Visits, Treatment/Procedure Visits, or Medication Administration.

      Analyses

      Baseline variables included age, sex, race, disease stage at initial diagnosis, ECOG PS, primary tumor location (GC/GEJC), and number of LoTs received. OS (defined as initiation of a LoT until death or date of last recorded visit) and duration of therapy (DoT; defined as time from first to last administration date) were reported for each LoT. Baseline demographics and patient characteristics at the index date were descriptively analyzed: frequencies and proportions were reported for categorical data, and means (standard deviations) and medians (ranges) were provided for continuous data. Median OS and 95% confidence intervals (95% CIs) were estimated by the Kaplan-Meier method. For comparisons between continuous variables, the Student t test was used if they were normally distributed; if they were non-normally distributed, the Wilcoxon rank-sum test was used. For categorical variables, the χ2 test and Fisher exact test were used.

      Results

      Baseline Patient Demographics and Disease Characteristics

      In total, 3291 patients with advanced/metastatic GC/GEJC adenocarcinoma who met eligibility criteria were identified (Figure 1); the median age at diagnosis of advanced/metastatic disease was 68 years. The majority of patients were ≥ 65 years of age (60%), were white (60%), and had GC as primary tumor location (57%) (Table 1). Most patients with available data for disease stage at initial diagnosis had confirmed stage IV disease (62%), and most patients with available ECOG PS data at index had an ECOG PS of 0 to 1 (78%); 2174 (66%) patients were tested for HER2 status, and 13% of all included patients were recorded as having HER2-positive tumors. When stratified by primary site of disease (GC vs. GEJC), patients with GC were significantly less likely to be male (59% vs. 83%; P < .0001), white (49% vs. 74%; P < .0001), and to be at least 65 years of age at diagnosis (58% vs. 63%; P < .05). A smaller proportion of patients diagnosed with GC had a positive HER2 status at baseline (15% vs. 26%; P < .0001) than patients with GEJC (Table 1). Of the 3291 patients identified (median duration of follow-up, 8.1 months [range, 1.0-87.7 months]), 821 (25%) received no treatment, and 2479 (75%) patients received at least 1 line of therapy after diagnosis (Table 2). Patients who received active therapy were significantly more likely to be male (71% vs. 64%; P < .05), younger (median age, 67 vs. 72 years; P < .0001), white (62% vs. 55%; P = .0001), to have GEJC (45% vs. 39%; P < .05) or to have been initially diagnosed with stage IV disease (63% vs. 56%; P < .05). In patients with available ECOG PS after index, those receiving active therapy were less likely to have an ECOG PS of ≥ 2 (19% vs. 40%; P < .0001), compared with patients who did not receive therapy; however, ECOG PS after index was unavailable for over 40% of patients. The proportion of patients with GC who received therapy was 73%; among patients with GEJC, the proportion who received therapy was 78%.
      Table 1Baseline Patient Demographics and Disease Characteristics in All Included Patients, and Also Stratified by Disease Site and by Receipt of Subsequent Systemic Therapy
      All Patients (N = 3291), n (%)GC (N = 1862), n (%)GEJC (N = 1429), n (%)P ValueReceived Therapy (N = 2479), n (%)Did Not Receive Therapy (N = 812), n (%)P Value
      Male sex2278 (69)1093 (59)1185 (83)<.00011757 (71)521 (64).0003
      Median age at index (adv/met diagnosis), y (range)68 (23-85)68 (23-85)69 (24-85).025567 (23-85)72 (29-85)<.0001
       ≥65 y1989 (60)1088 (58)901 (63).00721431 (58)558 (69)<.0001
      Practice type
       Community3107 (94)1776 (95)1331 (93).00562389 (96)718 (88)<.0001
       Academic184 (6)86 (5)98 (7)90 (4)94 (12)
      Race<.0001.0001
       Asian144 (4)130 (7)14 (1)116 (5)28 (3)
       Black/African American272 (8)235 (13)37 (3)206 (8)66 (8)
       White1981 (60)917 (49)1064 (74)1534 (62)447 (55)
       Hispanic/Latino21 (1)19 (1)2 (0.1)16 (1)5 (1)
       Other431 (13)309 (17)122 (9)310 (13)121 (15)
      Unknown/missing442 (13)252 (14)190 (13)297 (12)145 (18)
      Primary site of diseaseN/A.0028
       Gastric1862 (57)1862 (100)1366 (55)496 (61)
       Gastroesophageal junction1429 (43)1429 (100)1113 (45)316 (39)
      Disease stage at initial diagnosis<.0001<.0001
       Known2812 (85)1590 (85)1222 (86)2182 (88)630 (78)
       Stage I-II516 (18)242 (15)274 (22)368 (17)148 (23)
       Stage III565 (20)261 (16)304 (25)436 (20)129 (20)
       Stage IV1731 (62)1087 (68)644 (53)1378 (63)353 (56)
       Unknown479 (15)272 (15)207 (14)297 (12)182 (22)
      First ECOG PS after index (adv/met diagnosis)<.0001<.0001
       Reported1898 (58)1036 (56)862 (60)1600 (65)298 (37)
       0669 (35)363 (35)306 (35)588 (37)81 (27)
       1811 (43)441 (43)370 (43)713 (45)98 (33)
       2321 (17)176 (17)145 (17)243 (15)78 (26)
       388 (5)48 (5)40 (5)53 (3)35 (12)
       49 (0.5)8 (0.8)1 (0.1)3 (0.2)6 (2.0)
       Not reported1393 (42)826 (44)567 (40)879 (35)514 (63)
      Last HER2 status during observation period<.0001<.0001
       Tested2174 (66)1265 (68)909 (64)1749 (71)425 (52)
       Positive426 (20)187 (15)239 (26)351 (20)75 (18)
       Negative1594 (73)1001 (79)593 (65)1284 (73)310 (73)
       Equivocal/missing154 (7)77 (6)77 (8)114 (7)40 (9)
       Not tested1117 (34)597 (32)520 (36)730 (29)387 (48)
      Abbreviations: CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group performance status; GC = gastric cancer; GEJC = gastroesophageal junction cancer; HER2 = human epidermal growth factor receptor 2.
      Table 2Summary Treatment Patterns
      All Patients (N = 3291), n (%)
      Median follow-up in all patients, mos (range)8.1 (1.0-87.7)
      No therapy after diagnosis812 (25)
      Patients receiving ≥ 1L therapy2479 (75)
       Median follow-up, mos (range)9.1 (1.0-86.5)
       Median duration of 1L therapy, mos (range)2.2 (0.03-72.3)
      Patients receiving ≥ 2L therapy1053 (32)
       Median follow-up, mos (range)13.9 (1.4-81.1)
       Median duration of 2L therapy, mos (range)2.1 (0.03-65.2)
      Patients receiving ≥ 3L therapy469 (14)
       Median follow-up, mos (range)18.2 (4.4-81.1)
       Median duration of 3L therapy, mos (range)1.7 (0.03-34.8)
      Patients receiving 4L + therapy185 (6)
       Median follow-up, mos (range)23.0 (5.9-80.9)
       Median duration of 4L + therapy, mos (range)3.0 (0.03-37.8)
      Proportion of patients receiving regimen classes in 1L
       Platinum-based1963 (79.2)
       Taxane-based873 (35.2)
       Fluoropyrimidine-based1713 (69.1)
       Irinotecan-based85 (3.4)
       Ramucirumab-based74 (3.0)
       Trastuzumab-based268 (10.8)
       Immunotherapy-based (pembrolizumab, n = 9; nivolumab, n = 2; atezolizumab, n = 1)12 (0.5)
      Proportion of patients receiving regimen classes in 2L
       Platinum-based475 (45.1)
       Taxane-based450 (42.7)
       Fluoropyrimidine-based491 (46.6)
       Irinotecan-based139 (13.2)
       Ramucirumab-based247 (23.5)
       Trastuzumab-based143 (13.6)
       Immunotherapy-based (pembrolizumab, n = 16; nivolumab, n = 10)26 (2.5)
      Proportion of patients receiving regimen classes in 3L
       Platinum-based126 (26.9)
       Taxane-based168 (35.8)
       Fluoropyrimidine-based158 (33.7)
       Irinotecan-based116 (24.7)
       Ramucirumab-based121 (25.8)
       Trastuzumab-based52 (11.1)
       Immunotherapy-based (pembrolizumab, n = 17; nivolumab, n = 17)34 (7.2)
      Proportion of patients receiving regimen classes in 4L+
       Platinum-based69 (37.3)
       Taxane-based81 (43.8)
       Fluoropyrimidine-based89 (48.1)
       Irinotecan-based63 (34.1)
       Ramucirumab-based61 (33.0)
       Trastuzumab-based23 (12.4)
       Immunotherapy-based
      One patient received more than 1 line of immunotherapy in 4L.
      (pembrolizumab, n = 26; nivolumab, n = 15)
      41 (22.2)
      Regimen classes are not mutually exclusive categories.
      Abbreviations: 1L = first-line; 2L = second-line; 3L = third-line; 4L+ = fourth or more line.
      a One patient received more than 1 line of immunotherapy in 4L.

      Treatment Patterns

      Among the 2479 patients receiving active therapy after diagnosis, 1053 (42%) received 2L+, 469 (19%) received 3L+, and 185 (7%) received 4L+ (Table 2). The most frequently used regimens in 1L therapy were platinum- and fluoropyrimidine-based therapies (79% and 69% of patients, respectively) (Table 2); FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) was the most frequently used individual regimen (21.5% of patients; see Supplemental Figure 1 in the online version). Among patients receiving 1L therapy, doublet regimens (including trastuzumab) were most frequently received (56.5% of patients), with 21.7% of patients receiving 1L triplet regimens (including trastuzumab). In the 2L setting, the most common regimens used were platinum-, taxane-, and fluoropyrimidine-based (45%, 43%, and 47% of patients, respectively). The most frequently used individual regimen was paclitaxel plus ramucirumab (16.2% of patients); this was also the most frequently used regimen in the 3L (15.4% of patients) and 4L+ settings (15.1% of patients). The proportion of patients receiving irinotecan- (1L, 3.4%; 2L, 13.2%; 3L, 24.7%; 4L+, 34.1%), ramucirumab- (1L, 3.0%; 2L, 23.5%; 3L, 25.8%; 4L+, 33.0%), and I-O-based (1L, 0.5%; 2L, 2.5%; 3L, 7.2%; 4L+, 22.2%) regimens increased progressively with each advancing LoT. The proportion of patients receiving trastuzumab-based regimens remained broadly consistent across LoT (1L, 10.8%; 2L, 13.6%; 3L, 11.1%; 4L+, 12.4%). A total of 426 patients were confirmed as having HER2-positive disease after index, and 351 of these patients subsequently received therapy (Table 1); 205 (58.4%) of these received trastuzumab in 1L, 54 (15%) received 2L trastuzumab, and 13 (4%) received trastuzumab in the 3L+ setting. Of the 54 patients who received 2L trastuzumab, only 5 had HER2 status confirmed by both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) before starting 1L therapy.
      The total number of patients receiving active therapy each year since 2011, and the proportion of patients receiving chemotherapy, ramucirumab or I-O over the same time frame, are presented by LoT in Supplemental Figure 2 (in the online version). Across all LoTs, the total number of patients receiving treatment appears to be increasing over time. The vast majority of patients received chemotherapy in the 1L setting. Uptake of ramucirumab and I-O agents in the 2L setting has increased in recent years since their approval, in tandem with a decrease in the proportion of patients receiving 2L chemotherapy. This trend is also present among patients who receive therapy in the 3L+ setting. The median DoT (range) was generally short and consistent across LoTs (1L, 2.2 months; 2L, 2.1 months; 3L, 1.7 months; 4L+, 3.0 months) (Table 2). Among those who received 1L, 16% of patients received at least 6 months of therapy; 14% received more than 6 months of 2L therapy, 11% received more than 6 months of 3L therapy, and 32% received more than 6 months of 4L+.

      Survival Outcomes

      The median OS from start of 1L therapy was 10.7 months (2L, 7.6 months; 3L, 6.1 months; 4L+, 2.8 months) (see Supplemental Figure 3 in the online version); the median OS from diagnosis in untreated patients was 10.5 months. Landmark survival estimates at 1, 2, and 5 years after start of 1L therapy were 45%, 20%, and 5%, respectively (corresponding values from start of 2L therapy: 33%, 14%, and 4%). Landmark survival estimates 1 year after initiation of 3L and 4L+ were 9% and 2.1%, respectively. When stratifying by primary site of disease, the median OS across LoTs was broadly comparable between patients with GC and patients with GEJC (1L, 10.4 vs. 11.0 months; 2L, 7.7 vs. 7.5 months; 3L, 7.1 vs. 5.6 months; 4L+, 3.2 vs. 2.7 months) (Figure 2).
      Figure thumbnail gr2
      Figure 2Overall Survival in GC and GEJC Subgroups From Start of 1L (A); 2L (B); 3L (C); and 4L+ (D)
      Abbreviations: 1L = first-line; 2L = second-line; 3L = third-line; 4L+ = fourth or more line; CI = confidence interval; GC = gastric cancer; GEJC = gastroesophageal junction cancer; OS = overall survival.

      Discussion

      This real-world study found that over one-quarter of patients diagnosed with advanced/metastatic GC/GEJC had no record of receiving systemic therapy; patients who received therapy were more likely to be male, young, white, to have GEJC, and to have had stage IV disease at initial diagnosis. Another observational analysis (using SEER-Medicare linked data 2001-2009) assessed patients over 65 years of age with a diagnosis of GC, and reported that 26.5% of patients received no treatment (including surgery) for their disease.
      • Liu N.
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      • Lidor A.O.
      Underutilization of treatment for regional gastric cancer among the elderly in the USA.
      Patients who were older, male, or black were less likely to receive therapy. Data used in that study, however, were not specific to advanced/metastatic disease, and precede advances in chemotherapy of GC/GEJC and also more recent advances in targeted therapies and I-O therapies.
      Of the 75% of patients who did receive treatment for GC/GEJC, approximately one-half received 2L therapy, and less than one-fifth received 3L therapy. These findings are in agreement with previous real-world analyses in this clinical setting. One US-based real-world study (assessing electronic medical record data from the IMS oncology database and administrative claims data from Truven MarketScan from 2004 to 2012) reported that approximately 42% to 55% of patients receiving 1L therapy for advanced GC received 2L therapy, and only approximately 20% to 30% received 3L.
      • Hess L.M.
      • Michael D.
      • Mytelka D.S.
      • Beyrer J.
      • Liepa A.M.
      • Nicol S.
      Chemotherapy treatment patterns, costs, and outcomes of patients with gastric cancer in the United States: a retrospective analysis of electronic medical record (EMR) and administrative claims data.
      More recently, an observational analysis of data from a single center in the United Kingdom (2009-2015) reported that only 39% of patients who received 1L chemotherapy for advanced GC/GEJC/esophageal cancer subsequently received 2L therapy, and only 14% received 3L therapy.
      • Davidson M.
      • Cafferkey C.
      • Goode E.F.
      • et al.
      Survival in advanced esophagogastric adenocarcinoma improves with use of multiple lines of therapy: results from an analysis of more than 500 patients.
      The observation that only approximately 50% of patients with advanced/metastatic GC/GEJC progressed from 1L therapy to subsequent 2L therapy are similar to real-world findings in patients receiving treatment for other solid tumors.
      • de Castro J.
      • Tagliaferri P.
      • de Lima V.C.C.
      • et al.
      Systemic therapy treatment patterns in patients with advanced non-small cell lung cancer (NSCLC): PIvOTAL study.
      Our analysis supports these previous observations, but also includes data until April 2018, reflecting ongoing research and consequent updates to clinical guidelines in recent years. The attrition of treatment administration across advancing lines of therapy most likely represents a combination of progressive impairment in patients’ functional status, and a reluctance to use existing treatments with marginal benefit and significant toxicity; accordingly, we observed a decrease in chemotherapy use with a concomitant increase in ramucirumab and I-O therapy use. Most patients included in this analysis had stage IV disease at diagnosis; earlier diagnosis may be an important factor in improving patient outcomes.
      The majority of patients who received 1L therapy were given platinum- and fluoropyrimidine-based treatment regimens, broadly in line with clinical guidelines.
      National Comprehensive Cancer Network
      Clinical practice guidelines in oncology: Gastric cancer. Version 2.2018.
      However, a substantial proportion of patients received 1L therapy that deviated from the National Comprehensive Cancer Network (NCCN) preferred regimens, including taxanes in combination with platinum chemotherapies and ramucirumab. Most of the observed 1L therapies were given as doublet regimens, as recommended by clinical guidelines owing to the lower toxicity with doublet regimens compared with triplet regimens.
      National Comprehensive Cancer Network
      Clinical practice guidelines in oncology: Gastric cancer. Version 2.2018.
      In 2L, almost one-quarter of patients received ramucirumab, but platinum-, taxane-, and fluoropyrimidine-based regimens remained more frequently used; again, 2L treatment patterns used in routine clinical practice appear to diverge considerably from NCCN guidelines. Importantly, these statistics represent all eligible patients across the entire study period (January 2011 to April 2018); ramucirumab use appears to have increased since its approval and accounted for approximately one-third of patients receiving 2L therapy in 2017 and 2018. Similarly, I-O agents account for a relatively small proportion (2.5%) of the total cohort of patients receiving 2L therapy across the entire timeframe of this analysis, but this proportion has increased in recent years. It may be theorized that the contribution of I-O therapies may increase in the coming years as ongoing research and potential future approvals impact treatment guidelines.
      Flatiron Health data are obtained primarily (> 95%) from provider EHRs for patients at participating community centers; consequently, selection bias may exist and caution should be taken when applying these findings to a broader patient population. Additionally, as with any EHR database, data collection was intended for disease management rather than for research purposes; consequently, misclassification and incomplete data entry could have occurred. Lastly, patient medical histories may be incomplete for patients who previously received therapy in nonparticipating centers, and inpatient data are not reported in the Flatiron EHR.
      Treatment patterns in this predominately US community-based practice setting showed that over 25% of patients with advanced/metastatic GC/GEJC remained untreated, and the majority of patients receiving 1L treatment did not receive subsequent therapy. Furthermore, patients advanced quickly through lines of therapy, and outcomes remain poor for this disease. These data indicate a need for more effective and tolerable treatment options across all lines of therapy; in particular, early therapeutic options with improved efficacy and durability are likely to improve long-term outcomes within the GC/GEJC patient population.

      Clinical Practice Points

      • Few publications report real-world data on advanced/metastatic GC/GEJC.
      • Approximately 25% of patients never received any active therapy after diagnosis; of the 75% of patients who received 1L therapy, platinum- and fluoropyrimidine-based regimens were the most frequently used.
      • Subsequently, 32% of patients received 2L therapy, 14% received 3L therapy, and 6% received 4L+ of therapy
      • The median OS from start of 1L therapy was 10.6 months; the median OS was 7.6, 6.1, and 2.8 months, in 2L, 3L, and last line of therapy in patients receiving at least 4 lines.
      • Use of targeted and I-O therapies generally increased progressively with each subsequent line of therapy.

      Disclosure

      D.T. Le has received research funding from, and participated in advisory boards for, Bristol-Myers Squibb and Merck Serono , and has received speaker’s honoraria from Merck Serono. P.A. Ott has received research funding and/or consultancy fees from Amgen , ARMO Biosciences , Array , AstraZeneca , Bristol-Myers Squibb , Celldex , CytomX , Genentech , Merck Serono , Neon Therapeutics , Novartis , and Pfizer . B. Korytowsky, T.K. Le, Y. Zhang, P. Abraham, D. Patel, and T. Shangguan are employees of, and hold stock in, Bristol-Myers Squibb. H. Le and G.A. Maglinte were employed by Bristol-Myers Squibb at the time of analysis. I. Chau has participated in advisory boards for AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, Five Prime Therapeutics, Merck Serono, MSD, Oncologie International, Pierre Fabre, and Roche, and received honorarium and/or research funding from Eli Lilly , Janssen-Cilag , Merck Serono , and Sanofi .

      Acknowledgments

      This study was sponsored by Bristol-Myers Squibb . Medical writing assistance was provided by Martin Bell, PhD, of Evidence Scientific Solutions, and was funded by Bristol-Myers Squibb . Hannah Le and Gregory A. Maglinte were employees of Bristol-Myers Squibb at the time of the analysis.

      Supplemental Data

      Figure thumbnail fx1
      Supplemental Figure 1Top 20 Regimens Received in: 1L (n = 2479) (A); 2L (n = 1053) (B); 3L (n = 469) (C); and 4L+ (n = 185) (D). In 3L, Trastuzumab, Paclitaxel + Trastuzumab, Irinotecan + Trastuzumab, FOLFIRI + Trastuzumab, and Capecitabine + Ramucirumab Were all Received by the Same Number of Patients (n = 4; 0.9%)
      Abbreviations: 1L = first-line; 2L = second-line; 3L = third-line; 4L+ = fourth or more line; CAPEOX = capecitabine and oxaliplatin; FOLFIRI = folinic acid, 5-fluorouracil, and irinotecan; FOLFOX = folinic acid, 5-fluorouracil, and oxaliplatin.
      Figure thumbnail fx2
      Supplemental Figure 2Use of Chemotherapy, Ramucirumab, and Immunotherapies Over Time in 1L (n = 2479) (A); 2L (n = 1053) (B); 3L (n = 469) (C); and 4L+ (n = 185) (D). 2018 Values Based on Data From January 01, 2018 Until April 30, 2018
      Abbreviations: 1L =first-line; 2L = second-line; 3L = third-line; 4L+ = fourth or more line.
      Figure thumbnail fx3
      Supplemental Figure 3Overall Survival in Patients With Advanced/Metastatic GC/GEJC From Start of: 1L (A); 2L (B); 3L (C); and 4L+ (D)
      Abbreviations: 1L = first-line; 2L = second-line; 3L = third-line; 4L+ = fourth or more line; CI = confidence interval; GC = gastric cancer; GEJC = gastroesophageal junction cancer; OS = overall survival.

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