Metastatic Esophagogastric Adenocarcinoma Research Articles

TRIFLURIDINE/TIPIRACIL (FTD/TPI) with or without bevacizumab in previously treated patients with esophago-gastric adenocarcinoma, a randomised phase III trial

Trifluridine-tipiracil has shown a survival benefit compared with placebo in patients with chemorefractory metastatic esophago-gastric adenocarcinoma. We aimed to compare the efficacy of trifluridine-tipiracil plus bevacizumab vs trifluridine-tipiracil monotherapy in pre-treated patients with metastatic esophago-gastric adenocarcinoma. This investigator-initiated, open-label, randomized trial enrolled patients with metastatic esophago-gastric adenocarcinoma. The main inclusion criteria were patients with pre-treated metastatic esophago-gastric adenocarcinoma, and WHO performance status 0 or 1. Participants were randomly assigned (1:1) to receive oral trifluridine-tipiracil (35mg/m2 twice daily on days 1-5 and 8-12 every 28 days) alone or combined with bevacizumab (5mg/kg on days 1 and 15) until progression, unacceptable toxicity, or patient decision to withdraw. Randomisation was stratified by sex and treatment line. The primary endpoint was investigator-evaluated progression-free survival. All analyses were based on intention to treat. This trial is registered with EudraCT, 2018-004845-18. From Oct 1, 2019, to Sept 30, 2021, 103 patients were enrolled and randomly assigned to trifluridine-tipiracil (n=53) or trifluridine-tipiracil plus bevacizumab (n=50). The clinical cut-off date was March 1st, 2023, after a median follow-up of 36.6 months. Median progression-free survival was 3.1 months (95% CI 2.0-4.3) in the trifluridine-tipiracil group vs 3.9 months (3.0-6.3) in the trifluridine-tipiracil plus bevacizumab group (hazard ratio 0.68, 95% CI 0.46-1.02; p=0.058). The most frequent grade 3 or worse adverse event was neutropenia, observed in 26 (49%) patients in the trifluridine-tipiracil group vs 23 patients (46%) in the trifluridine-tipiracil plus bevacizumab group. At least one hospitalization was observed in 21 patients (40%) in the trifluridine-tipiracil group and 22 patients (44%) in the trifluridine-tipiracil plus bevacizumab group. No deaths were deemed treatment related. In patients with pre-treated metastatic esophago-gastric cancer, trifluridine-tipiracil plus bevacizumab, compared to trifluridine-tipiracil monotherapy, did not significantly prolong progression-free survival. The combination of trifluridine-tipiracil with bevacizumab was well tolerated without increase in severe neutropenia and no new safety signals. Servier, Roche.

Ramucirumab, Avelumab, and Paclitaxel as Second-Line Treatment in Esophagogastric Adenocarcinoma

Adding immune checkpoint inhibitors to chemotherapy has been associated with improved outcomes in metastatic esophagogastric adenocarcinoma, but treatment combinations and optimal patient selection need to be established. To investigate the efficacy and tolerability of the programmed cell death ligand 1 (PDL-1) inhibitor avelumab with paclitaxel plus ramucirumab. This multicenter, single-group, phase 2 nonrandomized controlled trial was conducted among patients with second-line metastatic esophagogastric adenocarcinoma. Patients pretreated with platinum plus fluoropyrimidine between April 2019 and November 2020 across 10 German centers (median follow-up, 27.4 months [95% CI 22.0-32.9 months]) were included. Data analysis was performed from January to December 2022. Patients received ramucirumab at 8 mg/kg on days 1 and 15, avelumab at 10 mg/kg on days 1 and 15, and paclitaxel at 80 mg/m2 on days 1, 8, and 15 every 4 weeks. The prespecified primary end point was overall survival (OS) rate at 6 months, with the experimental therapy considered insufficiently active with an OS rate of 50% or less and a promising candidate with an OS rate of 65% or greater. Of 60 enrolled patients, 59 patients (median [range] age, 64 [18-81] years; 47 males [70.7%]) were evaluable, including 30 patients with metastatic adenocarcinoma of the stomach and 29 patients with gastroesophageal junction. All patients were pretreated with platinum plus fluoropyrimidine, and 40 patients (67.8%) had received prior taxanes; 24 of 56 evaluable patients (42.9%) had a PDL-1 combined positive score (CPS) of 5 or greater, centrally assessed. The OS rate at 6 months was 71.2% (95% CI, 61.5%-83.7%). The median OS in the intention-to-treat population (59 patients) was 10.6 months (95% CI, 8.4-12.8 months) overall. Among patients assessable by central pathology, median OS was 9.4 months (95% CI, 7.2-11.7 months) in 32 patients with a PDL-1 CPS less than 5 and 14.0 months (95% CI, 6.0-22.1 months) in 24 patients with a PDL-1 CPS of 5 or greater (P = .25). Treatment was generally well tolerated, without unexpected toxicities. Patients with higher vs lower than median T cell repertoire richness showed an increased median OS of 20.4 months (95% CI, 7.7-33.0 months) compared with 8.3 months (95% CI, 3.7-12.9 months; hazard ratio, 0.43; 95% CI, 0.23-0.81; P = .008). Patients with lower vs higher than median cell-free DNA burden had a median OS of 19.2 months (95% CI, 8.9-29.6 months) compared with 7.3 months (95% CI, 3.2-11.4 months; hazard ratio, 0.30; 95% CI, 0.16-0.59; P < .001). In this study, the combination of avelumab with paclitaxel plus ramucirumab showed favorable efficacy and tolerability in the second-line treatment for metastatic esophagogastric adenocarcinoma. A PDL-1 CPS score of 5 or greater, cell-free DNA level less than the median, and T cell repertoire richness greater than the median were associated with increased median OS. ClinicalTrials.gov Identifier: NCT03966118.

Ramucirumab, avelumab and paclitaxel (RAP) as second line treatment in esophagogastric adenocarcinoma: Final results of the phase 2 RAP trial (AIO-STO-0218).

4032 Background: The addition of immune checkpoint inhibitors to chemotherapy has improved outcomes in patients (pts) with metastatic esophagogastric adenocarcinoma (EGA), but treatment combinations and optimal pt selection need to be established. Objective: To investigate efficacy and tolerability of the programmed death-ligand 1 (PD-L1) inhibitor avelumab with ramucirumab and paclitaxel in the second line treatment of pts with metastatic EGA (NCT03966118). Methods: In this phase 2 multicenter single-arm clinical trial the reported results are based on a median follow-up of 27.4 months. Patients with previously treated metastatic EGA, adequate organ function, and eligibility for immunotherapy were included. Interventions: Pts with metastatic EGA after progression on platinum/ fluoropyrimidine based palliative first line treatment, checkpoint-inhibitor naive, received ramucirumab 8 mg/kg (d1,15), avelumab 10 mg/kg (d1,15) and paclitaxel 80 mg/m² (d1,8,15) q4w. Results: The pre-specified primary end point was overall survival rate at 6 months (mo) (H0≤50%, H1≥65%). A total of 60 patients (pts) were enrolled, 59 were evaluable (intention to treat, ITT). Participants had a median age of 64.0 yrs (range 18-81) and 80% were men. Baseline Eastern Cooperative Oncology Group performance status was 0 in 23 pts (39.0%) and 1 in 36 pts (61.0%); 29 pts (48.2%) had EGA localized in the esophagogastric junction and 30 in the stomach (51.8%). all pts had received prior platin/ 5-FU based chemotherapy, 40pts (67.8%) had prior taxanes. Central post-hoc biomarker analysis (56 pts) showed PD-1 ligand 1 (PD-L1) combined positive score of 5 or greater in 24 pts (42.9%). The observed overall survival (OS) rate at 6 mo was 71% (95% CI 61-84%) and at 12 mo 43% (95% CI 32-58%). The median OS (ITT) was 10.6 mo (95% CI 8.4-12.8); 9.4 mo (95% CI 7.2-11.7) in pts with PD-L1 CPS &lt; 5 and 14.0 mo (95% CI 6.0-22.1; p = 0.25) in those with PD-L1 CPS≥5. Treatment was generally well tolerated without unexpected toxicities. Translational research identified subgroups with a longer survival possibly due to a higher treatment benefit. Pts with higher than median T cell repertoire (TRB) richness showed an elevated median OS of 20.4 mo compared to pts with lower than median TRB richness (med OS 8.3 mo; HR 0.43, 95% CI 0.23-0.81; p = 0.0079). Pts with lower than median cfDNA burden had a median OS of 19.2 mo compared to pts with higher than median cfDNA (med OS 7.3 mo; HR 0.30, 95% CI 0.16-0.59; p = 0.00022). Conclusions: In this multicenter clinical trial, ramucirumab and paclitaxel combined with avelumab showed favorable efficacy and tolerability in the second line treatment of pts with metastatic EGA. PD-L1 CPS≥ 5, cfDNA below the median or T cell richness above the median seem to predict for even better outcomes with median OS hardly seen before in the second line setting. Clinical trial information: NCT03966118 .

STAR-221: A randomized, open-label, multicenter, phase 3 trial of domvanalimab, zimberelimab, and chemotherapy versus nivolumab and chemotherapy in previously untreated, locally advanced, unresectable or metastatic gastric, gastroesophageal junction, and esophageal adenocarcinoma.

TPS4206 Background: The addition of programmed cell death/ligand protein 1 (PD-[L]1) inhibitors to standard chemotherapy has improved outcomes in patients with HER2-negative unresectable or metastatic esophago-gastric adenocarcinomas. Current first-line (1L) treatment for these patients comprises FOLFOX (oxaliplatin, leucovorin, and fluorouracil) and CAPOX (capecitabine and oxaliplatin) chemotherapy, with or without the addition of a PD-1 inhibitor. Domvanalimab (dom) is an Fc-silent humanized IgG1 monoclonal antibody (mAb) that blocks T cell Immunoglobulin and ITIM domains (TIGIT), reducing immunosuppression of T/natural killer (NK) cells and promoting antitumor activity. Zimberelimab (zim) and nivolumab are mAbs that bind to PD-1 on T/NK cells, preventing the immunosuppressive effects of PD-L1 and leading to enhanced immune-mediated tumor cell death. Prior studies (including ARC-7) have demonstrated that the combination of dom + zim is safe, tolerable, and has promising activity in patients with lung cancer and esophago-gastric cancers. This study will investigate whether adding anti-TIGIT therapy to the standard combination of anti-PD-1 therapy and chemotherapy in patients with locally advanced unresectable or metastatic gastric, GEJ, and esophageal adenocarcinoma provides additional clinical benefit. Methods: STAR-221 (NCT05568095) is a global, phase 3, randomized, open-label study. Eligible patients are adults with locally advanced unresectable or metastatic gastric, GEJ, or esophageal adenocarcinoma treated in the 1L setting with ≥1 measurable lesion(s) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with known HER2-positive tumors are not eligible. Approximately 970 patients will be randomized 1:1 into 1 of 2 treatment arms. Patients randomized to Arm A will receive either dom 1600 mg + zim 480 mg every 4 weeks (Q4W) in addition to FOLFOX chemotherapy once every 2 weeks (Q2W) or dom 1200 mg + zim 360 mg once every 3 weeks (Q3W) in addition to CAPOX chemotherapy Q3W. Patients randomized to Arm B will receive either nivolumab 240 mg Q2W + FOLFOX Q2W or nivolumab 360 mg Q3W + CAPOX Q3W. Randomization will be stratified by PD-L1 expression (tumor area positivity [TAP] ≥ 5% vs TAP &lt; 5%), ECOG performance status (0 vs 1), and region (USA, Canada, and EU5 countries vs Asia vs rest of world). The dual primary endpoints are overall survival (OS) in the intent-to-treat population and OS in patients with high PD-L1 expression (TAP ≥ 5%). Secondary endpoints include progression-free survival, objective response rate, duration of response, and safety and tolerability. STAR-221 is currently enrolling globally. Clinical trial information: NCT05568095 .

P-30 Ramucirumab beyond progression plus TAS-102 in patients with advanced or metastatic esophagogastric adenocarcinoma, after treatment failure on a ramucirumab-based therapy – final results of the phase II RE-ExPEL study

P-30 Ramucirumab beyond progression plus TAS-102 in patients with advanced or metastatic esophagogastric adenocarcinoma, after treatment failure on a ramucirumab-based therapy – final results of the phase II RE-ExPEL study

Final survival results of ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in previously untreated HER2 positive esophago gastric adenocarcinoma: The randomized AIO INTEGA trial.

4026 Background: In metastatic esophagogastric adenocarcinoma (EGA), the addition of PD-1 inhibitors (i) to chemotherapy has improved the outcome in selected patient populations. The randomized INTEGA trial investigated trastuzumab and PD-1i with FOLFOX or CTLA-4i in 1st line treatment of advanced HER2+ EGA. Methods: Patients with previously untreated, metastatic HER2+ (local IHC3+ or 2+/ISH+) EGA, and adequate organ function were randomized to trastuzumab and nivolumab (1mg/kg Q3W x4 /240mg Q2W for up to 12 months) in combination with ipilimumab (3mg/kg x4 Q3W; Ipi arm) or mFOLFOX6 (FOLFOX arm) accompanied by a large translational program. The primary endpoint was the 12month overall survival (OS) rate. The trial was registered at ClinicalTrials.gov, NCT03409848. Results: Between March 2018 and May 2020, 97 patients were enrolled and 88 randomized across 21 German sites with the following baseline characteristics: female/male 18/70, median age 60.5 (range 41-80), ECOG 0/1 54/34, GEJ/stomach 66/22. Central post hoc biomarker analysis on 82 evaluable patients showed PD-L1 CPS≥1/≥5 in 59/46 patients and confirmed HER2 (central IHC3+ or 2+/ISH+) positivity in 77 patients. The observed OS rate at 12 months was 70% (95% confidence interval (CI) 54-81%) in the FOLFOX arm, and 57% (95% CI 41-71%) in the Ipi arm. The progression free survival was 10.7 and 3.2 months, and the overall response rate was 53.5% and 34% in the FOLFOX and the Ipi arm, respectively. Although these data are in favor of the FOLFOX arm, the overall survival curves crossed with increased follow-up (median follow-up of 18.8 months) and thus the final median OS was 22.1 and 23.3 months, numerically favoring the Ipi arm. According to the centrally assessed CPS the OS was: 22.1 and 32.2 months in the CPS&lt;5 group, and 22.7 and 12.6 months in the CPS≥5 group for the FOLFOX and the Ipi arm, respectively. Notably, the median tumor burden calculated as the sum of target lesions was numerically lowest in the Ipi arm with higher than median OS. Conclusions: In contrast to limited short term efficacy of the Ipi arm as reflected by the lower PFS, the Ipi arm showed favorable OS, that was inversely correlated to the CPS status. Further analysis of baseline clinical and molecular data to better identify the subgroup of patients benefitting the most of trastuzumab/nivolumab/ipilimumab will be presented at the meeting. Clinical trial information: NCT03409848 . [Table: see text]

S-1 maintenance therapy in Caucasian patients with metastatic esophagogastric adenocarcinoma–final results of the randomized AIO MATEO phase II trial

Platinum-fluoropyrimidine combinations are standard of care for treatment of metastatic esophagogastric adenocarcinoma. The optimal duration of first-line chemotherapy is unknown, however, and maintenance strategies have not yet been established. MATEO is an international randomized phase II trial exploring efficacy and safety of S-1 maintenance therapy in human epidermal growth factor receptor 2 (HER2)-negative advanced esophagogastric adenocarcinoma. After 3 months of first-line platinum-fluoropyrimidine-based induction therapy, patients without progression were randomized in a 2 : 1 allocation to receive S-1 monotherapy (arm A) or to continue combination chemotherapy (arm B). The primary objective was to show non-inferiority of overall survival in the S-1 maintenance group. Progression-free survival, adverse events, and quality of life were secondary endpoints. From 2014 to 2019, 110 and 55 patients were randomized in arm A and arm B, respectively (recruitment closed prematurely). Median overall survival from randomization was 13.4 months for arm A and 11.4 months for arm B [hazard ratio 0.97 (80% confidence interval 0.76-1.23), P= 0.86]. Median progression-free survival from randomization was 4.3 and 6.1 months for arm A versus arm B, respectively [hazard ratio 1.10 (80% confidence interval 0.86-1.39), P= 0.62]. Patients in arm A had numerically fewer treatment-related adverse events (84.9% versus 93.9%) and significantly less peripheral sensory polyneuropathy ≥grade 2 (9.4% versus 36.7%). S-1 maintenance following platinum-based induction therapy leads to non-inferior survival outcomes compared with the continuation of platinum-based combination. Toxicity patterns favor a fluoropyrimidine maintenance strategy. These data challenge the continued use of platinum combination chemotherapy after response to 3 months induction therapy in patients with advanced human epidermal growth factor receptor 2-negative esophagogastric adenocarcinoma.

Modified FOLFOX plus/minus nivolumab and ipilimumab vs FLOT plus nivolumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: The randomized phase 2 IKF-S628 Moonlight trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

4050 Background: FOLFOX plus nivolumab has become standard of care for first-line therapy of patients (pts) with esophagogastric adenocarcinomas (EGA). The AIO-STO-0417 trial (Moonlight) is a multi-cohort treatment optimization trial that evaluates the combination of FOLFOX alone (Arm B) vs FOLFOX plus nivolumab (nivo) and ipilimumab (ipi) administered in parallel (Arm A/A1) or sequentially (Arm A2) and FLOT plus nivolumab administered in parallel (Arm C) for 1L-treatment of metastatic or advanced inoperable Her-2 negative EGA. The aim is to generate signals whether a. dual checkpoint inhibition or b. a triplet chemotherapy is beneficial in the context of nivolumab therapy for this disease. Methods: Pts were randomized 1:1 to Arm A (mFOLFOX q2w plus nivo 240 mg q2w + ipi 1 mg/kg q6w administered in parallel) or B (mFOLFOX alone). In a subsequent phase pts were randomized 1:2 to Arm A1 (identical to Arm A) or A2 (three cycles of mFOLFOX followed by nivo q2w + ipi q6w, with optional repetition). In a final phase, all pts were allocated to single Arm C (FLOT q2w + nivo q2w). The primary endpoint was progression-free survival (PFS) based on the ITT population for Arm A vs Arm B and PFS rate at 6 months (PFS@6) for Arms A2 and C. Main secondary endpoints were PFS and ORR. Here, we present results for Arms A/A1, A2 and B. Results: A total of 262 pts were enrolled, Arm A (n=60), Arm B (n=60), Arm A1 (n=30), Arm A2 (n=60) and Arm C (n=52, results presented elsewhere). Baseline characteristics were comparable in all arms. Overall PD-L1 expression (CPS ≥1) was low with 41% and balanced between Arms A/A1, A2 and B. Analysis of pooled Arms A/A1 (n=90) showed an increase in toxicity (pts with AEs grade ≥3 88% vs 65% in Arm B and 75% in Arm A2, treatment related SAEs grade ≥3 A/A1 41% vs B 18% vs A2 17%) but not in activity. Arm A/A1 compared with Arm A2 was more effective in terms of PFS@6 (48% vs 30%), median PFS 5.8 vs 4.0 months and objective response rate (ORR) 46% vs 30%. Conclusions: Albeit the small number of pts in each cohort we conclude that in the first-line setting of metastatic EGA. a) Chemo plus dual checkpoint inhibition administered in parallel is associated with an increase in toxicity but not activity. b) Although associated with lower toxicity the use of sequential chemo followed by IO monotherapy is insufficient. The relatively low numbers of patients with PD-L1 CPS ≥1 may have impacted these results. Clinical trial information: NCT03647969 .

Exploratory Analysis of Patients With Gastric/Gastroesophageal Junction Adenocarcinoma With or Without Liver Metastasis From the Phase 3 RAINBOW Study.

Liver metastasis (LM) is reported in approximately 40% of patients with advanced/metastatic gastric/gastroesophageal junction adenocarcinoma (metastatic esophagogastric adenocarcinoma; mGEA) and is associated with a worse prognosis. This post-hoc analysis from the RAINBOW trial reported the efficacy, safety, and biomarker outcomes of ramucirumab and paclitaxel combination treatment (RAM+PAC) in patients with (LM+) and without (LM-) LM at baseline. Patients (n=665) were randomly assigned on a 1:1 basis to receive either RAM+PAC (LM+: 150, LM-: 180) or placebo and paclitaxel (PL+PAC) (LM+: 138, LM-: 197). The overall survival (OS) and progression-free survival (PFS) were evaluated using stratified Kaplan-Meier and Cox regression models. The correlation of dichotomized biomarkers (VEGF-C, D; VEGFR-1,2) with efficacy in the LM+ versus LM- subgroups was analyzed using the Cox regression model with reported interaction P-values. The presence of LM was associated with earlier progression than those without LM, particularly in patients receiving PL+PAC (hazard ratio [HR], 1.68). RAM+PAC treatment improved OS and PFS irrespective of LM status but showed greater improvement in LM+ than that in LM- (OS HR, 0.71 [LM+] vs. 0.88 [LM-]; PFS HR, 0.47 [LM+] vs. 0.76 [LM-]). Treatment-emergent adverse events were similar between patients with and without LM. No predictive relationship was observed between biomarker levels (VEGF-C, D; VEGFR-1,2) and efficacy outcome (OS, PFS) (all interaction P-values >0.05). RAM provided a significant benefit, irrespective of LM status; however, its effect was numerically stronger in patients with LM. Therefore, RAM+PAC is a clinically meaningful therapeutic option for patients with mGEA and LM. ClinicalTrials.gov Identifier: NCT01170663.

SOURCE beyond first-line: A survival prediction model for patients with metastatic esophagogastric adenocarcinoma after failure of first-line palliative systemic therapy.

Prior models have been developed to predict survival for patients with esophagogastric cancer undergoing curative treatment or first-line chemotherapy (SOURCE models). Comprehensive clinical prediction models for patients with esophagogastric cancer who will receive second-line chemotherapy or best supportive care are currently lacking. The aim of our study was to develop and internally validate a new clinical prediction model, called SOURCE beyond first-line, for survival of patients with metastatic esophagogastric adenocarcinoma after failure of first-line palliative systemic therapy. Patients with unresectable or metastatic esophageal or gastric adenocarcinoma (2015-2017) who received first-line systemic therapy (N=1067) were selected from the Netherlands Cancer Registry. Patient, tumor and treatment characteristics at primary diagnosis and at progression of disease were used to develop the model. A Cox proportional hazards regression model was developed through forward and backward selection using Akaike's Information Criterion. The model was internally validated through 10-fold cross-validations to assess performance. Model discrimination (C-index) and calibration (slope and intercept) were used to evaluate performance of the complete and cross-validated models. The final model consisted of 11 patient tumor and treatment characteristics. The C-index was 0.75 (0.73-0.78), calibration slope 1.01 (1.00-1.01) and calibration intercept 0.01 (0.01-0.02). Internal cross-validation of the model showed that the model performed adequately on unseen data: C-index was 0.79 (0.77-0.82), calibration slope 0.93 (0.85-1.01) and calibration intercept 0.02 (-0.01 to 0.06). The SOURCE beyond first-line model predicted survival with fair discriminatory ability and good calibration.

Efficacy of Ipilimumab vs FOLFOX in Combination With Nivolumab and Trastuzumab in Patients With Previously Untreated ERBB2-Positive Esophagogastric Adenocarcinoma

In metastatic esophagogastric adenocarcinoma (EGA), the addition of programmed cell death 1 (PD-1) inhibitors to chemotherapy has improved outcomes in selected patient populations. To investigate the efficacy of trastuzumab and PD-1 inhibitors with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors or FOLFOX in first-line treatment of advanced ERBB2-positive EGA. This phase 2 multicenter, outpatient, randomized clinical trial with 2 experimental arms compared with historical control individually was conducted between March 2018 and May 2020 across 21 German sites. The reported results are based on a median follow-up of 14.3 months. Patients with previously untreated, metastatic ERBB2-positive (local immunohistochemistry score of 3+ or 2+/in situ hybridization amplification positive) EGA, adequate organ function, and eligibility for immunotherapy were included. Data analysis was performed from June to September 2021. Patients were randomized to trastuzumab and nivolumab (1 mg/kg × 4/240 mg for up to 12 months) in combination with mFOLFOX6 (FOLFOX arm) or ipilimumab (3 mg/kg × 4 for up to 12 weeks) (ipilimumab arm). The primary end point was survival improvement with a targeted increase of the 12-month overall survival rate from 55% (trastuzumab/chemotherapy-ToGA regimen) to 70% in each arm. A total of 97 patients were enrolled, and 88 were randomized (18 women, 70 men; median [range] age, 61 [41-80] years). Baseline Eastern Cooperative Oncology Group performance status was 0 in 54 patients (61%) and 1 in 34 patients (39%); 66 patients (75%) had EGA localized in the esophagogastric junction and 22 in the stomach (25%). Central post hoc biomarker analysis (84 patients) showed PD-1 ligand 1 (PD-L1) combined positive score of 1 or greater in 59 patients (72%) and 5 or greater in 46 patients (56%) and confirmed ERBB2 positivity in 76 patients. The observed overall survival rate at 12 months was 70% (95% CI, 54%-81%) with FOLFOX and 57% (95% CI, 41%-71%) with ipilimumab. Treatment-related grade 3 or greater adverse events (AEs) and serious AEs occurred in 29 and 15 patients in the FOLFOX arm and in 20 and 17 patients in the ipilimumab arm, respectively, with a higher incidence of autoimmune-related AEs in the ipilimumab arm and neuropathy in the FOLFOX arm. Liquid biopsy analyses showed strong correlation of early cell-free DNA increase with shorter progression-free and overall survival and emergence of truncating and epitope-loss ERBB2 resistance sequence variations with trastuzumab treatment. In this randomized clinical trial, trastuzumab, nivolumab, and FOLFOX showed favorable efficacy compared with historical data and trastuzumab, nivolumab, and ipilimumab in ERBB2-positive EGA. The ipilimumab arm yielded similar OS compared with the ToGA regimen. ClinicalTrials.gov Identifier: NCT03409848.

SOURCE beyond first-line: A survival prediction model for patients with metastatic esophagogastric adenocarcinoma after failure of first-line palliative systemic therapy.

4037 Background: Prediction models for survival may aid shared decision making between physicians and patients. Prior models have been developed that predict survival for patients with potentially curable esophagogastric cancer and patients with metastatic esophageal cancer who start first-line therapy (the SOURCE models). The aim of this study was to develop and internally validate a registry-based clinical prediction model, called SOURCE beyond first-line, for survival of patients with metastatic esophagogastric cancer after failure of first-line palliative systemic therapy. Methods: Patients with unresectable or metastatic (synchronous or metachronous) esophageal or gastric cancer who received first-line systemic therapy (N = 1067) between 2015-2017 were selected from the Netherlands Cancer Registry. Follow-up data were retrieved in 2019. Patient, tumor and treatment characteristics at primary diagnosis and at progression of disease, were used to develop the prediction model. A Cox proportional hazards regression prediction model was developed through forward and backward selection using Akaike’s Information Criterion. The model was internally validated through 10-fold cross-validations to assess performance on unseen data. Model discrimination (C-index) and calibration (slope and intercept) were used to evaluate performance of the complete and cross-validated models. Results: The final model consisted of 10 patient, tumor and treatment characteristics. The C-index was 0.75 (0.74-0.77), the calibration slope 0.99 (0.98-0.99) and the calibration intercept 0.02 (0.01-0.02). Internal cross-validation of the model showed that the model performed adequately on unseen data: C-index 0.79 (0.76-0.80), calibration slope 1.02 (1.00-1.04) and calibration intercept -0.01 (-0.01-0.02). Conclusions: The SOURCE beyond first-line model predicted survival with fair discriminatory ability and good calibration, and is a valuable addition to the existing SOURCE prediction models. In the future this model will be integrated in an online decision support tool that can be used in clinical practice to aid personalized treatment.

O-4 Trifluridine/tipiracil (TAS-102) with or without bevacizumab in patients with pretreated metastatic esophago-gastric adenocarcinoma (mEGA): A Danish randomized trial (LonGas)

Trifluridine/tipiracil (FTD/TPI, also known as TAS-102) prolongs survival in patients with heavily pretreated metastatic gastric cancer (Shitara, Lancet Oncol 2018). The randomized Danish Lonsurf trial showed that a combination of FTD/TPI and bevacizumab prolonged PFS and OS in patients with chemo-refractory metastatic colorectal cancer (Pfeiffer, Lancet Oncol 2020). Inspired by these results, we designed the present investigator-initiated randomized trial testing FTD/TPI and bevacizumab in patients with pretreated mEGA. The main inclusion criteria were histologically confirmed mEGA, previous therapy with a fluoropyrimidine and platinum, PS 0-1. In arm A, FTD/TPI was administered orally at the dose of 35 mg/m2/dose bid from days 1-5 and 8-12 and in arm B the same dose of FTD/TPI was combined with bevacizumab at a dose of 5 mg/kg on day 1 and on day 15 of a 28-day treatment cycle. A total of 96 patients were needed to show an increase in progression-free survival (PFS – primary endpoint) from 2.0 months to 4.0 months. To ensure at least 96 evaluable patients we included 103 patients. Here we report efficacy and safety data of all randomized patients (intention-to-treat population). 103 pretreated patients with mEGA were randomized from October 2019 to September 2021 at 4 Danish University Hospitals. Baseline characteristics were (arm A/arm B): median age 66/64 years, females 19%/22%; PS 0 47%/44%, median number of metastatic sites 2/2, at least 2 prior lines of therapy 42%/42%. Baseline characteristics including blood tests were well balanced. There was no significant difference in PFS (6 months PFS 28% vs 40%, 12 months PFS 6% vs18%, median PFS 3.7 vs 3.9 months; HR 0.71, p=0.11), median OS (9.0 vs 9.9 months; HR 0.86, p=0.53), response rate (2% vs 6%; p=0.35) or disease control rate (47% vs 56%; p=0.43)b. Therapies were well tolerated with adverse events as expected and with no significant difference in severe toxicity. Neutropenia ≥ grade 3 was observed in 49%/46% of patients, but only febrile neutropenia in 8%/10%. Other severe adverse events were fatigue 4%/10% and nausea 6%/6%. In patients with pretreated mEGA, FTD/TPI + bevacizumab did not improve efficacy compared with FTD/TPI monotherapy in patients previously treated with fluoropyrimidine and platinum. Both regimens produced encouraging PFS and OS and both regimens were well tolerated with adverse events as expected. Compared to the heavily pretreated patients in TAGS, only 42% of patients in LonGas had received at least 2 lines of therapy. This may account for the unexpected long PFS in patients receiving FTD/TPI monotherapy.

A population-based study in synchronous versus metachronous metastatic esophagogastric adenocarcinoma.

Background:Real-world data on treatment and outcomes in patients with synchronous metastatic disease compared with patients with metachronous metastatic disease in esophagogastric cancer have not been published before. The aim of our study was to explore treatment, overall survival (OS), and time to treatment fialure (TTF) in patients with synchronous and metachronous metastatic esophagogastric adenocarcinoma.Methods:Patients with synchronous metastatic disease (2015–2017) and patients with metachronous metastatic disease initially treated with curative intent for nonmetastatic disease (2015–2016) were selected from the Netherlands Cancer Registry. OS and TTF were assessed from metastatic diagnosis for patients with synchronous, early metachronous (⩽6 months) or late metachronous (>6 months) metastatic disease using Kaplan–Meier curves with two-sided log-rank test.Results:Median OS was 4.2, 2.1, and 4.4 months in patients with synchronous, early metachronous, and late metachronous metastatic disease, respectively (p < 0.001). The proportion of patients receiving systemic treatment was 41.3%, 21.5%, and 32.5% for synchronous, early metachronous, and late metachronous metastatic disease, respectively (p = 0.001). Among patients receiving systemic treatment, median OS was 8.8, 4.5, and 9.1 months (p < 0.001) and median TTF was 6.1, 3.8, and 5.7 months (p < 0.001) in synchronous, early metachronous, and late metachronous metastatic disease, respectively.Conclusion:Patients with early metachronous metastatic disease have a worse survival compared with patients with synchronous or late metachronous metastatic disease. These patients less often receive systemic treatment, and even when treated, survival is worse compared with patients with synchronous or late metachronous metastatic disease, suggesting a more aggressive tumor behavior.

1449P Hospital volume and beyond first-line palliative systemic treatment administration in metastatic esophagogastric adenocarcinoma: A population-based study

1449P Hospital volume and beyond first-line palliative systemic treatment administration in metastatic esophagogastric adenocarcinoma: A population-based study

Ipilimumab or FOLFOX with Nivolumab and Trastuzumab in previously untreated HER2-positive locally advanced or metastatic EsophagoGastric Adenocarcinoma - the randomized phase 2 INTEGA trial (AIO STO 0217)

BackgroundEsophagogastric adenocarcinoma (EGA) currently represents a main cause of cancer related death. Despite an intensified treatment for locally advanced or metastatic EGA with a doublet chemotherapy consisting of a platinum compound and a fluoropyrimidine in combination with trastuzumab for HER2-positive disease or in selected cases with docetaxel, survival remains poor. Recently, immune-oncology based strategies relevantly improved the treatment of different solid tumors and showed some promise in late or later stage trials in EGA. Notably, the combination of immunotherapy with trastuzumab to enhance anti-tumor immunity through activation of innate and adaptive immunity was beneficial in preclinical studies or clinical studies in breast cancer.MethodsThe INTEGA study is an open-label, randomized, multicenter, exploratory phase II trial designed to assess clinical performance, safety and tolerability of ipilimumab or 5-FU/folinic acid and oxaliplatin (FOLFOX) in combination with nivolumab and trastuzumab in patients with previously untreated HER2-positive, locally advanced or metastatic EGA. The primary objective is to determine the clinical performance of ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in terms of overall survival. Secondary objectives are safety and tolerability, efficacy in terms of progression-free survival and objective response rate and blood-based signatures (e.g. immune response or suppression of anti-HER2 resistance) that may correlate with treatment response.DiscussionRecent evidence from the phase II NCT02954536 study (oxaliplatin, capecitabine, trastuzumab and pembrolizumab) suggests the clinical feasibility of combining chemotherapy, trastuzumab and checkpoint inhibition in EGA. However, evidence for a chemotherapy-free regimen is also mounting in HER2-positive disease (NCT02689284) i.e. margetuximab and Pembrolizumab. Both studies excelled with high overall response rates and manageable toxicities. The INTEGA study aims to comparatively assess these results and select a promising new 1st line regimen which then needs to be confirmed in a randomized phase III trial. Further, the translational part of the study might help to better stratify patients and tailor treatment of either arm.Trial registrationNCT03409848 24.01.2018.

Irinotecan with or without capecitabine as a beyond 2nd line regime for esophago-gastric adenocarcinomas.

e16545 Background: Purpose: The aim of this retrospective study was to assess the efficacy and toxicity of irinotecan +/- capecitabine for patients with metastatic esophago-gastric (EG) adenocarcinomas previously treated with at least two chemotherapy regimens including platinum-based, fluoropyramidines and taxanes. Introduction: Treatment for metastatic EG cancer beyond 2nd line remains controversial. Recently, the TAGS phase III trial (Shitara et al., 2018) showed overall survival benefit with Trifluridine/tipiracil of 2.1 months compared to placebo as a third line. Apatinib is also approved for use as third line in China (Li et al., 2013). Based on minimal evidence (Kang et al., 2013), irinotecan in combination with capecitabine is used in the UK. We performed a retrospective study to assess the efficacy and toxicity of irinotecan as a beyond 2nd line regime in metastatic EG adenocarcinomas in one of Europe’s largest cancer centres, The Christie. Methods: Data was collected retrospectively from all metastatic EG adenocarcinoma patients who were treated with irinotecan +/- capecitabine as a beyond 2nd line palliative treatment at the Christie Hospital from January 2014 to December 2019. Irinotecan was either given 2 or 3 weekly at dose of 180 mg/m² with or without capecitabine 800 mg/m². Response rate (RR) was calculated according to RECIST version 1.1, overall survival measured and toxicity data collected. Results: Fifty-six patients received irinotecan as beyond 2nd line palliative chemotherapy. Out of the thirty-seven patients with measurable disease on their scans, the overall response rate was 8.1% and the disease control rate was 51.4% as per RECIST 1.1. Median overall survival was 5 months (95% CI 4.2-5.8). The presence of grade 3-4 toxicities was 16% (9 patients) and included neutropenia, fatigue, nausea and diarrhea. On average, 3.7 cycles were administered, 32% (18 patients) required dose reductions, mainly secondary to grade 2 diarrhea and fatigue. Conclusions: Irinotecan in combination with capecitabine is efficacious as a beyond 2nd line regime in metastatic EG with an acceptable toxicity profile with a limited role in patients with resistant disease to first line platinum-based chemotherapies with fluoropyramidines.

813P - Increased assessment of HER2 in metastatic gastroesophageal cancer patients: A nationwide population-based cohort study

BackgroundAddition of trastuzumab to first-line palliative chemotherapy in esophagogastric cancer patients with HER2 overexpression has shown to improve survival and is therefore considered standard of care. The aim of this study was to assess HER2 testing, trastuzumab administration and overall survival (OS) in a nationwide cohort of metastatic esophagogastric cancer patients. MethodsPatients with synchronous metastatic esophagogastric adenocarcinoma diagnosed between 2010-2016 that received palliative systemic treatment (N=2846) were identified from the Netherlands Cancer Registry. Details on HER2 assessment were extracted from pathology reports from the Dutch Pathology Registry. For determination of HER2 positivity or negativity, the criteria on HER2 assessment of the ToGA trial were used. Proportions of HER2 tested patients were analyzed between hospital volume categories using Chi-square tests, and over time using trend analysis. OS was tested using the Kaplan Meier method and log rank test. ResultsHER2 assessment was performed in 54% of all 2846 patients that received palliative chemotherapy, and increased from 18% to 88% between 2010 and 2016 (P<0.01). Median OS of all patients increased from 6.9 (IQR 3.5-12.0) months in 2010-2013 to 7.9 (IQR 3.6-13.6) months in 2014-2016 (P<0.001). Between the hospitals, the proportion of tested patients varied between 29-100%, and was the highest in high-volume hospitals (P<0.01). HER2 status was positive in 19%, negative in 67% and unknown in 14% of the 1524 tested patients. Overall, 77% of the HER2 positive patients received trastuzumab. Median OS was significantly higher in patients with both positive (8.8 months) and negative (7.4 months) HER2 status that were diagnosed in 2015-2016, compared with non-tested patients (5.6 months; P<0.05). ConclusionsDaily practice management of metastatic esophagogastric cancer patients has changed due to increased determination of HER2 status and administration of trastuzumab, which might have contributed to the improved survival in these patients. Advances in clinical practice could include a further increase in awareness of HER2 testing among pathologists and clinicians, especially in low-volume hospitals, and in the administration of trastuzumab in case of HER2 overexpression. Legal entity responsible for the studyThe authors. FundingRoche. DisclosureR.H.A. Verhoeven: Research grant / Funding (institution): BMS; Research grant / Funding (institution): Roche. N. Haj Mohammad: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD. J. de Vos-Geelen: Non-remunerated activity/ies: BTG; Research grant / Funding (institution), Non-remunerated activity/ies: Servier; Advisory / Consultancy: Shire. T. Van Voorthuizen: Non-remunerated activity/ies: Astellas; Non-remunerated activity/ies: Ipsen; Non-remunerated activity/ies: Roche; Non-remunerated activity/ies: Bayer. M. van Oijen: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Amgen. H.W.M. van Laarhoven: Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Philips; Research grant / Funding (institution): Roche. All other authors have declared no conflicts of interest.

Phase I Dose Escalation Study with Expansion Cohort of the Addition of Nab-Paclitaxel to Capecitabine and Oxaliplatin (CapOx) as First-Line Treatment of Metastatic Esophagogastric Adenocarcinoma (ACTION Study).

First-line triplet chemotherapy including a taxane may prolong survival in patients with metastatic esophagogastric cancer. The added toxicity of the taxane might be minimized by using nab-paclitaxel. The aim of this phase I study was to determine the feasibility of combining nab-paclitaxel with the standard of care in the Netherlands, capecitabine and oxaliplatin (CapOx). Patients with metastatic esophagogastric adenocarcinoma received oxaliplatin 65 mg/m2 on days 1 and 8, and capecitabine 1000 mg/m2 bid on days 1–14 in a 21-day cycle, with nab-paclitaxel on days 1 and 8 at four dose levels (60, 80, 100, and 120 mg/m2, respectively), using a standard 3 + 3 dose escalation phase, followed by a safety expansion cohort. Baseline tissue and serum markers for activated tumor stroma were assessed as biomarkers for response and survival. Twenty-six patients were included. The first two dose-limiting toxicities (i.e., diarrhea and dehydration) occurred at dose level 3. The resulting maximum tolerable dose (MTD) of 80 mg/m2 was used in the expansion cohort, but was reduced to 60 mg/m2 after three out of eight patients experienced diarrhea grade 3. The objective response rate was 54%. The median progression-free (PFS) and overall survival were 8.0 and 12.8 months, respectively. High baseline serum ADAM12 was associated with a significantly shorter PFS (p = 0.011). In conclusion, albeit that the addition of nab-paclitaxel 60 mg/m2 to CapOx may be better tolerated than other taxane triplets, relevant toxicity was observed. There is a rationale for preserving taxanes for later-line treatment. ADAM12 is a potential biomarker to predict survival, and warrants further investigation.

Current and future therapies for targeting HER2 mutations in gastrointestinal cancer

ABSTRACTIntroduction: Gastrointestinal (GI) cancers altogether represent the most common cancer type. HER2 is found to be present in nearly all histologic types of GI cancers in variable degrees of expression. Over the last decade, substantial advances have been made in targeting HER2-positive cancers.Areas covered: The present review summarizes the current progress and future directions for HER2 targeted therapies in GI cancers, including esophagogastric, pancreaticobiliary, and colon cancers. To date trastuzumab is the only anti-HER2 therapy approved for metastatic esophagogastric adenocarcinoma. Efforts are ongoing to expand the therapeutic role of HER2 to other GI cancers and overcome mechanisms of drug resistance. Novel agents and combinations are being tested in most HER2 positive GI cancers including early stage disease. These are of recent interest in colorectal cancer with studies indicating that HER2 overexpression might increase resistance to anti-EGFR therapy and may be potentially targeted.Expert commentary: With the current ability to sequence tumors and detect genetic alterations, emphasis should be put on genomically-selected pan-tumor targeted therapies. HER2 is a perfect example of a promising drug target in GI cancers.