Advanced Gastric Adenocarcinoma Research Articles

Evidence to Date on the Therapeutic Potential of Zolbetuximab in Advanced Gastroesophageal Adenocarcinoma.

Gastric adenocarcinoma (GAC) continues to be a prevalent worldwide malignancy and a leading cause of cancer death, and it is frequently cited as incurable. Targeted therapy in GAC has lagged behind other solid tumors. The human epidermal growth factor receptor-2 (HER-2) represented the single target in GACs for many years, seen in approximately 20% of patients with advanced GAC. Recent advances in management now include the addition of immunotherapy checkpoint inhibition to select front-line advanced GACs. Unfortunately, outcomes remain poor for most patients. We anticipate finding a key to future discoveries in GACs in next-generation sequencing and more targeted approaches. Claudin 18.2 (CLDN18.2) has emerged as a therapeutic target in GACs. CLDN18.2 is reportedly expressed in 14-87% of GACs, and CLDN18.2 is available for monoclonal antibody (mAb) binding as it is expressed on the outer cell membrane. Here, we review the exploration of CLDN18.2 as a target in GACs via the use of zolbetuximab (IMAB362). Zolbetuximab is now under priority FDA review for GACs, and we eagerly await the review outcome.

Overcoming resistance to programmed cell death protein 1 (PD-1) blockade with allogeneic invariant natural killer T-cells (iNKT).

Gastric cancer is the 5th most common malignancy worldwide with only 36% of patients with metastatic disease surviving beyond 5 years. Despite therapeutic improvements with the advent of immune checkpoint inhibitors, most patients with gastric cancer develop disease progression related to tumor resistance. Novel immunotherapeutic approaches, including invariant natural killer (iNKT) cells, are in clinical development and represent potential therapeutic options to overcome resistance. AgenT-797 is an allogeneic human unmodified iNKT derived from healthy donors. Activation of iNKT cells by tumor lipid antigens can trigger direct cytotoxicity and promote indirect anti-tumor immune responses such as recruitment and activation of T cells, NK cells, and dendritic cells through secretion of cytokines and IFNγ. We describe immune modulation leading to durable tumor response in a patient with microsatellite instability-high (MSI-H) advanced gastric adenocarcinoma treated with agent-797 after progression on standard chemotherapy and anti-PD-1 therapy.

Real-world comparison of treatment outcomes between advanced esophagogastric junction adenocarcinoma and gastric adenocarcinoma.

267 Background: The characteristics of esophagogastric junction adenocarcinoma (EGJA) differ from those of gastric adenocarcinoma (GA). Although chemotherapy for advanced GA has been adapted for advanced EGJA, its efficacy remains unknown. This study aims to elucidate the effectiveness of chemotherapy for advanced EGJA in real-world practice. Methods: This retrospective study compared treatment outcomes between advanced GA and EGJA in patients with performance status (PS) 0 to 2 who received doublet or triplet chemotherapy, including platinum agents, as first-line treatment at our hospital between 2010 and 2020. Patients with non-curative resection factors limited to positive peritoneal cytology, or those who relapsed during adjuvant chemotherapy or within 6 months after its completion, were excluded. Results: Out of the total 825 patients, 765 had GA and 60 had EGJA. The baseline characteristics of the GA and EGJA groups were as follows, respectively: median age 65.0 and 59.5 years (p = 0.02); PS 0, 35.9% and 33.3%; PS 1, 57.5% and 65.0%; PS 2, 6.5% and 1.7% (p = 0.28); HER2 positive, 16.1% and 26.7% (p = 0.06); diffuse histology, 52.7% and 26.7% (p < 0.01); lymph node metastasis, 74.0% and 93.3% (p < 0.01); peritoneal metastasis, 66.4% and 25.0% (p < 0.01); liver metastasis, 26.4% and 40.0% (p = 0.03); lung metastasis, 6.5% and 16.7% (p < 0.01). The proportions of fluoropyrimidine, taxanes, and irinotecan in all treatment lines did not differ between the two groups (fluoropyrimidine, 99.7% vs. 100%; taxanes, 70.1% vs. 73.3%; irinotecan, 23.0% vs. 23.3%). However, the EGJA group used ramucirumab, trastuzumab, and immune checkpoint inhibitors (ICIs) significantly more frequently than the GA group (ramucirumab, 27.8% vs. 43.3%, p = 0.02; trastuzumab, 15.4% vs. 26.7%, p = 0.03; ICIs, 21.0% vs. 41.7%, p < 0.01). Overall survival did not differ between the two groups (median, 14.8 months vs. 18.5 months, HR 0.80; 95% CI, 0.59-1.10, p = 0.17). Moreover, multivariate analysis revealed that EGJA and GA had a comparable prognosis (HR 1.23; 95% CI, 0.87-1.72, p = 0.24). HER2 positivity was a favorable prognostic factor in multivariate analysis, whereas diffuse histology, poor PS, lymph node metastasis, liver metastasis, and the presence of peritoneal metastasis were poor prognostic factors. There was no difference in time-to-treatment failure between the two groups for first-line (median, 6.1 vs. 4.9 months, HR 0.96; 95% CI, 0.73-1.28, p = 0.80), second-line (median, 2.9 vs. 3.5 months, HR 0.99; 95% CI, 0.73-1.34, p = 0.93), and third-line treatment (median, 1.9 vs. 2.7 months, HR 0.78; 95% CI, 0.53-1.13, p = 0.62). Conclusions: In real-world practice, the efficacy of chemotherapy for advanced EGJA was comparable to that for advanced GA.

Tislelizumab plus chemotherapy (chemo) versus placebo plus chemo as first-line treatment for locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: RATIONALE-305 European/North American patient subgroup.

330 Background: Tislelizumab (TIS), an anti-programmed cell death protein 1 monoclonal antibody, plus chemo, demonstrated significant overall survival (OS) benefit vs placebo (PBO) plus chemo (15.0 vs 12.9 months [mo], hazard ratio [HR]=0.80, 95% confidence interval [CI]: 0.70, 0.92, P=0.0011) as first-line therapy in patients (pts) with advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC) in the randomized, double-blind, global, phase 3 RATIONALE-305 study (NCT03777657). Here we present results from the European/North American (Eu/NA) pts subgroup analysis. Methods: This double-blind, global, phase 3 study evaluated adult pts with previously untreated, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable, or metastatic GC/GEJC, regardless of programmed death-ligand 1 (PD-L1) expression status. Eligible pts were randomized (1:1) to receive TIS 200 mg or PBO intravenously once every 3 weeks plus investigator chosen chemo (5-fluorouracil + cisplatin or capecitabine + oxaliplatin). The primary endpoint was OS in the PD-L1+ (patients with tumor area positivity score ≥5%) and intent-to-treat (ITT) analysis sets. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. Results: Of 997 pts enrolled, 249 (25.0%) were from Eu/NA (TIS plus chemo arm, n=125; PBO plus chemo arm, n=124). In the Eu/NA pts subgroup, after a minimum follow-up of 26.6 mo at final analysis, TIS plus chemo resulted in OS improvements vs PBO plus chemo in the PD-L1+ (HR=0.75, [95% CI: 0.52, 1.07]; 24 mo rate 27.6% vs 12.5%) and ITT analysis sets (HR=0.71, [95% CI: 0.54, 0.94]; 24 mo rate 27.6% vs 13.6%). TIS plus chemo resulted in favorable PFS vs PBO plus chemo (HR=0.84, 95% CI: 0.63, 1.11), numerically higher ORR (36.0% vs 31.5%), and longer DoR (median 7.5 mo [95% CI: 4.4, 12.0] vs 5.0 mo [95% CI: 3.9, 6.7]). Sixty (48.8%) pts in the TIS plus chemo arm and 61 (49.2%) pts in the PBO plus chemo arm experienced grade ≥3 treatment-related treatment-emergent adverse events (TRAEs). Sixteen (13.0%) and seven (5.6%) pts discontinued treatment due to TRAEs in the TIS plus chemo and PBO plus chemo arms, respectively. Deaths due to TRAEs occurred in two (1.6%) pts in the TIS plus chemo arm and one (0.8%) pt in the PBO plus chemo arm. Conclusions: TIS plus chemo showed OS benefit compared with PBO plus chemo and a manageable safety profile in pts in the Eu/NA subgroup with previously untreated, HER2-negative, locally advanced unresectable, or metastatic GC/GEJC. These findings are consistent with the published results in the overall study population. Clinical trial information: NCT03777657 .

Phase 2 study of trastuzumab deruxtecan as neoadjuvant treatment for HER2-positive gastric and gastroesophageal junction adenocarcinoma (EPOC2003).

309 Background: Currently no HER2 directed therapy is available in the perioperative setting for gastric and gastroesophageal junction (GEJ) cancer. Trastuzumab deruxtecan (T-DXd) received regulatory approval based on the encouraging efficacy demonstrated in the DESTINY-Gastric01 and DESTINY-Gastric02 studies in pretreated patients (pts) with metastatic gastric and GEJ cancer. This multicenter phase 2 study aimed to evaluate the clinical activity and safety of neoadjuvant T-DXd for locally advanced gastric and GEJ cancer. Methods: Eligible pts possessed previously untreated locally advanced gastric and GEJ adenocarcinoma with clinical stage of T2-4 and/or N+ without distant metastasis. The main cohort enrolled pts exhibiting HER2-positivity, defined as IHC 3+ or IHC 2+ with ISH+ by local assessment. An exploratory cohort included patients with HER2-low expression (IHC1+ or 2+ with ISH negative) with serum HER2-ECD exceeded 11.6 ng/ml. Treatment included three cycles of T-DXd administered every 3 weeks, followed by surgery. The primary endpoint was the major pathological response (MPR) rate by central assessment, with an expected rate of 45% and a futility threshold of 20%. The planned sample size in the main cohort was 27 pts with one-sided alpha of 10% and power of 90%, while an additional 10 pts would be enrolled into the exploratory cohort. Pre- and post-treatment samples were subjected to biomarker analyses. Clinical trial identification: NCT05034887. Results: Between November 2021 and November 2022, 27 pts were enrolled into the main cohort from seven Japanese sites. The majority of the pts had IHC3+ (24pts). The primary sites were gastric (16 pts) and GEJ (11 pts). Clinical stages ranged from II/III/IVa: 2/21/4 pts. Of the cohort, 26 pts completed planned 3 courses of T-DXd and one pt discontinued because of toxicity. R0 resection was achieved in 25 pts, with one undergoing R1 resection. The MPR rate as the primary endpoint was 14.8% (80% CI 6.6 % - 27.5 %) which did not surpass the predefined 20%. The pCR rate was 3.7% (95% CI 0.1 % - 19.0 %). There were no new safety signals during T-DXd treatment and during the post-surgery phase. Biomarker analyses remain ongoing. Conclusions: T-DXd monotherapy showed modest single agent activity for locally advanced HER2-positive gastric or GEJ adenocarcinoma in this phase 2 study. An additional cohort combining perioperative T-DXd with capecitabine and durvalumab is planned, to assess whether treatment efficacy and outcomes can be enhanced. Clinical trial information: NCT05034887 .

Clinical outcomes of conversion surgery following immune checkpoint inhibitors and chemotherapy in stage IV gastric cancer with peritoneal metastasis.

281 Background: Although anti-PD-1 antibody in combination with chemotherapy and/or targeted therapy has shown promising antitumor activity in advanced gastric adenocarcinoma (GC), the evidence of conversion therapy for initially GC with peritoneal metastasis is limited. This study aimed to clarify the clinical outcomes of conversion therapy for such patients. Methods: In this retrospective single institution cohort study, we analyzed 83 GC patients with peritoneal metastasis who received first-line anti-PD-1 antibody and chemotherapy and/or target therapy (trastuzumab) between November 2019 and June 2023. In patients who respond well to treatment, when preoperative imaging studies, multidisciplinary team discussions, and staged laparoscopy indicated the absence of peritoneal metastasis and the possibility of R0 resection, patients were offered conversion surgery. In this study, palliative surgery was not included. Patients were divided into two groups: conversion therapy group and palliative therapy group. Results: All patients underwent staging laparoscopy at their initial visit and underwent at least 2 treatment cycle, with a median follow-up time of 20.3 (16-24.6) months. Of the 83 patients, 32 patients presented a clinical response and underwent re-laparoscopy. Negative peritoneal metastasis and peritoneal cytology were confirmed in 25 patients who proceeded to undergo the conversion surgery. Compared with palliative therapy group, surgery group had a significantly better median progression-free survival (PFS) (20.3 vs 5.1 months; p < 0.001) and a prolonged median overall survival (OS) (33.4 vs 11.7 months; p < 0.001). In the surgery group, 24 (96%) of 25 patients were performed laparoscopic gastrectomy radical laparoscopic gastrectomy with more than D2 lymph node dissection (only one patient underwent open gastrectomy), 19 (76%) patients achieved R0 resection, 2 (8%) patients achieved pathologic complete response (pCR) and 4 (16%) patients reached tumor regression grade (TRG) 0-1. It was observed that patients with PCI score ≤ 2 experienced a longer median OS in comparison to those with PCI scores > 2 ( unreached vs 28.5 months, P < 0.031). And multivariate analysis associated with PFS among surgery cases identified signet ring cell carcinoma as an independent adverse prognostic factor (HR 4.66; 95% CI 1.19–18.22; p = 0.027). No serious treatment-related adverse events resulted in termination of treatment or death. Conclusions: Conversion surgery following first-line anti-PD-1 antibody in combination with chemotherapy and/or targeted therapy represented a promising treatment strategy for GC patients with peritoneal metastasis. When immunochemotherapy is effective, active second-look staging laparoscopy should be performed to clarify the possibility of conversion surgery.

Safety and efficacy of nanosomal docetaxel lipid suspension (NDLS) in patients with advanced gastric adenocarcinoma.

348 Background: Nanosomal docetaxel lipid suspension (NDLS) was developed to overcome toxicity issues associated with conventional docetaxel. Docetaxel, cisplatin, 5-fluorouracil (5-FU; DCF) or modified DCF (mDCF) is one of the recommended first-line regimens for patients with metastatic gastric adenocarcinoma (GAC). However, majority of the patients experienced grade 3/4 toxicities with DCF regimen using conventional docetaxel. The present study evaluated the safety and efficacy of NDLS-based mDCF/DCF regimens in patients with metastatic GAC. Methods: In this multicentric, open-label, clinical trial, patients with previously untreated metastatic GAC were enrolled. Patients received either mDCF [NDLS 40 mg/m2 on day 1 (D1), C 40 mg/m2 on D2 or D3, 5-FU 400 mg/m2 bolus on D1, leucovorin 400 mg/m2 on D1, 5-FU 1000 mg/m2/day continuous infusion D1 & 2; q2w] for 9 cycles, or DCF [NDLS 75 mg/m2 on D1, C 75 mg/m2 on D1, 5-FU 750 mg/m2/day for 5 days given as continuous infusion; q3w] for 6 cycles. Prophylactic GCSF (Granulocyte Colony Stimulating Factor)/Peg-GCSF support was allowed in all patients. The primary endpoint was overall response rate (ORR) at week 18. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety outcomes. Patients were followed up to 1 year. Results: Fifty-two patients were enrolled, with mean (±SD) age of 52 (±9.6) years & male:female ratio of 32:20. Thirty-eight patients qualified for modified intent-to-treat (mITT) analysis for efficacy evaluation (mDCF: 33; DCF:5). At week 18, ORR was 57.9% & DCR was 81.6% in mITT population. In the per-protocol population (n=26), ORR was 61.5% at 18 weeks (mDCF:63.6%; DCF:50%). Safety set included all 52 patients. Any grade adverse events (AEs) were reported in 90.4% (n=47) of the patients; with 40.4% experiencing grade 3/4 AEs. All-grade AEs reported in ≥10% of the patients included anemia, neutropenia, abdominal pain, diarrhea, nausea, vomiting, fatigue, mucositis, decreased appetite, peripheral neuropathy; with majority of AEs being grade 1/2. Most common grade 3/4 AE was neutropenia; observed in 17.3% (n=9) patients (mDCF: 14%; DCF: 33.3%). Conclusions: NDLS-based regimens demonstrated efficacy & improved safety profile in the treatment of metastatic GAC. Clinical trial information: CTRI/2018/01/011450 . [Table: see text]

CLDN18.2 chimeric antigen receptor T cell therapy for patients with advanced gastric and pancreatic adenocarcinoma: Results of ELIMYN18.2 phase 1b clinical trial.

356 Background: Autologous anti-claudin 18.2 (CLDN18.2) CAR T cell, satricabtagene autoleucel (satri-cel), was developed to treat solid tumors. We report the completed results of the Phase 1b ELIMYN18.2 study (Cohort A) in gastric/gastroesophageal junction (GC/GEJ) and pancreatic cancer (PC). Methods: This single-arm, open-label, Phase 1b/2 study (NCT04404595) evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced GC/GEJ or PC. Cohort A consisted of a modified 3+3 design. After a conditioning regimen of fludarabine, cyclophosphamide, and nab-paclitaxel, patients were administered 1-3 cycles of satri-cel. The primary objectives were safety and determination of the recommended Phase 2 dose (RP2D). Adverse Events (AEs) were graded per CTCAE 5.0, objective response rate (ORR), and clinical benefit rate (CBR) including CR, PR, and ≥6-month SD were assessed by the investigator per RECIST 1.1. Results: As of May 14, 2023, twenty-four patients underwent leukapheresis in Cohort A. Nineteen patients (7 GC/GEJ and 12 PC) with a median of 3 (range: 1-8) prior therapeutic lines had satri-cel at three dose levels (DLs) between 250×106 and 600×106 cells. Seven patients received a 2nd dose and two patients received a 3rd dose of satri-cel at a median of 113 and 259 days, respectively, post-first infusion. All 19 patients experienced at least one AE. No DLTs occurred and 17 patients experienced cytokine release syndrome (CRS). Two cases of Grade 3 CRS were reported, and all other CRS were Grade 1 or 2. Two Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred. All CRS and ICANS were resolved. No severe gastrointestinal-related AEs were found. No increased toxicities were reported after any reinfusion. No satri-cel treatment-related death occurred. For all patients, the best ORR was 26.3%, the median DOR was 3.7 months and the CBR was 42.1%. The median PFS was 5.2 months, and overall survival was 12.8 months (95% CI 5.7-NE) after leukapheresis, and the median PFS was 3.3 months, and overall survival was 8.9 months (95% CI 3.3-NE) after the first infusion. In the GC/GEJ group, the ORR was 42.9% (3/7), the median DOR was 6.9 months and the CBR was 57.1%. In the PC group, the ORR was 16.7% (2/12), the median DOR was 3.4 months and the CBR was 33.3%. An ORR of 42.9% (3/7) and a CBR of 71.4% were reported at the DL3 of 600×106 cells which was selected as RP2D. At DL3, one GC patient achieved a CR and two PC patients had PR, suggesting the PC group achieved an ORR of 40% (2/5) and the GC group achieved an ORR of 50% (1/2). In addition, tumor shrinkage was detected in 73.7 % (14/19) of patients. Conclusions: The safety profile and therapeutic efficacy of satri-cel were shown to be promising in heavily pretreated patients with CLDN18.2-positive advanced GC/GEJ and PC . In the Phase 2 study, the first patient with GC received satri-cel in May 2023. Clinical trial information: NCT04404595 .

SWOG S2303: Randomized phase II/III trial of 2nd line nivolumab + paclitaxel + ramucirumab versus paclitaxel + ramucirumab in patients with PD-L1 CPS ≥ 1 advanced gastric and esophageal adenocarcinoma (PARAMUNE).

TPS430 Background: Anti-VEGFR2 antibody (ramucirumab) has efficacy in gastric cancer (GC), both as monotherapy & in combination with paclitaxel based on the REGARD & RAINBOW trials that led to its FDA approvals in the 2nd line setting. Preclinical data demonstrate significant tumor immune microenvironment modulatory effects from antiangiogenic agents, supporting the clinical study of dual VEGFR with immune checkpoint blockade. This has resulted in at least 7 FDA-approved combinations of anti-VEGF/VEGFR with anti-PD-1/PD-L1 agents in lung, renal, endometrial & liver cancers. Recent data showed encouraging activity with ramucirumab plus nivolumab & other trials with pembrolizumab and durvalumab in GC & esophageal adenocarcinoma. Notably, the addition of nivolumab to 2nd line ramucirumab plus paclitaxel was evaluated in a multi-center phase I/II trial. Study population consisted of 60% (26/43) harboring tumors positive for PD-L1 CPS ≥ 1. Results revealed encouraging efficacy (ORR 37.2%, 6-month PFS 46.5%) in the overall population. Median PFS and OS were found to be numerically higher in PD-L1 CPS ≥ 1 (6.4 months & 13.8 months respectively) compared to CPS-negative participants (5.1 months & 8.0 months), suggesting a predictive impact of PD-L1 CPS in this treatment setting. Methods: SWOG2303 is a national, randomized, open label, phase II/III trial to assess the efficacy and safety of nivolumab + paclitaxel + ramucirumab versus paclitaxel + ramucirumab in adult patients with advanced stage MSS/pMMR PD-L1 CPS ≥ 1 gastric and esophageal adenocarcinoma. Patients must have documented MSI and PD-L1 CPS status by standard of care tissue-based analysis, evaluable disease on imaging, and Zubrod performance status (PS) 0-1. They should also have clinical or radiographic progression or intolerance to frontline standard of care systemic therapy with PD-1 inhibitor containing fluoropyrimidine based chemotherapy regimen. Patients with HER2 positive disease are excluded as well as patients with prior significant immunotherapy related adverse events (iRAEs) that prompted permanent discontinuation of the PD-1 agent. Planned enrollment is 224. Participants will be randomized using a dynamic balancing algorithm with stratification based on Zubrod PS (0 vs 1), tumor location (gastric vs GEJ or esophageal) and PD-L1 CPS (≥5 vs <5). Primary endpoints are PFS for phase II and OS for phase III. Secondary endpoints include overall response rate, disease control rate, & safety. Baseline and pharmacodynamic changes in cellular and plasma angiogenic, inflammatory, and immune biomarkers will be explored & correlated with the efficacy. Other endpoints include health quality of life measured using the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga). Enrollment is ongoing.

Fruquintinib combined with sintilimab as a second-line therapy for advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC): A phase II, single-arm, prospective study.

332 Background: The KEYNOTE-061 trial showed that anti-PD-1 monotherapy did not improve overall survival compared to chemotherapy in the second-line treatment of advanced GC/GEJC. Preclinical and clinical data have demonstrated the synergistic anti-tumor effect of fruquintinib, a highly selective oral VEGFR 1/2/3 inhibitor, in combination with immune checkpoint inhibitors (ICIs). Additionally, the phase III study (NCT03223376) of fruquintinib combined with paclitaxel in second-line GC/GEJC has yielded positive topline results. This study aims to assess the safety and efficacy of fruquintinib combined with sintilimab (an anti-PD-1 antibody) as a second-line therapy for GC/GEJC. Methods: In this phase II, open-label trial (NCT05625737), patients (pts) aged 18-75 years who were HER2-negative and had failed first-line standard therapy were enrolled. Eligible pts received fruquintinib at 4mg/day orally on days 1-14 and sintilimab at 200 mg intravenously on day 1, with treatment repeated every 3 weeks. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. An optimal Simon two-stage design was employed: if more than 1 pt achieved objective responses in the first stage (n = 7), the study would proceed to the second stage and enroll an additional 19 pts; otherwise, the study would be terminated. Results: At data cut-off (August 31, 2023), 7 pts were enrolled in the first stage and additional 7 pts in the second stage. Pts characteristics included: median age 50 (range 33–71); 29% male; 57% with ECOG PS 1; 57% with peritoneal metastasis, and 71% having previously received immunotherapy. Of the 12 pts evaluable for tumor response, 4 achieved partial responses, and 4 had stable disease, resulting in a confirmed ORR of 33.3% (95% CI: 9.9-65.1%) and a DCR of 66.7% (95% CI: 34.9-90.0%). The median PFS was 5.09 months (95% CI: 2.69–NA), while OS results were pending maturity. Grade 1-2 treatment-emergent adverse events (TEAEs) occurred in ≥20% of pts, including decreased white blood cell count (36%), hypertriglyceridemia (29%), abdominal pain (29%), decreased lymphocyte count (21%), and elevated aspartate transaminase and alanine transaminase (21%). Grade 3/4 TEAEs occurred in only one patient, consisting of increased blood bilirubin levels, aspartate transaminase elevation, and alanine transaminase elevation. No treatment-related deaths were reported. Conclusions: The combination of fruquintinib and sintilimab as a second-line therapy has demonstrated promising anti-tumor activity and an acceptable safety profile in pts with advanced GC/GEJC. The trial is ongoing, and further data analysis and reporting are anticipated. Clinical trial information: NCT05625737 .

Atezolizumab and trastuzumab plus chemotherapy in patients with HER2+ locally advanced resectable gastric cancer or adenocarcinoma of the gastroesophageal junction: A multicenter, randomized, open-label phase II study.

312 Background: Currently, there are no standard perioperative regimens for human epidermal growth factor receptor 2 positive (HER2+) gastric cancer (GC) or gastroesophageal junction (GEJ) cancer. Furthermore, despite advances in neoadjuvant or perioperative chemotherapy, the efficacy of treatment for locally resectable advanced GC or GEJ cancer remains unsatisfactory. To address this need, we evaluated the effectiveness of adding atezolizumab (programmed death ligand-1 inhibitor) to treatment with trastuzumab (a HER2 antibody) + capecitabine and oxaliplatin (XELOX) compared with trastuzumab + XELOX in patients eligible for surgery with HER2+ locally advanced GC or adenocarcinoma of the GEJ. Methods: Patients aged 18–75 years were randomized 1:1 to atezolizumab + trastuzumab + XELOX (Arm A) or trastuzumab + XELOX (Arm B) and received the regimen for three neoadjuvant cycles (3 weeks per cycle) and five adjuvant cycles. Treatment administration was atezolizumab 1200 mg, trastuzumab 6 mg/kg, oxaliplatin 130 mg/m2 intravenously on Day 1, and capecitabine 1000 mg/m2 orally twice daily on Days 1–14 of each 3-week cycle. The primary endpoint was the pathological complete regression (pCR) rate. Secondary endpoints were the objective response rate (ORR) during neoadjuvant systemic therapy (NAST) and the R0 resection rate. Time-to-event endpoints are not reported because of immaturity. Efficacy endpoints were analyzed in the intention-to-treat population. The clinical cutoff date for the primary analysis was 12 March 2023. Results: Forty-two Asian patients who provided informed consent were screened and randomized to Arm A (n = 21) or Arm B (n = 21); all patients completed NAST. Most patients were male (92.9%), and the median (range) age was 61 (33–72) years in Arm A and 65 (49–72) years in Arm B. The pCR rate was 38.1% (8/21) in Arm A and 14.3% (3/21) in Arm B (treatment difference: 23.8% [90% confidence interval (CI), 1.3%–44.7%]). The pCR rate was significantly better in Arm A than in Arm B (P = 0.079 <0.1; lower limit of the 90% CI >0). Subgroup analysis showed that age <65 years, male sex, and intestinal Lauren classification were associated with a better pCR rate for the atezolizumab inclusive treatment arm (Arm A); however, these results require further confirmation in future studies. No significant difference was detected between the two arms in ORR during NAST or the R0 resection rate. Conclusions: The addition of atezolizumab to trastuzumab + XELOX therapy was effective in patients with HER2+ locally advanced resectable GC or adenocarcinoma of the GEJ. Clinical trial information: NCT04661150 .

Phase II trial of cabozantinib (cabo) plus durvalumab (durva) in chemotherapy refractory microsatellite stable (MSS) patients with advanced gastric and esophageal (G/E) adenocarcinoma: CAMILLA G/E cohort results.

373 Background: Cabo is a multi-tyrosine kinase inhibitor harboring anti-VEGFR2, MET, AXL, MER and TYRO3 activity. Immunomodulatory and synergistic anti-tumor activity of cabo in combination with PD-1/L1 inhibitors have been demonstrated preclinically and in prior studies in various solid tumors. The phase Ib gastrointestinal (GI) basket CAMILLA trial evaluating cabo + durva confirmed manageable toxicity and anti-tumor activity, leading to the expansion into a multi-cohort phase 2 study. Herein, we report the results of the phase II G/E adenocarcinoma cohort. Methods: Patients (Pts) enrolled in the phase II G/E adenocarcinoma cohort were administered cabo + durva at the RP2D of 40mg QD and 1500mg IV Q4W respectively. Enrolled pts must have progressed on >1 line(s) of systemic therapy. Prior exposure to PD-1/L1 inhibitors was allowed. Those with HER2 positive disease must have progressed on anti-HER2 therapies. The primary outcome was objective response rate (ORR). Secondary outcomes were treatment-related adverse events (TRAEs), disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Exploratory subgroup analyses were conducted in PD-L1 CPS >5. Results: 31 patients were enrolled, with 29 patients evaluable for efficacy. The median age was 61 years (range 32-79). 86% had an ECOG performance status of one. 48% had ≥ 2 prior lines of systemic therapies (range 1-4). Of the 29 pts evaluable for efficacy, 6 pts had confirmed objective responses (5 PR + 1 CR = ORR 20.69%). The most common TRAEs were fatigue (65%), anorexia (58%), elevated liver enzymes (39%), and diarrhea (35%). Grade >3 TRAEs occurred in 19% of pts. Grade >3 immune-related adverse events (irAE) rate was 6%. DCR was 86.2% (25/29). Median PFS and OS were 4.4 (95% confidence interval (CI) 2.2-5.4) and 5.6 months (95% CI 3.6-8.3) respectively. In patients with PD-L1 CPS >5 (12/29), ORR was 25%, and median PFS and OS were 5.5 months (95% CI 1.8-12.4) and 19.3 months (95% CI 2.3-28.2) respectively. Conclusions: Cabo + durva showed anti-tumor activity and manageable toxicity in advanced chemotherapy refractory G/E adenocarcinoma. Further evaluation in patients with high PD-L1 CPS ≥ 5 is warranted in a future randomized trial. Clinical trial information: NCT03539822 .

A two-arm randomized open-label prospective design superiority phase III clinical trial to compare the efficacy of docetaxel-oxaliplatin-capecitabine/5 fluorouracil (DOC/F) followed by docetaxel versus CAPOX/mFOLFOX-7 in advanced gastric cancers (DOC-GC study).

LBA248 Background: The choice of optimal chemotherapy in advanced (unresectable/metastatic) gastroesophageal junction and gastric (GEJ/G) adenocarcinomas remains undecided with regard to the addition of docetaxel to a FOLFOX/CAPOX backbone in improving outcomes with equipoise with regard to the optimal duration of chemotherapy as well. Methods: The DOC GC study is a multicentric open-label, randomized controlled phase III trial, in adults ≥18 years with advanced GEJ/G adenocarcinoma and adequate end-organ function. Patients were randomized 1:1 to one of two arms: Arm A - modified CAPOX (3 weekly) or modified FOLFOX-7 (2 weekly) for a maximum of 6 months and then observation OR Arm B: modified FLOT (5-FU/leucovorin /Oxaliplatin/Docetaxel) or DOX (docetaxel/oxaliplatin/capecitabine) every 2 weeks for a maximum of four months followed by Docetaxel (60mg/m2) every 3 weeks till disease progression, unacceptable toxicity, or patient's decision to withdraw. The primary endpoint of the study is Overall survival (OS), as calculated by Kaplan-Meier method, while key secondary endpoints include Progression-free survival, and adverse event rates. Results: Of the 324 patients randomized between July 2020 and November 2022, 305 patients were evaluable for analysis (Arm A: 156; Arm B: 149). With a median follow-up time of 19.2 months (95% CI: 16.5 – 21.9) for the entire cohort, the median OS was 10.1 months (95%: 9.2-10.9) in Arm A and 8.9 months (95% CI: 7.3-10.5) in arm B and this difference was not statistically significant [p=0.70]. There were no statistical differences in median PFS between the two arms [Arm A: 7.1 months (95% CI: 6.1-8.1); Arm B: 6.2 months (95% CI: 5.7 – 6.8); p=0.39]. An increased proportion of grade 3/4 neutropenia (21% vs. 5.1%; p<0.001) was seen in patients in Arm B, with other treatment related side effects being comparable between the two arms. A greater proportion of patients in Arm A tended to receive second line therapy compared to Arm B (38% vs. 26%; p=0.07). Conclusions: The addition of docetaxel to a doublet regimen comprising 5-fluorouracil/capecitabine and oxaliplatin did not improve overall survival in patients with advanced GEJ/G cancers. Continuing chemotherapy beyond six months also does not appear to improve survival in this group of cancers. Clinical trial information: CTRI/2020/03/023944 .

Management of nausea and vomiting (N/V) following first-line (1L) zolbetuximab + chemotherapy treatment in claudin-18.2 (CLDN18.2)+, HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Analysis from the phase 3 SPOTLIGHT and GLOW studies.

372 Background: The phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies showed clinically meaningful, statistically significant improvement in PFS and OS using 1L zolbetuximab + chemotherapy vs placebo (PBO) + chemotherapy in patients (pts) with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma. N/V were the most common treatment-emergent adverse events (TEAEs) reported in the zolbetuximab arm of these studies. We report an analysis of the incidence and management of N/V in SPOTLIGHT and GLOW. Methods: In SPOTLIGHT, pts (N = 565) were randomized 1:1 to zolbetuximab + mFOLFOX6 vs PBO + mFOLFOX6. In GLOW, pts (N = 507) were randomized 1:1 to zolbetuximab + CAPOX vs PBO + CAPOX. In both studies, neurokinin-1 receptor blockers (NK-1), selective serotonin receptor blockers (5-HT3), and other prophylactic antiemetic regimens were recommended to prevent and mitigate N/V per institutional care and guidelines. Results: A total of 279 pts in SPOTLIGHT and 253 pts in GLOW received zolbetuximab + chemotherapy. In SPOTLIGHT and GLOW combined, nausea occurred in 58% vs 18% of pts, and vomiting occurred in 43% vs 15% of pts in the first vs second zolbetuximab infusions, respectively; lower incidences of N/V were observed thereafter. During the first zolbetuximab infusion, the first episode of N/V occurred within 1 hour (median time, 48.0 min in SPOTLIGHT and 56.5 min in GLOW). Antiemetic usage and associated N/V rates are presented in the Table. The 96 pts in SPOTLIGHT and 52 pts in GLOW who had infusion modifications in cycle 1 due to TEAEs had numerically higher infusion rates than pts without infusion modifications; 85% of these modifications in SPOTLIGHT and 79% in GLOW were due to N/V. Zolbetuximab was discontinued within the first 9 weeks in 11 and 7 pts in SPOTLIGHT and 6 and 4 pts in GLOW due to nausea or vomiting, respectively. Conclusions: In SPOTLIGHT and GLOW, slower infusion rate and use of antiemetic combinations may have helped to mitigate N/V. These strategies will be important to support continued treatment and allow pts to achieve maximum clinical benefit with zolbetuximab + chemotherapy. Clinical trial information: NCT03504397 and NCT03653507 . [Table: see text]

Tislelizumab (TIS) plus chemotherapy (Chemo) vs placebo (PBO) plus chemo as first-line (1L) treatment of advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC): Health-related quality of life (HRQoL) outcomes in the RATIONALE-305 study.

290 Background: RATIONALE-305 (NCT03777657), demonstrated statistically significant and clinically meaningful improvements in overall survival (OS) with TIS + chemo (n=501) over PBO + chemo (n=496) as 1L treatment in patients (pts) with advanced G/GEJC. This analysis examined HRQoL outcomes of the RATIONALE-305 study at final analysis. Methods: Adults with previously untreated, unresectable, or metastatic GC/GEJC, were randomized (1:1) to TIS 200 mg or PBO IV once every 3 weeks plus investigator-choice of chemo. HRQoL was assessed using EORTC QLQ-C30 and the QLQ-STO22. A mixed model for repeated measures using PRO endpoints at clinical Cycles 4 and 6 was performed. Time to deterioration was examined. Results: TIS + chemo had improved outcomes than PBO + chemo (Table) as indicated by least-squares mean change from baseline to Cycle 6 for QLQ-C30 GHS/QoL (2.52 [95% CI:0.29 to 4.74]), physical functioning (2.46 [95% CI: 0.49 to 4.43]), fatigue (-3.01 [95% CI: -5.78 to -0.24]), and the STO22 index score (-1.62 [95% CI: -3.12 to -0.12]), as well as maintaining upper gastrointestinal (GI) symptoms (-1.74 [95% CI: -3.55 to 0.06)] and pain (-1.88 [95% CI: -4.03 to 0.27]). Pts receiving TIS + chemo had a lower risk for deterioration of GHS/QoL (0.77 [95% CI: 0.60 to 0.98]), physical functioning (0.72 [0.57 to 0.92]), STO22 index score (0.64 [0.45 to 0.92]), pain/discomfort (HR: 0.74 [0.58-0.96]), and upper GI symptoms (0.73 [0.56 to 0.95]). Conclusions: Pts treated with TIS + chemo had better HRQoL outcomes vs pts treated with PBO + chemo, particularly for GHS/QoL, physical functioning, fatigue, GC/GEJC symptoms, pain/discomfort, and upper GI symptoms These results, along with prolonging of OS and other secondary efficacy endpoints, as well as a tolerable safety profile, support the benefit of TIS + chemo as a potential 1L treatment option for GC/GEJC. Clinical trial information: NCT03777657 . [Table: see text]

Impact of DNA mismatch repair status on prognosis of patients with locally advanced gastric cancer in a Mexican population.

408 Background: Gastric cancer (GC) is among the five most frequent and mortal cancers in the world. In Mexico, GC is the second cause of death from cancer in men between 30 and 59 years old. The role of deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) in locally advanced gastric cancer (LAGC) is still controversial. We aimed to evaluate the overall survival (OS) of patients with LAGC, according to MMR status and treatment. Methods: Retrospective study included patients from the National Cancer Institute of México, with locally advanced gastric adenocarcinoma diagnosis between 2008 and 2017. The Kaplan Meier, Log Rank, and Cox Regression methods were used to analyze the relation between MMR status and overall survival in LAGC. MMR status was assessed using immunohistochemistry. Results: A total of 103 patients with LACG were enrolled for analysis. The prevalence of dMMR in GC was 13.59% (n=14). The median OS was 101.9 months in the dMMR group vs. 86.2 months in the proficient MMR (pMMR) group (HR 0.54, 95% CI 0.19 - 1.52, p=0.23), with a 3-year OS of 71.4% vs 65.1% respectively. Survival was also analyzed according to MMR status and choosing treatment. OS was 106.8 months in the dMMR surgery alone group, 78.4 months in the dMMR group treated with both surgery and chemotherapy, 33.1 months for pMMR group with surgery alone, and 89.2 months in the pMMR group treated with surgery plus chemotherapy (p=0.014). Conclusions: In this analysis, OS tended to improve in dMMR group. pMMR surgery alone patients had a superior OS than other groups, while adding chemotherapy to surgery treatment seems to have a role only in pMMR patients. [Table: see text]

Impact of the number of therapy lines on survival in advanced gastric and esophagogastric adenocarcinoma - a real-world retrospective analysis from Croatia.

The aim of the study was to conduct a retrospective database analysis to understand the current treatment patterns and outcomes to plan potential improvements in therapy delivery and patient selection. The electronic patient medical records of 225 patients with advanced gastric and esophagogastric adenocarcinoma treated at two Croatian high-volume tertiary centers from January 2018 to December 2021 were analyzed. Patients ineligible for chemotherapy (66 of 291, 22.7%) due to poor general condition or co-morbidities were not included in the study. The median overall survival (OS) for the whole cohort was 11.0 months (95% confidence interval (CI) 9.7-12.0). Of the 225 patients who received first-line therapy, 47.6%, 16.9%, and 3.1% received second-, third-, and fourth-line therapy, respectively. Survival correlated significantly with the number of treatment lines received (p<0.001), with a median OS from diagnosis of 7.8 (95% CI 6.6-9.4), 12.0 (95% CI 10.0-14.0), and 20.0 months (95% CI 18.0-23.0) for patients receiving 1, 2, and ≥3 lines of treatment, respectively. This study confirmed the positive impact of the number of chemotherapy lines on OS. This highlights the importance of the ratio of patients receiving multiple lines of therapy as well as the availability of new and effective drugs in real-life clinical practice. The selection of optimal therapy for each patient in the first-line therapy is important because a significant number of patients do not receive second-line therapy.

Sustained Clinical Complete Response after Discontinuation of Trastuzumab-deruxetecan Due to Interstitial Pneumonia for HER2-positive Gastric adenocarcinoma with Enteroblastic Differentiation (GAED): A Case Report.

Trastuzumab deruxtecan (T-DXd) has demonstrated remarkable efficacy as a third- or later-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric and gastroesophageal junction adenocarcinomas. However, it may cause pneumonitis, and its efficacy in rare histologies such as gastric adenocarcinoma with enteroblastic differentiation (GAED) remains unclear. A 74-year-old woman with unresectable HER2-positive GAED and lung metastasis received T-DXd as a fifth-line chemotherapy. Treatment was discontinued after 15 cycles owing to drug-induced pneumonitis; however, the patient achieved a sustained complete response for 14 months without subsequent chemotherapy or the exacerbation of pneumonitis. T-DXd was effective in HER2-positive GAED.

Interpretable machine learning for predicting the response duration to Sintilimab plus chemotherapy in patients with advanced gastric or gastroesophageal junction cancer.

Sintilimab plus chemotherapy has proven effective as a combination immunotherapy for patients with advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC). A multi-center study conducted in China revealed a median progression-free survival (PFS) of 7.1 months. However, the prediction of response duration to this immunotherapy has not been thoroughly investigated. Additionally, the potential of baseline laboratory features in predicting PFS remains largely unexplored. Therefore, we developed an interpretable machine learning (ML) framework, iPFS-SC, aimed at predicting PFS using baseline (pre-treatment) laboratory features and providing interpretations of the predictions. A cohort of 146 patients with advanced GC/GEJC, along with their baseline laboratory features, was included in the iPFS-SC framework. Through a forward feature selection process, predictive baseline features were identified, and four ML algorithms were developed to categorize PFS duration based on a threshold of 7.1 months. Furthermore, we employed explainable artificial intelligence (XAI) methodologies to elucidate the relationship between features and model predictions. The findings demonstrated that LightGBM achieved an accuracy of 0.70 in predicting PFS for advanced GC/GEJC patients. Furthermore, an F1-score of 0.77 was attained for identifying patients with PFS durations shorter than 7.1 months. Through the feature selection process, we identified 11 predictive features. Additionally, our framework facilitated the discovery of relationships between laboratory features and PFS. A ML-based framework was developed to predict Sintilimab plus chemotherapy response duration with high accuracy. The suggested predictive features are easily accessible through routine laboratory tests. Furthermore, XAI techniques offer comprehensive explanations, both at the global and individual level, regarding PFS predictions. This framework enables patients to better understand their treatment plans, while clinicians can customize therapeutic approaches based on the explanations provided by the model.

Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study

The benefit of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastro-oesophageal adenocarcinoma is unknown. We assess the antitumor activity of neoadjuvant and adjuvant pembrolizumab plus chemotherapy in patients with locally advanced resectable gastric or gastro-oesophageal adenocarcinoma. The KEYNOTE-585 study is a multicentre, randomised, placebo-controlled, double-blind, phase 3 study done at 143 medical centres in 24 countries. Eligible patients were aged 18 years or older with untreated, locally advanced, resectable gastric or gastro-oesophageal adenocarcinoma, and an Eastern Cooperative Oncology Group performance status 0-1. Patients were randomly assigned (1:1) by an interactive voice response system and integrated web response system to neoadjuvant pembrolizumab 200 mg intravenously or placebo (saline) plus cisplatin-based doublet chemotherapy (main cohort) every 3 weeks for 3 cycles, followed by surgery, adjuvant pembrolizumab or placebo plus chemotherapy for 3 cycles, then adjuvant pembrolizumab or placebo for 11 cycles. A small cohort was also randomly assigned (1:1) to pembrolizumab or placebo plus fluorouracil, docetaxel, and oxaliplatin (FLOT)-based chemotherapy (FLOT cohort) every 2 weeks for four cycles, followed by surgery, adjuvant pembrolizumab, or placebo plus FLOT for four cycles, then adjuvant pembrolizumab or placebo for 11 cycles. Patients were stratified by geographic region, tumour stage, and chemotherapy backbone. Primary endpoints were pathological complete response (reviewed centrally), event-free survival (reviewed by the investigator), and overall survival in the intention-to-treat population, and safety assessed in all patients who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov, NCT03221426, and is closed to accrual. Between Oct 9, 2017, and Jan 25, 2021, of 1254 patients screened, 804 were randomly assigned to the main cohort, of whom 402 were assigned to the pembrolizumab plus cisplatin-based chemotherapy group and 402 to the placebo plus cisplatin-based chemotherapy group, and 203 to the FLOT cohort, of whom 100 were assigned to the pembrolizumab plus FLOT group and 103 to placebo plus FLOT group. In the main cohort of 804 participants, 575 (72%) were male and 229 (28%) were female. In the main cohort, after median follow-up of 47·7 months (IQR 38·0-54·8), pembrolizumab was superior to placebo for pathological complete response (52 [12·9%; 95% CI 9·8-16·6] of 402 vs eight [2·0%; 0·9-3·9] of 402; difference 10·9%, 95% CI 7·5 to 14·8; p<0·00001). Median event-free survival was longer with pembrolizumab versus placebo (44·4 months, 95% CI 33·0 to not reached vs 25·3 months, 20·6 to 33·9; hazard ratio [HR] 0·81, 95% CI 0·67 to 0·99; p=0·0198) but did not meet the threshold for statistical significance (p=0·0178). Median overall survival was 60·7 months (95% CI 51·5 to not reached) in the pembrolizumab group versus 58·0 months (41·5 to not reached) in the placebo group (HR 0·90, 95% CI 0·73 to 1·12; p=0·174). Grade 3 or worse adverse events of any cause occurred in 312 (78%) of 399 patients in the pembrolizumab group and 297 (74%) of 400 patients in the placebo group; the most common were nausea (240 [60%] vs 247 [62%]), anaemia (168 [42%] vs 158 [40%]), and decreased appetite (163 [41%] vs 172 [43%]). Treatment-related serious adverse events were reported in 102 (26%) and 97 (24%) patients. Treatment-related adverse events that led to death occurred in four (1%) patients in the pembrolizumab group (interstitial ischaemia, pneumonia, decreased appetite, and acute kidney injury [n=1 each]) and two (<1%) patients in the placebo group (neutropenic sepsis and neutropenic colitis [n=1 each]). Although neoadjuvant and adjuvant pembrolizumab versus placebo improved the pathological complete response, it did not translate to significant improvement in event-free survival in patients with untreated, locally advanced resectable gastric or gastro-oesophageal cancer. Merck Sharp & Dohme.