Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial

Understanding mechanisms of primary resistance to checkpoint inhibitors will lead to precision immunotherapy of advanced gastric cancer

364 Background: The CheckMate 649 trial showed the superiority of first-line nivolumab plus chemotherapy (Nivo-CT) compared with chemotherapy alone for advanced gastric and gastroesophageal junction (GEJ) cancer with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) >5, while survival benefit was poor in PD-L1 CPS <1 and <5. However, there were few studies on correlation between PD-L1 CPS and efficacy of first-line Nivo-CT for advanced gastric or GEJ cancer in real world data. Methods: This multi-center retrospective study included patients with histologically confirmed advanced gastric or GEJ cancer who were started on first-line Nivo-CT between December 2021 and December 2023. PD-L1 CPS was assessed before the start of Nivo-CT by classified into three groups at each center: <1, 1~5 and >5, using the Dako PD-L1 immunohistochemistry 28-8 pharmDx assay. The efficacy was evaluated by overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Results: A total of 271 patients were included (median age, 70 [range 18–85] years; male/female, 64/36%; performance status (PS) 0/1/2, 47/49/4%; primary tumor site gastric/GEJ, 90/10%; status unresectable/recurrent, 81/19%; histology intestinal/diffuse, 30/70%). PD-L1 CPS status were evaluated 234 (86%) patients and PD-L1 CPS <1, 1~5 and >5 was found in 35 (15%), 76 (33%) and 123 (53%) patients, respectively. Median follow-up time was 11.3 (range 1-30) months. The median PFS was 9.7 (95%CI, 5.9-16.3), 8.8 (95%CI, 7.2-13.0) and 6.3 (95%CI, 5.3-9.0) months in the patient with PD-L1 CPS <1, 1~5 and >5, respectively. The median OS was 18.7 (95%CI, 17.4-NA), 23.4 (95%CI, 17.7-NA) and 18.3 (95%CI, 13.3-22.5) months, and the ORR were 30.8, 66.7 and 61.3% (p = 0.075) in the patient with PD-L1 CPS <1, 1~5 and >5, respectively. Liver metastases were found in 43 (35.0%) of the patients with PD-L1 CPS >5, significantly more than in the patients with PD-L1 CPS <5 (p < 0.001). Multivariate analysis indicated that PD-L1 CPS status was not associated with prognosis (PD-L1 CPS ≥5 vs. <1, HR 1.18 [95%CI, 0.75-1.86], p = 0.48). In the overall population, grade ≥3 adverse events were observed in 102 (37.6%) patients and grade ≥3 immune-related adverse events were observed in 26 (9.6%) patients. Conclusions: There were no significant differences in prognosis and response between PD-L1 CPS in first-line Nivo-CT for advanced gastric or GEJ cancer in real world data.

405 Background: Combinations of immune checkpoint inhibitors (ICI) and chemotherapy (CT) have been approved for gastric cancer. However, there is a hypothesis that this combination may blunt antitumor immune responses because most chemotherapeutic agents also target lymphocytes. The primary objective was to investigate that the ICI and CT does not interfere each other’s therapeutic effects in advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC) patients. Methods: The reconstructed individual patient data was electronically extracted from the Kaplan-Meier curve of phase III randomized controlled trials (RCTs). The observed PFS curve of each constituent monotherapies was used to estimate simulated PFS curves expected under a model of independent drug action. If the observed curve demonstrated significantly better PFS than simulated curve, the combination of ICI and CT may have a synergistic effect, implying a superior outcome compared to simply adding the component monotherapy. Results: The study included 2,538 unresectable advanced, recurrent, or metastatic GC or GEJC patients from three RCTs comparing pembrolizumab (KEYNOTE-061, KEYNOTE-062 and KEYNOTE-859). In patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater, the 1-year and median PFS of the observed and simulated curves were 28.0% vs. 27.9%, and 6.89 months vs. 6.88 months, respectively. One sample log-rank test showed no significant differences between the observed and simulated curves (p = 0.107). In the subgroups with PD-L1 CPS ≥10 or <1, the 1-year PFS of the observed and simulated curves was 34.7% vs 32.8%, and 28.5% vs 26.8%. Conclusions: The observed PFS of ICT involving pembrolizumab was comparable to the simulated PFS estimated from the data for each monotherapy regardless of the magnitude of PD-L1 CPS. Although it was not clear whether potential synergies existed for ICT, these findings at least suggest that the benefits of ICI and CT are not interfering each other, thereby providing theoretical support for the efficacy of ICT in patients with advanced GC or GEJC.

Encouraging results for PD-1 inhibition in gastric cancer

Claudin 18.2-targeting antibody-drug conjugate CMG901 in patients with advanced gastric or gastro-oesophageal junction cancer (KYM901): a multicentre, open-label, single-arm, phase 1 trial.

e23113 Background: The optimal use of programmed death-ligand 1 (PD-L1) expression to guide immunotherapy in advanced gastric or gastroesophageal junction cancer (GC/GEJC) remains uncertain. The inconsistencies in PD-L1 scoring methods (combined positive score (CPS) or tumor area positivity (TAP)) at various thresholds (1% vs. 1, 5% vs. 5, and 10% vs. 10) complicate clinical decision-making. This study evaluated the effectiveness and cost-effectiveness of CPS and TAP scoring methods across PD-L1 cut-off thresholds in GC/GEJC immunotherapy. Methods: This study developed a microsimulation model by using reconstructed patient-level data from the RATIONALE-305 and ORIENT-16 trials to simulate outcomes for six PD-L1 guided strategies using either sintilimab or tislelizumab, combined with chemotherapy. Primary endpoints included progression-free survival (PFS) and overall survival (OS). Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated from the perspective of the Chinese healthcare system. Results: For sintilimab-based strategies, CPS-5 and CPS-10 guided strategies showed statistically significant improvements in OS over TAP-5% and TAP-10% guided strategies, while CPS-1 guided strategies showed statistically significant improvements in PFS versus TAP-1% guided strategies. CPS-10 guided strategy was optimal for sintilimab with an ICER of $21,904/QALY. For tislelizumab-based strategies, no significant differences in OS or PFS were observed across scoring methods, with TAP-10% showing cost-effectiveness. Sensitivity analysis underscored the robustness of results, confirming TAP-10% as cost-effective for tislelizumab and CPS-10 for sintilimab. Conclusions: A 10 or 10% PD-L1 cut-off is the most cost-effective threshold for both sintilimab- and tislelizumab-based strategies. CPS is preferred for sintilimab and TAP for tislelizumab, highlighting the need for tailored PD-L1 scoring methods for different therapies to optimize both clinical and economic outcomes.

Background:The advent of immune checkpoint inhibitors has introduced innovative therapeutic paradigms for the management of human epidermal growth factor receptor 2 (HER2)-negative advanced gastric or gastroesophageal junction cancer (GC/GEJC). However, the efficacy and safety of programmed cell death protein 1 (PD-1) inhibitors combined with chemotherapy versus chemotherapy alone in patients with HER2-negative advanced GC/GEJC remain contentious. The comparability among different subgroups is not fully understood, necessitating the identification of optimal patient demographics and the exploration of potential biomarkers.Methods:This study identified 6 Phase III randomized controlled trials evaluating the first-line treatment of HER2-negative GC/GEJC with PD-1 inhibitors in combination with chemotherapy. The primary endpoints include overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), assessed using hazard ratios (HR), relative risk, and their respective 95% confidence intervals (CI). Secondary outcomes are treatment-related adverse events and immune-related adverse events. Prespecified subgroups encompass microsatellite instability, programmed death-ligand 1 (PD-L1) combined positive score (CPS), age, gender, previous surgery, primary location, liver metastases, Eastern Cooperative Oncology Group performance status score, histological subtype, chemotherapy regimen, race, and PD-L1 expression in tumor cells.Results:Incorporating data from 6 randomized controlled trials, this analysis included 6294 adult patients with HER2-negative advanced GC/GEJC. The combined PD-1 inhibitor and chemotherapy regimen significantly improved OS (HR = 0.79, 95% CI [0.75, 0.84], P < .00001) and PFS (HR = 0.75, 95% CI [0.70, 0.80], P < .00001), along with enhancing the ORR (relative risk = 1.22, 95% CI [1.15, 1.29], P < .00001). Subgroup analyses revealed benefits in OS, PFS, and ORR for patients with CPS ≥ 1, CPS ≥ 5, and CPS ≥ 10 when treated with first-line PD-1 inhibitors and chemotherapy, with higher PD-L1 expression levels correlating with greater efficacy. Furthermore, patients with high microsatellite instability exhibited a more pronounced extension in OS (HR = 0.35, 95% CI [0.21, 0.59], P < .0001). However, factors such as age, gender, previous surgery, primary location, liver metastases, Eastern Cooperative Oncology Group performance status score, histological subtype, chemotherapy regimen, race, and PD-L1 expression in tumor cells were not predictive of an OS benefit from PD-1 inhibitors combined with chemotherapy over chemotherapy alone. Regarding safety, the PD-1 inhibitor and chemotherapy combination led to a higher incidence of immune-mediated adverse events, though there was no significant difference in adverse events leading to death.Conclusion:First-line treatment with PD-1 inhibitors combined with chemotherapy surpasses chemotherapy alone in efficacy for patients with HER2-negative advanced GC/GEJC, particularly in those with CPS ≥ 10 or high microsatellite instability, with tolerable adverse events.

Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial

4524 Background: Patients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We investigated HX008, an Anti-PD1 Antibody, with irinotecan in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and/or fluoropyrimidine. Methods: This study is a multicenter, open, phase II clinical study of recombinant humanized anti-pd-1 monoclonal antibody HX008 injection plus Irinotecan that was conducted at 11 hospitals in China. Eligible patients are adults with histologically confirmed advanced gastric or gastro-oesophageal junction cancer. Subjects participating in this study are required to submit a archived tumor tissue specimen or newly obtained biopsy of tumor lesions at the site of no previous radiotherapy and peripheral blood (2mL) for detection of PD-L1 and MSI/MMR expression. The samples will be tested for expression of PD-L1 and MMR by immunohistochemistry (IHC) in the central laboratory, and MSI levels will be determined by polymerase chain reaction (PCR) and gel electrophoresis. Subjects received PD-1 monoclonal antibody HX008 at 200mg (d1, intravenous drip, once every 3 weeks) plus irinotecan at 160mg/m2 (d1, intravenous drip, 60 ~ 120min, once every 2 weeks). Response was assessed every 6 weeks in accordance with Response Evaluation Criteria in Solid Tumors version 1.1. Primary endpoints was objective remission rate (ORR). Results: Between October 2018 and September 2019, a total of 58 patients with advanced gastric or gastro-oesophageal junction cancer were enrolled in this study. Median (range) age was 61 (27-71) years, and most patients were male (72.4%). Among 53 patients who were evaluated, 15 (28.3%) experienced objective response and 22 (41.5%) experienced stable disease (SD). The median progression free survival (PFS) was 5.4 months, the one-year survival rate was 71.3%. The most common treatment-related adverse events of grade 3 or 4 included neutropenia(31.0%), anemia(15.5%), loss of appetite (6.9%), vomiting(5.2%), nausea(3.4%), diarrhea (1.7%) and fatigue (1.7%). There were no treatment-related deaths. Conclusions: HX008 injection plus Irinotecan demonstrated promising activity and manageable safety in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine. Clinical trial information: NCT03704246 .

Claudin-18 isoform 2-specific CAR T-cell therapy (satri-cel) versus treatment of physician's choice for previously treated advanced gastric or gastro-oesophageal junction cancer (CT041-ST-01): a randomised, open-label, phase 2 trial.

Advanced gastric and gastroesophageal junction cancer (G/GEJC) poses significant therapeutic challenges. Immune checkpoint inhibitors, particularly targeting programmed cell death ligand-1 (PD-L1), have emerged as promising agents to enhance patient outcomes. This meta-analysis evaluates the efficacy of PD-L1 inhibitors compared to chemotherapy in patients with advanced G/GEJC characterised by varying combined positive scores (CPS). We systematically searched PubMed, Google Scholar, and Web of science for clinical trial studies comparing PD-L1 inhibitors and chemotherapy in CPS-positive patients, focusing on studies published up to 10 April 2023. Studies were evaluated with risk of bias tools. The primary clinical endpoint analysed in this study was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). This study is registered with Prospero (CRD42023495607). A total of 10 studies comprising 4522 participants were included. Our analysis revealed no statistically significant difference in CPS values between PD-L1 inhibitors and chemotherapy groups (≥ 1 : 1.03 [95% CI: 0.86-1.24], ≤ 1 : 0.92 [95% CI: 0.77-1.11]). However, the pooled hazard ratio for OS favoured PD-L1 inhibitors (hazard ratios - HR, 0.83, [95% CI: 0.78-0.88] and p < 0.00001), while PFS was better after chemotherapy (HR 1.28, [95% CI: 1.04-1.58], p = 0.02). Program death ligand-1 inhibitors improve OS, while chemotherapy enhances PFS in advanced G/GEJC, warranting further investigation into the impact of CPS on treatment outcomes.

B37 - Trastuzumab plus chemotherapy in the treatment of HER-2 –positive, advanced, gastric or gastro-esophageal junction cancer: a single center experience

Comprehensive clinical and molecular characterization of claudin 18.2 expression in advanced gastric or gastroesophageal junction cancer

Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. The primary end point was overall survival time from randomization. Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. ClinicalTrials.gov Identifier: NCT03745170.

Background:Current therapeutic options have limited efficacy for patients with advanced gastric or gastroesophageal junction cancer. Immune checkpoint inhibition now has been increasingly used in advanced gastric or gastroesophageal junction cancer therapy. To further understand the efficacy and safety of anti-programmed cell death 1 (PD-1) and its ligand 1 (PD-L1) agents is critical for clinical practice. We conducted this systematic review and meta-analysis to assess the benefit and risk of PD-1 and PD-L1 inhibitors.Methods:The PubMed, EMBASE, Cochrane Library, and Web of Science online databases were searched up to Jun 16, 2019. Primary outcomes were overall survival (OS), progression-free survival (PFS). Second outcomes were objective response rate (ORR), disease control rate (DCR) and adverse events.Results:Six studies were assessed for inclusion in the final synthesis, of which 5 were eligible for meta-analysis. Compared with chemotherapy, the pooled hazard ratio (HR) for OS and PFS was, respectively, 1.01 (95% confidence interval [CI]: 0.88–1.15, P = .93) and 1.58 (95% CI: 1.38–1.81, P < .001) after treatment with PD-1/PD-L1 inhibitors. In patients treated with anti-PD-1/PD-L1 agents, the pooled ORR was 9.9% (95% CI: 4.4%–15.5%) and the pooled DCR was 30.8% (95% CI: 21.8%–39.9%). Sub-analysis for treatment related adverse events indicated that fatigue was the most common toxicity in anti-PD-1/PD-L1 therapy (incidence 10.6%, 95% CI: 5.6%–15.6%).Conclusion:PD-1/PD-L1 inhibitors appear to improve the antitumor activity in advanced gastric or gastroesophageal junction cancer patients. However, single-agent PD-1/PD-L1 inhibitor did not result in a relative improvement in OS and PFS compared with chemotherapy in the treatment of patients with advanced gastric or gastroesophageal junction cancer. Further randomized clinical trials are warranted to confirm our findings.