Metastatic Gastric Adenocarcinoma Research Articles

Abstract PO1-18-06: Phase 1/2a Open-label Clinical Trial of BI-1607, an Fc Engineered Monoclonal Antibody to CD32b (FcγRIIB), in Combination with Trastuzumab in Subjects with HER2-positive Advanced Solid Tumors – CONTRAST

Abstract Background The introduction of trastuzumab has dramatically changed outcomes in patients with human epidermal growth factor receptor 2 positive (HER2+) cancer. However, primary or acquired resistance to trastuzumab has been increasingly recognized as a major obstacle in the clinical management of this disease. Combination of anti-HER2 antibodies with other immunotherapies is likely to improve the quantity and quality of responses. BI-1607 is a human monoclonal antibody (mAb) targeting FcRIIB (CD32b) with antagonistic function capable of blocking the inhibitory function of FcRIIB on immune effector cells. BI-1607 has been engineered to lack a glycan in position N297Q in the constant domain (Fc), and thus cannot interact with FcγRs through its Fc. Given its high specificity and affinity for FcγRIIB, BI-1607 blocks other antibodies’ binding to FcγRIIB. As a result, BI-1607 is expected to shift tumor cells coated antibodies (here anti-HER2) to selectively engage activating FcγRs, thus augmenting FcγR-dependent therapeutic activity (ADDC, ADCP). Tumor-associated macrophages express high levels of FcγRIIB and are a major target of BI-1607 in the tumor microenvironment. This concept was demonstrated in preclinical in vivo models showing increased efficacy of the combination therapy with the murine surrogate of BI-1607 and an anti-HER2, an anti–cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and an anti-CD20 (rituximab) as compared to monotherapy. It important to note that BI-1607 will have no single-agent activity. Instead, its clinical use will be in combination with other immunotherapies and tumor-targeting antibodies such as trastuzumab. The choice of trastuzumab as the combination agent in this trial was based on promising preclinical studies, a recognized need for additional options for those patients who fail to respond or stop responding to trastuzumab, and promising results from the newly approved Fc-engineered anti-HER2 mAb margetuximab. Ultimately, if shown to be safe and effective in combination with trastuzumab, BI-1607 can also be used in combination with other cytotoxic or immunomodulatory antibodies for cancer treatment. Methods This is a Phase 1/2a, first-in-human, open-label, multicenter, dose-escalation, consecutive-cohort study of BI-1607 in combination with trastuzumab in subjects with HER2+ advanced solid tumors. Phase 1 aims to assess safety and tolerability and to determine the RP2D of BI-1607 in combination with trastuzumab. Phase 2a will explore efficacy at RP2D of BI-1607 in combination with trastuzumab in two separate expansion cohorts, a) in subjects with locally advanced or metastatic HER2+ breast cancer and b) in subjects with HER2+ metastatic gastric or gastroesophageal junction adenocarcinoma. Eligible patents must have a HER2+ locally advanced unresectable or metastatic solid tumors and have received standard of care or be intolerant to standard of care antineoplastic therapy, with progressive disease after the last line of treatment. Accrual/Planned Accrual As of June 222d, 2023 10 patients have been treated into trial and dosed with BI-1607 and trastuzumab at doses from 75-900 mg every 3 weeks (Q3W) in Phase 1. Phase 2a will enroll 15 subjects each in two cohorts of HER2+ advanced/metastatic breast cancer or HER2+ gastric/GEJ adenocarcinoma respectively. For information regarding the study, please contact: anna.ropenga@bioinvent.com Citation Format: Javier Cortés, Araceli Priego, Elena Garralda Cabanas, Katerin Rojas Lamito, Simon Lord, Thorsten Goetze, Sherko Küemmel, Simon Crabb, Marie Borggren, Ingrid Karlsson, Linda Mårtensson, Anna Ropenga, Ingrid Teige, Johan Wallin, Björn Frendeus, Andres McAllister. Phase 1/2a Open-label Clinical Trial of BI-1607, an Fc Engineered Monoclonal Antibody to CD32b (FcγRIIB), in Combination with Trastuzumab in Subjects with HER2-positive Advanced Solid Tumors – CONTRAST [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-06.

Effect of anti-claudin 18.2 monoclonal antibody zolbetuximab alone or combined with chemotherapy or programmed cell death-1 blockade in syngeneic and xenograft gastric cancer models

The development of targeted cancer therapies based on monoclonal antibodies against tumor-associated antigens has progressed markedly over recent decades. This approach is dependent on the identification of tumor-specific, normal tissue-sparing antigenic targets. The transmembrane protein claudin-18 splice variant 2 (CLDN18.2) is frequently and preferentially displayed on the surface of primary gastric adenocarcinomas, making it a promising monoclonal antibody target. Phase 3 studies of zolbetuximab, a chimeric immunoglobulin G1 monoclonal antibody targeting CLDN18.2, combined with 5-fluorouracil/leucovorin plus oxaliplatin (modified FOLFOX6) or capecitabine plus oxaliplatin (CAPOX) in advanced or metastatic first-line gastric or gastroesophageal junction (G/GEJ) adenocarcinoma have demonstrated favorable clinical results with zolbetuximab. In studies using xenograft or syngeneic models with gastric cancer cell lines, zolbetuximab mediated death of CLDN18.2-positive human cancer cell lines via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro and demonstrated anti-tumor efficacy as monotherapy and combined with chemotherapy in vivo. Mice treated with zolbetuximab plus chemotherapy displayed a significantly higher frequency of tumor-infiltrating CD8+ T cells versus vehicle/isotype control-treated mice. Furthermore, zolbetuximab combined with an anti-mouse programmed cell death-1 antibody more potently inhibited tumor growth compared with either agent alone. These results support the potential of zolbetuximab as a novel treatment option for G/GEJ adenocarcinoma.

Abstract CT104: Results from a phase 1 study of the anti-immunoglobulin-like transcript 4 (ILT4) monoclonal antibody MK-4830 plus pembrolizumab in patients with previously treated advanced solid tumors

Abstract Background: In the dose escalation phase of a first-in-human phase 1 study (NCT03564691), the anti-ILT4 IgG4 monoclonal antibody MK-4830 + pembrolizumab (pembro) had a manageable safety profile and demonstrated promising antitumor activity in patients (pts) with previously treated advanced solid tumors, including those with PD on immunotherapy. Here, we present safety, efficacy, and biomarker analyses for MK-4830 + pembro for the previously treated pancreatic adenocarcinoma, glioblastoma, head and neck squamous cell carcinoma (HNSCC), and gastric cancer cohorts of the expansion phase. Methods: Eligible pts were aged ≥18 y with metastatic pancreatic adenocarcinoma and 1-3 lines of prior therapy (cohort A), unresectable glioblastoma and 1 prior line of therapy (cohort B), recurrent or metastatic HNSCC that progressed on a platinum-based chemotherapy and PD-(L)1 inhibitor (cohort C), or recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma that progressed on ≥2 prior chemotherapy regimens (cohort I). Pts in cohorts A, B, and I had not previously received a PD-(L)1 inhibitor. All pts received MK-4830 800 mg + pembro 200 mg Q3W for 35 cycles or until PD, unacceptable toxicity, or study withdrawal. Primary objectives were to evaluate safety and ORR per RECIST v1.1 (cohorts A, C, and I) or Response Assessment in Neuro-Oncology (RANO) criteria (cohort B) by investigator assessment. Exploratory objectives included evaluating DOR and PFS per RECIST v1.1 (cohorts A, C, and I) or RANO criteria (cohort B) by investigator assessment. Results: At data cut-off (September 27, 2023), 33 pts were enrolled and received treatment in cohort A, 20 pts in cohort B, 35 pts in cohort C, and 35 pts in cohort I. Median follow-up duration was 38.4 mo (range, 35.5-39.9) in cohort A, 34.1 mo (32.3-36.2) in cohort B, 37.5 mo (33.4-42.1) in cohort C, and 29.5 mo (22.3-36.4) in cohort I. Treatment-related adverse events (TRAEs) occurred in 15 pts (45%) in cohort A, 13 pts (65%) in cohort B, 19 pts (54%) in cohort C, and 16 pts (46%) in cohort I; grade 3 or 4 TRAEs occurred in 3 pts (9%), 0 pts, 2 pts (6%), and 4 pts (11%), respectively. No deaths due to TRAEs occurred. ORR was 6% (95% CI, 1-20) in cohort A, 5% (0-25) in cohort B, 0% (0-10) in cohort C, and 20% (8-37) in cohort I. Median DOR was 14.3 mo (range, 14.0-14.7) in cohort A, 7.4 mo (7.4-7.4) in cohort B, and 9.6 mo (3.0-27.6+) in cohort I. Median PFS was 1.9 mo (95% CI, 1.6-2.0) in cohort A, 1.2 mo (1.1-1.4) in cohort B, 2.2 mo (1.9-4.1) in cohort C, and 1.4 mo (1.3-3.0) in cohort I. Conclusions: In pts with select previously treated advanced or metastatic solid tumors, MK-4830 + pembro had a manageable AE profile but no significant antitumor activity beyond that historically observed with pembro monotherapy. Other treatment options must be explored for these difficult-to-treat tumors. Citation Format: Lillian L. Siu, Marta Gil-Martin, Byoung Chul Cho, Ruth Perets, John Hilton, Ravit Geva, Iwona Lugowska, Martin Gutierrez, Marcelo Bonomi, Rafal Dziadziuszko, Drew Rasco, Eytan Ben-Ami, Cristina P. Rodriguez, Shabana Siddiqi, Nicole Myer, Leah Suttner, Douglas Wilson, Ombololaji O. Akala, Maria de Miguel. Results from a phase 1 study of the anti-immunoglobulin-like transcript 4 (ILT4) monoclonal antibody MK-4830 plus pembrolizumab in patients with previously treated advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT104.

Abstract LB417: Leveraging advanced human lung models to explore mechanisms underlying T-DXd-associated interstitial lung disease (ILD)

Abstract Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate approved for several indications, including HER2-positive unresectable or metastatic breast cancer that progressed on two or more prior therapies, HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen and HER2-mutant unresectable or metastatic non-small cell lung cancer (USPI-ENH-C9-1122-r006). While the safety profile of T-DXd is manageable, ILD is an important identified risk and considered as an Adverse Event (AE) of special interest (Powell et al ESMO Open 2022). The therapeutic options for patients that develop ILD are limited to steroid medications, including prednisone and methylprednisolone. Hence, a greater understanding of T-DXd-associated ILD pathophysiology has the potential to guide alternative interventions to prevent ILD progression and improve patient care. Here, we used advanced human lung models to explore if T-DXd can affect pulmonary epithelial cell homeostasis and function. Transcriptome and gene set enrichment analysis of bronchial epithelial cells cultured under air-liquid interface (ALI) conditions revealed that genes and pathways associated with senescence, inflammation, and barrier integrity were dysregulated upon treatment with T-DXd. These transcriptomic findings linked to senescence and inflammation were confirmed in follow-up ALI experiments where T-DXd was shown to activate the p53 pathway, and upregulate pro-senescence, -inflammatory and -fibrotic mediators. Similarly, T-DXd activated senescence- and inflammation-associated markers in a microphysiological alveolar lung-on-chip system, thus indicating that T-DXd has similar effects in alveoli epithelia. In addition, T-DXd induced epithelial injury of ALI cells, which was reflected by loss of barrier function and release of epithelial damage markers. These changes were also accompanied by upregulation of mesenchymal cell markers, suggesting cells transition to a partial epithelial-to-mesenchymal phenotype. Whereas the payload (deruxtecan; DXd) and IgG control antibody-DXd conjugate (IgG-DXd) could recapitulate effects measured with T-DXd on lung epithelial cells, trastuzumab did not have any effect, suggesting limited contribution of HER2 targeting to T-DXd-induced epithelial changes in the experimental models used. Altogether, these data demonstrate that DXd can drive epithelial mechanisms and pathways associated with pulmonary fibrosis, inflammation, and damage, which are dysregulated events observed in ILD. Ongoing studies aim to evaluate the translation of these discoveries to the clinic and to support the development of novel therapeutic strategies to manage or prevent ILD. Citation Format: Ingrid Lua, Lin Jia, Jeff Chen, Kevin Contrepois, Mary McFarlane, Anton I. Rosenbaum, Peter Newham, Sonia Terrillon. Leveraging advanced human lung models to explore mechanisms underlying T-DXd-associated interstitial lung disease (ILD) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB417.

Abstract 5939: Enhancing nab-paclitaxel chemotherapy response in gastric cancer preclinical models through Inhibition of the HGF/c-Met pathway with merestinib

Abstract Background: Current treatments for primary metastatic or recurrent gastric adenocarcinoma (GAC) primarily involve combination chemotherapy, but the median survival time remains under a year. Nab-paclitaxel has displayed significant antitumor activity in preclinical GAC studies. GAC often exhibits overexpression of various growth factors and their receptors, which play a critical role in its pathophysiology. Aberrant activation of the HGF/c-Met pathway has been reported in up to 50% of GAC patients. We investigated the therapeutic potential of merestinib, a novel inhibitor targeting c-Met, along with Axl and DDR1/2 pathways, in combination with nab-paclitaxel in GAC preclinical models. Methods: Animal survival studies were conducted using peritoneal dissemination xenografts in NOD/SCID mice implanted with MKN-45 cells. Tumor growth was assessed in subcutaneous xenografts using MKN-45 and SNU-1 cells in NOD/SCID mice. IHC analyses were performed to evaluate tumor cell proliferation and microvessel density. In vitro cell proliferation and protein expression were assessed using the WST-1 assay and Western blot analysis, respectively. Results: Animal survival significantly improved with nab-paclitaxel (118%) and merestinib (41%) individually. The combination of merestinib with nab-paclitaxel (153%) resulted in further increased animal survival. In MKN-45 xenografts with high c-Met expression, a substantial reduction in tumor growth was observed with nab-paclitaxel and merestinib, showing a synergistic response. The net change in tumor size in the control, nab-paclitaxel, merestinib, and combination groups was 503 mm3, 115 mm3, 91 mm3, and -9.7 mm3 (tumor regression). In low c-Met expressing SNU-1 xenografts, the effect of merestinib and nab-paclitaxel was less pronounced compared to MKN-45 xenografts. The net change in tumor size in the control, nab-paclitaxel, merestinib, and combination groups was 219 mm3, 105 mm3, 131 mm3, and 57 mm3. Tumor cell proliferation and microvessel density corroborated the tumor growth study results. Nab-paclitaxel and merestinib reduced in vitro cell proliferation, with an additive effect in combination. The reduction in cell proliferation by nab-paclitaxel (10 nM), merestinib (100 nM), and their combination was 87%, 82%, and 94% in MKN-45, 59%, 50%, and 82% in SNU-1, and 53%, 19%, and 66% in gastric fibroblasts. In MKN-45 cells, merestinib increased the expression of pro-apoptotic proteins and decreased the expression of phospho-c-Met, phospho-EGFR, phospho-IGF-1R, phospho-ERK, and phospho-AKT. Conclusion:Merestinib has strong antitumor activity in GAC, especially when administered with nab-paclitaxel, demonstrating a synergistic effect. These results provide compelling evidence for the potential clinical relevance of this combination therapy in improving the survival of GAC patients. Citation Format: Quinn Kaurich, Jennifer Huang, Sazzad Hassan, Urs von Holzen, Niranjan Awasthi. Enhancing nab-paclitaxel chemotherapy response in gastric cancer preclinical models through Inhibition of the HGF/c-Met pathway with merestinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5939.

Identification of prognostic factors for survival in patients with metastatic gastric adenocarcinoma in a Mexican population

Introduction and aimsGastric adenocarcinoma is among the high-ranking tumors, with respect to frequency and mortality, worldwide. The inflammatory process and immune system activity are associated with oncologic control. Our aim was to identify whether the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and other variables are prognostic factors for survival in patients with metastatic gastric cancer in a Mexican population. Material and methodsPatients diagnosed with metastatic gastric adenocarcinoma, hospitalized within the time frame of December 2011 to 2021, were analyzed. The NLR, PLR, and albumin and hemoglobin levels obtained from blood samples were calculated. Functional status (ECOG and Karnofsky), sex, histology, and the presence of signet ring cells were also considered possible prognostic factors. Each factor’s prognostic value for overall survival was determined through univariate and multivariate analyses. ResultsThe study included 956 patients diagnosed with metastatic gastric cancer, of whom 494 (51.7%) were men and 462 (48.3%) were women. The main histologic finding was diffuse adenocarcinoma (n = 619, 64.7%), followed by intestinal adenocarcinoma (n = 293, 30.6%), and the presence of signet ring cells was found in 659 (68.9%) patients. Diagnostic laparoscopy was performed on 238 patients (24.9%) to confirm peritoneal carcinomatosis. The multivariate analysis showed that an NLR above 3.2 (HR 1.51, 95% CI 1.27-1.8; p < 0.001), albumin below 3.5 g/dl (HR 1.25, CI 1.06 - 1.47; p = 0.006), and an ECOG performance status of 2 or higher (HR 1.39, CI 1.10-1.76; p = 0.005) were independent factors that predicted a lower survival rate, whereas a Karnofsky score above 70% (HR 0.69, CI 0.53-0.91; p = 0.008) was associated with a better survival rate. Lastly, the PLR was not statistically significant in the multivariate analysis. ConclusionsThe NLR, nutritional status assessed through albumin measurement, and functional status can act as independent prognostic survival factors in hospitalized Mexican patients diagnosed with metastatic gastric adenocarcinoma and be taken into account during therapeutic decision-making.

Aggressive HER2-Positive Gastric Cancer in a Young Patient, Refractory in Trastuzumab and Progressive with Trastuzumab-Emtansine Treatment

Gastric cancer remains a major global health problem. Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of cancer-related deaths in the world. The prognosis of the disease is poor because it is often diagnosed at later stages, especially at HER2-positive. Most patients diagnosed with gastric cancer present with advanced, incurable disease. This report details the case of a 30-year-old male patient diagnosed with metastatic gastric adenocarcinoma. Stage T3 N3 M1, PD-L1 0%, and HER2+.The patient was administered neoadjuvant palliative chemotherapy, eight cycles of FLOT, and the last two cycles of HER-FLOT. The patient constantly had elevated levels of liver enzymes, and therefore, endoscopic retrograde cholangiopancreatography with biliary stenting was performed. After chemotherapy followed by restaging, the tumor board, based on the findings, decided to remove the primary tumor from this young patient. The operation was performed as a palliative da Vinci-assisted total gastrectomy with lymphadenectomy. Then, trastuzumab monotherapy was prescribed. At that time, the patient's follow-up with PET-CT showed progression with hypermetabolic lymph nodes in the paraaortic and aortocaval regions, as well as left hydronephrosis. As a result, we started the second-line therapy with T-DM1, an antibody-drug conjugate trastuzumab-emtansine (KADCYLA), for five cycles. At the time of receiving the sixth cycle, the patient's condition changed dramatically due to liver and heart problems, pleural effusion, and bleeding. After two years of treatment, all oncological-specific therapies have been ended, and the patient has been put in palliative care to relieve suffering and to support the best possible quality of life. This case underlines the importance of identifying potential therapeutic targets and developing therapies to improve the outcomes of systemic treatment beyond those currently achieved with conventional chemotherapy and targets.

Efficacy and safety of Zolbetuximab plus chemotherapy for advanced CLDN18.2-positive gastric or gastro-oesophageal adenocarcinoma: a meta-analysis of randomized clinical trials

BackgroundThe benefit of adding Zolbetuximab to the treatment in patients with Claudin-18 isoform 2 (CLDN18.2)-positive, human epidermal growth factor receptor 2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GC/GEJ) is not yet fully elucidated.MethodsWe searched PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs) that investigated Zolbetuximab plus chemotherapy versus chemotherapy alone for GC or GEJ adenocarcinoma. We computed hazard-ratios (HRs) or odds-ratios (ORs) for binary endpoints, with 95% confidence intervals (CIs).ResultsThree studies and 1,233 patients were included. Comparing with Zolbetuximab plus chemotherapy versus chemotherapy alone, progression-free survival (PFS) rate (HR 0.64; 95% CI 0.49–0.84; p < 0.01) and overall survival (OS) rate (HR 0.72; 95% CI 0.62–0.83; p < 0.01) were significant in favor of the Zolbetuximab group. Regarding effectiveness, the Objective Response Rate (ORR) was (OR 1.15; 95% CI 0.87–1.53; p = 0.34).ConclusionsIn this comprehensive systematic review and meta-analysis of RCTs, the incorporation of Zolbetuximab alongside chemotherapy offers a promising prospect for reshaping the established treatment paradigms for patients diagnosed with advanced CLDN18.2-positive GC/GEJ cancer.

Who are optimal candidates for primary tumor resection in patients with metastatic gastric adenocarcinoma? A population-based study.

The research aimed to construct a novel predictive nomogram to identify specific metastatic gastric adenocarcinoma (mGAC) populations who could benefit from primary tumor resection (PTR). Patients with mGAC were included in the SEER database and divided into PTR and non-PTR groups. The Kaplan-Meier analysis, propensity score matching (PSM), least absolute shrink and selection operator (LASSO) regression, multivariable logistic regression, and multivariate Cox regression methods were then used. Finally, the prediction nomograms were built and tested. 3185 patients with mGAC were enrolled. Among the patients, 679 cases underwent PTR while the other 2506 patients didn't receive PTR. After PSM, the patients in the PTR group presented longer median overall survival (15.0 vs. 7.0 months, p < 0.001). Among the PTR group, 307 (72.9%) patients obtained longer overall survival than seven months (beneficial group). Then the LASSO logistic regression was performed, and gender, grade, T stage, N stage, pathology, and chemotherapy were included to construct the nomogram. In both the training and validation cohorts, the nomogram exhibited good discrimination (AUC: 0.761 and 0.753, respectively). Furthermore, the other nomogram was constructed to predict 3-, 6-, and 12-month cancer-specific survival based on the variables from the multivariate Cox analysis. The 3-, 6-, and 12-month AUC values were 0.794, 0.739, and 0.698 in the training cohort, and 0.805, 0.759, and 0.695 in the validation cohorts. The calibration curves demonstrated relatively good consistency between the predicted and observed probabilities of survival in two nomograms. The models' clinical utility was revealed through decision curve analysis. The benefit nomogram could guide surgeons in decision-making and selecting optimal candidates for PTR among mGAC patients. And the prognostic nomogram presented great prediction ability for these patients.

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 &amp; 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 &amp; 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% &amp; 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 &amp; improved safety profile in the treatment of metastatic GAC. Clinical trial information: CTRI/2018/01/011450 . [Table: see text]

Health-related quality of life (HRQOL) with pembrolizumab (pembro) plus trastuzumab (tras) and chemotherapy (chemo) in first-line HER2-positive (HER2+) advanced gastric cancer: KEYNOTE-811 trial results.

286 Background: In the phase 3 KEYNOTE-811 study (NCT03615326), first-line (1L) pembro with tras + chemo (pembro arm) yielded superior PFS and improved ORR with durable responses versus placebo (pbo) with tras + chemo (pbo arm) in pts with HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, notably in pts with PD-L1 combined positive score (CPS) ≥1. Key prespecified exploratory HRQOL outcomes supporting these data are presented. Methods: Pts with untreated histologically or cytologically confirmed advanced HER2+ G/GEJ adenocarcinoma, measurable disease per RECIST v1.1 by investigator, and ECOG PS of 0 or 1 were randomly assigned 1:1 to receive pembro 200 mg or pbo IV every 3 weeks (Q3W) with tras + chemo (cisplatin + 5-fluorouracil or capecitabine + oxaliplatin). HRQOL was evaluated in pts who received ≥1 dose of study treatment and completed ≥1 pt-reported outcome (PRO) assessment. End points were least squares mean (LSM) change from baseline, time to deterioration (TTD), and overall improvement/stability rate in prespecified subscales of EORTC QLQ-C30, QLQ-STO22, EuroQol EQ-5D-5L. LSM changes from baseline were analyzed at wk 24 when prespecified completion and compliance rates of ~60% and 80%, respectively, were met, based on review of blinded data. Results: In the PRO analyses, 685 pts were evaluable (345 pembro with tras + chemo; 340 pbo with tras + chemo). Median time from randomization to data cutoff (May 25, 2022) was 28.4 mo (range, 9.3-42.6). Completion rates were &gt;92% at baseline and &gt;55% at wk 24 for all assessments in both arms. Similar changes in PRO scores from baseline to wk 24 were observed for the pembro versus pbo arms (Table). Similar percentages of pts in each arm had improved or stable scores for the EORTC QLQ-C30 GHS/QOL and physical functioning scales and EORTC QLQ-STO22 subscales. TTD was similar between arms for all prespecified subscales. Conclusions: The addition of pembro to tras + chemo did not negatively affect HRQOL during treatment. Combined with safety and efficacy data, these results support the use of pembro with tras + chemo for first-line treatment of pts with HER2+ advanced gastric cancer. Clinical trial information: NCT03615326 . [Table: see text]

De novo metastatic versus recurrent gastroesophageal cancer: A single-centre retrospective analysis.

282 Background: Outcomes remain poor for patients with metastatic gastric, gastroesophageal and esophageal adenocarcinoma (GEAC) with median survival of 14 months with combination chemotherapy and immunotherapy as per the Checkmate 649 trial. There is limited data to clarify if any differences exist between denovo metastatic and recurrent GEAC in terms of survival and response to systemic therapy. We compare the baseline characteristics and outcomes for patients with denovo metastatic and recurrent GEAC in our cohort. Methods: A retrospective observational analysis was conducted to include patients with metastatic GEAC reviewed at Princess Margaret Cancer Centre between 2007 and 2021. Baseline characteristics including age, sex, race, performance status and Charlson Comorbidity index (CCI) were reviewed. Outcomes of interest included overall survival (OS), progression free survival on first line (PFS1) and second line (PFS2) systemic therapy and disease-free interval (DFI) in the recurrent group (defined as time between initial diagnosis and development of recurrent disease). OS was calculated from diagnosis of stage IV disease. Cox proportional hazards and Kaplan Meier curves were used to compare OS, PFS1 and PFS2. Outcomes were adjusted for baseline characteristics. The effect of DFI on outcomes was evaluated in the recurrent group. Results: Our cohort consisted of 619 cases, of which 456 (73.6%) were denovo metastatic and 163(26.4%) were recurrent. The majority (71%) were male, non-Asian (85%) and median age for the cohort was 60 years. There were no significant differences in baseline characteristics and biomarker status (HER2, MSI) between denovo and recurrent groups. Number of metastatic sites was significantly higher in denovo group (Mean:2.3 vs 1.8, p&lt;0.001). A significantly higher percentage of patients received immunotherapy in the first line setting in the recurrent group (8% vs 4%, p:0.04). Using multivariate cox regression and after adjusting for age, performance status and CCI, there was a significant difference in OS favoring recurrent group (aHR:0.70, 95% CI 0.57-0.86, p=&lt;0.001). Using Kaplan Meier curves, median OS was 18.08 months in the recurrent group vs 14.62 months in the denovo metastatic group. There was a significant difference in PFS1 using a multivariate model in favor of the recurrent group (aHR 0.81,95% CI 0.67-0.99, p=0.04), as well as similar improvement in PFS2 for the recurrent group (aHR:0.69,95% CI 0.52-0.92, p=0.01). In the recurrent group, OS did not differ significantly between DFI &lt;6 months, 6-12 months or &gt;12 months. Conclusions: Our results show a significantly better OS, PFS1 and PFS 2 for recurrent as compared to denovo metastatic GEAC for patients treated in the 1st line metastatic setting in a large single-centre retrospective analysis. More in depth analysis of molecular differences in patient tumors is underway and may help to explain better outcomes.

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 .

Comprehensive molecular characteristics of clinical responses to PD-1 inhibitors plus anti-angiogenic agents (PA) in metastatic HER2-negative gastric adenocarcinoma.

279 Background: Anti-angiogensis agents were reported to enhance the efficacy of PD-1 inhibitor by inhibiting the infiltration of suppressive immune cell populations. Clinical studies indicated the synergistic anti-tumor effect of the combination of PD-1 inhibitors and anti-angiogenesis agents (PA). We aim to assess the efficacy of PA versus chemo-PA regiment in mGC, as well as the potential predictive biomarkers. Methods: A total of 55 GC tumors were analyzed using the next-generation sequencing (NGS), immunohistochemistry (IHC), and the tumor immune microenvironment (TIME) by multiplex immunofluorescence (mIHC). Clinical outcomes [Disease Control Rate (DCR), Progression-free survival (PFS) and overall survival (OS)] were compared between patients receiving PA treatment (n=32) and chemo-PA (n=23) treatment. Exploratory biomarker analyses were conducted for the prediction for the efficacy of PA/chemo-PA treatment. Results: Patients receiving PA regiment had comparable DCR (69% vs 50%, P =0.25) and PFS (median PFS: 6.53 vs 4.73 months, HR=0.70, 95%CI: 0.27-1.78, P =0.52), compared with those treated with combination of chemo-PA regiment as second or later-line treatment in mGC. Patients with HMCN1 wild-type showed significant improvements in DCR (77% vs 0%, P =0.023) and PFS (median PFS: 6.53 vs 1.17 months, P =0.0017), versus those with HMCN1 mutations in PA treatment cohort. HMCN1 mutations are associated with lower infiltration of endothelial cells and lower score of VEGF ligand-receptor interaction, according to the EPIC and pathway enrichment analysis ( P &lt; 0.05). In addition, analysis of TIME by mIHC revealed that the fraction of CD68+ tumor-associated macrophages in the tumor center was higher in responders than non-responders before treatment (median: 17.59% vs 2.45%, P=0.016). Conclusions: PA regiment and chemo-PA regiment had similar efficacy in second or later line treatment of mGC. HMCN1 mutations maybe a predictive marker for PA regiment in HER2-negative mGC, which should be further validated in a large cohort.

Efficacy and safety of nivolumab and CapeOX in patients with previously untreated FGFR2-positive, PD-L1-positive advanced gastric cancer: A single-arm, multicenter, phase 2 study NIVOFGFR2.

303 Background: Nivolumab in combination with chemotherapy has been approved in the first-line treatment of PD-L1-positive metastatic gastric cancer (GC). Fibroblast growth factor receptor 2 (FGFR2) is overexpressed in 30% of patients with GC and is a potential new target for targeted therapy with monoclonal antibodies1 or allosteric extracellular inhibitors.2 The aim of the NIVOFGFR2 study was to evaluate the preliminary efficacy of nivolumab in metastatic GC co-expressing PD-L1 and FGFR2. Methods: In this single-arm, multi-center, phase 2 study, eligible patients had metastatic untreated HER2-negative gastric adenocarcinoma with centrally confirmed expression of PD-L1 (CPS≥5; DAKO 28-8) and FGFR2 (moderate (2+) and strong (3+) membranous staining in more than 1% of tumor cells; Abсam EPR24075-418). Patients received nivolumab 360 mg with CapeOX (capecitabine and oxaliplatin) every 3 weeks. The primary endpoint was 1-year progression-free survival (PFS). Secondary endpoints included median PFS and overall survival (OS), objective response rate (ORR) and Grade ≥3 adverse events rate. Results: Seventy-four HER2-negative patients were screened and23 (31%) patients were enrolled (median age 61 years, men 74%, Caucasian 91%, ECOG PS 1-2 78%, organs with ≥2 metastases 78%; CPS (5-9) 22%, (≥10) 78%). 1-year PFS rate was 30,4%. The median PFS was 6.2 months (95% CI 4.4-7.6). The ORR was 21.7% with 1 complete response. With a median follow-up of 11.8 months at data cutoff, the median OS was not reached. Grade ≥3 treatment-related adverse events were reported in 9 (39.1%) patients. Conclusions: An interim analysis demonstrates modest efficacy and an acceptable safety profile of nivolumab in combination with chemotherapy in patients with FGFR2-positive, PD-L1-positive metastatic GC. Further follow-up is ongoing. 1. Wainberg, Lancet Oncol. 2022. 2. Tsimafeyeu, Invest New Drugs. 2023. Clinical trial information: NCT05859477 .

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]

Safety and efficacy of zolbetuximab for CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: A systematic review and meta-analysis of randomized controlled trials.

370 Background: Monoclonal antibody (Nivolumab, Trastuzumab, Bemarituzumab) with chemotherapy has shown benefit for patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Zolbetuximab, a new monoclonal antibody against Claudin (CDLN) 18.2 has demonstrated interesting results in clinical trials, however, there is still a need to find a safe and effective first-line treatment, especially for epidermal growth factor receptor (HER) 2-negative patients. Therefore, we aimed to perform a meta-analysis exploring the use of combined immunotherapy (Zolbetuximab) and standard chemotherapy versus chemotherapy alone. Methods: We searched PubMed, Embase and Cochrane Central for randomized controlled trials (RCTs) comparing Zolbetuximab to chemotherapy alone in patients with CLDN18.2-positive gastric or GEJ adenocarcinoma. The outcomes evaluated were Overall Survival (OS), Progression Free-Survival (PFS), Objective Response Rate (ORR) and Treatment-Emergent Adverse Events (TEAE). We pooled hazard ratio (HR) for PFS and OS endpoints and risk ratio (RR) for ORR and TEAE, with 95% confidence intervals (CI). Statistical analyses were performed using R software version 4.3.1 with a random-effects model. I² analysis was used to assess heterogeneity. Adverse Events (AE) were graded according to the National Cancer Institute Common Terminology Criteria for AE. Results: From sixty-six studies, three were included, with a total of 1349 patients. 671 (49.7%) were part of the intervention group, 769 (57.0%) were male, 360 (26.7%) underwent prior gastrectomy and 1304 (96.7%) had a more than 70% CLDN18.2 cellular staining rate. Age range was 21-83 years. Treatment with Zolbetuximab was associated with significantly higher PFS (HR 0.64; CI 0.49-0.84; p = 0.0011; I² = 59.6%) and OS (HR 0.70; CI 0.59-0.84; p&lt;0.0001; I² = 40.0%). TEAEs grade ≥ 3 (RR 1.09; CI 1.03-1.16; p = 0.0051; I² =0.0%) were greater for the intervention group. ORR and serious TEAE had no difference when compared with the control group. Most frequent AEs were nausea (34.6%), vomiting (30.2%) and decreased appetite (18.6%). Conclusions: In summary, the use of Zolbetuximab alongside standard chemotherapy reduces mortality and disease progression, although it might increase the risk for grade ≥ 3 treatment-emergent AEs.

Nivolumab Toxicity Meets Leptomeningeal Carcinomatosis: A Case Report

Nivolumab (Opdivo) is an immune checkpoint inhibitor used in the treatment of multiple cancers including gastric adenocarcinoma. The diagnosis of antineoplastic therapy toxicity, such as nivolumab toxicity, occurs commonly in those receiving treatment with symptoms ranging from a rash to potentially death, which is an uncommon side effect. Patients who have cancer can develop the diagnosis of leptomeningeal carcinomatosis (LMC), which is considered rare, occurring in 2-4% of all cancers. The initial presentation with primarily neurological symptoms can occur in both diseases, however the prognosis and treatment varies greatly. In this case report, we discuss a patient with metastatic gastric adenocarcinoma reportedly in remission, who was initially being treated as having nivolumab toxicity, however 72 hours later he was found to have leptomeningeal carcinomatosis.

NCI10066: a Phase 1/2 study of olaparib in combination with ramucirumab in previously treated metastatic gastric and gastroesophageal junction adenocarcinoma

BackgroundOur preclinical work revealed tumour hypoxia induces homologous recombination deficiency (HRD), increasing sensitivity to Poly (ADP-ribose) polymerase inhibitors. We aimed to induce tumour hypoxia with ramucirumab thereby sensitising tumours to olaparib.Patients and methodsThis multi-institution single-arm Phase 1/2 trial enrolled patients with metastatic gastroesophageal adenocarcinoma refractory to ≥1 systemic treatment. In dose escalation, olaparib was evaluated at escalating dose levels with ramucirumab 8 mg/kg day 1 in 14-day cycles. The primary endpoint of Phase 1 was the recommended Phase 2 dose (RP2D), and in Phase 2 the primary endpoint was the overall response rate (ORR).ResultsFifty-one patients received ramucirumab and olaparib. The RP2D was olaparib 300 mg twice daily with ramucirumab 8 mg/kg. In evaluable patients at the RP2D the ORR was 6/43 (14%) (95% CI 4.7–25.6). The median progression-free survival (PFS) was 2.8 months (95% CI 2.3–4.2) and median overall survival (OS) was 7.3 months (95% CI 5.7–13.0). Non-statistically significant improvements in PFS and OS were observed for patients with tumours with mutations in HRD genes.ConclusionsOlaparib and ramucirumab is well-tolerated with efficacy that exceeds historical controls with ramucirumab single agent for gastric cancer in a heavily pre-treated patient population.

Sintilimab Plus Chemotherapy for Unresectable 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.