Metastatic Gastroesophageal Adenocarcinoma Research Articles

Three biomarkers (HER2, PD-L1, and microsatellite status) in a large cohort of metastatic gastroesophageal adenocarcinomas: The MD Anderson Cancer Center experience.

Human epidermal growth factor receptor-2 (HER2), programmed death-ligand 1 (PD-L1), and microsatellite (MS) status are well-established biomarkers in gastroesophageal adenocarcinomas (GEAs). However, it is unclear how the combination of these biomarkers is associated with clinicopathological factors and prognosis. This retrospective study included baseline metastatic GEA patients who were tested for all three biomarkers (HER2, PD-L1, and MS status) at the MD Anderson Cancer Center between 2012 and 2022. Stratification was performed according to the combination of biomarker profiles: triple negative (TN), single positive (SP), and multiple positive (MP). Comparative analyses of clinicopathological factors and survival using combinations of biomarkers were performed. Among the 698 GEA patients analyzed, 251 (36.0%) were classified as TN, 334 (47.9%) as SP, and 113 (16.1%) as MP. The MP group showed a significant association with tumors located in the esophagus (p < .001), well to moderate differentiation (p < .001), and the absence of signet ring cells (p < .001). In the survival analysis, MP group had a significantly longer overall survival (OS) compared to the other groups (MP vs. TN, p < .001 and MP vs. SP, p < .001). Multivariate Cox regression analysis revealed that MP serves as an independent positive prognostic indicator for OS (hazard ratio = 0.63, p < .01). Our findings indicate that MP biomarkers are associated with a favorable prognosis in metastatic GEA. These results are reflective of clinical practice and offer valuable insights into how therapeutics and future biomarkers could influence therapy/prognosis.

Global prevalence of claudin 18 isoform 2 in tumors of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma.

Limited data exist for global prevalence of claudin 18 isoform 2 (CLDN18.2) positivity and association of CLDN18.2 status with clinical and tumor characteristics in patients with locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. We report prevalence of CLDN18.2 positivity (phase 3; SPOTLIGHT, NCT03504397; GLOW, NCT03653507) and concordance of CLDN18.2 status between a subset of pair-matched tumor samples (phase 2, ILUSTRO, NCT03505320; phase 1, NCT03528629) from clinical studies of zolbetuximab. Tumor samples from patients with LA unresectable or mG/GEJ adenocarcinoma were tested for CLDN18.2 status by immunohistochemistry. Human epidermal growth factor receptor 2 (HER2) expression was tested per central or local assessment. Across SPOTLIGHT and GLOW, the prevalence of CLDN18.2 positivity (≥ 75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining) was 38.4%. Prevalence was similar in gastric versus GEJ adenocarcinoma samples and regardless of collection method (biopsy versus resection) or collection site (primary versus metastatic). CLDN18.2 positivity was most prevalent in patients with diffuse-type tumors. In ILUSTRO and the phase 1 study, concordance of CLDN18.2 positivity was 61.1% between archival (i.e., any time before treatment) and baseline (i.e., ≤ 3 months before first treatment) samples, and concordance of any CLDN18 staining (≥ 1% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining) was 88.9%. CLDN18.2 was a highly prevalent biomarker in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma. CLDN18.2 positivity remained relatively stable over time in many patients. Biomarker testing for CLDN18.2 should be considered in standard clinical practice in these patients.

A phase II study of cabozantinib and pembrolizumab in advanced gastric/gastroesophageal adenocarcinomas resistant or refractory to immune checkpoint inhibitors.

Most patients with metastatic gastroesophageal adenocarcinoma (mGEA) progress on immune checkpoint inhibitors (ICIs). Novel approaches to overcome resistance to ICI in mGEA are needed. Cabozantinib is a multi-tyrosine kinase inhibitor thought to enhance the immunomodulatory effects of ICI. This study evaluated the combination of cabozantinib and pembrolizumab in ICI refractory or resistant mGEA. Investigator-initiated, single-arm, single institution, and phase II study in patients with mGEA. Patients had progressed on ICI and/or had PD-L1 CPS score ≤10%. Cabozantinib dose was 40 mg p.o. daily on days 1-21 of a 21-day cycle, with pembrolizumab 200 mg i.v. on day 1. The primary endpoint was progression-free survival at 6 months (PFS-6). Twenty-seven patients were enrolled. Median age 58 years (24-87), female (n = 14), ECOG 0/1 = 13/14, GC/GEJ = 16/11, and non-Hispanic White/Hispanic/Asian = 12/8/7. The primary endpoint was met. After a median follow-up of 31.4 months (range 3.3-42.5), PFS-6 was 22.2% (95% CI 9.0-39.0). The median PFS and OS are 2.3 months (95% CI 1.7-4.1) and 5.5 months (3.1-14.0), respectively. The most common mutations were TP53 (78.3%) and CDH1/PIK3CA/CTNNB1 (17.4% each). The most common grade (G) treatment-related adverse events (TRAE) were diarrhea (25.9%), fatigue (18.5%), hypertension, and muscle cramps (14.8% each). G3-4 TRAE were seen in n = 3 patients (hypertension, thromboembolic event, esophageal perforation; each n = 1). No G5 was observed. The addition of cabozantinib to pembrolizumab shows clinical benefit in ICI-resistant or refractory mGEA with a tolerable safety profile. (ClinicalTrials.gov Identifier: NCT04164979. IRB Approved: UCI 18-124, University of California Irvine IRB#20195426.).

FS-1502 in patients with HER2 high expression, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: An open-label, multicenter, phase II study.

e15000 Background: FS-1502 is an antibody-drug conjugate composed of an anti-HER2 antibody, linker, and Monomethylauristatin F. In this study, we conducted an open-label, multicenter, two-cohort phase II trial to evaluate the efficacy and safety of FS-1502 in HER2- positive locally advanced or metastatic gastric or gastroesophageal junction cancer. Methods: Pts with HER2-positive (IHC 3+ or 2+/FISH+) who had received ≥1 prior treatment regimens were eligible and received FS-1502 2.3 mg/kg alone every 3 weeks. The study consists of Cohort 1 for pts received ≥2 lines of previous therapy and Cohort 2 for pts only received first-line of previous therapy, respectively. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival (OS), duration of response, disease control rate, and safety. Results: At data cutoff (Dec 24,2023), 46 pts were enrolled (intent-to-treat [ITT]), 35 pts were confirmed HER2-positive (IHC 3+ or IHC 2+/ISH+, Efficacy Evaluable Set [ES]) by central laboratory. In the ES, the median age was 58.3 years, 48.6% were IHC3+ and primary tumor location in 77.1% of pts was GC. 45.7% (16/35) pts had assigned to cohort 1 and 54.3% (19/35) pts had assigned to cohort 2. In cohort 1, median study follow-up time was 10.1 months, the investigator-assessed ORR was 37.5% (95% CI, 15.2-64.6), median PFS and OS were 4.3 months (95% CI, 1.5-5.8 months) and 10.0 months (95% CI,5.1-NA months), respectively. In cohort 2, median study follow-up time was 12.5 months, the investigator-assessed ORR was 52.6% (95% CI, 28.9-75.6). PFS and OS were 4.4 months (95% CI, 3.0-7.3 months) and 14.6 months (95% CI, 8.7-NA months), respectively. Grade≥3 treatment-related TEAEs were reported in 12 (26.1%) pts, ≥5% were hypokalemia (6.5%) and fatigue(6.5%). No adverse events leading to drug discontinuation or death. Efficacy and safety data are shown in table. Conclusions: FS-1502 showed promising activity with tolerable and manageable safety profile, which warrants further development in HER2-postive, advanced gastric or gastroesophageal junction adenocarcinoma who had received ≥1 prior treatment regimens. [Table: see text]

Triple combination treatment of trastuzumab, chemotherapy and immune checkpoint inhibitor in HER2 positive unresectable, locally advanced, metastatic gastric and esophageal adenocarcinoma: A systematic review and meta-analysis.

e16071 Background: The current standard of care for unresectable, locally advanced or metastatic HER2 positive gastric, esophageal and gastroesophageal junction adenocarcinomas is the combination of the anti HER 2 antibody trastuzumab and cytotoxic chemotherapy. In recent years, the addition of immune checkpoint inhibitors to this combination has been studied to determine if it can improve clinical outcomes for this disease. This systematic review and meta-analysis evaluated high-quality data from clinical trials to determine the role and efficacy of this triple combination treatment. Methods: A systematic search of English-language articles on PubMed, Cochrane and Google scholar was done to identify randomized trials (RCTs) investigating the use of triple combination treatment of anti-Her 2 antibody, chemotherapy and immune checkpoint inhibitor in the treatment of unresectable, locally advanced, or metastatic HER2 overexpression positive gastric, esophageal and gastroesophageal junction adenocarcinoma. Quality of the studies was assessed using the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). Inverse variance was the statistical method used with random effects as the analysis model in the production of the Forest plot and calculation of risk ratio (RR) at 95% confidence intervals (CI). Results: Four (4) RCTs (N = 866) were included for quality assessment and data extraction. Two (2) of these RCTs (N = 80) were single arm studies which both showed favorable outcomes in terms of objective response rate and progression free survival. The two (2) other RCTS (N = 786), each had two arms (triple regimen versus comparator) and were used in the meta-analysis. Risk of bias was low and heterogeneity was low (I2 below 50%). Pooled results showed that in patients given triple combination regimen, there is statistically significant improvement in progression free survival (RR 1.55 95% CI 1.20-2.00, p 0.0007). There is also an increase in overall response rate in favor of the triple combination regimen, albeit not statistically significant (RR 1.31 95% CI 0.99-1.74, p = 0.06). Conclusions: The addition of an immune checkpoint inhibitor to the current standard of care of anti Her 2 antibody and chemotherapy provides meaningful results in terms of tumor response and progression free survival in Her 2 positive locally advanced or metastatic gastric and esophageal adenocarcinomas. More robust trials, and data on overall survival supporting the use of this triple regimen may help re-shape the current standard of care for this disease.

Multicenter randomized phase II study of short course FOLFOX + nivolumab (Nivo) followed by maintenance Nivo +/- radiation (RT) in the first line treatment of metastatic or unresectable gastroesophageal adenocarcinoma (mGEA).

4060 Background: Standard 1L treatment of mGEA is chemotherapy with checkpoint inhibition (CPI). However, prolonged cytotoxic therapy can impair CPI efficacy by reducing effective immune infiltration over time. Alternatively, radiotherapy (RT) can augment CPI efficacy in multiple malignancies. In this randomized phase II multicenter study, we examined short course chemotherapy and the potential of RT in improving the efficacy of CPI. Methods: This was a multicenter study of FOLFOX + Nivo for 3 months followed by maintenance Nivo with or without RT (20Gy in 5 fractions to the dominant lesion). Eligible patients had adequate end organ function, measurable disease, and were CPI candidates, regardless of PD-L1 CPS expression. Patients without progression at 2 months were randomized 1:1 to Nivo or Nivo + RT. The primary objective was to demonstrate that adding RT to Nivo in the maintenance setting improved efficacy as measured by 12-month progression free survival (PFS) rate. A secondary objective was to demonstrate that the efficacy of short course chemo is similar to continuing FOLFOX until progression (from CM649, 12-mo PFS 34% [95% CI: 30-38%] all pts). Results: Seventy-three evaluable pts enrolled from 7/11/2019 to 4/13/2023. Mean age 63.1, M:F 2.7:1. PD-L1 distribution: CPS &gt; 5 in n=37 (50.7%), CPS 1-4 16 (22%), CPS &lt;1 20 (27.4%). Seven (9.6%) patients progressed at 2 months and had a median OS of 90d (95%CI 44-178d). The remaining 66 patients were randomly assigned to Nivo maintenance (n=32), or Nivo + RT (n=34). The objective response rate for all evaluable pts is 43.8% (95%CI 32.5-55.2%). The 12-month and median PFS for all evaluable pts (n=73) is 29.5% (19.2- 40.7%) and 7.4 mo (5.7-8.6mo); for Nivo alone 34.4% (18.8- 50.6%) and 7.5mo (5.4-14.2mo), and Nivo + RT 30.0% (14.9-46.8%) and 7.8 mo (5.7-9.6mo) respectively (p=NS). The 12-month and median OS for all evaluable pts (n=73) is 60.9% (48.6-71.1%) and 16mo (10.8-22.4mo); for Nivo alone 71.9% (52.9- 84.3%) and 22.4mo (13.2-NAmo), and Nivo + RT 62.8% (43.7-76.9%) and 17.9 mo (10.3-24.5mo) respectively (p=NS). Forty-nine patients progressed after randomization, of which 30 patients were rechallenged with FOLFOX or CAPOX with continued response – median time to 2nd progression 3.93mo (range 0.5-15.2mo). Amongst patients who were rechallenged with oxaliplatin based therapy, the median time to oxaliplatin failure was 13.76 mo (range 4.4–30mo). Conclusions: Short course FOLFOX + Nivo followed by maintenance Nivo has a similar progression free and overall survival to continuing FOLFOX + Nivo until progression. Patients who receive short course chemotherapy can successfully be rechallenged with oxaliplatin. The addition of RT to maintenance Nivo does not improve CPI efficacy. Short course FOLFOX with CPI is a safe and effective 1L option for mGEA. Clinical trial information: NCT04021108 .

397MO Tislelizumab (TIS) plus chemotherapy (CT) vs placebo (PBO) plus CT in HER2-negative advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma (GC/GEJC): PD-L1 biomarker analysis from RATIONALE-305

397MO Tislelizumab (TIS) plus chemotherapy (CT) vs placebo (PBO) plus CT in HER2-negative advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma (GC/GEJC): PD-L1 biomarker analysis from RATIONALE-305

446P A prospective study for real-world data (RWD) of ramucirumab plus paclitaxel in patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma (KCSG ST21-06)

446P A prospective study for real-world data (RWD) of ramucirumab plus paclitaxel in patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma (KCSG ST21-06)

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial

ObjectiveTo evaluate the efficacy and safety of tislelizumab added to chemotherapy as first line (primary) treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma compared with placebo plus chemotherapy.DesignRandomised, double blind,...

Docetaxel, Oxaliplatin with Capecitabine (TEX Regimen) in Metastatic Gastric and Gastroesophageal Adenocarcinoma: A Prospective Single-Arm Observational Study from a Tertiary Cancer Center in Kashmir

Abstract Background Metastatic gastric and gastroesophageal adenocarcinoma (MGGEAC) is a challenging disease with limited treatment options. The Taxotere, Eloxatin, and Xeloda (TEX) regimen has shown promising results in several clinical trials. There exists a dearth of data pertaining to the efficacy and tolerance of the treatment approach in the populace of Kashmir. Methods This study was performed at the Department of Medical Oncology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir. Patients with MGGEAC received treatment with biweekly TEX regimen that included docetaxel 50 mg/m2-D1, oxaliplatin 85 mg/m2-D1, and capecitabine 1250 mg/m2/day, twice daily orally, for 14 days. The effectiveness of the regimen was assessed based on the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), along with the prognostic factors, safety, and tolerability of the regimen. Results The ORR was 63.5% after four cycles. The median PFS and OS were 9.1 and 13 months, respectively. Univariate and multivariate analysis showed that a higher number of sites of metastases is associated with poor PFS. The TEX regimen was well tolerated. The most observed grade 3 to 4 toxicities were neutropenia (36.7%), anemia (20%), fatigue (20%), and febrile neutropenia (16.7%). Conclusion Using the TEX regimen in MGGEAC showed better response rates and a slightly longer PFS. A higher number of sites of metastases is a poor prognostic factor in MGGEAC, as seen in our study. The toxicity profile shows that the regimen is tolerable. We recommend a randomized controlled study comparing CapeOx with TEX to test this regimen further.

The optimal threshold of PD-L1 combined positive score to predict the benefit of PD-1 antibody plus chemotherapy for patients with HER2-negative gastric adenocarcinoma: a meta-analysis

BackgroundImmune checkpoint inhibitors (ICIs) combined with chemotherapy have become the first-line treatment of metastatic gastric and gastroesophageal adenocarcinomas (GEACs). This study aims to figure out the optimal combined positive score (CPS) cutoff value.MethodsWe searched for randomized phase III trials to investigate the efficacy of ICIs plus chemotherapy for metastatic GEACs compared with chemotherapy alone. Pooled analyses of hazard ratios (HRs) based on PD-L1 expression were performed.ResultsA total of six trials (KEYNOTE-062, KEYNOTE-590, KEYNOTE-859, ATTRACTION-04, CheckMate 649, and ORIENT-16) were included, comprising 5,242 patients. ICIs plus chemotherapy significantly improved OS (HR: 0.79, 95% CI 0.72–0.86 in global patients; HR: 0.75, 95% CI 0.57–0.98 in Asian patients) and PFS (HR: 0.74, 95% CI 0.68–0.82 in global patients; HR: 0.64, 95% CI 0.56–0.73 in Asian patients) compared with chemotherapy alone. The differences in OS (ratio of HR: 1.05, 95% CI 0.79–1.40; predictive value: − 5.1%) and PFS (ratio of HR: 1.16, 95% CI 0.98–1.36; predictive value: − 13.5%) were not statistically significant between the global and Asian patients. Subgroup analyses indicated that the optimal CPS threshold was at ≥ 5 for OS and ≥ 10 for PFS with the highest predictive values.ConclusionsThe benefit derived from ICIs plus chemotherapy is similar between Asian and global GEAC patients. However, those with a PD-L1 CPS < 5 or CPS < 10 may not have significant benefits from ICIs therapy. Therefore, it is advisable to routinely assess PD-L1 expression in GEAC patients considered for ICIs treatment.

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.

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.

First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report 3-year efficacy and safety results from the phase III CheckMate 649 trial. Patients with previously untreated advanced or metastatic gastroesophageal adenocarcinoma were randomly assigned to nivolumab plus chemotherapy or chemotherapy. Primary end points were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in patients whose tumors expressed PD-L1 combined positive score (CPS) ≥5. With 36.2-month minimum follow-up, for patients with PD-L1 CPS ≥5, the OS hazard ratio (HR) for nivolumab plus chemotherapy versus chemotherapy was 0.70 (95% CI, 0.61 to 0.81); 21% versus 10% of patients were alive at 36 months, respectively; the PFS HR was 0.70 (95% CI, 0.60 to 0.81); 36-month PFS rates were 13% versus 8%, respectively. The objective response rate (ORR) per BICR was 60% (95% CI, 55 to 65) with nivolumab plus chemotherapy versus 45% (95% CI, 40 to 50) with chemotherapy; median duration of response was 9.6 months (95% CI, 8.2 to 12.4) versus 7.0 months (95% CI, 5.6 to 7.9), respectively. Nivolumab plus chemotherapy also continued to show improvement in OS, PFS, and ORR versus chemotherapy in the overall population. Adding nivolumab to chemotherapy maintained clinically meaningful long-term survival benefit versus chemotherapy alone, with an acceptable safety profile, supporting the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastroesophageal adenocarcinoma.

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.

Development and application of an ultra-sensitive ctDNA mutation profiling assay in monitoring therapy response and drug resistance.

264 Background: Next-generation sequencing (NGS) assays offer efficient high-throughput profiling methods for analyzing circulating tumor DNA (ctDNA) in blood or other liquid biopsy specimens. The ctDNA mutant allele fractions of patients after treatment is often very low and below the detection limit of regular cfDNA assays. Here we report the development and clinical application of a CLIA-certified ultra-sensitive NGS cfDNA assay in detecting the low-frequency ctDNA mutations and monitoring therapy response and drug resistance in patients with metastatic gastroesophageal adenocarcinoma under combined blockade treatments. Methods: PredicineCARE ULTRA cfDNA assay with 100,000X sequencing depth was validated under CLIA settings. Limit of blank (LoB) and limit of detection (LoD) were established by profiling 38 healthy donor plasma samples, 23 contrived human cfDNAs samples from patients with various cancers, and 30 replicates of well-established ctDNA reference standards. In silico down-sampling of FASTQ files was carried out to test the sensitivity of this assay with a lower coverage (50,000X). This assay was then adopted for longitudinal sequencing of 57 serial plasmas from 6 patients with HER2+ gastroesophageal adenocarcinomas (GEC) who underwent combined treatments (capecitabine, oxaliplatin, bevacizumab and trastuzumab) at different time points (baseline, response, and progression). Results: PredicineCARE ULTRA cfDNA assay exhibited exceptional sensitivity in calling single-nucleotide variants and indels, with a 98.0% detection rate at a LoD of 0.075% mutant allele frequency (MAF) for 60 ng cfDNA. This is significantly lower than the LoD (0.25% MAF) of a standard PredicineCARE cfDNA assay. The ultra-sensitive assay also displayed decent analytical specificity (&gt;99.99%) and precision (intra-assay 100%; inter-assay 99.41%). In 6 GEC patients’ longitudinal samples, PredicineCARE ULTRA cfDNA assay detected 36 additional somatic mutations with the MAFs spanning in a range from 0.024% to 0.1% beyond 124 baseline mutations identified using standard PredicineCARE. In two representative cases presented here, all baseline mutations (genes TP53 and PIK3CA etc.) were consistently reported in the follow-up time points with a noticeable MAF reduction (lowest MAFs from 0.046% to 0.024%) during response. Subsequent elevations were observed in more genes, including low-frequency mutations (KRAS and ERBB2) not detected at baseline or only detected in PredicineCARE ULTRA. Conclusions: This study demonstrated the promise and clinical utility of the ultra-sensitive cfDNA molecular profiling at 100,000X sequencing depth in treatment selection, therapy monitoring, and drug resistance studies.

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 .

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.