Gastroesophageal Junction Adenocarcinoma Research Articles

Camrelizumab plus apatinib and SOX as first-line treatment in patients with alpha-fetoprotein–producing gastric or gastroesophageal junction adenocarcinoma: A single-arm, multi-center, phase 2 trial.

351 Background: Patients (pts) with AFP-producing G/GEJ adenocarcinoma generally respond poorly to first-line standard chemotherapy. We aimed to assess the efficacy and safety of first-line camrelizumab plus apatinib given concurrently with chemotherapy, followed by camrelizumab plus apatinib in AFP-producing G/GEJ adenocarcinoma pts. Methods: In this open-label, single-arm, multi-center, phase 2 trial (NCT04609176), pts with aged ≥18 years, clinical stage III-IV, unresectable/recurrent or metastatic G/GEJ adenocarcinoma with no prior systemic therapy, serum AFP > 2×ULN or AFP positive by the IHC staining method were enrolled. Pts received 4 cycles of standard S-1 plus oxaliplatin (SOX) and camrelizumab (200mg, iv, d1, q3w) plus apatinib (250mg, po, qd). Pts without disease progression then continued to receive camrelizumab plus apatinib for up to 24 months, or until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST v1.1; secondary endpoints included the duration of response (DoR), disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. Results: A total of 36 pts were enrolled and received treatment between Dec 4, 2020 and Aug 4, 2023. 35 pts were evaluable for tumor response. Median age was 63 years (range: 28, 78), with 30 pts (83.3%) were male. 13 pts (36.1%) presented with GEJ. 34 pts (94.5%) were diagnosed with stage IV. 20 pts (55.6%) had distant lymph node involvement, 18 (50.0%) had liver metastasis, 8 (22.2%) had peritoneal metastasis, and 2 (5.6%) had lung metastasis. Median serum AFP level was 739.8 ng/ml (range: 77.7, 321847.0). At data cut-off (Sep 1, 2023), the median follow-up duration was 6.4 months (range: 0.7, 27.0). Efficacy was assessed in the FAS population (n = 36). 2 pts showed complete response (CR, all confirmed), 22 had partial response (PR, 18 confirmed) and 7 had stable disease (SD). In consequent, the unconfirmed ORR was 66.7% (24/36) and DCR was 86.1% (31/36), with a confirmed ORR of 55.6% (20/36). The median PFS and OS were still immature. However, the estimated 12-month PFS rate was 42.1%. Any grade treatment-related adverse events (TRAEs) occurred in 33 pts (91.7%) and grade ≥ 3 in 13 (36.1%) pts. The most common grade ≥ 3 TRAEs were decreased neutrophil count (13.9%), hypertension (8.3%) and diarrhea (5.6%). 16 pts (44.4%) experienced immune-related adverse events (irAEs) of any grade. No new safety signals were reported. Conclusions: In AFP-producing G/GEJ adenocarcinoma pts who had not previously received systemic therapy, camrelizumab plus apatinib with SOX followed by camrelizumab plus apatinib showed promising antitumor activity and acceptable safety profile. Clinical trial information: NCT04609176 .

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

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

A modified triplet combination of docetaxel, oxaliplatin, and fluorouracil for gastric cancer (GC) with peritoneal carcinomatosis (PC) and inoperable malignant bowel obstruction (MBO): A multi-center, non-randomized, three-cohort, phase II trial (Zhen Jing).

TPS426 Background: For GC, PC is ranked as the most common in relapse and the second common in metastasis. MBO is a frequent and preterminal complication of PC, which has been reported to have a poor overall survival (OS) of only 3 months without effective treatment. Medical therapy of gastroenteric drainage and symptomatic drugs is the cornerstone management for MBO, just alleviating symptoms. Interventional therapy and surgery are effective but indicated in limited patients (pts) with strict selection. Chemotherapy is the mainstay treatment for metastatic GC but its role in MBO is poorly defined. Only a few retrospective studies are available, showing conflicting results on obstruction clearance (OC) and OS. Methods: We are conducting the Zhen Jing trial in five Chinese centers to investigate the tolerability and efficacy of a dose-sense regimen of docetaxel, oxaliplatin and fluorouracil in MBO from GC. Cohort A is for pts in first-line setting. Cohort B is for second-line setting. Cohort C is for pts who have failed to two or more regimens. Eligible pts will receive the same experimental regimen every 28 days: docetaxel 25 mg/m2 on days 1, 8, 15; oxaliplatin 85 mg/m2 on days 1, 15; fluorouracil 1200 mg/m2 24-hour infusion on days 1, 8, 15. A Simon's two-stage optimal design is applied (table below). The primary endpoint is 60-day OC rate. Secondary endpoints are 30-day OC rate, time to OC, OC duration, safety, overall survival and quality of life. Till July 2023, a total of 34 pts has been enrolled (16 in cohort A, 9 in cohort B, 9 in cohort C). Inclusion Criteria: 18-75 years old; Eastern Cooperative Oncology Group performance status ≤ 3; adenocarcinoma of stomach or gastroesophageal junction; peritoneal carcinomatosis established by imaging data or pathological evidence; MBO below the Treitz ligament based on clinical grounds or radiological findings; inappropriate for operation judged independently by two surgeons; written informed consent. Exclusion Criteria: Treated by a combination regimen containing all the study drugs; allergy to any of the study drugs; HER-2 gene overexpression; high microsatellite instability or mismatch repair deficiency; strangulated obstruction; active gastrointestinal bleeding; uncontrolled active infection; unstable heart diseases; severe lung diseases; central nervous system diseases; concomitant cerebral or meningeal metastasis; surgery or stent are required. Clinical trial information: NCT04840264 . [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 >92% at baseline and >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]

A randomized, multicenter, open-label, phase 2 study of TRK-950 in combination with ramucirumab and paclitaxel as second-line therapy in patients with CAPRIN-1 positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

TPS420 Background: CAPRIN-1 is strongly expressed on the cell membrane of many cancer types including G/GEJ and on cancer stem cells. High expression is associated with enhanced in vitro colony-forming activity and in vivo tumorigenicity. TRK-950 is a first in class humanized antibody targeting CAPRIN-1.1 In the phase I study (NCT02990481), TRK-950 was well tolerated as monotherapy with no DLTs and MTD not reached at doses of 3-30mg/kg IV weekly. Subsequently the Phase 1b demonstrated that TRK-950 was well tolerated with a high potential for synergistic anti-tumor activity when used in combination with standard of care treatment(s) in selected advanced solid tumors (NCT03872947). Specifically, Regimen D which evaluated TRK-950 in combination with Ramucirumab and Paclitaxel in G/GEJ showed a DCR of 100% in all nine patients receiving 10 mg/kg and partial responses were seen in 5/9 (55%) patients. CAPRIN-1 strong expression was observed in 4/9 patients and an ORR of 100% was seen in those patients.2 A Phase II clinical trial in gastric/GEJ cancer patients with strong CAPRIN-1 is now enrolling patients. Methods: The phase II study is a multi-national, open-label, randomized, multicenter study evaluating the efficacy of TRK-950 in combination with ramucirumab (Ram) + paclitaxel (PTX) as compared with Ram + PTX treatment alone in patients with previously treated metastatic G/GEJ adenocarcinoma (NCT06038578). Patients enrolled across 10 sites in Japan, South Korea and the United States are randomized 1:1:1 by the permuted block method to (arm A) TRK-950 5mg/kg plus Ram + PTX, (arm B) TRK-950 10mg/kg plus Ram + PTX or (arm C) Ram + PTX alone. Inclusion criteria include patients with CAPRIN-1 positive (cutoff; 30% at ≥ 2+ staining) advanced/metastatic G/GEJ adenocarcinoma who have received first line therapy. Key exclusion criteria include HER2 positive disease. The primary endpoint is progression free survival (PFS) based on Independent Central Review (ICR) assessment per RECIST v1.1. Key secondary and exploratory endpoints include overall survival (OS), ORR, DoR, and biomarker evaluation. An interim analysis will be performed after 105 patients are randomized in stage 1 to determine the optimal dose of TRK-950 (5mg/kg or 10mg/kg) that will be evaluated in stage 2. In total 146 patients will be enrolled (40 patients in one arm and 53 patients in the other two arms). This study opened in September 2023. 1. Okano F, et al. Cancer Res Commun. 2023 Apr 18;3(4):640-658. 2. Cassier P, et al. J Clin Oncol. 2023 Vol. 41, No. 4, suppl. Clinical trial information: NCT06038578 .

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

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

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

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

Phase 1b/2, open-label dose-escalation and -expansion study evaluating trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with HER2+ and HER2-low gastric cancer (GC): DESTINY-Gastric03 (DG-03).

TPS424 Background: T-DXd is approved for treatment of advanced/metastatic HER2+ GC after a trastuzumab-based regimen. The efficacy of T-DXd in advanced HER2+ (IHC 3+ or IHC 2+/ISH+) GC has been shown (confirmed objective response rate [ORR], 43% vs 12% with standard chemotherapy) in previously treated Japanese or South Korean pts (DG-01) and in Western pts with progression on a trastuzumab-containing regimen (confirmed ORR, 42%; DG-02). Also, antitumor activity was shown in pts with HER2-low GC (confirmed ORR, 26.3% [IHC 2+/ISH−], 9.5% [IHC 1+]) in DG-01. Other studies have shown benefits of immunotherapies combined with trastuzumab and other chemotherapies for treatment of HER2+ GC. The DG-03 trial is evaluating the safety and efficacy of T-DXd in combination with chemotherapy and/or immunotherapy in HER2-expressing GC. Previously, confirmed ORRs of 50% and 43% were reported with T-DXd + 5-fluorouracil (5-FU) and T-DXd + capecitabine (Cap), respectively, in the second-line or later setting in part 1 of DG-03. The protocol was amended to add an additional arm in part 2 and a new part 3, which will investigate T-DXd in combination with a fluoropyrimidine and volrustomig (MEDI5752), a PD-1/CTLA-4 bispecific antibody, in pts with HER2+ and HER2-low (IHC 2+/ISH− or IHC 1+) GC. Methods: DG-03 (NCT04379596)is a multicenter, dose-escalation (part 1) and -expansion (parts 2 and 3) study in HER2-expressing, locally advanced or metastatic, unresectable gastric, gastroesophageal junction, or esophageal adenocarcinoma. In arm F of part 2, pts with previously untreated HER2+ GC will be treated with T-DXd + investigator’s choice of 5-FU or Cap + pembrolizumab. In part 3, pts with previously untreated HER2+ (arm 3A) or HER2-low (arm 3B) GC will receive T-DXd + investigator’s choice of 5-FU or Cap + volrustomig. The primary endpoint in parts 2 and 3 is investigator-assessed confirmed ORR per RECIST v 1.1. Secondary endpoints include safety, duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and immunogenicity. Clinical trial information: NCT04379596 .

Clinical pharmacology profile of the claudin 18.2 antibody zolbetuximab.

316 Background: Zolbetuximab is an investigational first-in-class chimeric (mouse/human) monoclonal antibody directed against the tight junction protein claudin 18.2 (CLDN18.2). Zolbetuximab is currently being developed as first-line treatment of patients with locally advanced unresectable or metastatic HER2 – gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, in combination with fluoropyrimidine- and platinum-containing chemotherapy. Methods: The clinical pharmacology of zolbetuximab (pharmacokinetics [PK] and impact of covariates, potential for drug-drug interactions and QTc prolongation, exposure-response [E-R] for efficacy and safety, immunogenicity [antidrug antibodies; ADAs]) was characterized from 9 studies in adults with advanced CLDN18.2-positive adenocarcinoma of the stomach, esophagus, or GEJ. Results: Zolbetuximab exhibited dose-proportional PK at doses of 33 to 1000 mg/m 2 . Based on population PK modeling using data from 714 participants, zolbetuximab exposure (Table) was not meaningfully affected by sex, race/ethnicity, age, mild/moderate renal impairment, or mild hepatic impairment. Gastrectomy was predicted to increase C ave by 36%. Coadministration of zolbetuximab with chemotherapy did not show clinically meaningful changes in drug exposures of zolbetuximab or chemotherapy. At therapeutic doses, zolbetuximab had no clinically meaningful effect on QTc prolongation. In phase 3 studies, zolbetuximab (800 mg/m 2 loading dose/600 mg/m 2 Q3W) had a manageable safety profile and was associated with significant prolongation of progression-free survival (PFS) and overall survival (OS). E-R analyses suggested that higher zolbetuximab exposure may further prolong PFS and OS but with increased probability of gastrointestinal events and infusion-related reactions. E-R model simulations suggested comparable zolbetuximab efficacy and safety between the 800/600 mg/m 2 Q3W regimen and an alternative 800/400 mg/m 2 Q2W regimen for use in combination with chemotherapy. ADAs were detected in 4.4% of patients in phase 3 studies with no apparent impact on zolbetuximab PK, efficacy, or safety. Conclusions: The clinical pharmacology of zolbetuximab was well characterized using data from 9 clinical trials. The integrated data support the proposed 800/600 mg/m 2 Q3W regimen as well as an 800/400 mg/m 2 Q2W regimen in combination with chemotherapy. Clinical trial information: NCT00909025 , NCT01671774 , NCT03528629 , NCT04086758 , NCT01197885 , NCT01630083 , NCT03505320 , NCT03504397 , NCT03653507 . Model-estimated exposure metrics of zolbetuximab. Mean (SD) First Dose(800 mg/m 2 ) Steady State(600 mg/m 2 Q3W) C max (µg/mL) 434 (96) 425 (91) AUC 21d (day·µg/mL) 2164 (589) 3359 (1254) C trough (µg/mL) 43.9 (25.1) 101 (51) C ave (µg/mL) – 140 (50) First dose simulation was for a 3-week interval after the first dose. For steady state, simulation was for a 3-week interval from Weeks 28–31. Estimated terminal elimination half-life was 43.6 days. Q3W, every 3 weeks.

Li Fraumeni Syndrome predisposes to gastro-esophageal junction tumours

Li-Fraumeni Syndrome (LFS), caused by germline pathogenic variants in TP53, predisposes to a wide range of young-onset malignancies, particularly sarcoma, breast and brain cancer. More recently, an increased risk of gastric adenocarcinoma has been recognised, although uptake of surveillance upper endoscopy is unclear. Our retrospective review of 65 patients with LFS, of whom 53.8% had undergone endoscopy, identified four patients (6.2%) with gastro-esophageal junction (GEJ) adenocarcinomas. Two cases were found on asymptomatic screening and were early stage. No cases had family history of gastrointestinal malignancy. Reviewing genomic data from The Cancer Genome Atlas Program, 76.4% of sporadic esophageal adenocarcinomas harboured somatic TP53 pathogenic variants, compared with 39.9% of non-cardia gastric cancers. This similar pattern observed in germline and sporadic cases warrants further investigation. We propose that upper endoscopy be recommended to all patients with LFS, with a focus on appropriate surveillance of the GEJ.

The Multidisciplinary Approach and Surgical Management of GE Junction Adenocarcinoma.

Gastroesophageal (GE) junction adenocarcinoma is an aggressive malignancy of growing incidence and is associated with public health issues such as obesity and GERD. Management has evolved over the last two decades to incorporate a multidisciplinary approach, including endoscopic intervention, neoadjuvant chemotherapy/chemoradiation, and minimally invasive or more limited surgical approaches. Surgical approaches include esophagectomy, total gastrectomy, and, more recently, proximal gastrectomy. This review analyzes the evidence for and applicability of these varied approaches in management, as well as areas of continued controversy and investigation.

Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial

Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of the standard-of-care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment (TME) in early disease remain largely unknown. We hypothesized higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with nonmetastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n = 21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by four cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well tolerated. There were grade 3 immune-related adverse events in two of 20 patients (10%) but no grade 4 or 5 immune-related adverse events, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent anti-programmed cell death ligand 1 (PD-L1) and the subsequent combination with chemotherapy on the TME. Twenty of 21 patients underwent surgery and were evaluable for secondary pathologic response and survival endpoints, and 19 were evaluable for exploratory translational analyses. A major pathologic response (≤10% residual viable tumor) was observed in 14 of 20 (70%, 95% confidence interval 46–88%) patients, including 9 (45%, 95% confidence interval 23–68%) pathologic complete responses. At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, and five of six nonresponders had died as a result of recurrence. Notably, baseline anti-programmed cell death protein 1 (PD-1)+CD8+ T cell infiltration was significantly higher in responders versus nonresponders, and comparison of TME alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy showed an increased immune activation on single-agent PD-1/L1 axis blockade. On the basis of these data, monotherapy anti-PD-L1 before its combination with chemotherapy warrants further exploration and validation in a larger cohort of patients with nonmetastatic G/GEJ cancer. ClinicalTrials.gov registration: NCT03448835.

Endoscopic Characteristics of Early Gastroesophageal Junction Adenocarcinomas and Assessment for Invasion Depth: A Case Series Study.

Early-stage gastroesophageal junction (GEJ) adenocarcinoma can be challenging to diagnose and treat promptly using endoscopy. This study aims to summarize the endoscopic characteristics of early GEJ adenocarcinoma and investigate their correlation with pathological grade and invasion depth. This retrospective case series study evaluated patients with early GEJ adenocarcinoma who underwent endoscopic or surgical resection at First Affiliated Hospital of Dalian Medical University between January 2016 and December 2022. A total of 71 patients were included in the analysis, with 59 males and a median age of 67 years. The majority of the lesions were located on the posterior side of the GEJ (40.8%) or the lesser curvature side (29.6%). Siewert II lesions accounted for 71.8% of cases, with most occurring on the posterior side (49.0%) and Siewert III lesions mostly occurring on the lesser curvature side (42.9%). Siewert I lesions accounted for only 7.0%, and all originated from Barrett mucosa. Paris classification of Is (P = .015) or IIc (P = .015), lesion size ≥12 mm (P = .017), red color with subsquamous extension (P = .038), and disordered microsurface with local fusion (P < .001) were independently and positively correlated with pathological grade and invasion depth by multivariable ordinal logistic regression. The posterior side and lesser curvature of the GEJ are the high-incidence sites of GEJ adenocarcinoma. Both forward and backward views during endoscopy should be combined to detect the lesion. Endoscopic characteristics such as Is or IIc morphology, larger size, red color with subsquamous extension, and disordered microsurface with local fusion may indicate a higher pathological grade and deeper invasion.

Diffuse-Type Histology Is Prognostic for All Siewert Types of Gastroesophageal Adenocarcinoma.

The optimal treatment for gastroesophageal junction adenocarcinoma (GEJA) remains controversial. We evaluated the treatment patterns and outcomes of patients with locally advanced GEJA according to the histological type. We conducted a single-institution retrospective cohort study of patients with locally advanced GEJA who underwent curative-intent surgical resection between 2010 and 2020. Perioperative therapies as well as clinicopathologic, surgical, and survival data were collected. The results of endoscopy and histopathological examinations were assessed for Siewert and Lauren classifications. Among the 58 patients included in this study, 44 (76%) were clinical stage III, and all received neoadjuvant therapy (72% chemoradiation, 41% chemotherapy, 14% both chemoradiation and chemotherapy). Tumor locations were evenly distributed by Siewert Classification (33% Siewert-I, 40% Siewert-II, and 28% Siewert-III). Esophagogastrectomy (EG) was performed for 47 (81%) patients and total gastrectomy (TG) for 11 (19%) patients. All TG patients received D2 lymphadenectomy compared to 10 (21%) EG patients. Histopathological examination showed the presence of 64% intestinal-type and 36% diffuse-type histology. The frequencies of diffuse-type histology were similar among Siewert groups (37% Siewert-I, 36% Siewert-II, and 33% Siewert-III). Regardless of Siewert type and compared to intestinal-type, diffuse histology was associated with increased intraabdominal recurrence rates (P=0.03) and decreased overall survival (hazard ratio, 2.33; P=0.02). With a median follow-up of 31.2 months, 29 (50%) patients had a recurrence, and the median overall survival was 50.5 months. Present in equal proportions among Siewert types of esophageal and gastric cancer, a diffuse-type histology was associated with high intraabdominal recurrence rates and poor survival. Histopathological evaluation should be considered in addition to anatomic location in the determination of multimodal GEJA treatment strategies.

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

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

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

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

Totally robotic total gastrectomy with D2 lymphadenectomy for gastric cancer via da Vinci Xi platform: Technical details and perioperative outcomes

BackgroundThis study reported the surgical details and outcomes in a case of totally robotic total gastrectomy (TRTG) using the da Vinci Xi robotic system, aiming to share surgical experience in difficult procedures during TRTG and add evidence supporting the feasibility and safety of TRTG. MethodsA 55-year-old male patient diagnosed with adenocarcinoma of gastroesophageal junction underwent TRTG via the da Vinci Xi robotic system in Sun Yat-sen University Cancer Center on January 10, 2024. The surgical details and perioperative outcomes were summarized. ResultsWith an estimated blood loss of 100 ​ml, the operation lasted 210 ​min, including an anastomosis time of 36 ​min. During a postoperative hospital stay of 7 days, the patient started liquid diet after the removal of gastric tube on the third day. There were no perioperative complications. Postoperative radiography demonstrated no evidence of anastomotic fistulas or luminal narrowing. The final pathology revealed a 4.5∗1.5 ​cm gastric adenocarcinoma with 10/61 positive lymph nodes. The pathological stage of this patient was pT3N3aM0 IIIB. ConclusionsThis successful surgery reflected the effectiveness of minimally invasive surgery for total gastrectomy through a totally intracorporeal robotic approach. Future research is warranted to further validate the feasibility and safety of performing TRTG.

Application of λ esophagojejunostomy in total gastrectomy under laparoscopy: a modified technique for post-gastrectomy reconstruction.

Common gastrectomy methods can significantly affect patients' postoperative quality of life. This study investigated the safety, feasibility, and short-term efficacy of λ-type esophagojejunostomy in total gastrectomy under total laparoscopy. We retrospectively analyzed the clinical and follow-up data of 50 patients with adenocarcinoma of the gastric/gastroesophageal junction who underwent total laparoscopic radical gastrectomy with λ-type esophagojejunostomy at the Beijing Friendship Hospital from January 2021 to July 2022. Data are reported as mean ± standard deviation. Patients comprised 27 males and 23 females, aged 42 to 76 (60.9 ± 5.6) years. There were 26 cases of gastroesophageal junction adenocarcinoma (16 Siewert type II and 10 Siewert type III) and 24 cases of adenocarcinoma of the proximal gastric body. All patients underwent radical total gastrectomy and D2 lymph node dissection with λ-type esophagojejunostomy for digestive tract reconstruction under total laparoscopy. The total operation time was 235-295 (249.4 ± 48.5) min, digestive tract reconstruction time was (48.2 ± 23.2) min, intraoperative blood loss was (63.4 ± 48.4) mL, recovery time of exhaust was (3.1 ± 2.2) d, first drinking or eating time was (4.1 ± 2.1) d, and hospital stay was (9.3 ± 4.4) d. Three patients had postoperative complications, including one with duodenal remnant leakage combined with abdominal infection. Anastomotic bleeding and postoperative inflammatory intestinal obstruction occurred in one patient each, all of whom were cured by conservative treatment. The Nutritional Risk Index of the whole group was 53.5 ± 8.4 preoperatively, 47.3 ± 5.6 one week postoperatively, 50.3 ± 5.6 six months postoperatively, and 52.4 ± 4.2 at 12 months postoperatively. Roux-en-Y stasis syndrome and bile reflux esophagitis occurred in one patient each (2.0%). There were no occurrences of recanalization of the closed end of the afferent loop of the esophagojejunostomy anastomosis, anastomotic stricture or obstruction, or tumor recurrence. λ-type esophagojejunostomy is safe and feasible for digestive tract reconstruction after total laparoscopic radical gastrectomy. This digestive tract reconstruction method not only maintains intestinal continuity but also simplifies surgical procedures, allowing patients to recover quickly with an excellent short-term effect.

A rare case of synchronous management of gastroesophageal junction adenocarcinoma and renal cell carcinoma: is it just another oesophagectomy?

A rare case of synchronous management of gastroesophageal junction adenocarcinoma and renal cell carcinoma: is it just another oesophagectomy?

Pembrolizumab Plus Trastuzumab and Chemotherapy for HER2-Positive Gastric or Gastro-oesophageal Junction Adenocarcinoma

he combination of pembrolizumab, and trastuzumab chemotherapy has long been investigated in the treatment of HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. HER2-positive gastric or gastroesophageal junction adenocarcinoma refers to cancers that overexpress the human epidermal growth factor receptor 2 (HER2), which is associated with more aggressive tumor behavior. Pembrolizumab is a monoclonal antibody that targets the programmed cell death protein 1 (PD-1) receptor, a checkpoint protein on immune cells. By blocking PD-1, pembrolizumab helps unleash the immune system to target and attack cancer cells. Trastuzumab is another monoclonal antibody that specifically targets HER2-positive cancer cells. It has been a standard treatment for HER2-positive breast cancer and has been explored in HER2-positive gastric and gastroesophageal junction cancers. Janjigian and colleagues revealed the interim analysis of a randomized, phase 3 KEYNOTE-811 trial which involved 168 medical centers in 20 countries worldwide. They found that compared with placebo, pembrolizumab significantly improved progression-free survival when combined with first-line trastuzumab and chemotherapy for metastatic HER2-positive gastro-oesophageal cancer, specifically in patients with tumors with a PD-L1 combined positive score of 1 or more. They stated that the overall survival follow-up is ongoing and will be reported at the final analysis. Lancet. 2023 Dec 9;402(10418):2197-2208. doi: 10.1016/S0140-6736(23)02033-0.