Immunological effects and activity of multiple doses of zolbetuximab in combination with zoledronic acid and interleukin-2 in a phase 1 study in patients with advanced gastric and gastroesophageal junction cancer.

PURPOSE: Zolbetuximab (IMAB362) is engineered to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity. We evaluated ADCC activity and the impact of the immune-modulating drugs zoledronic acid (ZA) and interleukin-2 (IL-2) as co-treatment with zolbetuximab on relevant immune cell populations and ADCC lysis activity. METHODS: This phase 1, multicenter, open-label study investigated the immunological effects and activity, safety, tolerability, and antitumor activity of multiple doses of zolbetuximab alone (n = 5) or in combination with ZA (n = 7) or with ZA plus two different dose levels of IL-2 (low dose: 1 million international units [mIU] [n = 9]; intermediate dose: 3 mIU [n = 7]) in pretreated patients with advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. RESULTS: Twenty-eight patients with previously treated advanced G/GEJ adenocarcinoma that was CLDN18.2-expressing were enrolled into four treatment arms. Treatment with zolbetuximab + ZA + IL-2 induced short-lived expansion and activation of ADCC-mediating cell populations, namely γ9δ2 T cells and natural killer cells, within 2 days after administration; this effect was more pronounced with intermediate-dose IL-2. Expansion and activation of regulatory T cells treated with either IL2 dose was moderate and short-lived. Strong ADCC activity was observed with zolbetuximab alone. Short-lived ADCC activity was observed in several patients treated with ZA + intermediate-dose IL-2, but not lower-dose IL-2. In the clinical efficacy population, the best confirmed response was stable disease (n = 11/19; 58%). CONCLUSIONS: Zolbetuximab mediates proficient ADCC in patients with pretreated advanced G/GEJ cancers. Co-treatment with ZA + IL-2 did not further improve this effect. TRIAL REGISTRATION: NCT01671774.

Long-Term Outcomes of Neoadjuvant Chemotherapy in Locally Advanced Gastric Cancer/Esophagogastric Junction Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has been defined as any preoperative chemotherapy scheme aiming to reduce tumor staging and to control preoperative micrometastasis, which has been extensively used as a treatment for resectable gastric cancer. However, its effect on the long-term survival of patients with locally advanced gastric cancer (AGC) or esophagogastric junction cancer (EGC) remains unknown. OBJECTIVE: This study aimed at investigating the long-term efficacy of NAC in locally AGC/EGC. METHODS: The following databases were searched for articles published from their inception to April 2020: PubMed, Web of Science, EBSCO, and Cochrane library. The primary outcomes were overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 19 articles were included in this meta-analysis, with a total of 4,446 patients. The results showed that NAC increased the patients' 3-year OS (HR: 0.56, 95% CI, 0.21 - 0.91, p < 0.001), 3-year PFS (HR: 0.76, 95% CI, 0.66 - 0.87, p < 0.001), 5-year OS (HR: 0.71, 95% CI, 0.64 - 0.78, p < 0.001), and 5-year PFS (HR: 0.70, 95% CI, 0.61 - 0.79, p < 0.001). Besides, subgroup analysis showed that Asian countries have benefited significantly from NAC (HR: 0.65, 95% CI, 0.55 - 0.74, p < 0.001), and other countries have also benefited (HR: 0.79, 95% CI, 0.68 - 0.89, p < 0.001). CONCLUSION: Compared with adjuvant chemotherapy and surgery alone, NAC can improve the long-term survival outcomes (OS and PFS) of patients with resectable AGC or EGC.

Perioperative FOLFOX in Patients With Locally Advanced Oesogastric Adenocarcinoma.

BACKGROUND: We hypothesized that perioperative FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) might be used as an alternative to standard FLOT (docetaxel, 5-fluorouracil, leucovorin, and oxaliplatin) in patients with locally advanced oesogastric adenocarcinomas (OGA), particularly those with frailties. PATIENTS AND METHODS: We reviewed the charts of 61 consecutives patients treated with FOLFOX for resectable OGA to estimate overall survival, recurrence-free survival, and safety. RESULTS: The median follow-up was 69.7 (range=3.6-97.9) months. Few patients experienced grade 3 adverse events during the preoperative (n=6; 10%) and postoperative (n=6; 16%) phases. One patient experienced a fatal grade 5 adverse events (cardiogenic shock). Median overall survival was 51.7 months [95% confidence interval (CI)=31.6-93.2 months] and the 5-year survival rate was 44.4% (95% CI=30.3%-57.5%). CONCLUSION: Regarding its comparable efficacy and its favourable toxicity profile, perioperative FOLFOX is a reasonable alternative to FLOT for frail patients with resectable OGA.

The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer.

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas1-3. More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours4. Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer5, there are preclinical6-19 and clinical20,21 rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma22 ( https://clinicaltrials.gov , NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate.

Efficacy and safety of sintilimab-based regimens against advanced gastric and gastroesophageal junction adenocarcinoma.

AIMS: Our study assessed the efficacy and safety of sintilimab-based regimens for real-world treatment of advanced gastric and gastroesophageal junction adenocarcinoma (G/GEJAC). MATERIALS AND METHODS: Cases of advanced nonresectable G/GEJAC treated with sintilimab-based regimens in the Department of Gastroenterology of Shanxi Provincial Cancer Hospital between December 2018 and September 2020 were retrospectively examined. Endpoints included median progression-free survival (mPFS), median overall survival (mOS), disease control rate (DCR), objective response rate (ORR), and adverse events (AEs). Univariate and multivariate analyses were conducted to determine the effect of stratification factors on efficacy. RESULTS: Among the 37 included patients, mPFS and mOS were 4.27 and 7.3 months, respectively. Efficacy was evaluated at least once in 32 of 37 patients. The ORR and DCR were 12.5% and 65.63%, respectively. Among four patients with mismatch repair deficiency/microsatellite instability-high (dMMR/MSI-H) lesions, two achieved partial remission, and two displayed stable disease, resulting in a DCR of 100%. The most observed AEs included leukopenia, neutropenia, thrombocytopenia, nausea, and skin rash. mPFS was 4.90 months in patients who received sintilimab in the first- or second-line setting, versus 3.00 months in other patients. A significant survival difference was found between these groups in univariate and multivariate analyses. CONCLUSIONS: The application of sintilimab-based regimens achieved good disease control and tolerability for the real-world treatment of advanced G/GEJAC. The treatment was more effective when administered in the first- or second-line setting. Patients with dMMR/MSI-H lesions may also benefit from sintilimab-based regimens.

Prognostic and predictive value of mismatch repair deficiency in gastric and gastroesophageal junction adenocarcinoma patients receiving neoadjuvant or adjuvant chemotherapy.

BACKGROUND AND OBJECTIVES: Evidence is inconclusive regarding the prognostic significance of deficient DNA mismatch repair (dMMR) in gastric and gastroesophageal junction (GEJ) adenocarcinoma patients receiving chemotherapy. We aim to explore such associations with a large cohort. METHODS: We retrospectively identified a consecutive cohort of patients who had histology proven gastric or GEJ adenocarcinoma and received neoadjuvant chemotherapy plus surgery or upfront surgery plus adjuvant chemotherapy. MMR status was assessed by immunohistochemistry staining on surgical specimen. The association of MMR status with tumor regression grade (TRG), overall survival (OS), and disease-free survival (DFS) were analyzed. RESULTS: In total, 1568 patients received neoadjuvant or adjuvant chemotherapy, of which 128 (8.2%) had dMMR tumors. No significant difference was found in the frequencies of TRG categories between proficient MMR (pMMR) and dMMR tumors (p = .62). Among patients receiving neoadjuvant chemotherapy, dMMR status was associated with better OS (log-rank p = .044) and DFS (log-rank p = .022) in the univariate analysis; this association became nonsignificant after adjusting for pathologic stages and other prognostic factors. Similar results were found for patients receiving adjuvant chemotherapy. CONCLUSIONS: dMMR status was not significantly associated with OS and DFS among gastric and GEJ adenocarcinoma patients with neoadjuvant and adjuvant platinum and fluorouracil-based chemotherapy.

Tumor downstaging after neoadjuvant chemotherapy determines survival after surgery for gastric adenocarcinoma.

BACKGROUND: Since 2006, surgery combined with perioperative chemotherapy is the standard of care for resectable gastric adenocarcinoma in Europe. Specific effects of neoadjuvant chemotherapy remain unknown. The aim was to evaluate the rate of tumor downstaging and its impact on survival in patients undergoing curative resection after neoadjuvant chemotherapy (NeoCT) for gastric adenocarcinoma. MATERIAL AND METHODS: All patients treated in a curative intent for gastric or esophagogastric junction adenocarcinomas between 1996 and 2016 in our high-volume center were retrospectively included. Tumor downstaging after NeoCT was defined as ypTN inferior to cTN. The accuracy of clinical staging was evaluated in patients treated by upfront surgery before 2006. RESULTS: During the study period, 491 patients were operated for gastric adenocarcinoma, and 449 patients were finally analyzed. Among the 163 (36.3%) patients who received NeoCT, 61 (37.4%) had tumor downstaging. Overall survival and disease-free survival were longer in patients with tumor downstaging compared to patients without it (5-year survival: 84.8% vs 49.7%; P = .002 and 61.7% vs 43.4%; P = .054). In multivariate analysis tumor downstaging was an independent prognosis factor for better overall survival (HR = 5.258; P = .002) and disease-free survival (HR = 2.286; P = .028). Moreover, 45.5% of patients staged cT1-T2N0, in whom upfront surgery was performed, were understaged and ultimately had a more advanced tumor on pathological analysis. CONCLUSION: Response to neoadjuvant chemotherapy constitutes a major prognostic factor for overall and disease-free survival. In the absence of predictive factors for tumor downstaging, the indication for perioperative chemotherapy should remain broad, in particular because of the low accuracy of pretherapeutic staging and therefore the high risk of understaging tumors.

PRODIGY: A Phase III Study of Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 Versus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer.

PURPOSE: Adjuvant chemotherapy after D2 gastrectomy is standard for resectable locally advanced gastric cancer (LAGC) in Asia. Based on positive findings for perioperative chemotherapy in European phase III studies, the phase III PRODIGY study (ClinicalTrials.gov identifier: NCT01515748) investigated whether neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 could improve outcomes versus standard treatment in Korean patients with resectable LAGC. PATIENTS AND METHODS: Patients 20-75 years of age, with Eastern Cooperative Oncology Group performance status 0-1, and with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging: T2-3N+ or T4Nany) were randomly assigned to D2 surgery followed by adjuvant S-1 (40-60 mg orally twice a day, days 1-28 every 6 weeks for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1-14 every 3 weeks for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary objective was progression-free survival (PFS) with CSC versus SC. Two sensitivity analyses were performed: intent-to-treat and landmark PFS analysis. RESULTS: Between January 18, 2012, and January 2, 2017, 266 patients were randomly assigned to CSC and 264 to SC at 18 Korean study sites; 238 and 246 patients, respectively, were treated (full analysis set). Follow-up was ongoing in 176 patients at data cutoff (January 21, 2019; median follow-up 38.6 months [interquartile range, 23.5-62.1]). CSC improved PFS versus SC (adjusted hazard ratio, 0.70; 95% CI, 0.52 to 0.95; stratified log-rank P = .023). Sensitivity analyses confirmed these findings. Treatments were well tolerated. Two grade 5 adverse events (febrile neutropenia and dyspnea) occurred during neoadjuvant treatment. CONCLUSION: PRODIGY showed that neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, is effective and tolerable in Korean patients with LAGC.

Phase III Study to Evaluate Efficacy and Safety of Andecaliximab With mFOLFOX6 as First-Line Treatment in Patients With Advanced Gastric or GEJ Adenocarcinoma (GAMMA-1).

PURPOSE: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9, an extracellular enzyme involved in matrix remodeling, tumor growth, and metastases. A phase I and Ib study of modified oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6) with ADX revealed encouraging antitumor activity in patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma. MATERIALS AND METHODS: This phase III, randomized, double-blinded, placebo (PBO)-controlled multicenter study investigated the efficacy and safety of mFOLFOX6 with and without ADX in patients with untreated human epidermal growth factor receptor 2-negative gastric or GEJ adenocarcinoma. Random assignment was 1:1 to mFOLFOX6 + ADX or mFOLFOX6 + PBO. ADX/PBO 800 mg was infused on days 1 and 15 of each 28-day cycle. Protocol therapy was given until disease progression or intolerance. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), objective response rate (RECIST 1.1), and safety. RESULTS: Between September 2015 and May 2017, 432 patients were randomly assigned, 218 to ADX and 214 to PBO. The median OS was 12.5 versus 11.8 months in the ADX and PBO groups, respectively. The median PFS was 7.5 versus 7.1 months in the ADX and PBO groups, respectively. The objective response rate was 51% in the ADX group and 41% in the PBO group. Among the subgroup analyses, patients of age ≥ 65 years had an improved OS and PFS with ADX versus PBO; the P values and CIs were not adjusted for multiplicity. There were no meaningful differences in the safety profile of the ADX versus PBO groups. CONCLUSION: The addition of ADX to mFOLFOX6 did not improve OS in unselected patients with untreated human epidermal growth factor receptor 2-negative gastric or GEJ adenocarcinoma.

Perioperative trastuzumab, capecitabine and oxaliplatin in patients with HER2-positive resectable gastric or gastro-oesophageal junction adenocarcinoma: NEOHX phase II trial.

INTRODUCTION: Perioperative chemotherapy improves overall survival (OS) and disease-free survival (DFS) compared with surgery alone in patients with resectable gastric adenocarcinoma (GA) or gastro-oesophageal junction adenocarcinoma (GEJA). The addition of trastuzumab to chemotherapy improves outcomes in patients with HER2-positive advanced gastric cancer (GC), and we aimed to explore its role in the perioperative setting. MATERIAL AND METHODS: This Spanish, multicentre, open-label phase II trial evaluated the efficacy and toxicity of perioperative capecitabine, oxaliplatin and trastuzumab (XELOX-T) in patients with HER2-positive resectable GA or GEJA. The primary end-point was 18-months DFS; and secondary end-points included pathological complete response (pCR) rate, R0 resection rate, OS and toxicity (NCT01130337). RESULTS: Thirty-six patients were included. After three cycles of preoperative treatment, 14 patients (38% of the intention-to-treat population) had partial response and 18 (50%) had stable disease. Surgery was performed in 31 patients: 28 (90%) had R0 resection, three (9.6%) had a pCR and three (9.6%) died due to surgical complications. A total of 24 patients received post-operative XELOX-T, 22 of whom completed trastuzumab maintenance. Main grade III/IV toxicities included diarrhoea (33%), nausea and vomiting (8%). After a median follow-up of 24.1 months, 18-month DFS was 71% (95% confidence interval [CI], 53-83%); and an update after 102 months of follow-up showed a median OS of 79.9 months and a 60-month OS of 58% (95% CI, 40-73%). CONCLUSIONS: These data suggest that perioperative XELOX-T in patients with HER2-positive GA and GEJA is feasible and active. Further investigation in randomised studies is warranted.

Executive Summary of the American Radium Society Appropriate Use Criteria for Operable Esophageal and Gastroesophageal Junction Adenocarcinoma: Systematic Review and Guidelines.

PURPOSE: Limited guidance exists regarding the relative effectiveness of treatment options for nonmetastatic, operable patients with adenocarcinoma of the esophagus or gastroesophageal junction (GEJ). In this systematic review, the American Radium Society (ARS) gastrointestinal expert panel convened to develop Appropriate Use Criteria (AUC) evaluating how neoadjuvant and/or adjuvant treatment regimens compared with each other, surgery alone, or definitive chemoradiation in terms of response to therapy, quality of life, and oncologic outcomes. METHODS AND MATERIALS: Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) methodology was used to develop an extensive analysis of peer-reviewed phase 2R and phase 3 randomized controlled trials as well as meta-analyses found within the Ovid Medline, Cochrane Central, and Embase databases between 2009 to 2019. These studies were used to inform the expert panel, which then rated the appropriateness of various treatments in 4 broadly representative clinical scenarios through a well-established consensus methodology (modified Delphi). RESULTS: For a medically operable nonmetastatic patient with a cT3 and/or cN+ adenocarcinoma of the esophagus or GEJ (Siewert I-II), the panel most strongly recommends neoadjuvant chemoradiation. For a cT2N0M0 patient with high-risk features, the panel recommends neoadjuvant chemoradiation as usually appropriate. For patients found to have pathologically involved nodes (pN+) who did not receive any neoadjuvant therapy, the panel recommends adjuvant chemoradiation as usually appropriate. These guidelines assess the appropriateness of various dose-fractionating schemes and target volumes. CONCLUSIONS: Chemotherapy and/or radiation regimens for esophageal cancer are still evolving with many areas of active investigation. These guidelines are intended for the use of practitioners and patients who desire information about the management of operable esophageal adenocarcinoma.

Codeine induces increased resistance at the esophagogastric junction but has no effect on motility and bolus flow in the pharynx and upper esophageal sphincter in healthy volunteers: A randomized, double-blind, placebo-controlled, cross-over trial.

BACKGROUND: Chronic opioid use can induce esophageal dysfunction with symptoms resembling achalasia and a manometric pattern of esophagogastric junction-outflow obstruction (EGJ-OO). However, the effect of opioids in acute setting on pharyngeal function and esophageal body contractility has not been investigated. METHODS: After positioning the high-resolution impedance manometry (HRiM) catheter, codeine (60 mg) or placebo (glucose syrup) was infused intragastrically. Forty-five minutes post-infusion, participants received liquid, semi-solid, and solid boluses to assess esophageal and pharyngeal function. HRiM analysis was performed adhering to the Chicago classification v3.0. (CC v3.0). Pressure flow analysis (PFA) for the esophageal body and the pharynx was performed using the SwallowGateway™ online platform. KEY RESULTS: Nineteen healthy volunteers (HV) [5 male; age 38.3] were included. After codeine administration, higher integrated relaxation pressure 4 s values resulted in significantly reduced deglutitive EGJ relaxation and distal latency was significantly shorter. Distal contractility was similar in both conditions. Bolus flow resistance at the EGJ and distention pressures increased significantly after codeine infusion. Based on CC v3.0, acute infusion of codeine induced EGJ-OO in six HV (p = 0.0003 vs. placebo). Codeine administration induced no significant alterations in any of the pharyngeal PFA metrics. CONCLUSIONS & INFERENCES: In HV, acute administration of codeine increased bolus resistance at the EGJ secondary to induced incomplete EGJ relaxation leading to major motility disorders in a subset of subjects including EGJ-OO. However, an acute single dose of codeine did not affect motility or bolus flow in pharynx and UES. ClinicalTrials.gov number, NCT03784105.

Hospital volume and beyond first-line palliative systemic treatment in metastatic oesophagogastric adenocarcinoma: A population-based study.

BACKGROUND: Beyond first-line palliative systemic treatment can be beneficial to selected oesophagogastric cancer patients, but experience with its administration may be limited and vary among hospitals. In a population-based study, we analysed the association between hospital systemic treatment volume and administration of beyond first-line treatment in oesophagogastric adenocarcinoma, as well as the effect on overall survival (OS). METHODS: Synchronous metastatic oesophagogastric adenocarcinoma patients (2010-2017) were selected from the Netherlands Cancer Registry. Hospitals were categorised in volumes quartiles. The association between hospital systemic treatment volume and the use of beyond first-line treatment was assessed using trend and multivariable logistic regression analyses. OS was compared between hospitals with high and low beyond first-line treatment administration and treatment strategies using Kaplan-Meier curves with log-rank test and multivariable Cox proportional hazard regression. RESULTS: Beyond first-line treatment was administered in 606 of 2,466 patients who received first-line treatment, and increased from 20% to 31% between 2010 and 2017 (P < 0.001). The lowest hospital volumes were independently associated with lower beyond first-line treatment administration compared to the highest volume (OR 0.62, 95% CI 0.39-0.99; OR 0.67, 95% CI 0.48-0.95). Median OS was higher in all patients treated in hospitals with a high versus low beyond first-line treatment administration (7.9 versus 6.2 months, P < 0.001). Second-line paclitaxel/ramucirumab was administered most frequently and independently associated with longer OS compared to taxane monotherapy (HR 0.74, 95% CI 0.59-0.92). CONCLUSION: Higher hospital volume was associated with increased beyond first-line treatment administration in oesophagogastric adenocarcinoma. Second-line paclitaxel/ramucirumab resulted in longer survival compared to taxane monotherapy.

Spatial and Temporal Heterogeneity of PD-L1 Expression and Tumor Mutational Burden in Gastroesophageal Adenocarcinoma at Baseline Diagnosis and after Chemotherapy.

PURPOSE: Intrapatient heterogeneity of programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in gastroesophageal adenocarcinoma (GEA) could influence their roles as predictive biomarkers for response to immune checkpoint inhibitors (ICI). In this retrospective analysis, we evaluated the spatiotemporal heterogeneity and prognostic relevance of PD-L1 expression and TMB in GEA. EXPERIMENTAL DESIGN: A cohort of 211 patients with stage II-IV GEA was retrospectively reviewed for a total of 407 tumor samples with PD-L1 expression data and 319 tumor samples with TMB data. PD-L1 status was defined as positive if combined positive score (CPS) ≥1 using the 22C3 pharmDx assay. TMB levels were categorized as low, intermediate, or high (≤5, 5-15, or >15 mutations/Mb), or using a single threshold (<10 or ≥10 mutation/Mb), determined by next-generation sequencing using a targeted gene panel. RESULTS: Of 407 tumors, 56% were PD-L1 negative and 44% PD-L1 positive. Of 319 tumors, 50% were TMB-low, 45% TMB-intermediate, and 5% TMB-high; 86% had <10 and 14% ≥10 mutations/Mb. TMB level was significantly associated with MSI-status. PD-L1 expression and TMB exhibited marked spatial heterogeneity between baseline primary and metastatic tumors (61% and 69% concordance), and temporal heterogeneity between tumors before and after chemotherapy (57%-63% and 73%-75% concordance). PD-L1 expression and TMB were not significantly associated with overall survival. CONCLUSIONS: PD-L1 expression and TMB exhibit marked spatial and temporal heterogeneity in GEA. This heterogeneity should be considered when obtaining tumor samples for molecular testing and when deciding whether ICI therapy is appropriate.See related commentary by Klempner et al., p. 6401.

Definitive chemoradiotherapy plus cetuximab for cancer in the oesophagus or gastro-oesophageal junction.

BACKGROUND: Chemoradiotherapy is standard treatment for localized oesophageal cancer unsuitable for surgery. We aimed to evaluate the efficacy of cetuximab in combination with chemoradiotherapy. METHODS: This non-randomised multicentre phase II trial recruited patients aged 18-75 with WHO performance status 0-2 having squamous cell carcinoma or adenocarcinoma in the oesophagus or gastro-oesophageal junction, T2-4, N0-3, M0 not suitable for surgery. Chemotherapy was three 21-day cycles of fluorouracil 750 mg/m2 D1-5 and oxaliplatin D1 (cycle 1:130mg/m 2, cycle 2-3:85 mg/m 2). Radiotherapy was 50Gy in 2Gy/fraction, 5 days a week, concurrent with cycle 2 and 3 and weekly cetuximab. The primary objective was loco-regional control at one year. RESULTS: 52 patients were included. 51 were eligible for toxicity and survival analysis and 46 for recurrence analysis. Full radiotherapy dose was delivered to 80%, 75% received all three cycles of chemotherapy and 75% received four or more doses of cetuximab. The most common related grade III-IV adverse events were gastro-intestinal(16), hypersensitivity(6) and infection(5). There were two drug-related deaths. Within six months from the end of treatment, six patients died from complications from fistulas. The loco-regional control rate at one year was 47.3%(95%CI 30.9%-62.1%). Overall survival at three years was 29.1%(95% CI 17.4-41.9%). CONCLUSIONS: Oxaliplatin and fluorouracil given concurrent with radiotherapy and cetuximab had an acceptable safety profile and showed a clinical response in patients with locoregionally advanced oesophageal cancer unsuitable for surgery. However, the primary end-point was not met, and the addition of cetuximab to definitive chemoradiotherapy cannot be recommended.

First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial.

BACKGROUND: Addition of trastuzumab to first-line chemotherapy improves overall survival in patients with HER2-positive metastatic gastric cancer. We assessed the safety and activity of pembrolizumab in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric (gastric, oesophageal, or gastroesophageal junction) cancer. METHODS: This study was an investigator-initiated, open-label, non-randomised, single-arm, single centre, phase 2 trial in patients aged 18 years or older with HER2-positive metastatic oesophagogastric cancer. Eligible patients had measurable or evaluable non-measurable disease, Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and left ventricular ejection fraction of at least 53%. Patients were eligible to receive an initial induction cycle of 200 mg flat dose of intravenous pembrolizumab and 8 mg/kg loading dose of intravenous trastuzumab. For subsequent cycles, patients received 130 mg/m2 of intravenous oxaliplatin or 80 mg/m2 of cisplatin on day 1, 850 mg/m2 of oral capecitabine twice a day for 2 weeks followed by 1 week off (or intravenous 5-fluorouracil, 800 mg/m2 per day on days 1-5), and a 200 mg flat dose of intravenous pembrolizumab, and 6 mg/kg of trastuzumab, administered on day 1 of each 3-week cycle. The primary endpoint was 6-month progression-free survival, defined as the proportion of patients alive and free of progression at 6 months, assessed in patients who received at least one dose of trastuzumab and pembrolizumab. The regimen would be considered worthy of further investigation if 26 or more of 37 patients were progression-free at 6 months. This trial is registered with ClinicalTrials.gov, NCT02954536, and is ongoing, but closed to enrolment. FINDINGS: Between Nov 11, 2016, and Jan 23, 2019, 37 patients were enrolled. At the time of data cutoff on Aug 6, 2019, median follow-up among survivors was 13·0 months (IQR 11·7-23·5). The primary endpoint was achieved; 26 (70%; 95% CI 54-83) of 37 patients were progression-free at 6 months. The most common treatment-related adverse event of any grade was neuropathy, which was reported in 36 (97%) of 37 patients. The most common grade 3 or 4 adverse events were lymphocytopenia (seven [19%] patients with grade 3 and two [5%] with grade 4), grade 3 decreased electrolytes (six [16%] patients), and grade 3 anaemia (four [11%] patients). Serious adverse events occurred in two patients patients (both grade 3 nephritis leading to treatment discontinuation). Four patients discontinued pembrolizumab because of immune-related adverse events. There were no treatment-related deaths. INTERPRETATION: Pembrolizumab can be safely combined with trastuzumab and chemotherapy and has promising activity in HER2-positive metastatic oesophagogastric cancer. A randomised phase 3 clinical trial assessing the efficacy and safety of pembrolizumab versus placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric cancer is underway. FUNDING: Merck & Co.

Significance of tumour regression in lymph node metastases of gastric and gastro-oesophageal junction adenocarcinomas.

The presence of lymph node (LN) metastases is one of the most important negative prognostic factors in upper gastrointestinal carcinomas. Tumour regression similar to that in primary tumours can be observed in LN metastases after neoadjuvant therapy. We evaluated the prognostic impact of histological regression in LNs in 480 adenocarcinomas of the stomach and gastro-oesophageal junction after neoadjuvant chemotherapy. Regressive changes in LNs (nodular and/or hyaline fibrosis, sheets of foamy histiocytes or acellular mucin) were assessed by histology. In total, regressive changes were observed in 128 of 480 patients. LNs were categorised according to the absence or presence of both residual tumour and regressive changes (LN-/+ and Reg-/+). 139 cases were LN-/Reg-, 28 cases without viable LN metastases revealed regressive changes (LN-/Reg+), 100 of 313 cases with LN metastases showed regressive changes (LN+/Reg+), and 213 of 313 metastatic LN had no signs of regression (LN+/Reg-). Overall, LN/Reg categorisation correlated with overall survival with the best prognosis for LN-/Reg- and the worst prognosis for LN+/Reg- (p < 0.001). LN-/Reg+ cases had a nearly significant better outcome than LN+/Reg+ (p = 0.054) and the latter had a significantly better prognosis than LN+/Reg- (p = 0.01). The LN/Reg categorisation was also an independent prognostic factor in multivariate analysis (HR = 1.23; 95% CI 1.1-1.38; p < 0.001). We conclude that the presence of regressive changes after neoadjuvant treatment in LNs and LN metastases of gastric and gastro-oesophageal junction cancers is a relevant prognostic factor.

Retrospective observational study of salvage line ramucirumab monotherapy for patients with advanced gastric cancer.

BACKGROUND: Ramucirumab monotherapy as a second-line treatment for advanced gastric cancer (AGC) prolongs survival compared to the best supportive care. However, in clinical practice, ramucirumab monotherapy is sometimes used as third- or later-line treatment for AGC refractory to fluoropyrimidine and taxanes. This study evaluated the efficacy and safety of salvage-line ramucirumab monotherapy for treating AGC. METHODS: The subjects of this retrospective study were advanced gastric or gastro-esophageal junction adenocarcinoma patients who received ramucirumab monotherapy after failure of 2 or more prior regimens containing fluoropyrimidine and taxanes but not ramucirumab. RESULTS: From June 2015 to April 2017, 51 patients were enrolled. The median progression-free survival (PFS) and overall survival (OS) were 1.8 (95% confidence interval [CI] = 1.6-2.2) and 5.1 (95% CI = 4.0-6.8) months, respectively. The objective response and disease control rates were 2 and 17%, respectively. Grade 3 adverse events (AEs; e.g., anemia, fatigue, hypertension, proteinuria, intestinal bleeding) occurred in seven (13%) patients, but no grade 4 AEs and treatment-related deaths were observed. A neutrophil-lymphocyte ratio (NLR) of < 2.5 and previous gastrectomy were associated with better PFS. CONCLUSIONS: Salvage-line ramucirumab monotherapy has acceptable toxicity and comparable efficacy to second-line treatment; therefore, we consider physicians might choose this therapy as a salvage-line treatment option for AGC refractory to the standard therapies.

Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study.

BACKGROUND: The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. PATIENTS AND METHODS: Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. RESULTS: The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. CONCLUSIONS: Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial.

Increased assessment of HER2 in metastatic gastroesophageal cancer patients: a nationwide population-based cohort study.

BACKGROUND: Addition of trastuzumab to first-line palliative chemotherapy in gastroesophageal cancer patients with HER2 overexpression has shown to improve survival. Real-world data on HER2 assessment and administration of trastuzumab are lacking. The aim of this study was to assess HER2 testing, trastuzumab administration, and overall survival (OS) in a nationwide cohort of metastatic gastroesophageal cancer patients. METHODS: Data of patients with synchronous metastatic gastroesophageal adenocarcinoma diagnosed in 2010-2016 that received palliative systemic treatment (n = 2846) were collected from the Netherlands Cancer Registry and Dutch Pathology Registry. The ToGA trial criteria were used to determine HER2 overexpression. Proportions of HER2 tested patients were analyzed between hospital volume categories using Chi-square tests, and over time using trend analysis. OS was tested using the Kaplan Meier method with log rank test. RESULTS: HER2 assessment increased annually, from 18% in 2010 to 88% in 2016 (P < 0.01). Median OS increased from 6.9 (2010-2013) to 7.9 months (2014-2016; P < 0.05). Between the hospitals, the proportion of tested patients varied between 29-100%, and was higher in high-volume hospitals (P < 0.01). Overall, 77% of the HER2 positive patients received trastuzumab. Median OS was higher in patients with positive (8.8 months) and negative (7.4 months) HER2 status, compared to non-tested patients (5.6 months; P < 0.05). CONCLUSION: Increased determination of HER2 and administration of trastuzumab have changed daily practice management of metastatic gastroesophageal cancer patients receiving palliative systemic therapy, and possibly contributed to their improved survival. Further increase in awareness of HER2 testing and trastuzumab administration may improve quality of care and patient outcomes.