Untreated Advanced Gastric Cancer Research Articles

First-Line Nivolumab and Relatlimab Plus Chemotherapy for Gastric or Gastroesophageal Junction Adenocarcinoma: The Phase II RELATIVITY-060 Study.

Open-label phase II study (RELATIVITY-060) to investigate the efficacy and safety of first-line nivolumab, a PD-1-blocking antibody, plus relatlimab, a lymphocyte-activation gene 3 (LAG-3)-blocking antibody, plus chemotherapy in patients with previously untreated advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC). Patients with unresectable, locally advanced or metastatic GC/GEJC were randomly assigned 1:1 to nivolumab + relatlimab (fixed-dose combination) + chemotherapy or nivolumab + chemotherapy. The primary end point was objective response rate (ORR; per RECIST v1.1 by blinded independent central review [BICR]) in patients whose tumors had LAG-3 expression ≥1%. Of 274 patients, 138 were randomly assigned to nivolumab + relatlimab + chemotherapy and 136 to nivolumab + chemotherapy. Median follow-up was 11.9 months. In patients with LAG-3 expression ≥1%, BICR-assessed ORR (95% CI) was 48% (38 to 59) in the nivolumab + relatlimab + chemotherapy arm and 61% (51 to 71) in the nivolumab + chemotherapy arm; median progression-free survival (95% CI) by BICR was 7.0 months (5.8 to 8.4) versus 8.3 months (6.9 to 12.1; hazard ratio [HR], 1.41 [95% CI, 0.97 to 2.05]), and median overall survival (95% CI) was 13.5 months (11.9 to 19.1) versus 16.0 months (10.9 to not estimable; HR, 1.04 [95% CI, 0.70 to 1.54]), respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 69% and 61% of all treated patients, and 42% and 36% of patients discontinued because of any-grade TRAEs in the nivolumab + relatlimab + chemotherapy and nivolumab + chemotherapy arms, respectively. RELATIVITY-060 did not meet its primary end point of improved ORR in patients with LAG-3 expression ≥1% when relatlimab was added to nivolumab + chemotherapy compared with nivolumab + chemotherapy. Further studies are needed to address whether adding anti-LAG-3 to anti-PD-1 plus chemotherapy can benefit specific GC/GEJC patient subgroups.

First-line camrelizumab (a PD-1 inhibitor) plus apatinib (an VEGFR-2 inhibitor) and chemotherapy for advanced gastric cancer (SPACE): a phase 1 study

Patients with advanced gastric cancer typically face a grim prognosis. This phase 1a (dose escalation) and phase 1b (dose expansion) study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma. The primary endpoints included maximum tolerated dose (MTD) in phase 1a and objective response rate (ORR) across phase 1a and 1b. Phase 1a tested three dose regimens of camrelizumab, apatinib, oxaliplatin, and S-1. Dose regimen 1: camrelizumab 200 mg on day 1, apatinib 250 mg every other day, oxaliplatin 100 mg/m² on day 1, and S-1 40 mg twice a day on days 1–14. Dose regimen 2: same as dose regimen 1, but oxaliplatin 130 mg/m². Dose regimen 3: same as dose regimen 2, but apatinib 250 mg daily. Thirty-four patients were included (9 in phase 1a, 25 in phase 1b). No dose-limiting toxicities occurred so no MTD was identified. Dose 3 was set for the recommended phase 2 doses and administered in phase 1b. The confirmed ORR was 76.5% (95% CI 58.8–89.3). The median progression-free survival was 8.4 months (95% CI 5.9-not evaluable [NE]), and the median overall survival (OS) was not mature (11.6-NE). Ten patients underwent surgery after treatment and the multidisciplinary team evaluation. Among 24 patients without surgery, the median OS was 19.6 months (7.8-NE). Eighteen patients (52.9%) developed grade ≥ 3 treatment-emergent adverse events. Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer (ChiCTR2000034109).

SO-11 Bemarituzumab for treatment of previously untreated advanced and/or metastatic gastric and gastroesophageal cancer (GC): Final analysis of a randomized phase 2 trial (FIGHT)

SO-11 Bemarituzumab for treatment of previously untreated advanced and/or metastatic gastric and gastroesophageal cancer (GC): Final analysis of a randomized phase 2 trial (FIGHT)

Abstract 6756: Ramucirumab plus paclitaxel as second-line treatment in patients with advanced gastric cancer who previously treated with first-line nivolumab plus chemotherapy

Abstract Background: For human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (AGC), a combination of fluoropyrimidines and platinum agents was the standard first-line treatment. After the failure of the first-line therapy, ramucirumab plus paclitaxel was the standard second-line treatment. In the CheckMate 649 study, nivolumab plus chemotherapy has been considered a new standard first-line treatment in previously untreated AGC. However, the role of ramucirumab plus paclitaxel as 2nd line after the failure of nivolumab plus chemotherapy is not confirmed. Methods: We analyzed AGC patients with ramucirumab plus paclitaxel as second-line therapy, who failed the nivolumab plus chemotherapy (capecitabine plus oxaliplatin (XELOX) or 5-fluorouracil plus oxaliplatin (FOLFOX)) as frontline therapy at Samsung Medical Center, South Korea. Results: Under the routine clinical practice, 23 AGC patients, who progressed after first-line chemotherapy with nivolumab plus chemotherapy, were treated with ramucirumab plus paclitaxel between Dec 2021 to Sep 2022. The median age was 56 (range, 24-76), and 18 (78.3%) patients received nivolumab plus XELOX, while 5 (21.7%) patients received nivolumab plus FOLFOX. The overall response rate (ORR) to ramucirumab plus paclitaxel was 10.0% (2 of PR) and the disease control rate was 55.0%. At the median follow-up of 4.5 months, the median progression-free survival (PFS) from second-line ramucirumab plus paclitaxel commencement was 2.7 months (95% confidence interval (CI), 1.7-3.7); 6.9 months (95% CI, not calculated) in the first nivolumab plus chemotherapy responders(n=7), and 2.3 months (95% CI, 1.6-3.0) in non-responders(n=15) (p=0.232). At the time of data cutoff, 6 patients continued to receive ramucirumab plus paclitaxel and the median OS was 6.3 months (95% CI, 4.9-7.7). Conclusions: This analysis showed that ramucirumab plus paclitaxel as 2nd line therapy was not sufficient in AGC patients after the failure for nivolumab plus chemotherapy. The new innovative 2nd line therapy might be needed in AGC patients after nivolumab plus chemotherapy. Citation Format: Youngkyung Jeon, Sun Young Jeong, Jaeyeon Jang, Ye Ji Jung, Daeho Choi, Joohyun Hong, Seung Tae Kim, Won ki Kang, Jeeyun Lee. Ramucirumab plus paclitaxel as second-line treatment in patients with advanced gastric cancer who previously treated with first-line nivolumab plus chemotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6756.

Association of inflammatory markers with survival in patients with advanced gastric cancer treated with immune checkpoint inhibitors combined with chemotherapy as first line treatment.

The emergence of immune checkpoint inhibitors has changed the landscape of first-line treatment of patients with advanced gastric cancer. Currently, the prognostic significance of inflammatory markers in first-line immunotherapy combined with chemotherapy for gastric cancer is currently unclear. This study aimed to identify inflammatory markers with potential to predict treatment outcome in advanced gastric cancer patients receiving immunotherapy combined with chemotherapy. This retrospective study enrolled untreated advanced or metastatic gastric or gastro-esophageal junction cancer patients from 5 clinical trials (the clinical trial cohort) and the real world (the real-word cohort). Inflammatory markers included in the analysis included neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and derived neutrophil-to-lymphocyte ratio (dNLR). Receiver operating characteristic (ROC) curves were constructed to identify optimal cut-off values. The prognostic potential of the markers was determined using Kaplan-Meier analysis, univariate and multivariate Cox-regression analyses in the clinical trial cohort and the findings were validated in the real-world cohort. In the clinical trial cohort (n=45), MLR, PLR and SII were associated with PFS but not OS (All P<0.05), while dNLR was not correlated with PFS or OS. Only NLR was associated with PFS and OS and identified as an independent prognostic predictor in the univariate and multivariate analyses. The prognostic value of NLR was validated in the real-world cohort (n=55). NLR was a strong predictor of PFS and OS in patients with advanced gastric cancer receiving immune checkpoint inhibitors combined with chemotherapy. Further prospective studies are required to validate our results.

Phase 2 randomized controlled trial of intravenous or intraperitoneal paclitaxel plus mFOLFOX6 vs. mFOLFOX6 as first-line treatment of advanced gastric cancer.

ObjectiveWe conducted a phase 2 trial to compare the safety and efficacy of intravenous paclitaxel or intraperitoneal paclitaxel plus mFOLFOX6 vs. mFOLFOX6 in untreated advanced gastric cancer.MethodsParticipants with untreated advanced gastric cancer were randomly assigned (1:1:1) to: intravenous paclitaxel 135 mg/m2 or intraperitoneal paclitaxel 80 mg/m2 plus mFOLFOX6 omitting bolus fluorouracil; or mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil 400 mg/m2 bolus, fluorouracil 2,400 mg/m2 46-h continuous infusion). Treatment was every 14 days for up to 9 cycles followed by S-1 maintenance. The primary outcome was progression-free survival.ResultsOf 90 enrolled participants, 30 in the intravenous paclitaxel group, 29 in the intraperitoneal paclitaxel group, and 30 in the mFOLFOX6 group were included in the analyses. The median progression-free survival was 6.52, 5.83, and 4.55 months, respectively, for the intravenous paclitaxel group, intraperitoneal paclitaxel group, and mFOLFOX6 group. The hazard ratios were 0.56 (95% CI: 0.33–0.94; p = 0.026) and 0.56 (95% CI: 0.33–0.96; p = 0.037), respectively, for the intravenous paclitaxel group and the intraperitoneal paclitaxel group vs. the mFOLFOX6 group. The most common grade 3/4 adverse events for the intravenous paclitaxel group, intraperitoneal paclitaxel group, and mFOLFOX6 group, respectively, were neutropenia (30.0%, 34.5%, 33.3%), diarrhea (13.3%, 20.7%, 13.3%), and leukopenia (10.0%, 13.8%, 10.0%). No treatment-related death occurred.ConclusionThe findings of this phase 2 trial suggest that adding intravenous paclitaxel or intraperitoneal paclitaxel to mFOLFOX6 for untreated advanced gastric cancer improved progression-free survival with manageable adverse events.

1250P Camrelizumab plus apatinib combined with POF in patients with untreated advanced gastric cancer (UAGC): A single-center, open-label, single-arm, phase II trial (SYLT-017)

Previous reports of POF demonstrated promising efficacy for patients with AGC (ASCO-GI 2019). Apatinib, a small molecule tyrosine kinase inhibitor, can be safely administered up to 850 mg daily combined with POF in AGC (ESMO 2019). The PD-1 inhibitor nivolumab provided superior OS, along with PFS benefit, in combination with chemotherapy in UAGC in the CheckMate-649 study. Camrelizumab, in combination with apatinib, has been demonstrated clinical benefits in multiple advanced solid tumors. On the basis of these results, we conducted this trial to evaluate the safety and efficacy of first-line camrelizumab plus apatinib combined with POF in patients with UAGC.

Trial in progress: Phase 3 study of bemarituzumab + mFOLFOX6 versus placebo + mFOLFOX6 in previously untreated advanced gastric or gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-101).

TPS4164 Background: Fibroblast growth factor receptor 2b (FGFR2b) is overexpressed in approximately 30% of non-human epidermal growth factor receptor 2 (non-HER2) positive gastric cancer (Wainberg, 2021). Bemarituzumab is a first-in-class monoclonal antibody that specifically blocks FGFR2b, inhibiting downstream tumor proliferation and enhancing antibody-dependent cellular cytotoxicity (Catenacci, 2020; Xiang, 2021). In the phase 2 FIGHT study (Wainberg, 2021; Catenacci, 2021), bemarituzumab + mFOLFOX6 improved progression-free survival (PFS; HR, 0.68; 95% CI, 0.44‒1.04; p = 0.07) and led to a 5.7 month longer median overall survival (OS; 19.2 months vs 13.5 months; HR, 0.60; 95% CI, 0.38-0.94) compared with placebo + mFOLFOX6. Methods: FORTITUDE-101 (NCT05052801) is a double-blind, placebo-controlled phase 3 study in patients with untreated, unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma not amenable to curative therapy. Approximately 516 patients aged ≥18 years with IHC-confirmed FGFR2b overexpression by central testing will be enrolled and randomized 1:1 to bemarituzumab + mFOLFOX6 or placebo + mFOLFOX6. Additional key eligibility criteria include Eastern Cooperative Oncology Group performance status 0-1, evaluable disease per RECIST v1.1, adequate hematologic and organ function, and no contraindication to receive mFOLFOX6 chemotherapy. Key exclusion criteria include prior treatment for metastatic or unresectable disease except one dose of mFOLFOX6 during screening, positive HER2 status, untreated or symptomatic CNS metastasis and leptomeningeal disease, history or evidence of ongoing ophthalmologic abnormalities, and prior treatment with any FGF-FGFR pathway inhibitor. Patients randomized to bemarituzumab will receive 15 mg/kg every 2 weeks (Q2W) with an additional 7.5 mg/kg dose on cycle 1 day 8. mFOLFOX6 will be administered at a fixed dose Q2W. Patients will receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint is OS; secondary endpoints include PFS, objective response (defined as best overall response of complete or partial response), and treatment-emergent adverse events. Tumor responses and PFS will be assessed locally per RECIST v1.1. The concurrent phase 1b/3 FORTITUDE-102 study (NCT05111626) will evaluate the efficacy and safety of bemarituzumab + mFOLFOX6 + nivolumab versus placebo + mFOLFOX6 + nivolumab. Clinical trial information: NCT05052801.

Trial in progress: Phase 1b/3 study of bemarituzumab + mFOLFOX6 + nivolumab versus mFOLFOX6 + nivolumab in previously untreated advanced gastric and gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-102).

TPS4165 Background: Fibroblast growth factor receptor 2b (FGFR2b) is overexpressed in approximately 30% of non-human epidermal growth factor receptor 2 (non-HER2) positive gastric cancer (Wainberg, 2021). Bemarituzumab is a first-in-class monoclonal antibody that specifically blocks FGFR2b, inhibiting downstream tumor proliferation and enhancing antibody dependent cellular cytotoxicity (Catenacci, 2020; Xiang, 2021). In the phase 2 FIGHT study (Wainberg, 2021; Catenacci, 2021), progression-free survival (PFS) was improved (HR, 0.68; 95% CI, 0.44-1.04; p = 0.07) and a 5.7 month longer median overall survival (OS) was observed (19.2 months vs 13.5 months; HR, 0.60; 95% CI, 0.38-0.94) with bemarituzumab + mFOLFOX6 vs placebo + mFOLFOX6. Preclinical studies indicate that bemarituzumab modulates the tumor microenvironment to sensitize tumors to anti-PD1 monoclonal antibodies (Powers, 2016; Xiang, 2021) providing rationale for combination with nivolumab. Methods: FORTITUDE-102 (NCT05111626) is a phase 1b/3 study in patients (pts) with unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma not amenable to curative therapy. Part 1 is an open-label safety lead-in; Part 2 is a double-blind, placebo-controlled study to evaluate efficacy and safety. Approximately 702 pts ≥18 years will be enrolled (Part 1, ̃20; Part 2, ̃682). Key eligibility criteria include Eastern Cooperative Oncology Group performance status 0-1, evaluable disease per RECIST v1.1, adequate hematologic and organ function, and no contraindication to receive mFOLFOX6 chemotherapy or nivolumab; for part 2, IHC-confirmed FGFR2b overexpression by central testing is required and no prior treatment for metastatic or unresectable disease allowed except 1 dose of mFOLFOX6 ± nivolumab. Key exclusion criteria include positive HER2 status and untreated or symptomatic CNS metastasis and leptomeningeal disease. Pts on bemarituzumab will receive 15 mg/kg every 2 weeks (Q2W) with an additional 7.5 mg/kg dose on cycle 1 day 8. mFOLFOX6 + nivolumab will be at a fixed dose Q2W. The dose-limiting toxicity (DLT) period is 28 days; observed safety data will influence additional enrollment to Part 1, de-escalation of bemarituzumab, or the recommended phase 3 dose (RP3D). For Part 1, primary endpoints are DLTs and adverse events; secondary endpoints include OS, PFS, and objective response (OR). For Part 2, pts will be randomized 1:1 to mFOLFOX6 + nivolumab Q2W plus either bemarituzumab at RP3D or placebo. Primary endpoint for Part 2 is OS; secondary endpoints include PFS, OR, and safety. The concurrent phase 3 FORTITUDE-101 study (NCT05052801) will evaluate bemarituzumab + mFOLFOX6 vs placebo + mFOLFOX6. Clinical trial information: NCT05111626.

Molecular profile of exosomal miRNA differential expression in ascites of untreated advanced gastric cancer patients with peritoneal metastases.

e16086 Background: The incidence of gastric cancer is high, and the proportion of peritoneal metastases among patients with early-stage operable gastric cancer is about 10%-20%, while the proportion of peritoneal metastases among patients with stage 3 (stage III) gastric cancer is as high as 40%. The prognosis of gastric cancer patients with peritoneal metastases is poor, with a median survival of 7 months. Exosomes are considered to be carriers of intercellular communication and abundant miRNAs (miRNAs) are enriched in patients' ascitic fluid exosomes. Methods: Ascites exosomes were characterized according to ISEV2018. The pro-tumor proliferation and metastatic ability of ascites exosomes in gastric cancer patients with peritoneal metastases was observed by small animal in vivo imaging. Six untreated ascites exosomes from gastric cancer patients with peritoneal metastases were selected for miRNA sequencing with five ascites exosomes from patients with benign disease to determine differentially expressed molecular profiles. The target mRNAs of selected miRNAs were predicted by miRhybrid, TargetScan database, and enriched in KEGG database for the function of target mRNAs. Results: Compared to ascites exosomes from patients with benign disease, or ascites exosomes removed from gastric cancer patients with peritoneal metastases, ascites exosomes from gastric cancer patients with peritoneal metastases had a significant contribution to tumor proliferation and metastasis. Among them, molecules such as miR-196 were expressed up-regulated in all six samples of gastric cancer peritoneal metastasis group, and the difference was significant. The target mRNAs of differentially expressed miRNAs were associated with motility, adhesion, stromal degradation, hypoxia tolerance, apoptosis, and angiogenesis (biological behaviors involved in this process of gastric cancer peritoneal metastasis). Conclusions: Molecules such as miR-196 are important for the clinical problem of peritoneal metastasis of gastric cancer and can be used as biomarkers for disease assessment and potential therapeutic target.

High prevalence of severe hypovitaminosis D in patients with advanced gastric cancer treated with first-line chemotherapy with or without anti-EGFR–directed monoclonal antibody (EXPAND trial) showing no prognostic impact

PurposeThe goal of our analysis was to study pretherapeutic circulating 25-OHD plasma levels in patients with previously untreated advanced gastric cancer treated in the randomised controlled phase III Erbitux (cetuximab) in combination with Xeloda (capecitabine) and cisplatin in advanced esophago-gastric cancer (EXPAND) trial (NCT00678535) and to explore whether low 25-OHD plasma levels are associated with worse prognosis and may compromise the clinical efficacy of cetuximab. MethodsSix hundred thirty patients with available pretherapeutic 25-OHD plasma levels and treated with chemotherapy based on capecitabine and cisplatin, or chemotherapy and cetuximab, were included. The Cox proportional hazard regression model was used to analyse the association between low 25-OHD and survival in both treatment arms. ResultsMajority of study patients were found to have severe vitamin D deficiency. No prognostic impact of 25-OHD plasma levels could be found in our patient cohort, and there was no indication of an interference of 25-OHD plasma levels and the efficacy of treatment with the anti–epidermal growth factor receptor monoclonal antibody cetuximab. ConclusionsAlthough majority of patients with advanced gastric cancer show hypovitaminosis D deficiency, there is no proof for a negative impact on survival or reduced treatment response. A prospective study is needed to investigate the potential benefit of vitamin D supplementation in this patient cohort during first-line chemotherapy.

Integrin β5 in plasma-derived exosomal protein predicting liver-specific metastasis in advanced gastric cancer patients.

e14521 Background: Gastric cancer (GC) is the second leading cause of cancer death in China. Liver metastasis (LM) is a highly frequent event of the advanced GC, and the patients with LM always present dismal prognosis. A predicted factor of LM is urgently established to screen out the population in high risk of LM. Tumor-derived exosomes play critical roles in cancer metastasis process. Exosomes integrin (ITG) αvβ5 is uptake by liver resident cells and linked to LM in cell lines. This study is designed to evaluate the association between exosomes ITG αvβ5 and liver metastasis, especially in HER2 positive gastric cancer. Methods: 74 untreated advanced GC patients with matched blood and tumor tissue samples and clinical features were collected in the study. Exosomal HER2, ITG αv and β5 expression were measured by enzyme-linked immunosorbent assay (ELISA) after the exosomes isolated from plasma. HER2 status of tumor tissue was determined by IHC and/or FISH. Results: Based on HER2 status of tumor tissue, we initially proved the feasibility of detecting HER2 expression from exosome. ROC curves showed the optimum exosomal HER2 expression diagnostic cutoff for HER2 positive patients was 266.38 pg/ml (sensitivity 71.4% and specificity 72.6%). In total, 27 patients were LM and the rest (n = 47) was non-LM. The median expression value of ITG αv and β5 were 57.55 pg/ml and 836.00 pg/ml, respectively. And these two median value were identified as the cutoff value for subsequent analysis, respectively. HER2 expression was merely linked to ITG β5 expression (P = 0.019), not ITG αv (P &gt; 0.050). There was no relationship between ITG αv and LM (P = 0.629), however, ITG β5 expression presented significant association with LM (P = 0.016). We further probed the relationship between ITG and other metastasis. Results showed no correlation between any ITG and other non-liver organic metastases, like lung, bone, ovarian, lymph, and peritoneal metastasis. Besides, ITG β5 expression was also associated with LM in the HER2-positive GC patients. Conclusions: Exosomes might serve as a potential non-invasive diagnostic and screening tool. In clinical samples, ITG β5, not αv, was linked to LM, and might be a valuable biomarker in the use of predicting LM of GC, even in the HER2-positive patients.

FIGHT: A phase 3 randomized, double-blind, placebo controlled study evaluating (bemarituzumab) FPA144 and modified FOLFOX6 (mFOLFOX6) in patients with previously untreated advanced gastric and gastroesophageal cancer with a dose finding phase 1 lead-in.

TPS4135Background: FGFR2b overexpression and FGFR2 gene amplification occurs in approximately 10% of patients with gastric cancer (GC) and is associated with a poor prognosis and the presence of me...

CheckMate 649: A randomized, multicenter, open-label, phase III study of nivolumab (NIVO) + ipilimumab (IPI) or nivo + chemotherapy (CTX) versus CTX alone in patients with previously untreated advanced (Adv) gastric (G) or gastroesophageal junction (GEJ) cancer.

TPS192 Background: Pts with adv G/GEJ cancer have an OS of ≈ 1 y, indicating an unmet medical need for new first-line treatments. Expression of PD-L1 is observed in up to 40% of pts with G/GEJ cancer and is associated with poor prognosis. In the randomized phase 3 ATTRACTION-2 study, NIVO demonstrated superior overall survival vs placebo with a 38% reduction of the risk of death (median OS, 5.3 vs 4.1 mo; HR, 0.62 P&lt; 0.0001) and increased the OS rate at 12 mo (27% vs 12%; Boku N et al ESMO 2017) in pts with adv CTX-R (≥ 2 lines) G/GEJ cancer. In the phase 1/2 CheckMate-032 study in pts with CTX-R G/GEJ/esophageal cancer (79% ≥ 2 prior Tx lines), NIVO 1 mg/kg + IPI 3 mg/kg had a manageable safety profile and resulted in 24% ORR (40% ORR in pts with PD-L1+ tumors), a median OS of 6.9 mo, and a 35% OS rate at 12 mo (Janjigian Y et al ASCO 2017). In the phase 1 CheckMate-012 trial, NIVO + CTX had clinical activity and manageable safety in pts with NSCLC (Rizvi NA et al J Clin Oncol 2016). These positive results support investigation of NIVO, NIVO + IPI, and NIVO + CTX in earlier lines of treatment for G/GEJ cancer. The open-label, phase 3 CheckMate 649 trial will evaluate NIVO + IPI and NIVO + CTX vs CTX alone as first-line treatment for pts with adv G/GEJ cancer (NCT02872116). Methods: 1266 pts aged ≥ 18 y with untreated, inoperable adv/metastatic G/GEJ cancer (histologically confirmed adenocarcinoma) regardless of PD-L1 status will be randomized to receive either NIVO + IPI, NIVO + CTX (capecitabine/oxaliplatin [XELOX] or fluorouracil/leucovorin/oxaliplatin [FOLFOX]), or investigator choice of XELOX or FOLFOX. Tumor tissue for determination of PD-L1 status (Dako assay) must be provided from ≤ 6 mo before study treatment. No prior systemic treatment, including HER2 inhibitors, are allowed. Pts with known HER2+ status, suspected autoimmune disease, grade &gt; 1 peripheral neuropathy, or active infection are excluded. Primary endpoint is OS in pts with PD-L1+ (≥ 1%) tumors. Other endpoints include OS in all pts; PFS and time to symptom deterioration in all pts and in pts with PD-L1+ tumors; and safety. Clinical trial information: NCT02872116.

777TiP - ATTRACTION-04 (ONO-4538-37): A randomized, multicenter, phase 2/3 study of nivolumab (Nivo) plus chemotherapy in patients (Pts) with previously untreated advanced or recurrent gastric (G) or gastroesophageal junction (GEJ) cancer

777TiP - ATTRACTION-04 (ONO-4538-37): A randomized, multicenter, phase 2/3 study of nivolumab (Nivo) plus chemotherapy in patients (Pts) with previously untreated advanced or recurrent gastric (G) or gastroesophageal junction (GEJ) cancer

CheckMate 649: A randomized, multicenter, open-label, phase 3 study of nivolumab (nivo) + ipilimumab (ipi) or nivo + chemotherapy (CTX) vs CTX alone in pts with previously untreated advanced (adv) gastric (G) or gastroesophageal junction (GEJ) cancer.

TPS4132 Background: Pts with adv G/GEJ cancer have an OS of ≈ 1 y, indicating an unmet medical need for new first-line treatments (Tx). Expression of the PD-1 ligands PD-L1/PD-L2 is observed in up to 40% of pts with G/GEJ cancer and is associated with poor prognosis. In a phase 3 study of the PD-1 inhibitor nivo vs placebo in pts with adv CTX-refractory (CTX-R; ≥ 2 lines) G/GEJ cancer, nivo reduced the risk of death by 37% (HR, 0.63; P &lt; 0.0001) and increased the OS rate at 12 mo (27% vs 11%; Kang YK, et al. J Clin Oncol. 2017;35 (suppl 4S) [abstract 2]). In a phase 1/2 study in pts with CTX-R G/GEJ/esophageal cancer (79% ≥ 2 prior Tx lines), nivo 1 mg/kg + ipi 3 mg/kg had a manageable safety profile and resulted in 26% ORR (44% ORR in pts with PD-L1+ tumors), a median OS of 6.9 mo, and a 34% OS rate at 12 mo (Janjigian Y, et al. ASCO, 2016 [abstract 4010]). In the phase 1 CheckMate 012 trial, nivo + CTX had clinical activity and manageable safety in pts with NSCLC (Rizvi NA, et al. J Clin Oncol. 2016;34:2969-2979). These positive results support investigation of nivo, nivo + ipi, and nivo + CTX in earlier lines of Tx for G/GEJ cancer. The open-label, phase 3 CheckMate 649 trial will evaluate nivo + ipi and nivo + CTX vs CTX alone as first-line Tx for pts with adv G/GEJ cancer (NCT02872116). Methods: 1266 pts aged ≥ 18 y with untreated, inoperable adv/metastatic G/GEJ cancer (histologically confirmed adenocarcinoma) regardless of PD-L1 status will be randomized to receive either nivo + ipi, nivo + CTX (capecitabine/oxaliplatin [XELOX] or fluorouracil/leucovorin/oxaliplatin [FOLFOX]), or investigator choice of XELOX or FOLFOX. Tumor tissue for determination of PD-L1 status (Dako assay) must be provided from ≤ 6 mo before study Tx. No prior systemic Tx, including HER2 inhibitors, are allowed. Pts with known HER2+ status, suspected autoimmune disease, grade &gt; 1 peripheral neuropathy, or active infection are excluded. Primary endpoint is OS in pts with PD-L1+ (≥ 1%) tumors. Other endpoints include OS in all pts; PFS and time to symptom deterioration in all pts and in pts with PD-L1+ tumors; and safety. Clinical trial information: NCT02872116.

The relative efficacy and safety of targeted agents used in combination with chemotherapy in treating patients with untreated advanced gastric cancer: a network meta-analysis.

Gastric cancer is one of the leading mortal causes. Targeted therapy is a new type of cancer treatment, which precisely identifies and attacks cancer cells and significantly reduces side effects. In this network meta-analysis, we focused on the efficacy and safety of 12 targeted agents on gastric cancer among a total of 8,405 patients from 24 trials. Hazard ratio (HR) with 95% credible interval (CrI) were calculated for primary outcomes, including overall survival (OS) and progression-free survival (PFS), while odds ratio (OR) with 95% CrI were calculated for secondary outcomes. Surface under the cumulative ranking curve (SUCRA) were calculated to illustrate the rank probability of various agents for different outcomes. Compared with other analyzed treatments, ramucirumab is outstanding in survival outcomes. However, higher risk of hematological events should be noted during its application. Lapatinib is also efficacious in progression reduction, while it is always combined with severe gastrointestinal events. Trastuzumab is proposed for its high efficacy in improving survival rate and safety, which is proper for most patients. In conclusion, trastuzumab was recommended as the optimal targeted agent combined with chemotherapy for gastric cancer patients.

Checkmate 649: A randomized, multicenter, open-label, phase 3 study of nivolumab (Nivo) plus ipilimumab (Ipi) versus oxaliplatin plus fluoropyrimidine in patients (Pts) with previously untreated advanced or metastatic gastric (G) or gastroesophageal junction (GEJ) cancer.

TPS213 Background: The combination ofoxaliplatin and fluoropyrimidine is a standard-of-care (SOC) first-line treatment of pts with metastatic G/GEJ cancer, resulting in a median overall survival (OS) of 8–11 months and objective response rate (ORR) of 30%–50%. This is accompanied by up to 77% grade 3/4 toxicities. Therefore, new treatment options are needed to improve survival and decrease toxicity in G/GEJ cancer. Nivo, a fully human IgG4 monoclonal antibody (mAb) that targets programmed death 1 (PD-1) and ipi, a fully human IgG1 mAb that targets cytotoxic T-lymphocyte–associated protein 4, have demonstrated manageable safety profiles and efficacy in multiple tumor types and may have a synergistic effect. In a phase 1/2 study in chemotherapy-refractory pts with G/GEJ/esophageal cancer with or without PD-1 ligand 1 (PD-L1) expression, second-line nivo 1 mg/kg + ipi 3 mg/kg demonstrated a manageable safety profile and resulted in 26% ORR (44% ORR in pts with PD-L1+ tumors), median OS of 6.9 months, and a 34% OS rate at 12 months (Janjigian Y, et al. J Clin Oncol. 2016;34[suppl][abstract 4010]). This open-label, phase 3 trial will evaluate nivo + ipi as first-line therapy for pts with G/GEJ cancer (CheckMate 649; NCT02872116). Methods: In this study, 870 pts aged ≥ 18 years with untreated advanced or metastatic G/GEJ cancer with or without PD-L1 expression will be randomized to receive nivo + ipi (4 doses; followed by nivo monotherapy) or investigator’s choice of capecitabine/oxaliplatin (XELOX) or fluorouracil/leucovorin/oxaliplatin (FOLFOX). Tumor tissue for determination of PD-L1 status must be provided from ≤ 6 months before study treatment. Pts receiving chemotherapy or radiotherapy for G/GEJ cancer within the last 6 months or pts with suspected autoimmune disease, uncontrolled medical disorder, or active infection are excluded. Primary endpoint is OS in pts with PD-L1+ tumors. Secondary endpoints include OS in all pts and progression-free survival and time to symptom deterioration in all pts and pts with PD-L1+ tumors. Clinical trial information: NCT02872116.

Added value of pretreatment 18F-FDG PET/CT for staging of advanced gastric cancer: Comparison with contrast-enhanced MDCT

PurposeTo evaluate the added clinical value of pretreatment 18F-FDG PET/CT compared with conventional contrast-enhanced multidetector-row CT (CECT) alone for staging of advanced gastric cancer Materials and methodsWe studied 106 patients with locally advanced gastric cancer who underwent pretreatment CECT and 18F-FDG PET/CT. Two experienced reviewers assessed the diagnostic performance of both CECT alone and the combination of CECT and 18F-FDG PET/CT for the primary tumor, regional lymph node metastasis (N) and distant metastasis (M), rating their diagnostic confidence with a 5-point scoring system for each location. The two methods were compared using receiver operating characteristic (ROC) curve analysis for histopathologic findings, imaging, and clinical follow-up as the reference standards. ResultsAmong the 106 patients, 96 primary tumors (90.6%) were detected by CECT, while 101 (95.3%) were clearly identified by 18F-FDG PET/CT (p=0.074). Patient-based areas under the ROC curves for CECT alone versus the combination of CECT and 18F-FDG PET/CT for diagnosis of N stage, peritoneal dissemination, liver metastasis, distant lymph node metastasis, bone metastasis, metastasis at other sites and overall M stage were 0.787 vs. 0.858 (p=0.13), 0.866 vs. 0.878 (p=0.31), 0.998 vs. 1.0 (p=0.36), 0.744 vs. 0.865 (p=0.049), 0.786 vs. 0.998 (p=0.034), 0.944 vs. 0.984 (p=0.34), and 0.889 vs. 0.912 (p=0.21), respectively. The diagnostic performance of primary tumor detection and NM staging was not influenced by the histologic subtype. ConclusionAdding 18F-FDG PET/CT to CECT provides better diagnostic accuracy for detection of distant lymph node metastasis and bone metastasis in patients with untreated advanced gastric cancer.

2318 Prospective phase II trial of pazopanib plus CapeOX (capecitabine and oxaliplatin) in previously untreated patients with advanced gastric cancer

We designed a single-arm, open label phase II study to determine the efficacy and toxicity of the combination of pazopanib with CapeOx (capecitabine and oxaliplatin) in metastatic /recurrent advanced gastric cancer (AGC) patients. Previously untreated AGC patients received capecitabine (850 mg/m2 bid, day 1–14) plus oxaliplatin (130 mg/m2, day 1) in combination with pazopanib (800 mg, day 1–21) every three weeks. Treatment was continued until progression of the disease or intolerable toxicity was observed. In all, 66 patients were treated with pazopanib plus CapeOx. The median age of the patients was 51.5 years (range, 23.0–77), and the median ECOG performance status was 1 (0–1). Among all 66 patients, one complete response and 37 partial responses were observed (overall response rate, 62.4%; 95% confidence interval (CI), 45.7–73.5% accounting for the 2-stage design of this trial). Stable disease was observed in 23 patients (34.8%), revealing a 92.4% disease control rate. The median progression free survival and overall survival were 6.5 months (95% CI, 5.6–7.4) and 10.5 months (95% CI, 8.1–12.9), respectively. Thirty-four patients (51.5%) experienced a treatment-related toxicity of grade 3 or more. The most common toxicities of grade 3 or more were neutropenia (15.1%), anemia (10.6%), thrombocytopenia (10.6%), anorexia (7.6%), nausea (3.0%), and vomiting (3.0%). There were no treatment-related deaths. The combination of pazopanib and CapeOx showed moderate activity and an acceptable toxicity profile as a first-line treatment in metastatic / recurrent AGC patients (ClinicalTrials.gov NCT01130805).