bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized phase Ib/II study of niraparib (nira) plus nivolumab (nivo) or ipilimumab (ipi) in patients (pts) with platinum-sensitive advanced pancreatic cancer (aPDAC).
Authors: Reiss Kim Anna , Mick Rosemarie , Teitelbaum Ursina R. , O'Hara Mark H. , Schneider Charles John , Massa Ryan Campbell , Karasic Thomas Benjamin , Onyiah Chioma , Gosselin Mary Kate , Donze Alyssa , Domchek Susan M. , Vonderheide Robert H. 
Published: June 2022

4021 Background: Establishing alternatives to perpetual chemotherapy for pts with aPDAC has been proposed to address inevitable chemotherapy resistance and cumulative toxicity. Poly (ADP ribose) polymerase (PARP) inhibitors have shown clinical efficacy in this setting, and preclinical data suggest that the addition of immune checkpoint blockade (ICB) may offer synergistic tumor control. We performed a randomized, phase Ib/II study of nira plus anti-PD-1 (nivo) or nira plus anti-CTLA-4 (ipi) maintenance for pts with aPDAC who had not progressed after >4 mo of platinum-based therapy. Methods: After discontinuation of chemotherapy, pts were randomized 1:1 to nira 200mg PO daily plus either nivo 240mg IV q2 weeks (later amended to 480mg IV q4 weeks) or ipi 3mg/kg IV q3 weeks for four doses. Nira could be escalated to 300mg PO daily if tolerated. Pts were treated until progression or unacceptable toxicity. The primary endpoint was progression free survival at six months (PFS6) in each arm. Secondary endpoints included safety, OS, ORR, and outcomes by DNA damage repair (DDR) deficiencies. Pts were evaluable for safety if they had received > 1 dose of study treatment and for efficacy if they had also received > 1 follow-up imaging study. Based on historical data, the null hypothesis of PFS6 = 44% vs a 2-sided alternative hypothesis of PFS ≠ 44% was tested. 42 pts per arm provided 81% power for testing at a 5% significance level to detect inferior PFS6 < 27% or superior PFS6 > 61%. Results: As of Oct 2021, 91 pts were enrolled, of whom 84 were evaluable for efficacy (44 nira/nivo; 40 nira/ipi). The median potential follow-up was 23 mos. Most common treatment-related AEs were nira/nivo: thrombocytopenia (28%), arthralgia (25%), nausea (23%), and fatigue (23%) and nira/ipi: thrombocytopenia (45%), anemia (43%), fatigue (43%), nausea, (41%), AST increase (36%), rash (34%) and ALT increase (29%). 88% of AEs were grade 1-2. Efficacy results were: nira/nivo: PFS6 20.6% (95% CI 8.3-32.9, p = 0.0002), mPFS 1.9 mo and nira/ipi: PFS6 59.6% (95% CI 44.3-74.9, p = 0.045), mPFS 8.1 mo. Fifteen pts (8 nira/nivo; 7 nira/ipi) had pathogenic variants in BRCA or PALB2 . Excluding these: mPFS on nira/nivo was 1.9 mo (95% CI 1.8-1.9) and mPFS on nira/ipi was 7.6 mo (95% CI 4.0 – 11.1). Conclusions: In a randomized phase 1B/II study, nira/ipi as maintenance therapy met the primary endpoint of superior PFS6 while nira/nivo yielded inferior PFS6 for pts with aPDAC who had not progressed on first-line platinum-based chemotherapy. The benefit of nira/ipi maintenance persisted in pts without known DDR variants. Clinical trial information: NCT03404960. [Table: see text]
Tandem CAR-T cells targeting CLDN18.2 and NKG2DL for treatment of gastric cancer.
Authors: Xu Hui , Li Weiguang , Lv Huixia , Gu Dongying , Wei Xiaowei , Dai Hong-jiu 
Published: June 2022

4030 Background: Gastric cancer (GC) is one of most common malignant tumor which is fifth for melanoma incidence and second for mortality rates worldwide. Novel therapeutic strategies are urgently needed. Recently people are exploring the potential of chimeric antigen receptor T (CAR-T) cell therapy in GC, yet the clinical outcome is limited. Reportedly, the bispecific CAR-T cell with tandem scFvs exhibited superior response rates or synergistic response compared with CAR-T cell with single scFv. It's reported that Claudin18.2 (CLDN18.2) is the most potential target of gastric cancer. Here, we construct a novel bispecific CAR-T cells (KD-496), which simultaneously recognize NKG2D ligands and CLDN18.2, to show superior antitumor efficacy and safety in vitro and in vivo. Methods: Gastric cancer cell lines as well as GC patient tissue samples were evaluated for NKG2DL and CLDN18.2 expression. The KD-496 CAR-T cells showed antigen-specific stimulation by cytokine secretion and tumor cell cytotoxicity assay. The patient tumor tissue fragments (8 mm3) were implanted subcutaneously into B-NDG mice to establish PDX models. When the tumor volume reached 50-100mm3, the mice received a single treatment of 5 million KD-496 CAR-T cells intravenously. The effect of KD-496 CAR-T in vivo was detected by measuring tumor volume twice a week. Results: CLDN18.2 and NKG2DL were detected on NUGC4, AGS-18.2 and MKN-28-18.2 cells and most of screened BM patient samples. The bispecific CAR-T cell KD-496 was generated with CD8 hinge region and transmembrane region, 4-1BB costimulatory region and CD3 zeta region. The KD-496 expression was > 50% on the surface of T cells confirmed by flow cytometry. Co-incubation of KD-496 CAR-T cells with NUGC4 and MKN-28-18.2 cell specifically upregulates IFN-γ cytokines and strongly lysis tumor cells even at low E:T ratio (50-60% at 4:1). Strikingly, KD-496 CAR more efficiently eliminated xenograft tumors in vivo and did not exhibit significant treatment-related toxicity in the treated mice. No obvious pathological changes were found in the tested organs. Conclusions: Our work construct a tandem CAR molecule targeting two tumor-associated antigens, NKG2DL and CLDN18.2, and found that Tan-CAR-T cells（KD-496）distinctly recognize the antigens and exhibited superior antitumor effect. KD-496 CAR-T cells potently respond to GC and more efficient tumor elimination than single CAR such as KD-025 and KD-182 CAR-T cells in PDX model with no obvious safety issue. The results support future clinical trial of KD-496 CAR in patients with GC, where the need for effective treatment is great.
Perioperative ramucirumab in combination with FLOT versus FLOT alone for resectable esophagogastric adenocarcinoma (RAMSES/FLOT7) with high rate of signet cell component: Final results of the multicenter, randomized phase II/III trial of the German AIO and Italian GOIM.
Authors: Goetze Thorsten Oliver , Hofheinz Ralf-Dieter , Schmalenberg Harald , Strumberg Dirk , Goekkurt Eray , Angermeier Stefan , Zander Thomas , Potenberg Jochem , Kopp Hans-Georg , Pink Daniel , Siegler Gabriele Margareta , Schenk Michael , De Vita Ferdinando , Maiello Evaristo , Gaiser Timo , Sookthai Disorn , Brulin Tanita , Pauligk Claudia , Homann Nils , Al-Batran Salah-Eddin 
Published: June 2022

4042 Background: Periop. FLOT has become SOC for resectable, esophagogastric adenocarcinoma. However, patient’s outcome is still poor. This trial evaluates the addition of the VEGF-R2 inhibitor ramucirumab (RAM) to FLOT for resectable patients (pts). Methods: This is a prospective, international, randomized, investigator-initiated phase II/III trial. Pts with resectable, Her2-negative, adenocarcinoma of the stomach and GEJ type II and III (≥ cT2 or cN+) were enrolled. Pts were randomized to 4 pre-and post-operative cycles of FLOT (docetaxel 50 mg/m²; oxaliplatin 85 mg/m²; leucovorin 200 mg/m²; 5-FU 2600 mg/m², q2w) alone (Arm A) or the same regimen with RAM 8mg/kg q2w, followed by 16 cycles RAM (Arm B, FLOT-RAM). Important endpoints of phase II (exploratory) were major pathological (complete and nearly complete) response, centrally assessed acc. to Becker criteria, R0-resection rate, overall survival (OS), disease-free survival (DFS) and safety. GEJ type I tumors and pts requiring trans-thoracic esophagectomy were excluded for safety reasons during the conduct of the study. Results: In total, 152 pts were analyzed within the intention to treat population. Baseline characteristics were similar between arms (male, 70%; median age, 60y; cT3/T4, 82%; cN+, 77%; GEJ, 45%). The rate of cancers with signet-ring cell component was at 45%. The FLOT-RAM arm included more unfavorable pts with T4 (8% vs. 5%), impaired ECOG PS of 1 (32% vs. 20%), and concomitant disease (86% vs. 76%). 92% of pts with FLOT as well as with FLOT-RAM completed the 4 pre- cycles. R0-resection could be achieved in 82% of pts with FLOT and 96% of pts with FLOT-RAM (p = 0.0093). The rate of major path response was similar in both arms and was 29% for FLOT and 26% for FLOT-RAM. Median DFS was slightly improved in pts with FLOT-RAM (32 months vs. 21 months), while median OS was similar in both treatment arms (FLOT 45 months, FLOT-RAM 46 months). Surgical morbidity was observed in 32% of pts with FLOT and 41% of pts with FLOT-RAM. Mortality at 60 days after surgery was 4.1% with FLOT and 2.8% with FLOT-RAM. There were bit more G≥3 adverse events with FLOT-RAM (76% vs. 92%). Conclusions: In this phase II trial, the addition of ramucirumab to perioperative FLOT significantly improved R0-resection rates and slightly prolonged DFS without an impact on path response or overall survival. FLOT-RAM is feasible and safe, when type I tumors are excluded. Clinical trial information: NCT02661971.
FOLFOX versus FOLFOX plus nivolumab and ipilimumab administered in parallel or sequentially versus FLOT plus nivolumab administered in parallel in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: A randomized phase 2 trial of the AIO.
Authors: Lorenzen Sylvie , Thuss-Patience Peter C. , Riera Knorrenschild Jorge , Goekkurt Eray , Dechow Tobias Nicolaas , Hofheinz Ralf-Dieter , Luley Kim Barbara , Ettrich Thomas Jens , Pink Daniel , Lindig Udo , Folprecht Gunnar , Schuch Gunter , Bitzer Michael , Bolling Claus , Homann Nils , Junge Sabine , Pauligk Claudia , Gaiser Timo , Goetze Thorsten Oliver , Al-Batran Salah-Eddin 
Published: June 2022

4043 Background: FOLFOX plus nivolumab (nivo) has become standard of care for first-line therapy of patients (pts) with esophagogastric adenocarcinomas. The aim of Moonlight trial is to generate signals for whether (a) dual checkpoint inhibition or (b) a triplet chemotherapy is beneficial in the context of nivolumab therapy in this setting. Methods: The AIO-STO-0417 trial (Moonlight) is a four-arm investigator-initiated trial. Pts were randomized to FOLFOX alone (Arm B) or FOLFOX plus nivo 240 mg; q2w and ipilimumab (ipi) 1 mg/kg; q6w administered in parallel (Arm A/A1) or sequentially (Arm A2) or pts were treated in a non-randomized fashion with FLOT plus nivo 240 mg; q2w (Arm C). PD-L1 expression was centrally assessed. Primary endpoint is progression-free survival (PFS). Results: The study completed enrollment with 260 pts. Arms A1/A2 and C started later and will be analyzed in Mar 2022 and presented at the meeting. The abstract, therefore, focuses on Arms A (n = 60) vs B (n = 60). Baseline characteristics were: median age 62.5y, GEJ, 55%, intestinal type, 36%. Forty-one percent had PD-L1 CPS≥1 (available in 79% of pts). Pts received a median of 10 and 9 cycles Arms A and B. Adverse events of grade 3/4 were seen in 86% for Arm A and 60% for Arm B, respectively, and serious adverse events (SAE) in 78% in Arm A and 50% in Arm B. Median follow-up was 9.7 mo. No difference in PFS (5.7 and 6.6 mo), OS (10 vs. 12 mo) or objective response rate (45% and 48%) was seen in Arms A and B, respectively. The results were similar in the PD-L1+ group. Conclusions: FOLFOX plus dual checkpoint inhibition administered in parallel is associated with an increase in toxicity but not activity. This portion of the moonlight trial does not generate a signal for further trials on FOLFOX plus nivo and ipi for adenocarcinoma of stomach and GEJ. Clinical trial information: NCT03647969.
Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced gastric cancer.
Authors: Kwon Minsuk , Kim Seung Tae , Hong Jung Yong , Kim Gahyun , Smith Simon , Mortimer Peter G. , LoembE Bienvenu , Dean Emma , Kang Won Ki , Lee Jeeyun 
Published: June 2022

4045 Background: Alterations in DNA damage response (DDR) and repair are associated with genomic instability and increased somatic tumor mutational burden, and modulating DNA repair using specific inhibitors is a promising strategy to boost the efficacy of cancer immunotherapy. Ceralasertib is an oral inhibitor of the serine/threonine protein kinase Ataxia Telangiectasia and Rad3 Related (ATR), which is crucial to the cell’s response to replication stress. Methods: This phase 2 trial was designed to evaluate the efficacy and safety of ceralasertib in combination with durvalumab in patients with advanced gastric cancer (AGC). The study drug regimen was ceralasertib 240 mg BD days 15 to 28 in a 28-day cycle in combination with durvalumab at 1500 mg day 1 every 4 weeks. The primary end point was overall response rate (ORR) by RECIST (v1.1). Exploratory biomarker analysis was performed using fresh tumor biopsies in all enrolled patients. Results: 31 patients (median no. of prior lines, 2; range, 2-5) were enrolled between Jul 2019 and Mar 2020. All enrolled patients had confirmed microsatellite stable tumors, 5 patients were EBV positive, and 24 patients were PD-L1 positive (CPS≥1). Two patients had received prior anti-PD-1 treatment. At the time of data cut-off (Dec 2020), 30 patients were evaluable for response: 7 partial responses (one patient with prior anti-PD-1 treatment), 11 stable disease, and 12 disease progression were observed. The ORR was 22.6%, DCR 58.1 %, median PFS 3.0 months (95% confidence interval (CI), 2.1-3.9), median duration of response 5.7 months (95% CI, 4.9-6.5), and median OS was 6.7 months (95% CI, 3.8-9.6). A subgroup of patients (n = 11) who with loss of ATM expression and/or high proportion of mutational signature attributable to homologous repair deficiency (sig. HRD) demonstrated significantly longer PFS than those (n = 12) who had intact ATM and low sig. HRD (5.60 vs 1.65 months, hazard ratio 0.13, 95% CI 0.045-0.39, long-rank P < 0.001). The most common adverse events of any grade were fatigue (n = 22, 71.0%), nausea (n = 20, 64.5%) and anorexia (n = 19, 61.3%), and the most common adverse events of grade 3 or more were anemia and thrombocytopenia (n = 11, 35.5% each). Conclusions: Ceralasertib in combination with durvalumab demonstrated promising anti-tumor activity with durable responses in refractory AGC. Clinical trial information: NCT03780608.
A biological network approach for mining target genes in EBV-positive gastric cancer.
Authors: Barra Williams Fernandes , Mourao Ronald Matheus da Silva , Silva Jessica Costa , Anaissi Ana Karyssa , Demachki Samia , Ishak Geraldo , Calcagno Danielle Queiroz , Moreira Fabiano Cordeiro , Assumpção Paulo Pimentel 
Published: June 2022

4056 Background: Epstein–Barr virus (EBV) discriminates a molecular group of gastric cancer (GC) that seems to have peculiar treatment responses and prognosis. Nevertheless, the gene expression pattern of such tumors needs additional investigations due to the heterogeneity of the tumor microbiome and the small number of studied samples. Biological networks analysis of gene expression patterns, in this complex scenario, might lead to the discovery of putative "hubs" genes, supposed to have important roles in cancer occurrence and consequences. This study aimed to explore the biological value of hub genes in EBV-positive gastric cancer patients. Methods: Fresh tumor samples collected during gastrectomies from individuals with gastric adenocarcinoma (n = 41, 59.0±11.0 years) were included. Gene expression of tumor samples was evaluated in the Illumina sequencing platform. A weighted correlation network analysis (WGCNA) was used to find highly correlated gene patterns. The gene's correlation to EBV status was also explored, including eight EBV positive and 33 EBV negative cases. Gene Ontology (GO) term enrichment was performed to predict the involved biological functions. The expression level of the hubs gene was measured by differential expression analysis. Results: A gene cluster including 636 genes able to discriminate EBV status (ρ = 0.65, p-value = 6e-05) was identified. GO analysis (padj <0.05) showed that this cluster of genes is related to T cell activation, regulation of immune effector process, and response to the biotic stimulus. In this cluster, 54 genes were differentially expressed (log2FoldChange (FC) >1 and padj< 0.05). The top hub genes were LAPTM5, PTPN22, C1QA, CD84, CD53, ADAMDEC1, DPYD, TYROBP, RARRES3, IFI16, CYBB, CMKLR1, PHF21A, GPNMB, and C1QC, according to cluster significance and gene expression level. In positive EBV-GC, all hub genes were overexpressed (FC 1.24 - 2.49) (Table). The average area under the ROC curve (AUC) for hub genes was 0.9 (0.84-0.99). Overexpression of LAPTM5 (p-value = 0.013) and DPYD (p-value =0.0065) and low expression of ADAMDEC1 (p-value = 0.05) were strongly related to poor survival outcome. Conclusions: EBV-positive status was correlated with overexpression of hub genes. Genes found in this investigation have high sensitivity and specificity to discriminate EBV status in GC. Some of them seem to be related to patients' survival, opening an avenue for future scientific explorations in this field. The biological network's approach may be a promising tool for mining target genes for potential clinical applications. [Table: see text]
Comparison of four clinical prognostic scores in patients with advanced gastric and esophageal cancer.
Authors: Ma Lucy Xiaolu , Espin-Garcia Osvaldo , Bach Yvonne , Aoyama Hiroko , Allen Michael J , Wang Xin , Darling Gail Elizabeth , Yeung Jonathan , Swallow Carol Jane , Brar Savtaj Singh , Veit-Haibach Patrick , Kalimuthu Sangeetha , Wong Rebecca KS , Chen Eric Xueyu , O'Kane Grainne M. , Jang Raymond Woo-Jun , Elimova Elena 
Published: June 2022

4057 Background: While several clinical scoring systems exist to aid prognostication and patient (pt) selection for clinical trials in oncology, none are standardly used. We compared the ability of four prognostic scores to predict overall survival (OS) in pts with advanced gastric and esophageal (GE) cancer. Methods: Pts with advanced (unresectable or metastatic) GE cancer receiving first-line palliative-intent systemic therapy at the Princess Margaret Cancer Centre from 2007 to 2020 were included. High prognostic risk pts were identified using four scoring systems: Royal Marsden Hospital (RMH), MD Anderson Cancer Centre (MDACC), Gustave Roussy Immune Score (GRIm-S) and MD Anderson Immune Checkpoint Inhibitor (MDA-ICI) score. OS was estimated using the Kaplan-Meier method and compared between risk groups (high vs. not-high) for each scoring system using the log-rank test. Cox proportional hazards models were used to analyze the association between each prognostic score and OS, adjusting for baseline clinical factors. Harrell’s c-index was used to evaluate predictive discrimination of the models. Time-dependent AUCs were used to measure predictive ability for early death (within 90 days). Results: In total, 451 pts with advanced GE cancer were included. The median age was 59 years, 68% were male, 51% had ECOG status 0-1, 63% presented with de novo metastatic disease. The proportion of pts categorized as high risk was: RMH 25% (N=113), MDACC 13% (N=95), GRIm-S 24% (N=109), MDA-ICI 26% (N=117). In all scoring systems, high risk pts had significantly shorter OS (median OS 7.9 versus 12.2 months for RMH high vs. low risk, p<0.001; 6.8 vs. 11.9 months p<0.001 for MDACC; 5.3 vs. 13 months p<0.001 for GRIm-S; 8.2 vs. 12.2 months p<0.001 for MDA-ICI). On multivariable analysis, each prognostic score was significantly associated with OS (Table). The GRIm-S had the highest predictive discrimination (c-index 0.645 [0.612-0.678]) and highest predictive ability for early death (AUC 0.754 [0.675-0.832]). Conclusions: All four prognostic scoring systems compared had reasonable accuracy in predicting OS for patients with advanced GE cancer. The higher accuracy for predicting early death may render the GRIm-S as preferable. These tools can aid oncologists in discussions about prognosis, therapeutic decision-making and patient selection for clinical trials.[Table: see text]
Outcomes in patients undergoing curative surgery for gastric cancer by facility type and socioeconomic factors: An analysis of the National Cancer Database (NCDB).
Authors: Alqahtani Ali , Dykes Kaitlyn , Yin Chao , Geng Xue , Wang Hongkun , Weinberg Benjamin Adam 
Published: June 2022

4066 Background: Surgical and medical treatment for resectable gastric cancer is complex, and multidisciplinary team involvement is essential to provide optimal treatment outcomes. However, socioeconomic disparities influence the quality of medical care patients receive. We hypothesized that facility type, median income, insurance type, and location would impact patients' overall survival (OS). Methods: In a retrospective analysis of NCDB data, we identified patients with stage II and III gastric adenocarcinoma who underwent curative-intent surgical resection and chemotherapy between 2004-2018. Demographic and socioeconomic factors were studied, including treatment facility type, median household income, urban/rural residence, and insurance status. Multivariate Cox proportional hazard model was used to evaluate the impact of these variables on overall survival (OS). The Kaplan-Meier method was used to estimate OS. Log-rank test was used to compare the OS between groups. Results: Based on the criteria listed above, 36,318 patients were identified: 76.3% were Caucasian, 14.4% black, 7.2% Asian, and 2.0% other. 56.4% lived in large metropolitan areas (LM), 29.9% in small/medium metropolitan areas (SM), and 14.2% in rural areas (RA). Patients who were treated in academic/research programs had significantly better OS (mOS 40.5 months) compared to integrated-network cancer programs (mOS 34.0 months, HR 0.897, p < 0.0001), comprehensive community cancer programs (mOS 31.0 months, HR 0.89, p < 0.0001), and community cancer programs (mOS 29.5, HR 0.881, p < 0.0001). Patients from LM had better OS compared to those from SM and RA (mOS 39.0, 32.1, 29.9 months respectively, p < 0.0001). Privately insured patients had improved OS compared to Medicare-insured patients (mOS 40.8 vs 29.7 months, HR 0.758, p < 0.0001). Higher annual income (≥ $63,000) was positively associated with improved OS (p < 0.0001). Conclusions: Outcomes for patients with gastric cancer treated with surgery and chemotherapy are strongly influenced by socioeconomic variables, including place of residence, treatment setting, insurance, and income level. We highlight improved outcomes in patients who resided in LM and were treated at academic/research centers. A potential hypothesis for this trend is increased access to specialized, multidisciplinary care and clinical trials.