bluuebunny/crossref_metadata_2025_split huggingface dataset:
Management of nausea and vomiting (N/V) following first-line (1L) zolbetuximab + chemotherapy treatment in claudin-18.2 (CLDN18.2)+, HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Analysis from the phase 3 SPOTLIGHT and GLOW studies.
Authors: Shitara Kohei , Pophale Rupesh , Matsangou Maria , Park Jung Wook , Oh Mok , Bhattacharya Pranob P. , Ranganath Radhika 
Published: January 2024

372 Background: The phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies showed clinically meaningful, statistically significant improvement in PFS and OS using 1L zolbetuximab + chemotherapy vs placebo (PBO) + chemotherapy in patients (pts) with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma. N/V were the most common treatment-emergent adverse events (TEAEs) reported in the zolbetuximab arm of these studies. We report an analysis of the incidence and management of N/V in SPOTLIGHT and GLOW. Methods: In SPOTLIGHT, pts (N = 565) were randomized 1:1 to zolbetuximab + mFOLFOX6 vs PBO + mFOLFOX6. In GLOW, pts (N = 507) were randomized 1:1 to zolbetuximab + CAPOX vs PBO + CAPOX. In both studies, neurokinin-1 receptor blockers (NK-1), selective serotonin receptor blockers (5-HT3), and other prophylactic antiemetic regimens were recommended to prevent and mitigate N/V per institutional care and guidelines. Results: A total of 279 pts in SPOTLIGHT and 253 pts in GLOW received zolbetuximab + chemotherapy. In SPOTLIGHT and GLOW combined, nausea occurred in 58% vs 18% of pts, and vomiting occurred in 43% vs 15% of pts in the first vs second zolbetuximab infusions, respectively; lower incidences of N/V were observed thereafter. During the first zolbetuximab infusion, the first episode of N/V occurred within 1 hour (median time, 48.0 min in SPOTLIGHT and 56.5 min in GLOW). Antiemetic usage and associated N/V rates are presented in the Table. The 96 pts in SPOTLIGHT and 52 pts in GLOW who had infusion modifications in cycle 1 due to TEAEs had numerically higher infusion rates than pts without infusion modifications; 85% of these modifications in SPOTLIGHT and 79% in GLOW were due to N/V. Zolbetuximab was discontinued within the first 9 weeks in 11 and 7 pts in SPOTLIGHT and 6 and 4 pts in GLOW due to nausea or vomiting, respectively. Conclusions: In SPOTLIGHT and GLOW, slower infusion rate and use of antiemetic combinations may have helped to mitigate N/V. These strategies will be important to support continued treatment and allow pts to achieve maximum clinical benefit with zolbetuximab + chemotherapy. Clinical trial information: NCT03504397 and NCT03653507 . [Table: see text]
Genomic characterization of unresectable/recurrent early-onset gastric cancer by comprehensive genomic profiling tests.
Authors: Matsuguma Kunihito , Hirano Hidekazu , Fujii Hiroyuki , Shiraishi Kouya , Shoji Hirokazu , Hirose Toshiharu , Okita Natsuko Tsuda , Takashima Atsuo , Koyama Takafumi , Kato Ken ,   Division of Genome Biology, National Cancer Center Research Institute
Published: January 2024

393 Background: The incidence of early-onset gastric cancer (EOGC: age ≤45 years) is showing an increasing trend. Although EOGC has unique clinicopathological features compared with late-onset gastric cancer (LOGC: age>45 years), disparities in genetic alterations (GAs) between EOGC and LOGC are not fully understood in patients with unresectable/recurrent GC. We aim to investigate to elucidate unique GAs in unresectable/recurrent EOGC. Methods: We retrospectively reviewed data on patients with unresectable/recurrent GC who underwent comprehensive genomic profiling (CGP) tests and were registered as “Stomach adenocarcinoma (STAD)” cases in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan from June 2019 to April 2023. CGP tests were conducted by NCC Oncopanel System (NOP) or FoundationOne CDx (F1). We examined somatic GAs, microsatellite instability (MSI) status, and tumor mutation burden (TMB) of GC. TMB-high was defined as ≥10 mutations/Mb. Actionable GAs were counted if they were classified as “pathogenic/oncogenic” or “likely pathogenic/likely oncogenic variants”. Druggable GAs are actionable GAs that can be treated with drugs approved for GC or other types of cancer or have shown efficacy in clinical trials for either GC or different types of cancer. Results: In total,112 patients with EOGC and 810 patients with LOGC were identified. In EOGC group, most common actionable GAs included TP53 (59.8%), ARID1A (17.0%), KRAS (15.2%), CDKN2A (11.6%), FGFR2 (11.6%), and CDH1 (9.8%). Compared to the LOGC group, the EOGC group exhibited a significantly higher frequency of actionable GAs in FGFR2(11.6% vs. 4.6%, P=0.0059), CDH1 (9.8% vs. 4.1%, P=0.015) and BAP1 (3.6% vs. 0.6%, P=0.016). On the other hand, the EOGC group showed a significantly lower frequency of actionable GAs in ERBB2(7.1% vs. 20.1%, P=0.0004), CCNE1 (4.5% vs. 19.0%, P=0.0001), and AURKA (0% vs. 7.9%, P=0.0003) compared with the LOGC group. In the EOGC group compared to the LOGC group, the proportions of MSI-high were 0.9% vs. 2.6% (P=0.345), and those of TMB-high were 4.5% vs. 11.6% (P=0.011). Excluding ERBB2 amplification, druggable GAs in the ECOG group included FGFR2 amplification (9.8%), MET amplification (4.5%), EGFR amplification (1.8%), KRAS G12C mutation (1.8%), and MDM2 amplification (0.9%). Conclusions: Among unresectable/recurrent GC population, EOCG has displayed distinct genetic profiles of GAs compared to LOGC. CGP tests may be useful in expanding treatment opportunities for patients with unresectable/recurrent EOGC.
Atezolizumab plus bevacizumab (A+B) in patients with unresectable hepatocellular carcinoma (uHCC): Real-world experience from a US community oncology network.
Authors: Cosgrove David , Tan Amie , Osterland Andrew , Hernandez Sairy , Ogale Sarika , Mahrus Sami , Murphy John , Wilson Thomas W , Patton Gregory A. , Loaiza-Bonilla Arturo , Singal Amit G. 
Published: January 2024

447 Background: A+B is the standard first-line (1L) treatment for uHCC based on the IMbrave150 trial, which demonstrated superior efficacy over sorafenib with longer median overall survival (19.2 vs 13.4 months) and progression-free survival (6.8 vs 4.3 months) among patients with Child Pugh (CP) A cirrhosis. Evidence about A+B use and outcomes in routine clinical practice, including in patients with impaired liver function, remains limited. Methods: This retrospective observational study included adult patients who initiated 1L A+B for uHCC within The US Oncology Network between 1/1/2019 and 8/31/2022 (followed through 11/30/2022) using structured and unstructured electronic health records (EHR) based data. CP classes were reported by physicians or derived from risk factors. Kaplan-Meier methods were used to assess real-world overall survival (rwOS) and progression-free survival (rwPFS) from initiation of A+B. Exploratory subgroup analyses were conducted by CP class, albumin-bilirubin (ALBI) grade, liver disease etiology, and race/ethnicity. Results: We identified 374 patients with uHCC who initiated 1L A+B during the study period. Compared with patients enrolled in IMbrave150 (n=336), those treated with A+B in clinical practice were older (median age: 69 vs 64 years), had worse liver function (CP A: 61% vs 100%; ALBI Grade >1: 66% vs 43%), and had poorer performance status (ECOG PS>1: 18% vs 0%). At a median follow-up of 5.6 months, 78% (n=293) had discontinued treatment. Among them, 57% discontinued was progression and 4% discontinued due to toxicity alone. Median rwOS was 13.2 months (95%CI: 9.5–15.9) and median rwPFS was 6.4 months (95%CI: 5.1–7.7). Subgroup results are shown (Table). Conclusions: In community oncology settings, 1L A+B demonstrates effectiveness in diverse patient cohorts, including those with impaired liver function, non-viral liver disease, and racial/ethnic minorities. Predictive biomarkers can help identify subgroups who may most benefit from 1L A+B. [Table: see text]
Second-line regorafenib in patients (pts) with unresectable hepatocellular carcinoma (uHCC) after progression on first-line atezolizumab plus bevacizumab (Atezo-Bev): Phase 2 REGONEXT trial.
Authors: Yoo Changhoon , Cheon Jaekyung , Ryoo Baek-Yeol , Ryu Min-Hee , Kim Hyung-Don , Kim Kyu-Pyo , Kang Beodeul , Chon Hong Jae , Finn Richard S. 
Published: January 2024

477 Background: Atezo-Bev is the standard first-line therapy against uHCC. However, there is no globally established subsequent treatment after failure on first-line Atezo-Bev. We aimed to evaluate the efficacy and safety of second-line regorafenib in uHCC pts who progressed on first-line Atezo-Bev. Methods: This is a phase II investigator-initiated trial involving 2 academic centers in Korea. Key eligibility criteria include confirmed diagnosis of HCC; prior treatment with Atezo-Bev at least ≥ 2 cycles; Child-Pugh A; ECOG performance status 0-1. Eligible patients received regorafenib 160 mg once daily 3 weeks on/1 week off until progressive disease or intolerable toxicity. The primary endpoint is progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR) according to the RECIST v1.1, overall survival (OS) and treatment-related adverse event (TRAE). Results: Total 40 pts were recruited from Dec 2021 to May 2023. Pts characteristics were as follows: median age of 56 (range, 36-81); hepatitis B (77.5%), hepatitis C (10.0%), non-viral (12.5%); BCLC C stage (97.5%); and AFP ≥ 400 ng/ml (40.0%). As of the date of data cut-off (15 Aug 2023), the median follow-up duration was 6.6 mo (95% CI, 5.0-8.2). The median PFS was 3.5 mo (95% CI, 3.0-4.0). ORR and DCR were 10.0% and 82.5%. The median OS was 9.7 mo (95% CI, 8.3-11.1) and 6-month OS rate was 55.0%. The median OS since the start of prior Atezo-Bev was 16.6 mo (95% CI, 11.9-21.3). When stratified according to the duration of prior Atezo-Bev (<4 cycles [n=10] vs. ≥4 cycles [n=30]), pts with ≥4 cycles of prior Atezo-Bev showed better median OS (not reached vs 3.6 mo; p=0.001) and ORR (13.3% vs 0%; p=0.009), while there was a trend for better median PFS (3.8 mo vs 2.5 mo; p=0.107). The most common grade 3-4 TRAEs were thrombocytopenia (5.0%), palmar-plantar erythrodysesthesia (2.5%), and fatigue (2.5%). Conclusions: Regorafenib was effective as second-line therapy in uHCC pts who progressed on first-line Atezo-Bev. Efficacy and safety outcomes from our study were consistent with those observed in the pivotal phase 3 RESORCE trial which included sorafenib-tolerated/progressed pts. Clinical trial information: NCT05134532 .
The efficacy and safety of transarterial chemoembolization combined with cadonilimab and lenvatinib for unresectable hepatocellular carcinoma: A phase II clinical trial.
Authors: Liang Guo , Gu Shanzhi , Guo Yabing , Li Hailiang , Liu Jingfeng , Liu Jibing , Huang Ming , Zou Yinghua , Huang Luke , Zhang Yangyang , Liu Ting , Liu Wei , Wang Zhongmin , Li Baiyong , Xia Yu 
Published: January 2024

478 Background: Immune-checkpoint inhibitors, in combination with targeted therapy and local therapy, have been developed as promising treatment for unresectable hepatocellular carcinoma (uHCC) of intermediate stage. This study aimed to assess the efficacy and safety of cadonilimab(a tetravalent PD-1/CTLA-4 bispecific antibody) plus Lenvatinib (Len) and transarterial chemoembolization (TACE) in the treatment of intermediate HCC. Methods: This open label, multicenter phase II trial enrolled patients with histologically or clinically confirmed intermediate uHCC to receive TACE followed by cadonilimab 10mg/kg every 3 weeks plus Len until disease progression or intolerable toxicity. The primary endpoint was progression free disease (PFS) according to RECIST v1.1. The secondary endpoint includes safety, overall survival (OS), PFS according to modified RECIST (mRECIST), and objective response rate (ORR), disease control rate (DCR) and duration of response (DoR) by both RECIST v1.1 and mRECIST. Results: From June 2022 to May 2023, 78 patients were screened and 60 patients enrolled. As of August 15, 2023, 60 patients received at least once cadonilimab and the median duration of follow-up was 5.1 months. The average number of TACE procedures per patient was 1.70. The median PFS and OS were not reached, while the 6-month PFS rate was 77.1% (95% CI, 60.8-87.3) per RECIST v1.1 and 75.6% (95% CI, 59.5-86.0) per mRECIST. The ORR and DCR were 35.0% (95% CI, 23.1-48.4) and 96.7% (95% CI, 88.5-99.6) according to RECIST v1.1 and 85.0% (95% CI, 73.4-92.9) and 95.0% (95% CI, 86.1-99.0) according to mRECIST. 9 patients (15.0%) achieved complete response per mRECIST. The incidence of grade≥3 treatment-related adverse events (TRAEs) was 68.9%. The incidence of grade≥3 adverse events related to cadonilimab was 45.9%.The most common TRAEs included thrombocytopenia, aspartate aminotransferase increased, and alanine aminotransferase increased. Conclusions: Combination of TACE and cadonilimab plus len showed promising efficacy and manageable toxicity in intermediate uHCC. Benefit of control on tumor progression after TACE and lasting survival can be expected. Clinical trial information: NCT05319431 . [Table: see text]
Phase II study of atezolizumab and bevacizumab combination therapy for patients with advanced hepatocellular carcinoma who previously received systemic treatment.
Authors: Terashima Takeshi , Yamashita Tatsuya , Yamamoto Makoto , Yanagi Masahiro , Nakagawa Hidetoshi , Seki Akihiro , Nio Kouki , Arai Kuniaki , Toyama Tadashi , Yamashita Taro 
Published: January 2024

495 Background: Atezolizumab plus bevacizumab (AteBev) has been established as a standard of care for patients with untreated advanced hepatocellular carcinoma (HCC). Lenvatinib was once the first choice and remains a treatment option for such patients; however, no subsequent treatment to date has proven a similar level of efficacy. This study aimed to evaluate the efficacy of AteBev in patients with HCC previously treated with lenvatinib. Methods: In this single-center, open-labeled, single-arm, phase II study, patients with advanced HCC previously treated with at least one systemic treatment were enrolled to receive 1,200 mg of atezolizumab and 15 mg/kg of bevacizumab intravenously every 3 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, tumor control rate, and frequency of adverse events. The threshold and expected PFS were 3 months and 6.8 months, respectively, at a one-sided significance level of 0.05, and statistical power of 80%. Based on these data, the number of patients required was estimated to be 26. Results: Among 29 patients enrolled between November 2020 and October 2022, 26 previously treated with lenvatinib were included in the primary efficacy analysis. Median PFS was 9.70 [90% confidence interval (CI), 5.10–14.24] months. Median overall survival was 17.23 (90% CI, 3.18–27.85) months, and response rate and tumor control rate were 34.6% and 69.2%, respectively. Severe adverse events were observed in six patients (23.1%), six patients (23.1%) discontinued treatment because of immune-related adverse events or treatment-refractory ascites, and 10 patients (38.5%) required the withdrawal of treatment mainly because of proteinuria. There were no treatment-related deaths. Conclusions: AteBev for patients with advanced HCC previously treated with lenvatinib had a comparable efficacy to that in patients with no prior treatment. It may therefore be a treatment option for patients with advanced HCC previously treated with lenvatinib. Clinical trial information: jRCT1041200068 .
Genomic predictors of sensitivity to chemotherapy and immunotherapy in cholangiocarcinoma.
Authors: Patel Riya Jayesh , Rosario Spencer , Sonti Sahithi , Kapoor Ankita , Vadehra Deepak , Mukherjee Sarbajit , Thanikachalam Kannan , Iyer Renuka V. 
Published: January 2024

540 Background: Cholangiocarcinoma (CCA) has seen a surge immunotherapy (IO) use. Data on the sensitivity and resistance to chemotherapy and IO in CCA is limited, making it difficult to identify predictive biomarkers for guiding treatment. We hypothesize that transcriptional signatures differentiating PD-L1 high from PD-L1 low patients (pts), can be leveraged to better understand IO sensitivity. These signatures could potentially facilitate personalized treatment strategies and mitigate therapeutic resistance. Methods: We explored transcriptomic signatures related to chemotherapy and IO sensitivity in the CCA cohort of The Cancer Genome Atlas (TCGA-CHOL). We divided the pts (n=36) into 2 groups based on PD-L1 (CD274) expression levels. Pts were designated as PD-L1 high (n=11) if PD-L1 ≥ average PD-L1 expression, and PD-L1 low (n=25) if PD-L1 ≤ average expression PD-L1in the cohort. Transcriptional dysregulation was assessed by comparing transcriptional profiles of the 2 groups. Differential expression analysis, using Limma, was utilized for Gene Set Enrichment Analysis (GSEA), to assess the predicted function of transcriptional dysregulation that occurs between the 2 groups. Immune deconvolution by using the Tumor IMmune Estimation Resource (TIMER) deconvolution software to assess differences in immune infiltration and resulting scores from this analysis were used to assess how immune cell population estimates correlated with immune factors, like PD-L1 expression. Results: GSEA revealed PD-L1 low pts showed significant alterations in metabolic pathway genes that regulate cholesterol, amino acid transport and cellular respiration. As expected, GSEA revealed alterations to immune cell pathways associated with PD-L1 expression, assessed using TIMER revealed several significant correlations between immune cell deconvolution scores: CD4+ and CD8+ T-Cell (R=-0.35, p=0.02), CD8+ and neutrophils (R=0.42, p=0.009), and CD8+ and myeloid dendritic cells (R=0.3348, p=0.04). We noted significant correlations between immune cells deconvolution scores with PD-L1 expression, including PD-L1 and B Cells (R=0.54, p=0.0005), macrophages (R=0.41, p=0.01), CD8+ T Cells (R=0.43, p=0.008), neutrophils (R=0.56, p=0.0003), and myeloid dendritic cells (R=0.48, p=0.002). Significant differences in immune deconvolution scores of CD8+ T Cells, macrophages, neutrophils were noted between PD-L1 high and low pts. Conclusions: PD-L1 high pts with CCA exhibit expected differential enrichment of immune signatures. Notably, we report for the first time that CCA PD-L1 low patients uniquely enrich for differential metabolic signatures. This could lay the groundwork for understanding mechanisms that underlie IO response differences, provide valuable insights if confirmed in IO treated cohorts and serve as evidence for the utility of metabolism-targeted therapies to overcome therapeutic resistance in CCA.
Assessment of hematological toxicity in patients with advanced neuroendocrine tumors and extensive/innumerable bone metastases undergoing lutetium-177 DOTATATE treatment.
Authors: Mosalem Osama M , Coston Tucker , Pai Tanmayi , Sonbol Bassam Bassam , Parent Ephraim E. , Young Jason R. , Johnson Geoffrey , Kendi Ayse T. , Halfdanarson Thorvardur Ragnar , Starr Jason S. 
Published: January 2024

592 Background: The introduction of peptide receptor radionuclide therapy (PRRT) using Lutetium-177 (177Lu) DOTATATE has led to a paradigm shift in the treatment of neuroendocrine tumors (NETs). Hematological toxicity is a well-recognized adverse effect (AE) of 177Lu DOTATATE. Most cytopenias are transient, with an estimated incidence of 10-25%, typically mild to moderate in severity (grade G1-2). The most dreaded AE of PRRT is therapy-related myeloid neoplasm (t-MN), with an estimated 2-8% incidence and a higher incidence reported in patients who also received prior chemotherapy. We sought to evaluate the hematological safety of 177Lu PRRT in the setting of NETs with extensive (i.e., innumerable) bone metastases. Methods: We retrospectively reviewed the medical records of all Mayo Clinic patients (pts) with extensive/innumerable osseous metastases, defined as >50% skeletal involvement by positron emission tomography (PET) DOTATATE, who were treated with 177Lu DOTATATE. Pts characteristics and laboratory results were collected before, during, and after 177Lu DOTATATE treatment. Hematotoxicity was graded according to the NCI-CTCAE v5. Results: Out of 27 pts, 13(48%) developed cytopenia(s) of any grade after treatment with one or more cycles of 177Lu DOTATATE. In total, there were 13(48%) pts with anemia, 13(48%) with thrombocytopenia, and 6(22%) with neutropenia. Six (22%) pts had severe hematological toxicity (G3-4). Twelve months post-PRRT, 7(26%) pts continued to experience cytopenia(s) of any grade, of whom 4(15%) had G3-4 hematotoxicity. One pt developed t-MN, and two pts had myelophthisis on bone marrow biopsy from infiltrating NET. 16(59%) pts received cytotoxic chemotherapy before PRRT, and 7(25.9%) developed subsequent cytopenia(s). Overall, 15(55%) pts completed four cycles, while 3 pts didn’t complete four cycles of 177Lu DOTATATE due to hematotoxicity. Conclusions: Pts with advanced NETs and extensive/innumerable bone metastases treated with PRRT could be at higher risk for myelosuppression than historical controls. Our study highlights the importance of carefully monitoring and assessing hematological parameters in pts being considered for 177Lu DOTATATE with extensive/innumerable bone metastasis. [Table: see text]
Risk of second cancers in long term survivors of neuroendocrine tumors of the large intestine.
Authors: Fort Callie , Surapaneni Chaitra , Surapaneni Rakesh 
Published: January 2024

600 Background: There is an increasing incidence of neuroendocrine tumors (NET) of the colon and rectum likely related to increased screening colonoscopy and availability of better diagnostics. Most of these tumors identified during screening are low grade early-stage tumors with high cure rates. Data on long term risk of recurrence of NET and other second cancers is lacking. We studied the incidence rates of all second malignancies in survivors of NET of the colon and rectum. Methods: We analyzed data from the Surveillance, Epidemiology and End Results (SEER), Research Data 17 Registries, Nov 2022 Sub (2000-2022) to determine the risk of second malignancies in patients with an initial cancer diagnosis of NET of the colon and rectum. With these criteria we had overall 17,907 patients and 157,720 patient years of follow up. The relative risk of subsequent malignancies is reported as a standardized incidence ratio (observed incidence [O]/expected incidence [E]). Incidence ratios are analyzed over time from initial diagnosis to assess long term risk. Results: Survivors of NET of the large intestine are at highest risk of malignancy of the rectum (O/E: 6.4, CI: 7.26 - 5.61, N= 239) and this increased risk of rectal cancer persists even 10 years after the initial diagnosis (0/E: 3.8, CI: 5.37- 2.6, N= 32). There is no increased risk of cancer of the colon excluding rectum (O/E: 0.98, CI: 1.18-0.81, N= 114). Even after 10 years from diagnosis there is increased risk of second cancers for NET of the Colon (O/E: 1.28, CI: 1.55-1.06, N=110) and NET of the Rectum (O/E: 1.12, CI: 1.23- 1.02, N= 433). There is also increased incidence of small intestine cancer (O/E: 2.92, CI: 4.17- 1.97, N=30), Prostate cancer (O/E: 1.28, CI: 1.41- 1.15, N=400), Kidney and renal pelvis cancer (O/E: 1.53, CI: 1.86 -1.25, N= 104), Thyroid cancer (O/E: 1.63, CI: 2.12-1.23, N= 55) and Nodal Non-Hodgkins Lymphoma (O/E: 1.34, CI: 1.71-1.03, N=64). Conclusions: Survivors of NET of the large intestine are at risk of developing subsequent malignancies. The information presented may help physicians in effectively monitoring survivors for second cancers at various timeframes from their initial diagnosis.