bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of organ preservation program using short-course radiation and FOLFOXIRI for rectal cancer (SHORT-FOX).
Authors: Pollom Erqi L. , Fisher George A. , Shelton Andrew , Johnson Tyler Paul , Chen Christopher , Jackson Scott , Shaheen Shagufta , Holden Thomas , Bien Jeffrey , King Daniel , Morris Arden M. , Kin Cindy , Dawes Aaron , Kirilcuk Natalie , Gahagan John , Vitzthum Lucas , Sheth Vipul , Brown Eleanor , Pratapneni Aniket , Chang Daniel Tandel
Published: June 2024

3600

Background: Patients (pts) with rectal cancer who achieve a clinical complete response (cCR) after neoadjuvant therapy may be safely observed and spared the long-term sequela of total mesorectal excision (TME). We hypothesized that a novel neoadjuvant regimen (short-course radiation with boost and FOLFOXIRI chemotherapy) would achieve higher cCR rates than historical controls. Methods: We conducted a single-arm, phase II study of short-course radiation followed by FOLFOXIRI for pts with >T2N0 or low T2N0M0 rectal adenocarcinoma (NCT04380337). Pts underwent radiation (25 Gy/5 fractions + 5 Gy/1 fraction boost) followed by 8 cycles of FOLFOXIRI. Pts were assessed for primary endpoint (cCR) at 8 weeks following chemotherapy. Those who achieved a cCR or near cCR were surveilled. cCR required no tumor on MRI, endoscopy, and if applicable, digital rectal exam. A Simon 2-stage design addressed our primary objective, with interim analyses for futility and toxicity. Assuming a one-sided type 1 error of 0.1, power of 0.9, a null cCR of 0.2 versus an alternate cCR of 0.4, our sample size was 37 pts. Results: Between May 2020 and April 2023, 37 pts enrolled (Table). 25 pts (67.5%) had at least one high risk feature (cT4, extramural vascular invasion [EMVI], N2, threatened circumferential resection margin [CRM], positive lateral node). All pts completed radiation; 32 pts (86.5%) completed all 8 cycles of chemotherapy. Criteria for futility and safety were met at interim analysis. At primary outcome assessment, 9 (24.3%) pts achieved a cCR and 8 (21.6%) pts achieved a near cCR. 3 pts who initially had a cCR developed local regrowth and underwent TME. Of the pts who had a near cCR, 5 developed local regrowth and underwent TME while 3 pts achieved delayed cCR. Serious adverse events occurred in 5 (13.5%) pts; 1 patient had non-hematologic grade 4 toxicity at least possibly related to treatment. There were no treatment-related deaths. The12-month TME-free survival for all patients was 37.2%, and for patients with T3 and T4 tumors was 44.3% and 12.5%, respectively. Conclusions: Short-course radiation followed by FOLFOXIRI was feasible and safe. In this high-risk cohort of pts with rectal cancer, 24.3% of pts had a cCR at time of primary assessment. Clinical trial information: NCT04380337 . [Table: see text]
T cell receptor and immune gene expression pharmacodynamics for durvalumab monotherapy and in combination with tremelimumab or bevacizumab in unresectable hepatocellular carcinoma (uHCC).
Authors: Kelley Robin Kate , Lee Young S , Conway James , Kurland John F , Negro Alejandra , McCoon Patricia
Published: June 2024

4022

Background: Study 22 (NCT02519348), a Phase 2 trial of immune checkpoint inhibitor (ICI) monotherapy and combination regimens in uHCC, showed higher rates of objective response (ORR) with STRIDE (Single Tremelimumab [T] Regular Interval Durvalumab [D]) or D plus bevacizumab (B) than with D (1,2). Pharmacodynamic analyses showed that improved efficacy with STRIDE versus D was associated with increased expansion of T cell clones at the end of cycle 1 (C1) versus D (3). We performed further T cell clone analyses to include D+B and compared gene expression signatures (GES) associated with each treatment arm to explore commonalities and differences in mechanistic biomarkers underpinning the efficacies associated with STRIDE and D+B. Methods: Participants (pts) with uHCC and no prior ICI therapy received STRIDE (T 300 mg + D 1500 mg [1 dose during C1] then D 1500 mg once every 4 weeks [Q4W]), T75+D (T 75 mg + D 1500 mg Q4W [4 doses] then D 1500 mg Q4W, D (1500 mg Q4W), T (750 mg Q4W [7 doses] then Q12W), or D+B (D 1120 mg + B 15 mg/kg Q3W). DNA and RNA were isolated from PAXgene-preserved whole blood collected at baseline and at the end of C1. CDR3 sequencing of T cell receptor β using the immunoSEQ Assay (Adaptive Biotechnologies, Seattle, WA) and RNA sequencing (Q Squared Solutions, Morrisville, NC) were performed. ImmunoSeq results and immunologic gene expression changes were reported with ORR across treatment arms. Results: ImmunoSeq did not show significant differences in baseline T cell clonality across treatment arms. In contrast to STRIDE versus D, the number of expanded T cell clones at the end of C1 for D+B versus D was unchanged, and no association between expanded T cell clones and ORR was observed (Table). While increases in Type I and II interferon and mitotic GES were seen for both STRIDE and D+B, more changes in immune-related peripheral GES, with greater magnitude of change, were associated with STRIDE. Significant changes in CD8 T cell, M1 macrophage, and Treg GES were only observed for STRIDE. Conclusions: While STRIDE and D+B both had higher ORRs than D monotherapy in uHCC, only STRIDE was associated with an increased expansion of T cell clones versus D. This, in addition to the differences in magnitude and type of GES changes, suggest that STRIDE and D+B have distinct and potentially complementary mechanisms of action. 1. Kelley, et al. J Clin Oncol 2021. 2. Lim, et al. J Clin Oncol2022, A436. 3. McCoon, et al. J Clin Oncol2021, A4087. Clinical trial information: NCT02519348 . [Table: see text]
Non-colorectal GI malignancies in the young: Incidence trends, demographic disparities, and survival analysis.
Authors: Vadehra Deepak , Advani Shailesh M , George Anthony , Attwood Kristopher , Brown Timothy J , Siromoni Beas , Sonti Sahithi , Mukherjee Sarbajit
Published: June 2024

4023

Background: The incidence of gastrointestinal (GI) cancers is rising within the younger populations. Previously, we have detailed the increasing incidence of colorectal cancer (CRC) in the adolescent/young adult (AYA) population, defined as 15-39 years old. In this analysis, we seek to further describe incidence, mortality, and demographic differences in the AYA population for non-CRC GI malignancies compared to their older counterparts (≥50 years old). Methods: We queried the Surveillance, Epidemiology, and End Results Program (SEER) database from 2000-2020. The demographic, clinical, and secondary cancer characteristics were summarized in the overall sample (and within racial subgroups) by disease site. The summary statistics were reported for baseline covariates, with comparisons made using the Kruskal-Wallis or chi-square test. Overall survival (OS) and disease-specific survival (DSS) were reported using the Kaplan-Meier method and comparisons were made using the log-rank test. Univariate and multivariate Cox regressions assessed the association between baseline covariates and time-to-event. Changes over time were assessed by annual percentage change (APC). Results: We identified 21,677 AYA patients with non-CRC GI malignancies (esophageal, stomach, small intestine, anal, hepatobiliary, pancreas, and primary peritoneal) from 2000-2020. Most were male (58%), White (47%), and living in metro areas (90%). The median age of diagnosis was 38 years. The AYA population had a higher percentage of Black, Asian, and Hispanic patients (14%, 12%, and 25%, respectively) affected compared to the ≥50 group (11%, 10%, and 14%). The most common non-CRC GI malignancies in the AYA group were stomach, pancreas, and liver (27%, 20%, and 19 %, respectively). Stomach cancer was found to be much higher in the AYA group compared to the ≥50 group (27 vs 17%). More patients in the AYA group underwent surgery (46 vs 30%) and chemotherapy (54 vs 42%) compared to the ≥50 group. More patients in the AYA group began treatment within 1 month (35 vs 22%). OS and DSS were significantly better in the AYA group (Median OS 24 vs 9 months, Median DSS 52 vs 13 months, p<0.001). Overall, the incidence of non-CRC GI cancers significantly increased from 2000-2019 based on APC (p < 0.05). Specifically, the incidence of small bowel, anal, and liver cancer increased during this period. Univariate and multivariate analysis revealed that male sex, African American race, income <$45k/year, no surgery, and delayed time to treatment were all predictors of worse OS and DSS (p<0.01). Conclusions: Non-CRC GI malignancies are increasing within the AYA population, and specific socio-demographic disparities notably affect survival in this age group. Further study is needed to define the underlying mechanisms of these findings and to ultimately reverse these observed trends.
Circulating immune protein biomarkers of early response and resistance in patients with metastatic HER-2–negative esophagogastric cancer (mEGC) treated with pembrolizumab and chemotherapy.
Authors: Nixon Andrew B. , Howard Lauren , Kar Amrita , Liu Yingmiao , Brady John C. , Niedzwiecki Donna , Strickler John H , Rucevic Marijana , Uronis Hope Elizabeth
Published: June 2024

4024

Background: Immune checkpoint inhibition (ICI) in combination with chemotherapy is standard of care for first line HER2- mEGC. Tissue-based biomarkers can improve patient selection for ICI therapy, but these biomarkers require invasive biopsy, and the optimal cutoff for treatment benefit is controversial. Longitudinal plasma samples were collected from patients (pts) enrolled in the KeyLargo trial (NCT03342937), a single-arm phase II study of pembrolizumab (pembro) combined with oxaliplatin and capecitabine in first line HER2- mEGC, to identify novel prognostic and predictive circulating protein biomarkers. Methods: We employed large scale Next generation multiplex proteomics (Olink Explore) to evaluate 1536 functional protein biomarkers in 36 pts, including markers known to drive tumor biology and immune response. Samples at baseline (n=36), one week of pembro monotherapy (C1D8) (n=28), C2D1 (n=25), first restaging (n=26), and progression (n=20) were analyzed. Cox models assessed univariable associations between each marker and outcome at baseline. Markers that changed from baseline to C1D8 with effect size >0.5, and to other time points with effect size >1, were deemed most important, all with p<0.05 (paired t-test). Results: At baseline, high PREB, EPHA10, GHRHR, BAMBI and GDF15 levels were associated with worse progression-free survival (PFS) (p<0.001); high SPINK1, S100P, LDLR, GDF15 and PM20D1 levels were associated with worse overall survival (OS) (p<0.003). On-treatment analyses revealed that circulating PDL1 levels were significantly elevated in the presence of pembro at all time points (p<10-16). After one week of pembro monotherapy (C1D8), 6 immune-related biomarkers (TNFRSF8, CXCL9, CCL19, IFNγ, IL10, CXCL10) exhibited significant change (effect size >0.5). At C2D1 and first restaging, the addition of chemotherapy to IO revealed a shift as key metabolic and hormone-regulating proteins (KRT19, GCG, ARG2) were most significantly altered (effect size >1). However, at progression an immune-related phenotype re-emerged as IL10, IL17A and GPA33 significantly changed (effect size >1). Subsequent pathway analyses aligned with the individual markers, highlighting the impact of immune cell signaling after IO monotherapy while cell signaling pathways, hormone-controlled pathways, and extracellular matrix degradation were activated at later times. Conclusions: Multiple prognostic biomarkers were identified that implicate proteins related to hormone metabolism and TGFβ biology in mEGC, including GDF15, a key molecule regulating obesity, tumor metastasis, immunomodulation, and cachexia. Significant changes in immune-related cytokines were seen early (C1D8) as well as at progression, highlighting a potential role for circulating immune protein biomarkers in mEGC.
Clinical impact of oncogenic KRASdosage variation in pancreatic cancer.
Authors: Jung Kwangrok , Lee Jong-Chan , Kim Jaihwan , Hwang Jin-Hyeok
Published: June 2024

4027

Background: Some studies have reported that KRAS oncogenic dosage variation plays a critical role in the biology and phenotype diversification of pancreatic ductal adenocarcinoma (PDA). However, this has not been confirmed in large-scale data. Therefore, this study aims to validate the clinical impact of oncogenic KRAS dosage variation using a large Korean clinico-genomic dataset. Methods: We conducted whole exome sequencing (WES) in 205 human PDA tissues. Tumor cellularity, ploidy, and allele-specific copy number (CN) were derived from WES data using the SEQUENZA software. Subsequently, allele-specific CN for both of mutant and wild-type KRAS was assigned based on tumor cellularity and variant allele fraction (VAF) of mutant KRAS. Finally, we defined mutant KRAS allelic imbalance as a condition where the mutant KRASCN exceeded that of the wild-type KRAS and assessed its clinical significance. Results: Out of 205 PDA patients, 183 (89.3%) patients harbored KRAS mutation and 166 (81.0%) patients were evaluable for mutant KRAS allelic imbalance. Among 166 patients, mutant KRAS allelic imbalance was identified in 62 (37.3%) patients. There was no significant difference in the proportion of stage IV PDA between the imbalance and balance group (59.7% vs. 51.0%, p = 0.353). Nevertheless, a significant disparity was noted in the metastatic pattern, indicating a higher incidence of liver metastasis in the imbalanced group compared to the balanced group (81.1% vs. 52.8%, p = 0.011). In the survival analysis, the imbalance group exhibited significantly shorter progression-free survival and overall survival compared to the balance group (4.6m vs 8.0m, p = 0.009 and 12.5m vs. 17.9m, p = 0.002, respectively). This statistical significance persisted even after adjusting for several variables such as age, sex, stage, and treatment course. Conclusions: Our findings underscore the role of oncogenic KRAS dosage variation, as assessed by mutant KRAS allelic imbalance, in shaping clinical phenotypes and prognosis in PDA. [Table: see text]
Nivolumab (NIVO) + chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 4-year follow-up of CheckMate 649.
Authors: Elimova Elena , Shitara Kohei , Moehler Markus H. , Ajani Jaffer A. , Shen Lin , Garrido Marcelo , Gallardo Carlos , Wyrwicz Lucjan S. , Yamaguchi Kensei , Cleary James M. , Bruges Maya Ricardo Elias , Karamouzis Michalis , Skoczylas Tomasz , Bragagnoli Arinilda , Liu Tianshu , Tehfe Mustapha , Feeney Kynan , Wang Rui , Nathani Raheel , Janjigian Yelena Y.
Published: June 2024

4040

Background: NIVO + chemo demonstrated superior overall survival (OS) and clinically meaningful progression-free survival (PFS) benefit vs chemo and an acceptable safety profile in previously untreated, advanced non-HER2+ GC/GEJC/EAC, leading to approvals in many countries. NIVO + chemo continued to demonstrate clinically meaningful improvement in efficacy at 2 and 3-yr follow-ups. We present 4-yr follow-up results for NIVO + chemo vs chemo from CheckMate 649. Methods: Adults with previously untreated, unresectable advanced, or metastatic GC/GEJC/EAC were enrolled, regardless of programmed death ligand 1 (PD-L1) expression. HER2+ patients (pts) were excluded. Randomized pts received NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 1581 pts were randomized to NIVO + chemo or chemo. At the 48-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). OS benefit with NIVO + chemo was observed in most prespecified subgroups. Objective response rates (ORR) were higher and responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts (Table). In the exploratory analysis of OS by response at the 18-week landmark timepoint, there were numerically more pts achieving response with NIVO + chemo vs chemo, and median OS (95% CI) with NIVO + chemo was numerically longer in responders vs non-responders both in pts with PD-L1 CPS ≥ 5 (20.5 [17.5–25.0] vs 14.0 [11.6–15.7]) and all randomized pts (19.4 [17.5–21.7] vs 13.1 [11.6–14.4]). No new safety signals were identified, consistent with the 3-yr follow-up. Conclusions: NIVO + chemo is the first PD-1 inhibitor/chemo combination to demonstrate long-term efficacy and acceptable safety after 4 yrs of follow up in previously untreated advanced GC/GEJC/EAC. These results are consistent with earlier follow-ups, further supporting NIVO + chemo as a standard 1L treatment in these pts. Clinical trial information: NCT02872116 . [Table: see text]
Enfortumab vedotin (EV) in previously treated gastric/esophageal cancers cohorts of EV-202.
Authors: Muro Kei , Chin Keisho , Maron Steven Brad , Braiteh Fadi S. , Mitani Seiichiro , Hara Hiroki , Kuboki Yasutoshi , Mulcahy Mary F , Baranda Joaquina Celebre , Gardner Faithlore Patrice , Jin Ning , Hamauchi Satoshi , Kaplan Jason , Gorla Seema Rao , Liu Shubin , Wozniak Michele , Meng Changting , Kondo Shunsuke
Published: June 2024

4046

Background: Gastric/esophageal cancers have moderate/high Nectin-4 expression. EV is a Nectin-4–directed antibody–drug conjugate approved for use in locally advanced or metastatic (la/m) urothelial carcinoma. We report antitumor activity and safety of EV monotherapy in esophageal and/or gastric cancer in EV-202 (NCT04225117). Methods: This open-label, multicohort, phase 2 study enrolled adults with la/m solid tumors and ECOG performance status 0–1. In the esophageal squamous cell carcinoma (ESCC) and gastric/esophageal adenocarcinoma (GEA; gastric cancer, gastroesophageal junction/esophageal adenocarcinoma) cohorts, patients (pts) had prior treatment with 1 platinum-based and ≤2 lines of cytotoxic therapy in the la/m setting and disease not amenable to curative intent. Inclusion required prior HER2-directed therapy if HER2-positive and prior PD-1/L1 inhibitor. Nectin-4 expression was assessed retrospectively. Pts received EV 1.25 mg/kg intravenously on days 1, 8, and 15 per 28-day cycle. Primary endpoint was investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1; ≥7 out of 40 responders are needed to conclude promising antitumor activity. Secondary endpoints were investigator-assessed duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) per RECIST v1.1; overall survival (OS); and safety/tolerability. Results: Of the 44 (as of June 2, 2023) and 42 pts (as of Mar 3, 2023) in the ESCC and GEA cohorts, respectively, median age was 66 and 62 y, 82% and 71% of pts were male, and 68% and 69% had ≥2 prior lines of systemic therapy in the metastatic setting. Efficacy data are shown in the table. Efficacy was generally better in pts with <3 (n=22) vs ≥3 (n=21) prior therapy lines in the ESCC cohort. Common treatment-related adverse events (TRAEs) were pruritus (n=12, 27%), maculopapular rash (n=12, 27%), and dysgeusia (n=11, 25%) for ESCC and pruritus (n=16, 38%), alopecia (n=15, 36%), and dysgeusia (n=13, 31%) for GEA. Grade ≥3 TRAEs (>1 pt) were hypercalcemia, hyperglycemia, maculopapular rash, and decreased neutrophil count (each n=2, 5%) for ESCC and maculopapular rash (n=3, 7%), decreased neutrophil count (n=2, 5%), and hyperglycemia (n=2, 5%) for GEA. For ESCC and GEA, respectively, TRAEs of special interest included skin reactions (n=27, 61%; n=23, 55%), peripheral neuropathy (n=9, 20%; n=7, 17%), and hyperglycemia (n=3, 7%; n=3, 7%). Conclusions: In pts with pretreated gastric/esophageal cancers, EV demonstrated safety consistent with the known profile of EV. Promising antitumor activity was observed in pts with ESCC. Clinical trial information: NCT04225117 . [Table: see text]
First-line osemitamab (TST001) plus nivolumab and capox for advanced g/GEJ cancer (TranStar102): Results of cohort G from a phase I/IIa study.
Authors: Zhang Xiaotian , Guo Zengqing , Zhang Jingdong , Guo Weijian , Sun Meili , Xu Nong , Qi Charlie , Zhu Xuelian , Zhang Lijuan , Qian Xueming , Germa Caroline , Shen Lin
Published: June 2024

4048

Background: TST001 is a humanized monoclonal antibody with improved affinity to claudin 18.2 (CLDN18.2) and enhanced ADCC activity. In vivoanti-tumor activity of TST001 plus an anti-PD-1 antibody and chemotherapy is significantly stronger than chemotherapy plus anti-PD-1 antibody or chemotherapy plus anti-CLDN18.2 antibody, regardless of the CPS PDL1 levels. Promising efficacy of osemitamab plus CAPOX chemotherapy as 1st line treatment of G/GEJ cancer has been observed in cohort C of TranStar102, making the triple combination of TST001, nivolumab and CAPOX an attractive combination to explore. Methods: Cohort G from TranStar102 (NCT04495296) is designed to evaluate the safety and preliminary efficacy of TST001 (at 2 doses: 3mg/kg or 6mg/kg Q3W) plus nivolumab and CAPOX as 1st line treatment in patients with G/GEJ cancer, with a safety lead-in and expansion phase. 40 patients were planned to be enrolled in each dose cohort. Eligible patients include HER2 negative or unknown, unresectable locally advanced or metastatic G/GEJ cancer, regardless of CLDN18.2 or PD-L1 expression. CLDN18.2 and PD-L1 status are analyzed retrospectively using IHC 14G11 LDT assay and PD-L1 IHC 28-8 pharmDx. Results: As of Jan 19, 2024, 82 patients have been dosed with a median follow-up of 9.7 months, 40 patients at 3mg/kg, 42 patients at 6mg/kg. All patients experienced treatment-related adverse events (TRAEs). The most common TRAEs were hypoalbuminemia (67.1%), nausea (63.4%), and vomiting (59.8%). The incidence of nausea (69% vs 57.5%) and hypoalbuminaemia (76.2% vs 57.5%) was higher at 6mg/kg than 3mg/kg. Most of the TRAEs are grade 1 or 2. The most common TRAE grade 3 or higher were neutrophil decreased (n=10), platelet count decreased (n=8), nausea (2 at 3mg/kg, 1 at 6mg/kg) and vomiting (2 at 3mg/kg). No new safety signal was detected when nivolumab was added to TST001 in combination with chemotherapy. 79 patients had measurable disease at baseline including 25 CLDN18.2 negative patients. 51/79 patients had partial response as of cut-off date, out of which 45 were confirmed (ORR 57%), with no significant difference between the 2 dose levels. 17 patients had stable disease. The disease control rate (DCR) was 91.9% in all patients across CLDN18.2 expression levels and CPS PD-L1 levels. The progression-free survival (PFS) and duration of response (DoR) are immature and need longer follow-up. Conclusions: Preliminary data indicate that the combination of TST001 6mg/kg Q3W plus nivolumab and CAPOX for the 1st line treatment of patients with G/GEJ cancer is safe and well tolerated with encouraging preliminary anti-tumor activities. Updated clinical data, including PFS and DoR will be reported at the time of the conference. Clinical trial information: NCT04495296 .
The use of micronuclei DNA from erythrocytes for the detection of early-stage gastrointestinal cancers.
Authors: Sun Haobo , Yao Xingyun , Han Yuehua , Jiao Yurong , Kong Xiangxing , Liu Chengcheng , Guo Qingqu , Meng Fei , Liang Honghao , Fan Xiuqin , Li Jun , Ding Kefeng , Gao Xiaofei
Published: June 2024

4085

Background: Gastrointestinal (GI) cancers account for over a third of cancer deaths. However, their early detection remains a challenge. Micronuclei (MN) are extranuclear bodies containing damaged chromosome segments indicative of genomic instability. Increased MN frequency in hematopoietic cells is observed in patients with solid tumors. We have developed a method (WO2021/228246 A1) for purifying and characterizing micronuclei DNA (MN-DNA) in erythrocytes from peripheral blood. By comparing MN-DNA from healthy donors (HDs) and GI cancer patients, we identified significant changes in read densities at specific genomic locations in patients, which were termed as tumor-associated MN-DNA (taMN-DNA) signatures. Here, we evaluated the potential of these signatures for early-stage GI cancer detection, including colorectal (CC), gastric (GC) and esophageal (EC) cancers. Methods: Peripheral blood (1-2 ml) was collected from healthy donors (HD) and cancer patients MN-DNA isolation and purification from erythrocytes. Participants were randomly divided into training, validation and independent test cohorts in a 7:2:1 ratio, maintaining similar cancer types, CC/GC/EC/HD ratio, gender and age distribution. Distinct MN-DNA features between cancer patients and HDs were identified using sequencing data. Logistic regression algorithms were applied using these features for cancer detection. Results: The study enrolled 1753 participants, including 987 HDs, 420 CC, 282 GC and 64 EC cases. Of these, over half were diagnosed with early-stage diseases; TNM stage 0-I accounted for 40.57%, stage II for 23.32%, stage III for 29.25% and stage IV for 6.87%. The cancer detection model with MN-DNA features yielded an overall accuracy of 87.43%, with a sensitivity of 83.66% and specificity of 90.36%. For individual caner types, sensitivity was 85.37% for CC, 79.31% for GC and 92.31% for EC. For early-stage (stage 0-II) CC, GC and EC, the model demonstrated sensitivities of 95.12%, 86.05% and 100.00%, respectively, at 90.36% specificity. Conclusions: Unlike cell-free DNA, MN-DNA are chromosomal fragments in the cytoplasm. The abundance of erythrocytes in peripheral blood provides an easily accessible source for MN-DNA enrichment. This pilot study illustrates the potential of MN-DNA as a tool for early GI cancer detection, contributing to large-scale efforts towards developing an effective GI cancer screening test.
Genomic signature analysis and survival outcomes in cholangiocarcinoma (CCA) using oncology research information exchange network (ORIEN) database.
Authors: Patel Riya Jayesh , Rosario Spencer , Sonti Sahithi , Hsiao Hua-Hsin , Pawlik Timothy M. , Tsilimigras Diamantis I , Siegel Erin M. , Berim Lyudmyla Derby , Turk Anita Ahmed , Masood Ashiq , Salhia Bodour , Kolesar Jill , Davis S. Lindsey , Le Tri Minh , Nevala-Plagemann Christopher Duane , Chan Carlos H.F. , Churchman Michelle , Thanikachalam Kannan , Iyer Renuka V.
Published: June 2024

4101

Background: Immunotherapy (IO) is standard of care for advanced CCA patients (pts) regardless of PD-L1 expression. Lack of biomarkers that predict prolonged benefit or resistance to therapies are unmet gaps in this field that we attempted to fill using transcriptional and survival data in the ORIEN dataset. Methods: Through an ORIEN intermember project, we accessed an avatar dataset for clinical characteristics and transcriptional data of the CCA cohort. We first identified clinical factors highly associated with transcriptional variability and conducted principal component analysis (PCA), focusing on factors linked to the first principal component (PC1). Both specimen site and type (p<0.01) were found highly associated with PC1 and were included as co-variates in subsequent models. Then, immune deconvolution using XCell was performed on the ORIEN-CCA RNA-sequencing cohort to determine the transcriptome portion attributed to effector T cell (Teff) and regulatory T cell (Treg) for each patient. Teff:Treg ratios were calculated and used to divide patients into cold (low Teff:Treg) and hot (high Teff:Treg) cohorts based on their median (mTeff:Treg = 0.0004). Differential gene expression analysis comparing hot and cold tumors yielded 72 significantly differentially expressed genes (FC <1.5, adjusted p<0.05). Gene Set Enrichment Analysis (GSEA) of transcriptomic changes revealed enrichment for immune and metabolic pathway alterations. Results: The ORIEN avatar dataset comprised of 78 pts, with 39 designated as immune hot and 39 as immune cold (demographics in Table). Median overall survival (mOS) was 3.17 years in hot and 2.65 years in cold group . These groups exhibited significantly different Teff:Treg ratio (p<0.0001). Differential gene expression identified 72 altered genes, including upregulated immune genes (e.g., IL2RA, CD80, GBP5) in the hot group and metabolic genes (e.g., AZGP1) in the cold group. GSEA of these genes revealed immune pathway enrichment in hot tumors, with increased antigen presentation, NK cell function, and B-cell activation. Surprisingly, cold tumors were enriched of pathways involved in lipogenesis, oxidation, and proliferation. Conclusions: ORIEN-CCA cohort analysis revealed immune hot and cold tumors with distinct transcriptional alterations and differences in mOS. Correlating these alterations with IO use, and further studies of enriched pathways in cold tumors are warranted. [Table: see text]
Genomic and transcriptomic biomarkers of nab-paclitaxel plus gemcitabine-cisplatin in patients with advanced biliary tract cancer.
Authors: Woo Seonjeong , Kang Beodeul , Lee Sung Hwan , Kim Jung Sun , Kang Haeyoun , Yang Seok Jeong , An Chansik , Kim Gwangil , Hwang Sohyun , Kim Chan , Chon Hong Jae
Published: June 2024

4104

Background: Nab-paclitaxel plus gemcitabine-cisplatin (GemCis/nab-P) showed promising clinical outcomes in phase II trials for advanced biliary tract cancer (BTC) but did not demonstrate superiority over the control treatment in subsequent phase III clinical trials.In this study, we investigated predictive biomarkers of response to GemCis/nab-P in patients with advanced BTC using comprehensive genomic and transcriptomic analyses. Methods: This prospective cohort study (NCT04871321) enrolled 119 patients with advanced BTC who received GemCis/nab-P at CHA Bundang Medical Center, Korea from July 2021 to December 2022. Targeted genomic (Oncomine Comprehensive Assay) and whole-transcriptome sequencing data for tissue samples collected before the initiation of systemic chemotherapy were used for biomarker discovery (n = 108). To identify genomic and transcriptomic features related to overall survival (OS) and progression-free survival (PFS), the log-rank test, Cox proportional hazards model, and Lasso Cox regression model were used. Results: Among the 119 enrolled patients, 39.5% had intrahepatic cholangiocarcinoma, 37.0% had extrahepatic cholangiocarcinoma, and 23.5% had gallbladder cancer. Most patients had metastatic or recurrent disease (68.9%). The median follow-up duration was 23.7 months (range 0.8–30.2), median PFS was 8.3 months (95% Confidence interval (CI), 7.0–11.5), and median OS was 19.8 months (95% CI, 15.3–not reached). The most common genetic aberrations were TP53 (53.7%), KRAS (29.6%), and ARID1A (16.7%) alterations. TP53 mutations were associated with a poor OS (p = 0.001) and PFS (p = 0.005). In the transcriptome analysis, genes associated with immune responses, especially tumor-associated macrophages, were upregulated in patients with worse OS and PFS. We constructed a Lasso-Cox regression model and identified VSIG4 (hazard ratio (HR): 3.0, p = 2.0 × 10-4 for OS; HR: 2.4, p = 4.0 × 10-4 for PFS), ITGA3 (HR: 2.6, p = 0.001 for OS; HR: 1.7, p = 0.020 for PFS), and CCL8 (HR: 1.6, p = 0.110 for OS; HR: 1.6, p = 0.039 for PFS) as effective predictors of poor clinical outcomes during GemCis/nab-P treatment. Conclusions: GemCis/nab-P showed promising survival outcomes in advanced BTC. Further, patients with TP53 mutations or high tumoral levels of VSIG4, ITGA3, and CCL8 showed a poor prognosis after GemCis/nab-P treatment. Clinical trial information: NCT04871321 .
Efficacy and safety of envafolimab plus lenvatinib combined with TACE in initially unresectable hepatocellular carcinoma: An open-label, single-arm, phase II study.
Authors: Bai Xueli , Chen Yiwen , Zhang Junlei , Hu Wendi , Li Xiang , Shen Yan , Zhang Min , Wu Jian , Gao Shunliang , Yu Jun , Que Risheng , Zhang Yun , Yang Fuchun , Xia Weiliang , Zhang Aibin , Tang Xiaofeng , Liang Tingbo
Published: June 2024

4108

Background: TACE-based conversion therapies are warranted for over 70% of patients with intermediate-advanced unresectable hepatocellular carcinoma (uHCC). This study aimed to investigate the efficacy and safety of envafolimab plus lenvatinib and TACE as conversion therapy in uHCC. Methods: This is an open-label, prospective, single-arm, phase II study. Eligible patients with uHCC (Barcelona Clinic Liver Cancer Stage B or C) were consecutively enrolled. Patients will receive envafolimab subcutaneously (300 mg, Q3W) and Lenvatinib orally daily (12 mg/day (body weight ≥ 60 kg) or 8 mg/day (<60 kg)) during TACE sessions. TACE will be conducted every 6 weeks on demand according to investigators’ evaluation, mainly based on the proportion of viable tumors. The primary endpoint was the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version1.1 (RECIST 1.1). Secondary endpoints were disease control rate (DCR) and duration of response (DoR) per RECIST 1.1 and mRECIST, progression-free survival (PFS), overall survival (OS), and safety. Results: Between February 2022 and July 2022, 38 patients were enrolled and included for primary efficacy and safety analysis. As of December 13, 2023, the median follow-up of 16.9 months (95CI, 6.7 to 24.2). The ORR and DCR were 47.4% (95%CI, 31.0% to 64.2%) and 78.9% (95%CI, 62.7% to 90.5%) per RECIST 1.1, respectively (with ORR and DCR of both 78.9% per mRECIST). The median PFS (mPFS) was 8.78 months (95CI, 5.23 to not avaliable (NA)), and the median OS (mOS) was immature with 1-year OS of 88.9%. The median DoR assessed per RECIST 1.1 was 6.7 months (7.7 months per mRECIST). Of 38 patients, 17 patients were assessed as successful conversion with a conversion success rate of 44.7%. Sixteen patients underwent surgery with the R0 resection rate of 100%, the pathological complete response (pCR) rate of 31.3%, and major pathological response (MPR) rate of 56.3%. Of 38 patients, overall incidences of AEs of any grade was 97.4%. Grade ≥3 treatment-related adverse events (TRAEs) were observed in 20 (52.6%) patients, which mainly included increased AST (34.2%), increased ALT (18.4%), and decreased platelet count (15.8%). No treatment-related death occurred. Conclusions: Envafolimab combined with lenvatinib and TACE yielded promising survival outcomes and conversion rate with a manageable safety profile in uHCC, representing a potential and feasible conversion therapy regimen for this population. Clinical trial information: NCT05213221 .
Sorafenib plus hepatic arterial infusion of oxaliplatin and fluorouracil vs sorafenib plus transarterial chemoembolization for advanced hepatocellular carcinoma: A biomolecular exploratory, randomized, phase III trial (SHATA-001).
Authors: Lai Zhicheng , Kan Anna , He MinKe , Du Zefeng , Shi Ming
Published: June 2024

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Background: Several recent studies had demonstrated the superiority of Sorafenib/lenvatinib plus transcatheter arterial chemoembolization (TACE) over sorafenib/lenvatinib alone in advanced hepatocellular carcinoma (HCC). Herein, we compared the efficacy and safety between sorafenib plus TACE (SoraTACE) and sorafenib plus hepatic arterial infusion chemotherapy (SoraHAIC) in advanced HCC. Additionally, we validated a predictive model from our previous phase III trial (NCT02973685, cohort1). Methods: In this phase III trial (NCT02856126), patients with advanced HCC were enrolled. Eligible patients were randomly assigned (2:1) to receive Sorafenib (400mg orally twice daily) plus HAIC with oxaliplatin & fluorouracil per 3 weeks or TACE (50mg of epirubicin and lobaplatin mixed with lipiodol and polyvinyl alcohol) until disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS). Whole-Exome Sequencing and RNA Sequencing of tumor biopsy samples were performed for predictive biomarker exploration (cohort 1) and validation (SHATA-001). Results: Between August 4, 2016, and October 25, 2020, 207 patients were assigned to treatment (SoraHAIC, n=141; SoraTACE, n=66). Primary endpoint was met, with the median OS of 15.6 (95% CI, 12.7-18.6) months in SoraHAIC group and 11.2 (7.6-14.6) months in SoraTACE group (HR, 0.53 [0.38-0.74], p<0.001). Median progression-free survival was 6.9 (5.4-8.5) months and 4.2 (2.9-5.3) months in the respective groups (HR, 0.51[0.37-0.69], p<0.001). Safety analyses (n=200) showed frequencies of grade 3-4 elevated alanine aminotransferase (5% vs 21.7%; p<0.001) and elevated aspartate aminotransferase (16.4% vs 35%; p<0.001) significantly higher with SoraTACE than SoraHAIC. Serious adverse events occurred more frequently with SoraTACE (56.7%) than SoraHAIC (39.3%) (p=0.023). In cohort 1, we analyzed the metabolic activity of fatty acid degradation (FAD) pathway using FAD score, which was positively correlated with longer OS, especially in patients received TACE. Furthermore, we found a down regulation of FAD activity in patients enrolled in SHATA-001. And higher FAD score showed a better tumor response to SoraTACE, while FAD had no difference between responders and non-responders in SoraHAIC. Conclusions: This trial demonstrated SoraHAIC significantly improved OS over SoraTACE in patients with advanced HCC. However, patients with high FAD activity might have a better tumor response and survival benefit to SoraTACE than SoraHAIC. Clinical trial information: NCT02856126 .
A phase 2 study of BOLD-100 in combination with FOLFOX chemotherapy in patients with pretreated advanced biliary tract cancer: Efficacy and safety analysis (BOLD-100-001).
Authors: O'Kane Grainne M. , Oh Do-Youn , Spratlin Jennifer , Rha Sun Young , Elimova Elena , Kavan Petr , Goodwin Rachel Anne , Cha Yongjun , Kim Seung Tae , McAllister E. Russell , Jones Michelle , Snow Malcolm , Lemmerick Yasmin , Spera Gonzalo , Pankovich Jim
Published: June 2024

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Background: BOLD-100 is a first-in-class ruthenium-based anticancer agent in Phase 2 clinical development for the treatment of advanced gastrointestinal (GI) cancers in combination with FOLFOX. BOLD-100 demonstrated synergy in established preclinical models in combination with various anticancer therapies. Methods: In this prospective Phase 2 study, patients with pretreated advanced biliary tract cancers (BTC) received BOLD-100 (625 mg/m2) in combination with FOLFOX on day 1 of each 14-day cycle until progressive disease or unacceptable toxicity. The primary objective was to evaluate the efficacy of BOLD-100 in three clinical endpoints (PFS, OS, and ORR). Disease Control Rate (DCR) was also determined. Bayesian modelling was used to continually reassess these endpoints, the posterior probability of superiority to an historical landmark for each endpoint. Results: As of 31 Dec 2023, 22 pts with advanced metastatic BTC (5 gall bladder, 5 intrahepatic, 8 distal, 1 perihilar, and 3 unk) were enrolled and treated in the study. At enrollment, pts had a median age of 61 years [range 33, 81] and had a median of 10.9 months from diagnosis of metastatic disease. All patients were ECOG ≤ 1. Patients had a median of 2 prior systemic therapies [range 1, 5] with 13 receiving 2 or more prior regimens. 21/22 BTC patients received prior GEM/CIS, 8 pts had prior 5-FU treatment and 6 prior IO. On study, pts received a median of 4 cycles BOLD-100 + FOLFOX [range 1, 41]. Median PFS was 6.0 [95% credible interval (CI) 3.8, 10] months, median OS 7.3 [CI 4.5, 13] months, ORR 6% [1,23] and DCR 83% [62, 95] in the 18 evaluable patients. Six patients had reductions in their target lesions with 1 partial response. Study treatment was well tolerated. For the 22 treated patients, 21 reported 1 or more treatment-related adverse events (AEs), most commonly neutrophil count decreased (n=10, 46%), nausea (n=8, 36%), fatigue (n=7, 32%), peripheral sensory neuropathy (n=6, 27%), and pyrexia (n=6, 27%). Nine patients (41%) reported G3/4 neutrophil count decreased. Conclusions: BOLD-100 combined with FOLFOX is an active and well-tolerated treatment regimen in Stage IV BTC. There were no new safety signals detected. The mPFS, mOS, ORR and DCR data in this advanced BTC cancer population indicate a treatment combination worthy of further study for this difficult to treat cancer. Clinical trial information: NCT04421820 .
PD-1 inhibitor (sintilimab) and lenvatinib plus TACE-HAIC as conversion therapy for initially unresectable HCC: A single-arm, phase 2 clinical trial (PLATIC).
Authors: Yuan Yunfei , Qiu Jiliang , Huang Zhenkun , He Wei , Yuan Yichuan , Wang Chenwei , Li Binkui
Published: June 2024

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Background: The current standard treatment for initially unresectable hepatocellular carcinoma (uHCC) is transarterial chemoembolization (TACE) or systemic treatments, but these approaches led to poor conversion resection rate. We aimed to investigate the clinical activity and safety of downstage conversion therapy with Sintilimab, a PD-1 inhibitor, Lenvatinib and TACE- HAIC (hepatic arterial infusion chemotherapy) in uHCC patients (PLATIC trial). Methods: This single-arm, Simon two-stage, phase 2 study was done at Sun Yat-sen University Cancer Center, Guangzhou, China. Patients received TACE-HAIC, followed by 200mg Sintilimab, Lenvatinib (8mg for BW < 60kg, 12mg for BW ≥ 60kg). The primary endpoint was the conversion to resection rate. Safety was analyzed in all patients who received at least one dose of treatment. This trial is closed to enrolment and is registered with ClinicalTrials.gov (NCT04814043). Results: Between May 19, 2021, and August 20, 2023, 57 patients were enrolled, and all were included in the efficacy and safety analysis set. The conversion to resection rate was 77.2% (44/57, 95% CI, 64.2 to 87.3) after a median 3 cycles of conversion therapy. Overall response rate was 77.2% per mRECIST and 42.1% per RECIST 1.1 criteria. The median duration of response (mDoR) was 11.5 months (95% CI, 9.8 to NA), and the median progression-free survival (mPFS) was 14.3 months (95% CI, 11.7 to 21.9). Treatment-related adverse events (TRAEs) of grade 3/4 were reported in 37 (64.9%) patients, with the most frequent being increased gamma-glutamyl transferase (36.8%), followed by abdominal pain (19.3%). Among 44 successful conversion patients, 29.5% (13/44) patients obtained a pathological complete response, with a mPFS of 15.3 months (95% CI, 11.9 to NA) and 12-month PFS rate of 59.4% (95% CI, 45.4 to 77.9). Conclusions: Sintilimab plus Lenvatinib and TACE-HAIC provided promising rate of conversion to resection in patients with initially unresectable HCC, with an acceptable TRAEs. Clinical trial information: NCT04814043 . [Table: see text]
Differences in genomic and transcriptomic landscapes of human papillomavirus (HPV)–positive neuroendocrine neoplasms and HPV-positive carcinoma.
Authors: Lou Emil , Krause Harris Benjamin , Elliott Andrew , Wahidi Marya , Rader Janet S. , Teoh Deanna Gek Koon , Park Soo J , Wallbillich John , Benjamin David Joseph , Rezazadeh Arash , Duerksen-Hughes Penelope , Morris Robert , Gogoi Radhika , Zaiem Fadi , Herzog Thomas J , Thaker Premal H. , Oberley Matthew James , Soares Heloisa P. , Ali-Fehmi Rouba
Published: June 2024

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Background: HPV is an infectious cause of several malignancies. Neuroendocrine neoplasms (NEN) are highly heterogeneous, ranging from low-grade indolent tumors to high-grade clinically aggressive carcinomas. Aside from cervical NENs, most have not traditionally been associated with HPV, but our initial studies uncovered a subset of NENs that are HPV 16/18 positive. To identify actionable differences between HPV+ NEN and non-NENs, genomic and transcriptomic landscapes were investigated. Methods: 101343 solid tumors were sequenced at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing of DNA (whole or hybrid exome) and RNA (whole or hybrid transcriptome) and assayed for HPV16/18 positivity (HPV+) via DNA sequencing. Mutation prevalence for pathogenic SNVs/indels (-Mt) and copy number amplification (CNA) were calculated. Expression of Ki-67 mRNA ( MKI67) was used to infer high grade vs low grade NEN. Gene expression profiles were analyzed for a transcriptional signature predictive of response to immunotherapy, interferon 𝛾">γ score (IFN). Differentially regulated pathways were assessed by gene set enrichment analysis (GSEA). Fisher’s exact/χ2 tests were applied as appropriate with p-values adjusted for multiple comparisons ( p < .05). Results: Among all solid tumor types, rates of HPV+ were highest in cervical carcinomas (70%, 1200/1716), followed by vulvar squamous cell carcinoma (31%, 126/410) and head and neck (HN) carcinomas (28%, 668/2413), with HPV+ tumors also found in NENs (6%, 96/1620). Within NENs, the highest HPV+ rates were observed for those with a tumor origin of cervical (76%, 55/58), anorectal (AR, 27%, 29/106), female genitourinary tract (23%, 12/52) and HN (19%, 7/36). Amongst HPV+ NEN, 93% were high grade compared to 54% of HPV- NEN (p < .001). Focusing on AR, cervical and HN primary sites, significant differences in the genomic landscape were observed between non-NEN v NEN tumors (Table 1). Non-NEN tumors had a significantly higher IFN compared to NEN across sites (Cervical: -0.20 v -0.61, AR: -0.33 v -0.58, HN: -0.16 v -0.54 arbitrary units, p < .001 all). Non-NEN tumors at AR, cervical and HN sites were significantly enriched for several genes sets related to immune response (Interferon α/γ, TNFα/NF-κβ, IL6/JAK/STAT3 and inflammatory response). Conclusions: Our data suggest that non-NEN HPV+ tumors are enriched for gene sets related to immunotherapy response, and that HPV+ NENs have alterations that vary by anatomic site. We uncover a category of HPV+ NENs with distinct genomic and transcriptomic landscapes compared to non-NEN tumors. [Table: see text]