tbuckley/cabot-search huggingface dataset:
Extra-hepatic (ehCCA) and intra-hepatic cholangiocarcinomas (iCCA): A genomic landscape comparison of peri-hilar (phCCA), common bile duct (cbdCCA) and gallbladder (gbCCA) with iCCA.
Authors: Parth J. Sampat, Dean Pavlick, Jeffrey S. Ross, Alina Basnet
Journal: Journal of Clinical Oncology (2025)

630 Background: Metastatic CCAs have poor prognosis. Comprehensive genomic profiling (CGP) was used to compare genomic alterations (GA) in phCCA, with cbdCCA, gbCCA and iCCA. Frequencies of GA in therapy targets such as FGFR2, IDH, ERBB2 &amp; BRAF, &amp; Immuno-oncology (IO) drug response predictors (MSI status, TMB &amp; PDL1) were examined. Methods: DNA extracted from 110 cases of phCCA, 743 cases of cbdCCA, 2983 cases of gbCCA and 9178 cases of ihCCA underwent hybrid capture based CGP to evaluate classes of genomic alterations (GA), MSI status, TMB levels, genomic ancestry, genomic signature, HRD score and germline status. phCCA cases were confirmed at surgery and pathology as originating from either left, right or common hepatic ducts. cbdCCA cases were confirmed by cbd biopsies or Whipple procedures. PD-L1 expression was determined by IHC using the Dako 22C3 assay using tumor proportional score (TPS) system. Results: The pt age distributions were similar; female gender was more frequent in gbCCA. gbCCA featured higher GA/tumor (P=.0001). The frequencies of FGFR2 &amp; IDH1 targetable GA in phCCA, cbdCCA and gbCCA were uncommon especially when compared iCCA (P&lt;.0001). GA in BRAF, CDKN2A, MTAP and PIK3CA in gbCCA were like phCCA and cbdCCA. At 16.5%, the frequency of GA in ERBB2 were highest in gbCCA and in all ehCCA when compared with iCCA (P&lt;.0001). The frequencies of KRAS GA including KRAS G12C were greater in both phCCA and cbdCCA when compared with gbCCA (P=.0015) and iCCA (P.0001). TP53 GA were highest in gbCCA (P=.0007). IO biomarker frequencies were similar in all. The frequencies of HRD positive (gLOH) status and MMR genomic signature were similar in all. Conclusions: ehCCA subtypes feature characteristic GA profiles that have potential to influence therapy selection with lower frequencies of FGFR2 &amp; IDH1 when compared with iCCA. In contrast, targetable ERBB2 &amp; KRAS G12C are more frequent in ehCCA than iCCA, and highest in gbCCA &amp; cbdCCA. peri-hilarCCA cbdCCA P-value (phCCA vs cbdCCA) gbCCA P-value (phCCA vs gbCCA) ihCCA P-value (phCCA vs iCCA) BRAF 3.6% 4.7% NS 2.4% NS 5.1% NS ERBB2 14.5% 10.6% NS 16.5% NS 5.1% 0.002 FGFR2 0.9% 2.0% NS 1.5% NS 11.7% 0.001 IDH1 3.6% 0.8% NS 0.6% NS 13.9% 0.006 KRAS 29.1% 46.2% 0.015 14.2% 0.0015 19.8% 0.071 TP53 45.5% 63.8% 0.011 65.7% 0.0007 33.9% 0.061 MSI-high 1.8% 1.3% NS 1.2% NS 1.8% NS TMB≥10 mut/mb 3.6% 4.2% NS 5.2% NS 3.6% NS PD-L1 low positive 21.1% 31.3% NS 23.5% NS 23.7% NS
Clinical outcomes and molecular characteristics of patients with locoregional ampullary carcinoma.
Authors: Cody Eslinger, Isabela Chang, Rodrigo Fonseca, Oudai Sahvan, Claire I. Yee, Mia Truman, Robert R. McWilliams, Hani M. Babiker, Rish Pai, Christina Wu, Daniel H. Ahn, Mitesh Borad, Tanios S. Bekaii-Saab, Mohamad B. Sonbol
Journal: Journal of Clinical Oncology (2025)

732 Background: Ampullary carcinoma (AC) is a rare malignancy arising from the ampulla of Vater which has a more favorable prognosis compared to other pancreatic malignancies. Current guidelines favor surgical resection followed by adjuvant therapy for average risk patients (pts), however the type of regimen as well as other perioperative treatment modalities are still being explored. The objective of this retrospective study aims to provide insight into the management of locoregional disease. Methods: Pathology records from Mayo Clinic (AZ, FL, MN) denoting AC between 2010 to 2024 were searched using Mayo Data Explorer and selected for retrospective review. Pt demographics, treatment courses, and next generation sequencing (NGS) data were collected. Statistical analysis was conducted using SAS version 9.04. Results: A total of 137 pts (62% male, n = 85) were identified with median age 66 years old. Histologic subtypes were 54% pancreatobiliary (44/81), 40% intestinal (32/81), 6% mixed (5/81), with 56 pts unknown. Stages at diagnosis were 81% resectable (111/137), 11% locally advanced (15/137), and 8% metastatic (11/137). Nearly all (93%, n = 103/111) pts with localized disease had resection with a 97% R0 resection rate (100/103). Majority (68%, n = 75/111) of resectable pts had perioperative chemotherapy with 5-FU or gemcitabine-based regimens (24%, n = 18/75 neoadjuvant vs. 76%, n = 57/75 adjuvant). Perioperative chemoradiation was given in 17% (19/111) of pts. At median follow up of 30.5 months, recurrence rates were 40% (41/103), primarily to the liver (18/41). Median recurrence free survival (RFS) was 29.3 months (95% CI 24.7 – NE). Median overall survival (OS) has not been reached. The 5-year RFS and OS rates were 0.37 (95% CI 0.25 - 0.55) and 0.69 (95% CI 0.58 - 0.82), respectively. Univariate analysis showed no difference in OS with the addition of neoadjuvant or adjuvant chemotherapy or chemoradiation. Somatic NGS testing showed pathogenic mutations in 90% of pts (63/70): 57% KRAS (36/63; 44% G12D, 19% G12V, 8% G12C, 8% G12D, 19% others); 13% homologous recombination (HR) (8/63); 6% ERRB2 /Her2 amplification (4/63), and 5% mismatch repair (MMR) (3/63). Conclusions: AC has a favorable prognosis in resectable pts. However, high recurrence rates indicate the need for better systemic therapies and improved selection of pts who would benefit from these treatments. Future research should focus on refining perioperative strategies to enhance outcomes and reduce recurrence.
A retrospective observational study to evaluate the efficacy of trifluridine/tipiracil ± bevacizumab in metastatic colorectal cancer with MSI-high/deficient MMR.
Authors: Rin Inamoto, Hiroko Hasegawa, Keiji Sugiyama, Naoki Izawa, Seiichiro Mitani, Takeshi Kawakami, Satoshi Yuki, Hidekazu Hirano, Saori Mishima, Tetsutaro Hamano, Toshiki Masuishi
Journal: Journal of Clinical Oncology (2025)

152 Background: MSI-high (MSI-H)/deficient MMR (dMMR) metastatic colorectal cancer (mCRC) have reported to be resistant to various cytotoxic agents including fluorouracil. On the other hand, preclinical study showed that trifluridine was effective to fluorouracil-refractory dMMR CRC cell lines. Previous studies on trifluridine/tipiracil (FTD/TPI) ± bevacizumab (BEV) for mCRC as later line treatment showed an objective response rate (ORR) of 1.1-5.6% and disease control rate (DCR) of 44-76.6%. However, there are no reports on the efficacy of FTD/TPI± bevacizumab in MSI-H/dMMR mCRC patients. Methods: We retrospectively evaluated the efficacy and safety of FTD/TPI ± BEV as second- or later-line treatment which patients with MSI-H/dMMR mCRC received between June 2012 and January 2023 at the 10 institutions. The primary endpoint was investigator-assessed objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse event rates. We also compared the FTD/TPI + BEV (FTB group) with FTD/TPI (FT group). Results: A total of 18 patients (FTB/FT, 9/9) were included. Patient characteristics were as follows (FTB/FT): median age, 70 (70/70) years; ECOG PS of 0/1, 7 (5/2)/11(4/7); primary tumor location of right side/left side, 12(6/6)/6(3/3); BRAF V600E mutant/wild-type, 6(3/3)/11(6/5); number of previous treatment lines of 1/≥2, 2(1/1)/16(8/8); number of metastatic sites of 1-2/≥3, 8(4/4)/10(5/5); prior use of anti-PD-1 therapy, 10(3/7). Efficacies in the whole population were as follows: ORR, 16.7% (95%CI, 3.6-41.4); DCR, 72.2%; median (m) PFS, 5.5 months; mOS, 11.8 months. Efficacies in each group (FTB vs. FT) were as follows: ORR (22.2% vs. 11.1%) and DCR (88.9% vs. 55.6%) were favored in FTB group than in FT group, while the median PFS were similar between two groups (5.6 months vs. 5.2 months). OS in FTB group was longer than in FT group (median, 18.9 months vs. 7.1 months; hazard ratio, 0.22; p value=0.03). Of 11 (FTB/FT, 7/4) patients who received subsequent treatment, 6 in FTB group and 1 in FT group received anti-PD-1 therapy. The most common grade 3 or more adverse events in each group (FTB vs. FT) were neutropenia (77.8% vs.77.8%), anemia (22.2% vs. 33.3%) and febrile neutropenia (0% vs. 22.2%). Conclusions: FTD/TPI ± BEV showed a promising efficacy and favorable safety. Although this was retrospective study with a small sample size, FTD/TPI ± BEV therapy may have better efficacies for MSI-H/dMMR mCRC than those for MSS/proficient MMR mCRC in previous prospective studies. Next generation sequencing as biomarker analysis using pretreated tissue samples is ongoing.
Anlotinib combined with penpulimab and nab-paclitaxel as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase II clinical trial.
Authors: Zhiwei Chang, Rui-Rui Wang, Xiao-Lei Liu, Dan-Dan Yu, Hui-Qiong Han, Jian He, Yanru Qin
Journal: Journal of Clinical Oncology (2025)

367 Background: Recently, PD-1 blockades combined with dual chemotherapy regimens in first-line setting exhibited encouraging efficacy for patients with ESCC. However, the safety profile of conventional dual chemotherapy remained unsatisfactory. Therefore, PD-1 blockades combined with anti-angiogenic tyrosine kinase inhibitors (TKIs) and single chemotherapy regimen might offer a promising strategy. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, demonstrated promising therapeutic activity as first-line combination therapy or second-line monotherapy for ESCC patients in China clinically. Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with penpulimab (PD-1 blockade) and nab-paclitaxel as first-line therapy in advanced ESCC. Methods: Patients with previously untreated metastatic or locally advanced ESCC were recruited and treated with anlotinib (12mg, po, d1~14, q3w) and penpulimab (200mg, iv, d1, q3w) plus nab-paclitaxel (220mg/m 2 , iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 using CT scans every two cycles. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 30. Primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and OS. Results: From Jul 2022 to Sep 2024, a total of 30 patients were enrolled, with 29 patients who had received first tumor response were included in this analysis. The best overall response indicated that there were 1 CR (3.4%), 23 PR (79.3%), 2 SD (6.9%) and 3 NE (10.3%). Therefore, the preliminary ORR was 82.8% (95%CI: 64.2%-94.2%), DCR was 89.7% (95%CI: 72.6%-97.8%). The primary median PFS of the 29 patients was 10.84 months (95%CI: 7.57-14.11). Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-emergent adverse events among the 29 patients with the incidence &gt;20% were anemia (62%), leukopenia (31%), peripheral neurotoxicity (28%) and rash (21%). Common grade ≥3 treatment-emergent adverse events were leukopenia (7%), glutamic-pyruvic transaminase was elevated (3%), glutamic oxalacetic transaminase increased (3%), hypertension (3%), diarrhea (3%) and rash (3%). Conclusions: The combination of anlotinib plus penpulimab and nab-paclitaxel as first-line therapy for advanced ESCC demonstrated promising efficacy and manageable safety profile. And the conclusions needed to be confirmed in subsequent trials. Clinical trial information: ChiCTR2400089133 .
Telotristat ethyl to promote weight stability in patients with advanced pancreatic cancer.
Authors: Olumide B. Gbolahan, Elham Babadi, Tarrant McPherson, Kathleen Coleman, Jeffrey Switchenko, Bassel F. El-Rayes, Olatunji B. Alese, Walid Labib Shaib
Journal: Journal of Clinical Oncology (2025)

747 Background: Cachexia a key feature of pancreatic ductal adenocarcinoma (PDAC), affects up to 80% of patients (pts), and is associated with worse outcomes. Serotonin, due to its tumorigenic potential and effect on gut function may contribute to weight loss in PDAC. Telotristat ethyl (TE) inhibits serotonin production and improves gut motility dysfunction. We developed a phase II trial to evaluate the impact of TE on the weight of patients with metastatic PDAC (mPDAC) receiving first-line chemotherapy. Methods: Treatment-naïve pts with mPDAC who had lost at least 10% of baseline weight (Group 1) received gemcitabine and nab-paclitaxel (GnP) in combination with TE (250mg administered orally three times a day). Pts with &lt; 10% weight-loss were recruited in Group 2 and received chemotherapy without TE. Serum serotonin was collected monthly during the study. The primary endpoint was weight stability, evaluated as % weight change at 3 months compared to baseline, with a goal of &lt; 5% decrease. A key secondary endpoint was change in serotonin levels at 3 months compared to baseline. The groups were analyzed independently. Results: We enrolled 22 pts, 14 in group 1 (planned 40) and 8 in group 2 (planned 40). The median age was 70 years (IQR 62-75), majority were male (n = 15; 68%) and 11 (50%) were Black. Mean weight at treatment start was 77.9 kg (SD 19.16) group 1, and 90.6kg (SD 24.71) group 2. Mean serotonin level at baseline was 165.07 ng/ml (SD 60.49) group 1, and 296.9 ng/ml (SD 166.65) group 2. Mean % weight change over 3 months in group 1 was -2% (90% CI -5.2 to 1.3, P &lt; -5% = 0.0595). Mean change in group 2 was -5.6% (90% CI -9.4 to -1.7%, P &lt; 5% = 0.53). At 3 months, the median change in serotonin level in group 1 was -37.8% (IQR -59.1 to -13, P = 0.064) and -42.6% (IQR-57.8 to -29.9, P = 0.016) for group 2. Adverse events (AE) were consistent with known AE for GnP and TE. The median overall survival was 10.7 months (95% CI 5.4-16.9) group 1 and 12.2 (95% 6.1 to 21.4) group 2, HR 1.41 (95% CI 0.57 to 3.52 P = 0.46). Conclusions: Among pts with mPDAC and cachexia, the addition of TE to chemotherapy led to weight stabilization. These pts experienced 2% weight loss on average during the study (the upper limit of the CI just crossed -5% at -5.2%). The average weight loss was 5.6% in those who did not receive TE suggesting a signal of activity. A larger study is warranted to evaluate the role of TE in the management of cachexia in mPDAC. Funded by Lexicon Pharmaceuticals (NCT03910387). Clinical trial information: NCT03910387 .
Cohort-level patient-derived organoid assays and prediction of clinical trial outcomes in PDAC.
Authors: Gustave Ronteix, Jean Bouteiller, Anna-Rose Gryspeert, Alice Boileve, Cartry Jerome, Jacques RR Mathieu, Sabrina Bedja, Michel Pierre Ducreux, Fanny Jaulin
Journal: Journal of Clinical Oncology (2025)

785 Background: Clinical trials are one of the major barriers in contemporary drug development. Improving the number of therapeutic solutions for patients whilst limiting the financial burden of healthcare systems will require dramatically improving clinical trial success rates. Functional assays based on patient-derived organoids (PDO) are a promising new tool for derisking clinical development of new therapies, but their use has been limited due to small cohort sizes and the absence of systematic validation studies. Methods: We have assembled a collection of 70 demographically relevant PDAC PDOs. Each PDO was screened with a 22-drug panel including standard of care, chemotherapies and targeted therapies. Using a best-in-class patient response prediction model we generate cohort scale estimations of overall response rates (ORR) and progression-free survival (PFS). The estimations are compared with data from published clinical trials to determine the validity of the approach. Results: The PDOs exhibit representative treatment histories in terms of number of lines of treatment (mean = 1.60) and treatment types (prior treatment types: folfirinox = 68.6%, gemcitabine = 50%). All the organoids’ mutational profile, past patient treatments and subsequent responses to future lines were analyzed and compared to the distributions observed in the clinic. The cohort-level drug efficacy on our PDO collection matches retrospective clinical trial ORRs reported in the literature. Furthermore, our preclinical assay predicts the relative performance of drugs in different clinical trial arms. Conclusions: We report that large-scale PDO-based assays predict clinical ORR and PFS with best-in-class accuracy. This work shows that well-characterized PDO collections can be used to improve the success rates of clinical studies for new potential treatments in PDAC.
SIL-204 siRNA encapsulated in extended release microparticles for the treatment of localized cancer that harbors a KRAS G12x or G13D mutation.
Authors: Mitchell Shirvan, Racheli M, Michal Yaron, Elina Zorde, Orit Shragai, Revital Maor Aloni, Adi Bernstein, Doron Shinar, Abraham Nyska, Ilan Hadar, Amnon Peled
Journal: Journal of Clinical Oncology (2025)

745 Background: In a Phase 2 trial, treatment of non-resectable locally advanced pancreatic cancer (LAPC) patients harboring the KRAS G12D or G12V mutations, with SiG12DLoder combined with chemotherapy resulted in superior median overall survival (OS) of 9.3 months over chemotherapy (not statistically significant) and Objective Response Rate of 55% (35% over the chemotherapy control), when administered once every 3 months (Clinical trial # NCT01676259, ESMO 2023, abstract FPN: 1626). SIL-204 which is a modified version of siRNA siG12D is composed of a 21-base sense and 23-base antisense strands, both chemically modified and linked to a lipid. SIL-204 is encapsulated in biodegradable PLGA microparticles (MP), for direct release and injection into KRAS mutated solid tumors using an endoscopic ultrasound procedure. The strategy of preventing the synthesis of KRAS mutated protein may have an advantage over other approaches targeting KRAS function using small molecules. Methods: Methods are presented in results section. Results: SIL-204 has an increase stability over siG12D.To enhance stability, base modifications and phosphorothiate bonds at cleavage sites were implemented. SIL-204 exhibited a half-life of more than 48 hours in human serum. SIL-204 has robust KRAS silencing . When tested in Hepa1-6 cells transfected with individual human KRAS mutations, SIL-204 effectively silenced the various G12x mutations found in pancreatic cancer (D,V,R,C) at sub-nanomolar concentration (IC50 range=0.19-0.59) as well as G13D (IC50 =0.37). Addition of a hydrophobic tail to a prototype of SIL-204, SIL-101, increased the silencing of KRAS. Using PANC-1 cells (KRAS G12D mutation), lipid conjugation of the siRNA doubled the siRNA’s silencing efficiency in these cells. In addition, release of SIL-204 from the MP was tested in rats and indicates a prolong and sustained release over our intended treatment regimen SIL-204-MP was administered to tumors from human pancreatic tumor cell lines Capan-1 (KRAS G12V mutation and labelled with luciferase) grown in NSG mice and Panc-1 (grown in Athymic Nude mice). Bioluminescence imaging of tumor growth showed that SIL-204-MP significantly reduced Capan-1 tumor growth compared to vehicle controls, p&lt;0.0005. Furthermore, histopathological analyses of tumor center slices from Capan-1 and Panc-1 models showed induction of significant tumor necrosis with SIL-204 compared to vehicle controls. Conclusions: The preclinical results of SIL-204-MP are promising and as the potential to further enhance the anti-tumor effect demonstrated by siG12DLoder in pancreatic patients. SIL-204 is now in toxicology studies as preparation for clinical trials in non-resectable pancreatic cancer.
Tislelizumab (Tisle) combined with POFI (irinotecan, paclitaxel, oxaliplatin and 5-FU/levoleucovorin) as first-line treatment of advanced gastric/gastroesophageal junction adenocarcinoma (AGC): OS analysis results of the SYLT-023.
Authors: Liyu Su, Zaisheng - Ye, Changhua Zhuo, Shenghong - Wei, Zhixiong Li, Shen Zhao, Rongbo Lin
Journal: Journal of Clinical Oncology (2025)

450 Background: Tisle is an anti-PD-1 antibody. The combination of Tisle + XELOX/FP is a first-line treatment of AGC in China. Both irinotecan and paclitaxel have also shown antitumor activity in AGC. In this phase I/II study, we explore the safety, tolerability, and efficacy of Tisle + POFI as first-line treatment of HER-2 negative, pMMR AGC. Methods: In a phase I dose finding study using a standard 3+3 design, subjects received four escalating dose levels (dl) of irinotecan/paclitaxel (mg/m 2 ): 135/45 (dl #1), 150/45 (dl #2), 135/67.5 (dl #3), and 135/90 (dl #4) in combination with tisle 200 mg plus oxaliplatin 85 mg/m 2 , levoleucovorin 200 mg/m 2 , and 5-FU 2400 mg/m 2 for 46 hours every 2 weeks. Primary endpoints were safety, tolerability, and RP2D. Results: Fifteen subjects with treatment naïve AGC were enrolled (3 each in dl #1, dl #2, and dl #3 and 6 in dl #4). The median age was 65 years (range 36-72); 80% were male. Two subjects (13.3%) were diagnosed with GE junction cancer, 11 (73.3%) had undifferentiated disease, and 5 (33.3%) had liver metastasis. PD-L1 CPS scores were: 5 (n=5); 1 (n=1); and 0 (n=9). All subjects were evaluated for DLT. One DLT (grade 4 neutropenia) occurred within 28 days in dl #4. No maximum tolerated dose was reached; the RP2D was dl #4. As of 18th Sep 2024, confirmed objective response rate in 13 subjects with measurable disease was 100% (1 CR, 12 PR) per RECIST 1.1. Of the 2 subjects with non-measurable disease, one was a CR and the other was non-CR/non-PD. The median PFS was 10.51 (95% CI: 7.44, 13.58) months (versus 6.9 [5.7-7.2] months for ITT population for RATIONALE 305, ESMO 2023), the median DOR was 7.39 (95% CI: 5.34, 9.44) months, and the median OS was 14.75 (95% CI: 5.48, 24.02) months. The OS showed no significant differences between CPS ≥ 1 and CPS &lt; 1. All subjects (100%) had AEs. Seven (n=7, 46.67%) of the 15 subjects reported grade ≥3 AEs, including neutropenia (n=7; 46.67%), leukopenia (n=3; 20%), anemia (n=2; 13.33%). Conclusions: Tisle+POFI was well tolerated and showed preliminary antitumor activity in AGC. A phase II study is ongoing. Clinical trial information: NCT05319639 .