tbuckley/cabot-search huggingface dataset:
A phase 1/2, safety lead-in and dose expansion, open-label, multicenter trial investigating the safety, tolerability, and preliminary activity of ivosidenib in combination with nivolumab and ipilimumab in previously treated subjects with IDH1-mutated nonresectable or metastatic cholangiocarcinoma.
Authors: Robin Kate Kelley, James M. Cleary, Vaibhav Sahai, Marina Baretti, John A Bridgewater, Zhaowei Hua, Camelia Gliser, Ying Bian, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2024)

TPS4197 Background: Cholangiocarcinoma (CCA) is a rare cancer with limited therapeutic options, though molecularly targeted therapies have demonstrated anti-tumor activity in certain subsets. Approximately 15% of patients with intrahepatic CCA harbor activating mutations in isocitrate dehydrogenase-1 (mIDH1), and treatment with the mIDH1 inhibitor, ivosidenib (IVO) improved progression-free survival in the phase 3 ClarIDHy trial. mIDH1 is associated with an immune-excluded tumor microenvironment, and anti-CTLA4 immune checkpoint inhibition (ICI) augments anti-tumor activity when combined with IVO in preclinical models. Preliminary anti-tumor activity of dual immune checkpoint inhibitors (IPI, NIVO) has been reported in biliary tract cancers. Methods: This is a phase 1/2, non-comparative, multicenter, open-label study of IVO, IPI, NIVO, in subjects with unresectable or metastatic CCA with mIDH1. Key eligibility criteria include: a histopathological diagnosis; tumor mIDH1 based on local testing; progression on and/or intolerance to 1-2 prior lines of systemic therapy, at least one of which contained either gemcitabine and/or 5-fluorouracil; prior anti-PD-(L)1 therapy is allowed in the safety lead in; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; at least 1 measurable lesion as defined by RECIST version 1.1. The study has a safety lead-in phase and an expansion phase with 2 different expansion cohorts: cohort 1, ICI-naive; cohort 2, prior ICI allowed. The primary objective is to evaluate the safety and tolerability of IVO in combination with IPI plus NIVO and determine the recommended combination dose (RCD). This phase will enroll ~6 to 12 dose-limiting toxicity (DLT)–evaluable patients. The first 6 patients enrolled will receive IVO 500 mg orally once daily in combination with IPI 1 mg/kg IV infusion and NIVO 3 mg/kg IV infusion concurrently once every 3 weeks for 4 doses followed by NIVO at 480 mg IV once every 4 weeks until progression or unacceptable toxicity (up to a maximum of 24 months of NIVO). DLTs will be evaluated during the first 2 cycles of treatment. An additional 6 patients may be enrolled to assess an alternative dose of ivosidenib 250 mg once daily. Upon determination of the RCD, the two expansion cohorts will be initiated to assess the clinical activity of the triplet combination in patients with and without prior ICI. First patient in occurred in November 2023. Clinical trial information: NCT05921760 .
Treatment duration of adjuvant immune checkpoint inhibitor in hepatocellular carcinoma after curative resection: A prospective cohort study.
Authors: Li-Xin Pan, Jia-Yong Su, Le Li, Xiao-Hui Fan, Liang Ma, Jian-Hong Zhong
Journal: Journal of Clinical Oncology (2024)

e16266 Background: Adjuvant immune checkpoint inhibitors (ICIs) improve the recurrence-free survival for patients with hepatocellular carcinoma (HCC) after hepatic resection. However, the appropriateness of the treatment duration is unknown. This prospective cohort study aims to evaluate the effect of adjuvant ICIs duration in patients with HCC at high risk of recurrence after curative hepatic resection. Methods: Recurrence-free survival, overall survival, and adverse events were compared in patients receiving adjuvant ICIs therapy for more than 6 months or up to 6 months between March 2019 and March 2023. Patients who with HCC recurrence within 6 months after hepatic resection were excluded. Results: Of the 118 patients, 53 (44.9%) received longer than 6 months of adjuvant therapy, 65 (55.1%) received up to 6 months of adjuvant therapy. Recurrence-free and overall survivalwere significantly longer among patients who received longer than 6 months of adjuvant therapy than among those who received up to 6 months adjuvant therapy (HR 0.47, 95%CI 0.24–0.92, P = 0.021; HR 0.28, 95%CI 0.08–0.93, P = 0.045). However, patients who received more than 6 months of adjuvant therapy had a higher rate of adverse events than those who received up to 6 months of adjuvant therapy, especially grade 2 adverse events. Conclusions: Six months of adjuvant ICIs therapy may not be enough, but prolonged adjuvant therapy can significantly increase the incidence of adverse events. This study highlights the need to optimize the duration of adjuvant ICIs after curative resection for HCC in order to minimize risk of not only recurrence but also adverse events.
A phase II study of cadonilimab plus mFOLFIRINOX as induction therapy for locally advanced pancreatic adenocarcinoma (LAPC).
Authors: Kuirong Jiang, Min Tu, Dong Xu, Nan Lv, Qianqian Wang
Journal: Journal of Clinical Oncology (2024)

TPS4213 Background: Locally advanced pancreatic adenocarcinoma (LAPC) constitutes a significant proportion of pancreatic cancer, which ranks among the most lethal malignancies globally. Treatment options specifically tailored for LAPC patients (pts) are scarce, and chemotherapy alone yields limited efficacy. Various studies have provided supportive evidence for the synergistic effects of combining immunotherapy with chemotherapy in the context of pancreatic cancer. Cadonilimab, a novel recombinant humanized bispecific antibody, holds the capability to concurrently inhibit PD-1 and CTLA-4 pathways, thereby restoring T-cell immune response to the tumor. This study aims to assess the efficacy and safety of combining cadonilimab with modified FOLFIRINOX for the treatment of LAPC. Methods: This ongoing phase II trial is enrolling pts with histologically or cytologically confirmed unresectable LAPC who have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1 and have not previously received systemic anti-tumor therapy. Eligible pts will be administered cadonilimab (6mg/kg, intravenous drip, Day 1, every 2 weeks) plus mFOLFIRINOX (oxaliplatin 85mg/m 2 , Day 2 + leucovorin 400mg/ m 2 , Day 2 + irinotecan 150mg/ m 2 , Day 2 + 5-fluorouracil 2,400mg/ m 2 , continuous infusion for 46 hours) for a total of 4 cycles (8 weeks). After the completion of every 4 treatment cycles, pts will undergo imaging examinations of tumor lesions. Pts will receive treatment continuously until surgical resection, disease progression, intolerable toxic reactions, initiation of new anticancer drug treatments, withdrawal from the study, death, or loss of follow-up. Following the 12th cycle of treatment, maintenance treatment will consist of capecitabine or S-1 in combination with cadonilimab. The primary endpoint of this study was the R0/R1 resection rate. The main secondary endpoints include the objective response rate (ORR) per RECIST 1.1, progression-free survival (PFS), overall survival (OS), and safety assessments. Additionally, pts will undergo peripheral blood next-generation sequencing (NGS) panel analysis before and after treatment to investigate the correlation between circulating tumor DNA (ctDNA) changes, surgical decisions, and prognosis. Enrollment is ongoing. Clinical trial information: NCT06153368 .
A randomized, multi-center, phase 2 study of ivaltinostat (Ival) plus capecitabine (Cape) versus capecitabine alone in the maintenance setting in patients with metastatic pancreatic adenocarcinoma (mPDAC).
Authors: Christos Fountzilas, Andrew H. Ko, Erkut Hasan Borazanci, James Thomas D'Olimpio, J. Randolph Hecht, Shou-Ching Tang, Anthony F. Shields, Mohamad Adham Salkeni, Glenn Michelson, Gene Cho, Lorna Liganor, Sangsook Ahn Cho, Evan Justin Walker
Journal: Journal of Clinical Oncology (2024)

TPS4206 Background: Front-line chemotherapy for patients (pts) with advanced or mPDAC typically consists of mFOLFIRINOX or gemcitabine/nab-paclitaxel given until disease progression or intolerable toxicity. For pts with durable disease control on front-line treatment, maintenance therapy that can effectively delay disease progression while preserving quality of life with minimal cumulative toxicity is highly desirable. Ivaltinostat (ival) is a pan-histone deacetylase inhibitor that increases histone acetylation, suppresses PDAC cell proliferation, and promotes apoptosis in PDAC cell lines. Preclinical data demonstrated synergy with 5-FU/cape in mouse models. RP2D of the Phase 1b combination study of ival and cape in advanced pancreatic cancer was ival 250mg/m 2 IV on days 1 and 8 with cape 1000mg/m 2 po days 1-14 of a 21-day cycle. Both ival and cape treatment-related AEs &gt;15% were fatigue, nausea, diarrhea, and decreased appetite. Palmar-plantar erythrodysaesthesia syndrome was also commonly observed; all events were attributed to cape. PK and PD demonstrated dose proportionality. Overall and progression-free survival (PFS) were immature, but 70% of pts who enrolled with measurable disease had stable disease as best response. Several pts remained on study with the longest duration of response about 10 months, as of the data cut off for ASCO GI 2024. Based on this data, a randomized phase 2 study is being conducted comparing the combination of ival and cape versus cape alone in the maintenance setting for pts with mPDAC after first line FOLFIRINOX, mFOLFIRINOX or NALFIRINOX therapy. Methods: Key eligibility criteria for the randomized Phase 2 study include: mPDAC; no evidence of disease progression following at least 16 weeks of front-line FOLFIRINOX or NALIRIFOX at full or modified doses; ECOG PS 0-1; and no known germline BRCA1/2 mutation. A total of 52 pts will be randomized 1:1 to receive cape with or without ival until disease progression, with tumor assessments occurring at 6-week intervals. The primary endpoint is investigator-adjudicated PFS, and the primary analysis will compare PFS distributions in the ival/cape and cape alone arms using a one-sided log rank test with an alpha=0.10. The assumed 6-mo PFS rates are 35% (cape), based on historic data, and 60% (ival/cape), corresponding to an HR of 0.487. Enrollment in the phase 2 study began in January 2024 across multiple sites in the US. Accrual is anticipated to complete 4Q2024. Clinical trial information: NCT05249101 .
Machine learning identification of hypoxia-related genes and prognostic risk-scoring model for effective survival stratification in hepatocellular carcinoma.
Authors: Huang Mohan, Wing Chi Chan
Journal: Journal of Clinical Oncology (2024)

e16261 Background: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality globally, where treatment and prognostic assessment have important implications in clinical practice. Hypoxia, as a common feature within solid tumors, can directly change the tumor microenvironment, which affects the efficacy of cancer treatment and prognosis. In this study, we constructed and validated a hypoxia-based prognostic model using bioinformatics and machine learning. Methods: Two public datasets, GSE14520 and GSE41666, were collected from the Gene Expression Omnibus: (1) HCC tumor tissues compared to adjacent normal tissues (N = 214) and (2) HepG2 cells under normoxic and hypoxic conditions (N = 6). Differential expression analysis was performed to identify HCC characteristic genes and hypoxia-related genes, including their common genes (HCC-Hypoxia Overlap genes, HHOs). Using RNA-seq data of HCC patients (N = 367) from the TCGA Liver Cancer (LIHC) database, univariate Cox regression models were identified, and the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm selected hypoxia-characteristic genes for the multivariate survival model. A hypoxia-related risk score was calculated based on the model of these characteristic genes and dichotomized cases into high-risk (HR) and low-risk (LR) groups. The model was validated using liver cancer cases (N = 232) from the International Cancer Genome Consortium database (ICGC-LIRI-JP). Results: Through differential expression analysis of the two datasets, we identified 52 HHOs. Univariate Cox analysis of these HHOs indicated that 21 genes were significantly associated with HCC patient survival. Through LASSO regression analysis, a total of 9 characteristic genes, including CENPA, KIF20A, DLGAP5, HMMR, UPB1, AFM, CABYR, PHLDA2, and N4BP2L1 were ultimately retained in the survival model. Based on these 9 genes, TCGA-LIHC samples were classified into HR and LR groups, and Kaplan-Meier (KM) analysis revealed significant differences in survival outcomes (p &lt; 0.032). Risk scoring of the ICGC-LIRI-JP validation set classified samples into HR and LR. KM analysis showed that the survival times of patients in the HR group were significantly shorter than those in the LR group (p &lt; 0.0001). Receiver Operating Characteristic Analysis analysis of the survival model showed area under the curve values of 0.815, 0.774, and 0.771 at 1, 2, and 3 years, respectively, demonstrating high performance in risk stratification. Conclusions: This study established a prognostic risk-scoring model based on 9 characteristic genes associated with hypoxia. This model can effectively stratify risks among HCC patients and demonstrate excellent performance in predicting survival. These findings may offer new biomarkers and therapeutic targets for the personalized treatment of HCC.
Risk factors associated with liver cancer in all US participants.
Authors: Chenxi Xiong, Jing Su, X Charlie Dong
Journal: Journal of Clinical Oncology (2024)

e16276 Background: Liver cancer incidence rates have risen in recent years, more than tripled since 1980, and the liver cancer-caused death rates have more than doubled during the same time. The objective of this research was to identify significant risk factors (both genetic and environmental) that may contribute to the liver cancer development. Methods: The study cohort was obtained from the All of Us (AoU) population with the latest data (data cutoff date 07/01/22) of 413,457 participants. The baseline survey data, genomics data, and electronic medical data have been queried for studying the risk factors to the liver cancer. Baseline demographics, comorbidities, AUDIT-C score (positive score, defined as &gt; = 5 for men and &gt; = 4 for women, was considered as with high risk of alcoholic hepatitis), social determinants of health (SDoH), and genetic variants were evaluated using the logistic regression models respecting the prevalence of liver cancer. Results: The study cohort included total 254,356 participants with their EMR data, genomics data, and AUDIT-C answers (median age 55 years, 61% women, 45% from minority groups, 19% Hispanics). Among them, 1,048 patients were diagnosed liver cancer. Using the logistic regression models, SDoHs showed association with the development of liver cancer. Retired groups demonstrated higher risk (adjusted odds ratio or aOR: 1.34, 95%CI:1.09-1.67) as well as the unemployed groups (aOR: 1.19, 95%CI: 0.98-1.46). C &gt; G variants at 22:43928847 (aOR: 1.18, 95%CI: 1-1.39), G &gt; G variants at 22:43937814 (aOR: 1.35, 95%CI: 0.97-1.82), and G &gt; A variants at 22:43932850 (aOR: 1.18, 95%CI: 0.99-1.39) of gene PNPLA3 were associated with higher risks. C &gt; T variants at 19:19268740 of gene TM6SF2 demonstrated higher risks (aOR: 1.23, 95%CI: 0.97-1.54) as well. The following demographic and comorbidities factors significantly contributed to the development of liver cancer: 45 to 65 age group (aOR: 6.89, 95%CI: 4.05-13), greater than 65 (aOR: 9.99, 95%CI: 5.84-18.91), hepatitis c virus infection (aOR: 12.46, 95%CI: 10.51-14.75), diabetes with chronic complications (aOR: 1.49, 95%CI: 1.25-1.78 ), diabetes without chronic complications (aOR: 1.81, 95%CI: 1.53-1.2.14). Conclusions: This study reveals that multiple risk factors are significantly associated with the liver cancer ranging from common genetic variants, socioeconomic conditions, age, viral infection, and diabetes. Thus, it is very important to take a comprehensive approach for the liver cancer prevention.
Temporal dynamics and prognostic significance of cancer free status in patients with intermediate stage hepatocellular carcinoma: A multicenter cohort study.
Authors: Lujun Shen, Chen Li, Wei-Jun Fan
Journal: Journal of Clinical Oncology (2024)

e16236 Background: A proportion of patients with intermediate stage hepatocellular carcinoma (HCC) can achieve cancer free status (CFS) during treatment, the prognostic value of CFS across the period of dynamic surveillance and treatment remained unknown. Methods: This longitudinal cohort study examined data from the electronic medical record system of four hospitals in China between January 1, 2007 to May 31, 2019. The data from Sun Yat-sen University Cancer Center served as the derivation cohort and other centers as testing cohort. The time-series data were converted into data of time slices, with an interval of three months. Image CFS is defined as patients with no evidence of disease based on imaging exams after treatment and Image-Bio CFS is defined as achievement of Image CFS, together with normal AFP level. Based on the dynamic changes of disease during treatment, patients at specific time slice were classified into either “Arrive”, “Maintain”, or “Not reached” CFS subgroups. The correlations between CFS subgroups and overall survival (OS) were determined by Cox regression. Results: A total of 945 (42.2%) and 741 (33.1%) patients in derivation cohort reached Image CFS and Image-Bio CFS during treatment, respectively. The corresponding rates for Image CFS and Image-Bio CFS in testing cohort were 155 (37.4%) and 130 (31.4%), respectively. Maintaining Image CFS or Image-Bio CFS, rather than just arrive Image CFS or Image-Bio CFS, had stable predictive value for improved OS across different time slices. The merged Hazard ratio of Maintain Image-Bio CFS was 0.23 (95%CI, 0.20-0.25, P &lt; 0.001). The patients achieved Image-Bio CFS could be further classified into three subgroups with differential prognosis based on duration of CFS (≤ 4.5months; 4.5-18.0 months; &gt; 18.0 months). Maintaining Image-Bio CFS for more than 18.0 months predicted long term survival (5-year OS: 91.2% in derivation cohort, 94.7% in testing cohort). Conclusions: Maintaining CFS, rather than just arrive CFS, is a key marker of favorable survival during dynamic management of intermediate stage HCC. A duration of Image-Biochemical CFS for more than eighteen months predicts long-term survival.
Adjuvant therapy with donafenib plus anti–PD-1 antibody for patients (pts) with hepatocellular carcinoma (HCC) at high risk of recurrence after resection (PATH study).
Authors: Yiwen Chen, Yan Shen, Min Zhang, Jian Wu, Shunliang Gao, Risheng Que, Jun Yu, Xiaofeng Tang, Xueli Bai, Tingbo Liang
Journal: Journal of Clinical Oncology (2024)

e16228 Background: There is no universally accepted standard treatment option or strategy for post-surgery adjuvant therapy for HCC. Among BCLC A/B patients with MVI, adjuvant TACE provided a 1-year recurrence-free survival rate (RFSR) of around 60-70%. We conducted a pilot study to explore the utility of donafenib combined with anti-PD-1 antibody as adjuvant therapy for pts with high risks of recurrence. Methods: It was planned to enroll 30 HCC pts who had undergone radical surgery and with at least one of the following risk factors: a) Presence of microvascular invasion (MVI); b) Presence of satellite nodule(s); c) &gt; 3 tumor nodules; d) Portal vein tumor thrombus. Pts with invasion of main portal venous were excluded. Donafenib plus anti-PD-1 antibody was initiated at 4 to 8 weeks after resection and continued for up to six months. No other adjuvant therapies were allowed before enrollment and during the study, except for anti-virus treatment. The primary endpoint was the cumulative 1-year RFSR. The secondary endpoints included recurrence-free survival (RFS), overall survival, and safety. Results: From June 2020 to November 2023, a total of 30 pts were recruited. 27 pts were included in efficacy analysis. The mean and median follow-up time was 347.9 days and 179.5 days. The mean and median time from surgery to enrollment was 42.5 days and 42.0 days. MVI was the most common risk factor (Table). Majority of the pts had only one risk factor. Relapse occurred in two pts (7.4%) and RFS was very immature. The RFSR at one year was 89.7% (90% CI, 70.6%-96.7%) in all the evaluable pts, and slightly higher in pts with M1 or only one risk factor (92.9% [90% CI, 68.1%-98.6%] and 93.3% [90% CI, 69.9%-98.7%], respectively). No deaths were observed. In 30 pts who had received at least one dose, the incidence of grade 3 treatment-related adverse events (TRAEs) was 40.0% (12/30). No grade 4 or 5 TRAEs were reported. The grade 3 TRAEs occurred in ≥2 pts were palmar-plantar erythrodysesthesia syndrome (13.3%), rash (13.3%), alanine aminotransferase increased (10.0%), and aspartate aminotransferase increased (6.7%). Conclusions: These results showed that a regimen of 6 months of adjuvant therapy with donafenib plus anti-PD-1 antibody may be efficient to reduce recurrence for BCLC A/B pts at high risk of recurrence, particularly those with ≤2 risk factors. No new safety issues were noticed. Clinical trial information: NCT04418401 . [Table: see text]