bluuebunny/crossref_metadata_2025 huggingface dataset:
Tislelizumab (TIS) versus sorafenib (SOR) in first-line (1L) treatment of unresectable hepatocellular carcinoma (HCC): The RATIONALE-301 European/North American (EU/NA) subgroup.
Authors: Vogel Arndt , Meyer Tim , Assenat Eric , Calvo Campos Mariona , Li Songzi , Chen Yaxi , Boisserie Frederic , Abdrashitov Ramil , Marino Donatella , Finn Richard S.
Published: June 2023

4082

Background: HCC is one of the most commonly diagnosed cancers globally. Most cases occur in Asia, although a number of patients (pts) are affected in Europe and North America. In the phase 3, open-label RATIONALE-301 trial (NCT03412773), TIS, a PD-1 inhibitor, showed non-inferior overall survival (OS) versus SOR (hazard ratio 0.85, 95% CI: 0.71, 1.02), and a favorable safety profile, in 1L treatment of pts with unresectable HCC. Here, efficacy and safety of TIS versus SOR in the RATIONALE-301 EU/NA subgroup were compared with the overall population (OP). Methods: Systemic therapy-naïve adults with histologically confirmed HCC were randomized (1:1) to receive TIS (200 mg IV Q3W) or SOR (400 mg orally BID) until disease progression, intolerable toxicity, or withdrawal. The primary endpoint was OS; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and duration of response (DoR) by blinded independent review committee per RECIST v1.1, and safety. Results: In the EU/NA subgroup (172/674 pts randomized), at data cutoff (July 11, 2022), median (m) OS follow-up was 37.9 months (mo) (TIS) vs 38.5 mo (SOR). At baseline, fewer pts in the EU/NA subgroup had Barcelona Clinic Liver Cancer (BCLC) Stage C disease (70% vs 78%) and extrahepatic spread (51% vs 62%), and more had a non-viral etiology (60% vs 24%) or underlying HCV infection (28% vs 13%) than in the OP, respectively. Distribution of other baseline characteristics was generally similar between the EU/NA subgroup and the OP. Efficacy data in the EU/NA subgroup were consistent with the OP. Numerically longer mOS and mDoR, higher ORR, and similar mPFS were observed with TIS versus SOR in the EU/NA subgroup. In the EU/NA safety population, incidence of ≥grade 3 treatment-emergent adverse events (TEAEs; 46% vs 66%), ≥grade 3 treatment-related TEAEs (TRAEs; 17% vs 50%), and TRAEs leading to discontinuation (9% vs 15%) was lower with TIS versus SOR, respectively, similar to the OP. Conclusions: In the RATIONALE-301 EU/NA subgroup, mOS of TIS was non-inferior versus SOR, consistent with the findings from the OP. Numerically longer mOS and mDoR, and a higher ORR was seen with TIS versus SOR in the EU/NA subgroup, which had a higher rate of pts with non-viral etiology and a slightly lower number of pts with advanced-stage disease (BCLC Stage C) compared with the OP. Clinical trial information: NCT03412773 . [Table: see text]
A novel patient-centric longitudinal data registry platform to generate insights into real-world cholangiocarcinoma (CCA) clinical practice.
Authors: Nottke Amanda , Javle Milind M. , Borad Mitesh J. , Azad Nilofer Saba , Brimble Elise , Martin Richard L , OBrien Conner , Lindsey Stacie , Bachini Melinda , Maithel Shishir K.
Published: June 2023

4084

Background: Treatment of advanced CCA has changed dramatically over the past five years with the advent of molecularly targeted therapy, now approved in the 2nd line and beyond. However, real world utilization of molecular profiling and targeted therapy is still unknown and these data are critical to empower treatment decision-making. Methods: In 2019, the Cholangiocarcinoma Foundation (CCF) and Ciitizen (a wholly owned subsidiary of Invitae Corporation) collaboratively launched a registry platform that directly consents patients and collects comprehensive medical records. De-identified data including clinical characteristics, molecular testing, interventions, and outcomes are extracted and standardized for research use. The data is longitudinal with regularly planned updates; registry participants can be re-engaged to obtain additional data and communicate tailored insights. Results: We quantified the rate of molecular testing, the presence of targetable biomarkers, and the utilization and outcomes on matched targeted therapies for 372 individuals with CCA. 328 (88.2%) individuals had molecular testing, with the identified targetable mutations and matched therapies reported. Of 328 individuals who had molecular testing, 111 (33.8%) individuals had one or more targetable mutations (116 mutations total). Only 46% (51) of individuals with targetable mutations received targeted therapy. Of the 54% (60) individuals with targetable mutations that did not receive any matched therapy, the majority (61.7%, 37) were in early disease or first line of treatment and therefore not yet eligible for targeted therapy. These individuals will be informed that based on their molecular profile, a targeted therapy may be an option, and suggest they discuss with their treating physician. Conclusions: A novel prospectively-maintained database registry for CCA has been formed in collaboration between a patient advocacy organization (CCF) and industry (Invitae). Prevalence of actionable biomarkers was higher than historically expected and may reflect patient utilization bias of the registry platform. Molecular profiling and access to targeted therapeutics remains suboptimal at this time in CCA. Future directions for the registry include identifying and targeting disparities in care and supporting biopharmaceutical development and regulatory decisions. [Table: see text]
Racial and socioeconomic disparities in time to chemotherapy and survival in patients with pancreatic cancer.
Authors: Shah Shivani , Rock James , Wegner Rodney E. , Monga Dulabh K.
Published: June 2023

4100

Background: Pancreatic cancer is traditionally known to be an aggressive malignancy, requiring timely diagnosis and treatment, including chemotherapy and/or surgery. Prior studies have evaluated variances in overall survival (OS) based on race or income; however, research regarding time to treatment based on racial and socioeconomic disparities is underwhelmingly studied. Our project sought to evaluate the impact of race and income on time to chemotherapy and OS in pancreatic cancer patients receiving neoadjuvant or adjuvant chemotherapy. Methods: The National Cancer Database (NCDB) from 2004-2020 was reviewed for patients with a diagnosis of pancreatic cancer, including all types and stages. Exclusion criteria included: no documented income level, time to first treatment surgery, or time to chemotherapy. Our patient population was then separated into two cohorts: neoadjuvant and adjuvant. Income level was stratified into the following: < $30,000, $30,000-34,999, $35,000-$45,999, and > $46,000. Race was also noted. We utilized a logistic regression to identify factors associated with longer time to chemotherapy (using median time to chemotherapy as a benchmark for early or later initiation of chemotherapy). A Cox proportional hazards model was used to identify factors associated with worse survival. A p-value < 0.05 was deemed significant. Results: Our final sample size included 64,640 patients. 6,887 (10.6%) of patients had an income less than $30,000. 55,340 (85.6%) of patients were Caucasian, 6,379 (9.9%) patients were African American, and 172 (0.002%) were American Indian. 18,679 (28.9%) received neoadjuvant chemotherapy, and 45,961 (71.1%) received adjuvant chemotherapy. Median time to chemotherapy was 27 [0-2048] days and 71 [0-1895] days in the neoadjuvant and adjuvant cohorts, respectively. Within both cohorts, income > $46,000 was noted to have significantly earlier time to chemotherapy compared to lower income levels. Those privately insured had significantly earlier time to chemotherapy compared to uninsured. The African American population was associated with a later time to first chemotherapy in comparison to Caucasians in both subgroups. A significantly less OS in the African American population was appreciated in the neoadjuvant cohort (HR 0.92, p-value 0.02), but not the adjuvant cohort. Conclusions: Our retrospective analysis emphasizes that minorities and/or those with a poor socioeconomic status have significant delay in time to chemotherapy in the neoadjuvant and adjuvant setting. Within the African American neoadjuvant cohort, a significantly worse OS was highlighted. This study emphasizes racial and socioeconomic disparities in our healthcare system. Limitations of our study include its retrospective nature and no information regarding the type of surgery the patients received, which could further account for differences in time to chemotherapy.
Association of a high E2F targets score with survival in hepatocellular carcinoma patients.
Authors: Chida Kohei , Oshi Masanori , Roy Arya Mariam , Yachi Takafumi , Nara Masaki , Yamada Kyogo , Matsuura Osamu , Hashizume Tadashi , Endo Itaru , Takabe Kazuaki
Published: June 2023

4106

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality. Multiple staging systems have all been proposed to date; however, the optimal tool for stratification of prognosis is still not universally accepted. E2F targets are the essential component of cell proliferation, thus we hypothesized that a score to quantify E2F activity is expected to reflect the aggressiveness and prognosis of HCC. Methods: Total of 655 HCC patients from TCGA (The Cancer Genome Atlas) -HCC ( n=358), GSE6764 ( n=75), GSE76427 ( n = 115), and GSE89377 ( n=107) cohorts were analyzed. The score was generated using MSigDb Hallmark E2F Targets gene set using Gene Set Variation Analysis. Results: The E2F targets scores of TGCA-HCC patients showed a bimodal distribution, thus high vs. low score groups were divided by median. As expected, high E2F targets enriched all of the Hallmark cell proliferation-related gene sets; E2F targets, G2M checkpoint, MYC targets v1 and v2, and Mitotic spindle. It also enriched gene sets known to aggravate cancer, such as Glycolysis, mTORC1 signaling, DNA repair, and Unfolded protein response. E2F targets were significantly associated with histological grade, tumor size, and stage, as well as proliferation score and MKI67 expression. Furthermore, a higher E2F targets score was significantly associated with higher intra-tumoral genomic heterogeneity and homologous recombination deficiency, suggesting greater tumor aggressiveness. In agreement, E2F targets score correlated with the pathological progression from normal liver, cirrhosis, dysplasia, to early and advanced HCC consistently in two cohorts (GSE6764 and GSE89377). Further, the abundance of hepatocytes, fibroblasts, adipocytes, and lymphatic endothelial cells were all significantly less in high E2F HCC, which reflects proliferative cancer. On the other hand, there was no relationship between E2F and mutation rates or neoantigens. High E2F was associated with high infiltration of anti-cancerous immune cells; CD8, CD4 memory, and Th1 cells, however, there was no difference in cytolytic activity, and it did not enrich any of immune response-related gene sets. High E2F HCC was associated with worse disease-free (DFS), disease-specific (DSS), and overall survival (OS), and this was the case in both early (I and II) and late (III and IV) stages. A multivariate analysis revealed that the E2F targets score was an independent prognostic factor for OS (HR=1.68, 95%CI= 1.15–2.46, p = 0.007) as well as DSS (HR=1.81, 95%CI=1.27–2.59, p = 0.001) in patients with HCC. Conclusions: We found that the E2F targets score not only indicates cell proliferation, but also is associated with cancer aggressiveness and worse survival. Our findings suggest a possible future use of the E2F targets score as a prognostic biomarker in patients with HCC.
Evaluating racial disparities for patients with advanced hepatocellular carcinoma (HCC) receiving first line immunotherapy within an equal access system.
Authors: Boyle Lauren Diaz , Alkadimi Munaf , Fierro Maria Elena , Lucero Kana , Franklin Kathleen , Mader Michael , Nooruddin Zohra
Published: June 2023

4109

Background: The incidence and mortality of HCC are increasing in the USA. HCC disparities have been reported across the entirety of the cancer timeline, from screening to local and systemic treatment and liver transplant. We aim to analyze the clinical characteristics, outcomes, and racial disparities in patients with advanced HCC receiving first-line Atezolizumab plus Bevacizumab (A+B) in the Veterans Health Administration (VHA) – the only health care system in the USA that provides equal access to all patients. Methods: Patients were followed from their A+B initiation date through the earliest of the last VHA visit, loss to follow-up, death, or end of study on Jan 31, 2023. Structured electronic health record and chart review data were retrospectively collected to determine patient baseline characteristics, including self-reported race, number of A+B doses, treatment response, subsequent line of treatment, length of follow-up, and overall survival (OS). The Chi-Squared test was used to compare rates, and Mann-Whitney test was used to compare medians. Results: Three hundred twenty-five patients were included. 64% were non-Hispanic White (NHW), and 36% were all other (AO) ethnicities or races combined (26% Black, 8% Hispanic, 2% Asian or Indigenous). The median age for each cohort was similar (66 years for AO vs. 68 for NHW), and ECOG performance was <1 in nearly 90% of each cohort. Viral hepatitis accounted for 70% and 48% of AO and NHW, respectively (p=0.0001). Despite clinical differences in OS and progression free survival (PFS), they were not statistically significant. Conclusions: Our VHA real-world data shows that despite having statistically significant etiologies, there was no statistically significant difference in the PFS and OS of patients with advanced HCC receiving first-line A+B in an equal access care system. This study supports our group’s findings in other malignant cohorts within VHA where equal healthcare access can mitigate other socio-demographic and biological factors. [Table: see text]
The clinical feasibility of circulating tumor DNA alterations in patients with advanced hepatocellular carcinoma.
Authors: Kim Gwangil , Hwang Sohyun , Kang Haeyoun , Cheon Jaekyung , Kang Beodeul , Kim Chan , Chon Hong Jae
Published: June 2023

4110

Background: Need for individualized treatment based on tumor attributes is being reinforced with the rapid development of targeted therapies and immune checkpoint inhibitors for hepatocellular carcinoma (HCC). Lack of mandatory tissue biopsy for the diagnosis of HCC, continues to be a challenge for development of precision medicine for HCC compared to other solid tumors. Liquid biopsy enables comprehensive genomic profiling of circulating tumor DNA (ctDNA) shed from tumors into the circulation. This could compensate for the lack of tissue-based analysis in HCC providing a non-invasive and safer option for genomic profiling. This study aims to address the concordance between commercially available ctDNA and tissue genomic profiling in patients with advanced HCC and to assess the feasibility of liquid biopsy in the treatment of patients with HCC. Methods: Patients subjected to tissue-based next-generation sequencing (NGS) before systemic therapy for advanced HCC at CHA Bundang Medical Center from June 2020 to October 2022 and also had sufficient plasma samples available for ctDNA analysis were included. Oncomine Comprehensive Assay (OCA) ThermoFisher was used for tissue-based NGS and Guardant360 for ctDNA based NGS. For the concordance assessment for the same patient, paired samples of ctDNA and tumor tissue, we investigated the common targeted regions across both the panels. Results: Out of hundred thirty patients included in this study, 98% percent of ctDNA samples for these patients were successfully sequenced; ctDNA were detected in 88% of the samples. For the assessment of concordance between intra-patient ctDNA and tumor tissues, we investigated only clinically important (AMP/ASCO/CAP guidelines tier 1 or 2) variants. When we considered the variants detected in tissues as true positive, the concordance between the mutations detected from ctDNA and tissue samples indicated 68.9% sensitivity and 63.1% positive predictive value (PPV). In ctDNA, targetable alterations were detected in 16.9% of samples, such as ARID1A mutations (7.7%), PTEN mutations (6.9%), PIK3CA hotspot mutations (1.5%), RAS mutations (1.5%), and one RET fusion (0.8%). Regarding the concordance between ctDNA and tumor tissue, the sensitivity for mutation was high for RAS mutation (100.0%), PTEN mutations (100.0%), and ARID1A mutations (75.0%) but low for PIK3CA hotspot mutations (0.0%). One RET fusion was identified only in ctDNA. Conclusions: ctDNA-based genotyping demonstrated clinically acceptable concordance with tissue genomic profiling in patients with advanced HCC. Thus, liquid biopsy using ctDNA help address any challenges associated with the limited use of tissue-based genomic profiling in HCC. Investigation of time between blood and tissue collection and the impact it has on concordance is ongoing.
Lenvatinib (LEN) combined with tislelizumab (TIS) plus transcatheter arterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (uHCC): A single-arm, phase II clinical trial.
Authors: Nong Xiang , Zhang Yu-Mei , Liang Jing-Chang , Xie Jin-Long , Zhang Zhi-Ming
Published: June 2023

4111

Background: uHCC still lacks effective treatments, combination of antiangiogenic targeted drugs and immune checkpoint inhibitors showed promising efficacy. TACE induces tumor necrosis and tumor antigen release, may synergize with immunotherapy. This study was to evaluate the efficacy and safety of TACE in combination with TIS and LEN in patients with uHCC. Methods: This study was a single-center, single-arm, open-label phase II exploratory clinical study (NCT05131698). Eligible patients were BCLC C stage and not candidates for surgical resection or liver transplantation, at least one target lesion evaluable, ECOG performance status of ≤ 1, and Child-pugh grade A or B. Enrolled patients received TACE treatment (loplatin + raltitrexed + iodine oil) followed by TIS (200 mg, IV, on Day 1 of a 21-day cycle) and LEN (body weight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day) daily. The primary endpoint was overall response rate (ORR) by mRECIST. The secondary endpoints included disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) and safety. Results: As of December 28, 2022, 31 enrolled patients with uHCC were treated. Median follow-up time is 11.3 months. Among all patients with BCLC C, 28 patients (90.3%) had microvascular invasion and 17 (54.8%) had portal vein tumor thrombus. As assessed by mRECIST, the ORR and DCR were 71.1% and 87.1%, respectively (2 CR, 6.6%; 20 PR, 64.5%; 5 SD, 16.1%), 4 patients developed tumor progression (12.9%). As assessed by RECIST 1.1, the ORR and DCR were 67.7% and 87.1%, respectively (1 CR, 3.2%; 20 PR, 64.5%; 6 SD, 19.4%), 4 patients developed tumor progression (12.9%). The median PFS was 10.2 months（95% CI: 4.5-NA）, and the median OS was not reached. Any grade treatment-emergent adverse events (TEAEs) occurred in 64.5% (20/31) patients. The most common TEAEs were Increased γ-glutamyl transpeptidase (35%), Increased aspartate aminotransferase (32%), thrombopenia (25%). Only 2 patients experienced grade 3 TEAE (pneumonia). No serious adverse events (SAEs) were reported. Conclusions: In this study, TACE combined with TIS and LEN showed preliminary antitumor efficacy and tolerable safety profile in uHCC. Clinical trial information: NCT05131698 . [Table: see text]
Molecular subtypes from comprehensive clustering from multi-omics dataset to predict the therapeutic efficacy of immunotherapeutic agent-based treatments in advanced hepatocellular carcinoma.
Authors: Chon Hong Jae , Lee Sung Hwan , Kim Gwangil , Kang Haeyoun , Cheon Jaekyung , Kang Beodeul , Kim Chan
Published: June 2023

4112

Background: In advanced hepatocellular carcinoma (HCC), combined treatment using anti-PD-L1 and anti-VEGF antibodies is a major therapeutic strategy in addition to using anti-PD-1 and anti-CTLA4 target agents. To identify clinically relevant molecular biomarkers for immunotherapeutic agents-based treatment in advanced HCC by comprehensive molecular profiling using genomics alterations and transcriptomic data. Methods: Multi-omics data from clinical tumor samples of patients treated with atezolizumab + bevacizumab (94 patients), nivolumab (40 patients), and ipilimumab + nivolumab (32 patients) were obtained from tumor biopsies or surgical resections in a single institution. The targeted panel sequencing was conducted via the Oncomine comprehensive assay (ThermoFisher, USA). QuantSeq mRNA sequencing (Lexogen, USA) was used to generate datasets for the genomic alterations and gene expression profiles. Results: A total of 166 target sequences for genomic alterations and 136 transcriptomic sequences were performed in patients with advanced HCC treated with immunotherapeutic agent-based treatment options. High tumor mutation burden was significantly associated with favorable therapeutic efficacy (disease control rate, P=0.036) and progression-free survival (P=0.037) in patients who had atezolizumab with bevacizumab treatment. The genomic alteration of CTNNB1 mutation correlated with the favorable therapeutic efficacy of nivolumab monotherapy (PFS, P=0.022), contrary to TP53 mutation (PFS, P=0.063) which demonstrated unfavorable outcomes. CD274(PD-L1) mRNA expression was significantly associated with a high drug response following nivolumab monotherapy (objective response rate, P=0.047) and oncologic outcomes (PFS, P=0.021). Interestingly, PLA2G4A, known as a downstream molecule of the VEGF signaling pathway, was highly correlated with unfavorable therapeutic efficacy of the combined atezolizumab with bevacizumab treatment (disease control rate, P=0.002) and related oncologic outcomes (PFS, P=0.003). We also identified the clinically relevant molecular subtypes from unbiased clustering using the ontologic pathway collection. We also used gene expression profiles to predict the therapeutic response and oncologic outcomes from immunotherapeutic agent-based treatment options. Conclusions: We identified clinically relevant molecular biomarkers from comprehensive clustering of a multi-omics dataset to predict the therapeutic efficacy and oncologic outcomes. Further prospective studies with clinical validation are warranted to confirm clinical implications.
Tracking the evolving ecosystem of recurrent hepatocellular carcinoma after liver transplantation.
Authors: Zhang Zijie , Wang Gaoyang , Ye Youqiong , Feng Hao , Xia Qiang
Published: June 2023

4114

Background: Liver transplant (LT) contributes to the cure of hepatocellular carcinoma (HCC) by extending the conventional surgical margin, while removing the concurrent tumor-favoring conditions of the diseased liver. Over the past two decades, HCC has emerged as a preferable indication for LT, accounting for 22-45% of the cases globally. However, despite the stringent selection criteria, recurrence still occurs in a substantial proportion of patients, leaving 10-13 months of median survival after tumor relapse. To address this challenge, a thorough exploration of molecular mechanism behind HCC recurrence after LT is required. Here, for the first time, we performed a comprehensive analysis to depict the evolving and unique ecosystem of HCC in the context of LT and immunosuppressant (IS) administration. Methods: We retrospectively reviewed our biobank and collected 91 paired (primary tumors (PT) from the explant after LT and relapsed tumors (RT) from hepatectomy) FFPE tumor samples from 15 patients for whole exome sequencing (WES). Also, from Jan 2021, we prospectively collected surgical tumor specimens and their adjacent non-tumor tissues from 15 primary and 6 post-LT intrahepatic recurrence patients for single-cell RNA sequencing. Moreover, 6 paired samples from 3 patients were used for spatial transcriptomic analysis. Results: By analysing WES data, we confirmed that RT samples represent recurrent, instead of de novo tumors. Also, the phylogenetic analysis demonstrated strong clonal relationship between PT and RT based on shared SNVs. As to mutation landscape differences of PT and RT, we identified a significantly enriched mutation panel from RT, including MUC16, FAT3, APOB, COL6A3 and POTEC. And the accuracy of this panel for post-LT HCC recurrence surveillance using plasma derived cfDNA sequencing has been preliminarily validated in a prospective cohort of 17 patients. From the single-cell profiling, distinct immune microenvironment between PT and RT is identified. As predicted, proliferating T cells are decreased in RT due to IS. Pseudotime analysis of T cells revealed that T cells from PT mainly distribute at the terminal end of cytotoxic stage whereas T cells from RT mostly represent a naïve state, further confirming the T cell blocking effect of IS. In terms of myeloid cells, we surprisingly found that FOLR2+ tumor associated macrophages, which is conventionally considered as a favorable prognosis factor, is increased in RT. Spatial transcriptomics and IHC also confirmed their active interplay with tumor cells at invasive margin. We postulate that such increase might be a result of the healthy nature of liver graft. Conclusions: Our comprehensive dissection of the HCC ecosystem provides deeper insights into the tumor relapse after LT. Targeting novel mutations and strengthen the antigen presenting process between increased TAM and disabled T cells can be the future direction in this field. Clinical trial information: NCT04506398 .
Geographical and baseline clinical characteristics of participants enrolled in hepatocellular carcinoma (HCC) trials: Analysis of US FDA approvals.
Authors: Horiba M. Naomi , Gandhy Shruti U. , Casak Sandra J. , Lemery Steven , Kluetz Paul , Pazdur Richard , Fashoyin-Aje Lola A.
Published: June 2023

4115

Background: Globalization of drug development is increasing, with reliance on data from patients accrued to large, randomized studies across continents. In addition to appropriate racial/ethnic representation, trials submitted to support FDA approvals should reflect the etiology and treatment patterns of HCC in the US. We conducted a pooled analysis of patient-level data from the HCC trials supporting approved marketing applications in the US to characterize geographical and baseline variables in clinical trials. Methods: Datasets from applications which received FDA approval for HCC between 2010-2022 were identified. The following data was abstracted: country, baseline disease characteristics (median age, HCC etiology, extent of tumor, and Child-Pugh score), and prior treatments received. Geographical region was recoded using categories observed by the United Nations M49 standard, based on country of enrollment reported in the datasets. Results: Variables that were defined differently across studies included region of enrollment, some categories of etiology, and prior therapy. Overall, the rate of HBV etiology was higher than that observed among patients with HCC in the US (20%), while the rate of HCV etiology was lower than in the US (50%). Conclusions: Variability in patient populations exist across trials submitted to FDA based on the regions that were targeted for enrollment and eligibility criteria. Global trials may be appropriate to support drug approvals for HCC; however, to ensure results are applicable to US patients, sponsors should select sites that represent a similar population with respect to racial/ethnic representation, disease etiology, and treatment patterns. [Table: see text]
Effect of MYC-targeting programmable epigenetic mRNA therapeutics on TME and immunotherapy responses.
Authors: Moore Yan , Senapedis William , Gallagher Kayleigh , Figueroa Elmer , Pacaro Madison , Yarar Defne , Lee Eugine , McCauley Thomas
Published: June 2023

4116

Background: c-MYC is a master transcription factor (TF) critical for multiple cell physiologies. As a pleiotropic TF, MYC regulates the tumor microenvironment (TME) and impacts cancer cell initiation, growth, and survival. Although MYC expression is normally tightly controlled in normal cells, its activity is frequently dysregulated in cancer (e.g., HCC, NSCLC, Burkitt’s lymphoma). A direct MYC targeting anti-cancer agent has remained elusive, largely due the absence of a drug binding pocket and tight autoregulation. The MYC gene and its regulatory elements reside alone within an insulated genomic domain and represents a potential target for gene regulation via an epigenetic approach. Methods: We are developing programmable epigenetic mRNA medicines designed to controllably tune gene expression pre-transcriptionally with high specificity and durability. We have rationally designed MYC-targeted Omega Epigenomic (MYC-OEC: clinical candidate OTX-2002; MYC Lung OEC; mouse surrogate muMYC-OEC) to downregulate MYC expression, thereby selectively killing cancer cells while sparing normal cells. We investigated the role of MYC-OECs in the modulation of the TME and demonstrated in human and mouse tumor models that MYC-OECs enhanced the host immune response. Results: In HCC and NSCLC cell lines (Hep 3B, SKHEP1, H2009 and H460), treatment with MYC-OECs in vitro significantly inhibited PD-L1 surface expression. Using the muMYC-OEC in vivo, we demonstrated tumor growth inhibition (TGI) in Hepa1-6 liver cancer syngeneic tumor models with 70% of the mice exhibiting complete tumor response with good tolerability. Cancer cells used to rechallenge the cured mice failed to grow, demonstrating that muMYC-OEC monotherapy induced immune memory. In addition to inhibiting tumor growth with either muMYC-OEC or checkpoint blockade immunotherapy (CBI; anti-PD-1 or anti-PD-L1) treatment, combination therapy further enhanced TGI. Tumor-infiltrating lymphocyte profiling demonstrated an increase in activated T cells and a reduction in Tregs following combination treatment, resulting in an increased effector T cell to Treg ratio over monotherapy. Depletion of CD4+, CD8+ and NK cells in vivo prior to single agent or combination treatment demonstrated a requirement for both CD4+ and CD8+ T cell activity for TGI. NK cells were dispensable. Taken together, these data demonstrate that the improved CBI/MYC-OEC combination activity is mediated through the recruitment of activated T cells and reduction of immune suppressive Tregs. Conclusions: These efficacy and tolerability data support the combination of MYC-OEC and CBI treatment in patients with solid tumors. OTX-2002 is currently being evaluated in a Phase 1/2 clinical trial as a monotherapy and in combination with SoC (i.e., TKI and CBIs) for patients with HCC and other solid tumor types known for an association with MYC.
Camrelizumab in combination with apatinib as a perioperative treatment for patients with hepatocellular carcinoma at high risk of recurrence: A prospective, single-arm, phase 2 study.
Authors: Cui Yunlong , Bao Xu , Yu Ge , Li Huikai , Fang Feng , Li Qiang , Zhang Wei , Wu Qiang , Chen Lu , Liu Chen , Song Tianqiang
Published: June 2023

4120

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and a rising cause of cancer-related mortality. To date, the optimal perioperative treatment strategy for HCC patients remains unclear. It is urgent to develop novel and reliable therapeutic interventions to reduce the risk of recurrence and improve survival in patients with locally advanced HCC. Methods: This prospective, exploratory, single-arm, phase 2 study enrolled patients with primary resectable HCC who had not received prior systemic therapy. Before surgery, patients received combination treatment with four cycles of camrelizumab (200 mg, Q2W) plus apatinib (250 mg, QD). Each cycle was two weeks. The feasibility of hepatic resection was assessed by radiographic imaging. After 4-8 weeks of surgery, patients continued combination therapy (camrelizumab [200 mg, Q2W] and apatinib [250 mg, QD]) for one year. Primary endpoint was major pathological response (MPR). Secondary endpoints were pathologic complete response rate (pCR), objective response rate (ORR), disease-free survival (DFS), and safety. Exploratory endpoint was microvascular invasion (MVI). This study is registered on Clinical Trials.gov, number NCT04701060. Results: Between Jan 12, 2021, and Aug 17, 2022, 31 patients with a median age of 54 years were enrolled. Among these, 21 patients (67.7%) had hepatitis B virus infection. Before surgical incision, two patients withdrew informed consent. Therefore, ORR based on RECIST 1.1 and mRECIST were 13.8% (4/29) and 48.3% (14/29), respectively. 26 patients underwent hepatic resection, R0 resection rate was 100%, 10 (38.5%) patients achieved MPR, and pCR rate was 7.7%. The reasons for patients not undergoing surgery were disease progression and serious adverse events (AEs). Among patients with MVI, M0 was found in 57.7% (15/26) patients, MI was found in 34.6% (9/26) patients, and M2 was found in 7.7% (2/26) patients. 1-year DFS rate was 77.4%, and median DFS was not reached. The most common AEs included increased aspartate aminotransferase (74.2%), increased alanine aminotransferase (70.1%), decreased platelet count (61.3%), anemia (58.1%), and decreased lymphocyte count (51.6%). Grade 4 AEs occurred in 7 of 31 patients, and there were no treatment-related deaths. Conclusions: Camrelizumab plus apatinib as a perioperative treatment is effective and tolerable in patients with HCC at high risk of recurrence. Preoperative neoadjuvant therapy has reduced the rate of MVI. Because of the short follow-up period, whether perioperative treatment can effectively reduce recurrence rates and improve long-term survival still needs further investigation. Clinical trial information: NCT04701060 .
Utility of circulating tumor DNA (ctDNA) as a predictive biomarker for disease monitoring in patients (pts) with cholangiocarcinoma (CCA) before and during adjuvant chemotherapy (ACT): Sub-analysis of the randomized phase 2 STAMP trial.
Authors: Yoo Changhoon , Laliotis George , Jeong Hyehyun , Jeong Jae Ho , Kim Kyu-Pyo , Lee Seonmin , Ryoo Baek-Yeol , Sharma Shruti , Dutta Punashi , Malhotra Meenakshi , Jurdi Adham A , Liu Minetta
Published: June 2023

4123

Background: Detection of circulating tumor DNA (ctDNA) in blood is a powerful predictive biomarker for identifying molecular residual disease (MRD) post-surgery. Not much is known about the utility of identifying MRD using ctDNA in pts with resected CCA, despite its associated poor prognosis. The STAMP trial (NCT03079427), a randomized phase 2 study comparing adjuvant capecitabine (CAP) to gemcitabine plus cisplatin (GemCis) showed no difference in recurrence-free survival (RFS) and overall survival (OS) between the 2 arms. The goal of this analysis was to evaluate the feasibility of monitoring ctDNA to predict the risk of recurrence in pts with resected CCA. Methods: A total of 254 plasma samples were collected from a cohort of 89 CCA (hilar, N = 43; distal, N = 46) pts post-surgery at 3 separate time points; pre-ACT (baseline, N = 89), on-ACT C5D1 (after 5 cycles of treatment) (N = 88), and on-ACT C8D1 (after 8 cycles of treatment) (N = 77). Longitudinal ctDNA testing was performed using a personalized, tumor-informed ctDNA assay (Signatera, bespoke mPCR-NGS assay). ctDNA results were analyzed and evaluated for its correlation with RFS and OS. Results: At the MRD timepoint (baseline, pre-ACT), 24.7% (22/89) pts were ctDNA-positive, 90.9% (20/22) of whom recurred demonstrating a trend for shorter RFS (HR = 1.7, 95%Cl 0.98-2.8, p = 0.069) compared to ctDNA-negative pts. All pts who remained ctDNA-positive on-ACT at C5D1 (N = 17) and C8D1 (N = 15), recurred clinically with a significantly shorter RFS (HR = 8.1, 95%Cl 4.3-15, p < 0.0001 and HR = 5.0, 95%Cl 2.7-9.4, p < 0.0001, respectively). The primary cancer site (hilar vs distal) or type of ACT (CAP vs GemCis) had no impact on RFS irrespective of ct-DNA result. Pts who remained ctDNA-negative on ACT (N = 56) showed significantly better RFS compared to pts who remained positive (N = 10, HR = 6.6, 95%Cl 3.1-14, p < 0.001), or who turned positive (N = 11, HR = 5.2, 95%Cl 2.54-10.5, p < 0.001). In multivariate analysis including primary tumor site, sex, pathological grade and ACT regimen, positive ctDNA status at baseline (pre-ACT) remained significant for poor RFS (HR = 1.82, 95%CI 1.04-3.18, p = 0.035). Conclusions: Personalized monitoring of ctDNA both pre and on-ACT is feasible and predictive for recurrence in pts with resected CCA. To our best knowledge, this is one of the first reports presenting the clinical implication of ctDNA monitoring on ACT, in pts with CCA. Our findings suggest ctDNA monitoring may help optimize clinical decision-making in pts with resected CCA. Larger prospective studies would be needed to validate the findings of this study. Clinical trial information: NCT03079427 .
Development and validation of a non-invasive cfDNA targeted sequencing assay for early-stage hepatocellular carcinoma detection using cfDNA methylation and fragmentomics.
Authors: Liu Rui , Guo De-Zhen , Huang Ao , Ma Cheng-Cheng , Xu Min-Jie , Liu Yi-Ying , Su Ming-Yang , Chen Hua , Zhang Yun-Zhi , He Qi-Ye , Su Zhi-Xi , Yang Xin-Rong , Fan Jia , Zhou Jian
Published: June 2023

4128

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers in China, and one of the leading causes of cancer-related deaths in the country. With a 5-year survival rate of only 15-20%, early detection is crucial to improve the treatment and survival of HCC patients. Currently, alpha-fetoprotein (AFP) is commonly used as a serum marker for HCC, but it is not a sufficiently specific and can cause false positive readings due to elevated levels caused by other liver conditions. An alternative method is to use circulating free DNA (cfDNA) released by tumor cells as cancer-screening targets, which has been shown to be a more sensitive and specific biomarkers for HCC detection. This study aims to develop a non-invasive screening assay based on cfDNA features to improve the detection of early-stage HCC. Methods: Candidate methylation markers for HCC detection were collected and evaluated using GEO, TCGA and in-house datasets, 1601 of which were incorporated into a targeted sequencing panel named HcSeer. Multiple types of cfDNA features were constructed from the sequencing data, which included methylation-related features such as methylation haplotype blocks (MHBs) and methylated haplotype fraction (MHF), and fragmentomics features such as end motif and CNV. For model building, Cancer and healthy plasma samples were randomly divided into a training and a testing set at a 2:1 ratio. A two-step deep neural network model was built to classify HCC using selected features of both types. Results: We previously enrolled a total of 401 plasma samples (200 healthy, 201 HCC) for model construction and the performance of the HcSeer model have been documented. An independent validation cohort of 421 plasma samples (280 healthy, 141 HCC) was currently collected from different centers. In this independent validation, the HcSeer model achieved an AUC of 0.98 with a sensitivity of 96.5% at a specificity of 96.4%. Importantly, HcSeer maintained a high sensitivity for HCC across all stages: 94.3%, 96%, 100% and 100% for stage I – IV cases, respectively. When compared to AFP, HcSeer achieved a significantly higher sensitivity of 94% than AFP’s 55% in 137 HCC cases having AFP level tested. When AFP level was combined with the HcSeer model, the sensitivity for HCC further increased to 96%. Conclusions: This study demonstrated that the DNA methylation and fragmentomics patterns of cfDNA can accurately distinguish HCC and healthy plasma samples, particularly in the early stages of HCC. The combination of the HcSeer and AFP further improved the accuracy of the prediction. Although this study was limited in sample size, it clearly showed the potential of the HcSeer assay for accurate HCC detection in blood.
Prevalence of germline variants in patients with pancreatic neuroendocrine tumors.
Authors: Mohindroo Chirayu , Baydogan Seyda , Agarwal Parul , Laheru Dan , Wright Robin , Prakash Laura , Mork Maureen E , Klein Alison , Maxwell Jess , Katz Matthew H. G. , Dasari Arvind , Kim Michael Paul , He Jin , McAllister Florencia , De Jesus-Acosta Ana
Published: June 2023

4135

Background: About 10% of pancreatic neuroendocrine tumors (pNETs) are thought to be related to inherited syndromes, including multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 4 (MEN4), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). Here, we report the prevalence of pathological/likely pathological germline variants (PV/LPV) in 2 cohorts: 1) High-risk and 2) Unselected. Methods: We retrospectively collected clinical data of patients with biopsy proven pNETs seen at MD Anderson Cancer Center (MDACC) and Johns Hopkins Hospital (JHH). Cohort 1 (high risk cohort) included 132 patients seen at MDACC, who underwent germline testing based on high-risk criteria such as early onset, personal or family history of cancer and syndromic features between 2013 -2019. Cohort 2 (unselected cohort) included 106 patients seen at JHH, who underwent germline testing following their diagnosis of pNETs between 2020 to 2022. Results: In the high-risk cohort (n = 132), 33% (n = 44) had PV/LPV, and 17 % (n = 22) had a variant of unknown significance (VUS). Amongst the 132 patients, 35% underwent multigene panel testing, 53% had targeted germline testing and 12% had a physician documented outside test diagnosis. The demographics consisted of 52%(n = 69) females, 67% (n = 88) white, 54%(n = 71) had metastatic disease, 58%(n = 76) underwent surgical resection. WHO grading (n = 77) is as follows G1 (39%), G2 (59%), G3 (2%). In the unselected cohort (n = 106), 21% (n = 22) had PV/LPV, 28 % (n = 30) had a VUS. Of these, 93% of the patients underwent multigene panel testing. The demographics consisted of 42% (n = 44) females, 67% (n = 88) white, 48% (n = 51) had metastatic disease, 60% (n = 64) underwent surgical resection, WHO grading (n = 93) is as follows G1 (37%), G2 (49%), G3 (14%). Conclusions: PV/LPV are prevalent in patients with sporadic pNET irrespective of high-risk features or family history. While in the high-risk patients there is a higher prevalence, we also identified a 21% prevalence of PV/LPV with universal germline testing in the unselected cohort. In both cohorts, we identified a high number of mutations in the DNA repair pathway not previously described, which could affect subsequent therapies and surveillance for patients and their family members. The findings support upfront universal germline testing in all patients with diagnosis of pNETs. [Table: see text]
Phase 2 trial of pembrolizumab and olaparib (POLAR) maintenance for patients (pts) with metastatic pancreatic cancer (mPDAC): Two cohorts B non-core homologous recombination deficiency (HRD) and C exceptional response to platinum-therapy.
Authors: Park Wungki , O'Connor Catherine , Chou Joanne F. , Schwartz Carly , Varghese Anna M. , Larsen Mary , Balogun Fiyinfolu , Brenner Robin , Yu Kenneth H. , Diguglielmo Erin , Umeda Shigeaki , Karnoub Elias , Keane Fergus , Zhang Haochen , Joshi Smita Suhas , Riaz Nadeem , Kelsen David Paul , Capanu Marinela , Iacobuzio-Donahue Christine A , O'Reilly Eileen Mary
Published: June 2023

4140

Background: Maintenance olaparib improves PFS in g BRCA1/2m (core HRD) in mPDAC (Golan, NEJM 2019). Whether other HRD indicators, such as gene mutations other than g BRCA1/2m (non-Core HRD, Cohort B) and exceptional platinum responders (Cohort C, response > 6 months) may benefit from PARPi in mPDAC remains unanswered. We hypothesized that pembrolizumab and olaparib (POLAR) combination may improve outcome by immunogenic cell death. Methods: We conducted an open-label, non-randomized, phase 2 trial of POLAR as maintenance therapy for pts with mPDAC whose disease had not progressed for 4 months (m) in Cohort B or 6 m in C. Herein, we report on Cohorts B & C. Eligibility: ECOG 0-1, mPDAC meeting eligibility of B or C. POLAR (Pembrolizumab 200mg IV Q3W+ OLApaRib 300mg BID) until disease progression or limiting toxicity. Objective response rate (ORR), median PFS (mPFS), median overall survival (mOS), disease control rate (DCR), CA 19-9, cfDNA and baseline HRD mutational signature were analyzed. Results: Cohorts B and C enrolled N=15 each. N=25 pts evaluable by RECIST 1.1. Median follow-up 9.9 (1.3-22.8) and 11.3 (5.8-23) m, respectively. Efficacy details are shown. G3-5 AEs related to treatment: 5/14 (36%): 1 diarrhea (7%), 1 hyperglycemia (7%), 2 anemia (14%), 1 lipase increased (7%). Cohort B: 9/15 (60%) ATM, 3 CHEK2, 2 MUTYH, 1 BLM, 1 FANCC. Canonical gene mutations for mPDAC were less common for pts in Cohort B, especially in ATM PA group (n=9) vs C. Median genomic instability score (GIS) was computed and higher 28 (0-38) vs 9 (0-24) in Cohort B vs C, p=0.052. Median tumor mutation burden (TMB) was not different between B and C (3.3 and 4.1). Conclusions: Clinical activity of POLAR maintenance observed in select pts in B and C. Although PFS was modest (mPFS of 4m [2.1-5.4] in B + C), an intriguing survival signal (mOS at 14m [10-NR] from first POLAR dose) was seen in select patients without chemotherapy. Extensive correlative analyses underway to evaluate response and resistance (SPORE: 1P50CA257881-01A1). Cohort A (core HRD) actively accruing. Clinical trial information: NCT04666740 . [Table: see text]