COMPANION-002 A clinical trial of investigational drug CTX-009 plus paclitaxel vs paclitaxel in second line advanced BTC.

Treatment options for patients with biliary tract cancer are limited, and the prognosis is poor. CTX-009, a novel bispecific antibody targeting both DLL4 and VEGF-A, has demonstrated antitumor activity in patients with advanced cancers as both a monotherapy and in combination with chemotherapy. In a phase II study of patients with advanced biliary tract cancer who had received one or two prior therapies, CTX-009 with paclitaxel demonstrated a 37.5% overall response rate (ORR). Described here is the design of and rationale for COMPANION-002, a randomized phase II/III study, which will evaluate the safety and efficacy of CTX-009 in combination with paclitaxel versus paclitaxel alone as second-line treatment for patients with advanced biliary tract cancer. The primary end point is ORR, and crossover is allowed.Clinical Trial Registration: NCT05506943 (ClinicalTrials.gov).

Looking for new options for patients with advanced biliary tract cancer? Explore COMPANION-002, Compass Therapeutics' phase II/III study of CTX-009 + paclitaxel as a second line treatment.#CMPX #biotech #healthcare #rarecancer.

Predictive and Prognostic Potential of Liver Function Assessment in Patients with Advanced Hepatocellular Carcinoma: A Systematic Literature Review.

Introduction: We conducted a systematic literature review to assess the utility of liver function assessments for predicting disease prognosis and response to systemic anticancer therapy in patients with advanced hepatocellular carcinoma (aHCC). Methods: This was a PRISMA-standard review and was registered with PROSPERO (CRD42021244588). MEDLINE and Embase were systematically searched (March 24, 2021) to identify publications reporting the efficacy and/or safety of systemic anticancer therapy (vs. any/no comparator) in liver-function-defined subgroups in phase 2 or 3 aHCC trials. Screening was completed by a single reviewer, with uncertainties resolved by a second reviewer and/or the authors. English-language full-text articles and congress abstracts were eligible for inclusion. Included publications were described and assessed for risk of bias using the GRADE methodology. Results: Twenty (of 2,579) screened publications were eligible; seven categorized liver function using the albumin-bilirubin system, nine using the Child-Pugh system, four using both. GRADE assessment classified ten, nine, and one publication(s) as reporting moderate-quality, low-quality, and very-low-quality evidence, respectively. Analyses of cross-trial trends of within-exposure arm analyses (active and control) reported a positive relationship between baseline liver function and overall survival and progression-free survival, supporting liver function as a prognostic marker in aHCC. There were also signals for a modest relationship between more preserved baseline liver function and extent of systemic treatment benefit, and with more preserved liver function and lower incidence of safety events. Conclusion: This review supports liver function as a prognostic variable in aHCC and highlights the value of a priori stratification of patients by baseline liver function in aHCC trials. The predictive value of liver function warrants further study. Findings were limited by the quality of available data.

Immune Checkpoint Inhibitors for Child-Pugh Class B Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Importance: Immune checkpoint inhibitors (ICIs) are increasingly used in patients with advanced hepatocellular carcinoma (HCC). However, data on ICI therapy in patients with advanced HCC and impaired liver function are scarce. Objective: To conduct a systematic review and meta-analysis to determine the efficacy and safety of ICI treatment for advanced HCC with Child-Pugh B liver function. Data Sources: PubMed, Embase, Web of Science, and Cochrane Library were searched for relevant studies from inception through June 15, 2022. Study Selection: Randomized clinical trials, cohort studies, or single-group studies that investigated the efficacy or safety of ICI therapy for Child-Pugh B advanced HCC were included. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guideline was followed to extract data. A random-effects model was adopted if the heterogeneity was significant (I2 > 50%); otherwise, a fixed-effect model was used. Main Outcomes and Measures: The objective response rate (ORR) and overall survival (OS) were considered to be the primary efficacy outcomes of ICI treatment for Child-Pugh B advanced HCC, and the incidence of treatment-related adverse events (trAEs) was set as the primary measure for the safety outcome. Results: A total of 22 studies including 699 patients with Child-Pugh B and 2114 with Child-Pugh A advanced HCC comprised the analytic sample (median age range, 53-73 years). Upon pooled analysis, patients treated with ICIs in the Child-Pugh B group had an ORR of 14% (95% CI, 11%-17%) and disease control rate (DCR) of 46% (95% CI, 36%-56%), with a median OS of 5.49 (95% CI, 3.57-7.42) months and median progression-free survival of 2.68 (95% CI, 1.85-3.52) months. The rate of any grade trAEs in the Child-Pugh B group was 40% (95% CI, 34%-47%) and of grade 3 or higher trAEs was 12% (95% CI, 6%-23%). Compared with the Child-Pugh A group, the ORR (odds ratio, 0.59; 95% CI, 0.43-0.81; P < .001) and DCR (odds ratio, 0.64; 95% CI, 0.50-0.81; P < .001) were lower in the Child-Pugh B group. Child-Pugh B was independently associated with worse OS in patients with advanced HCC treated with ICIs (hazard ratio, 2.72 [95% CI, 2.34-3.16]; adjusted hazard ratio, 2.33 [95% CI, 1.81-2.99]). However, ICIs were not associated with increased trAEs in the Child-Pugh B group. Conclusions and Relevance: The findings of this systematic review and meta-analysis suggest that although the safety of ICI treatment was comparable between patients with HCC with vs without advanced liver disease and the treatment resulted in a significant number of radiologic responses, survival outcomes are still inferior in patients with worse liver function. More study is needed to determine the effectiveness of ICI treatment in this population.

Polyunsaturated Fatty Acid-Bound α-Fetoprotein Promotes Immune Suppression by Altering Human Dendritic Cell Metabolism.

α-Fetoprotein (AFP) is expressed by stem-like and poor outcome hepatocellular cancer tumors and is a clinical tumor biomarker. AFP has been demonstrated to inhibit dendritic cell (DC) differentiation and maturation and to block oxidative phosphorylation. To identify the critical metabolic pathways leading to human DC functional suppression, here, we used two recently described single-cell profiling methods, scMEP (single-cell metabolic profiling) and SCENITH (single-cell energetic metabolism by profiling translation inhibition). Glycolytic capacity and glucose dependence of DCs were significantly increased by tumor-derived, but not normal cord blood-derived, AFP, leading to increased glucose uptake and lactate secretion. Key molecules in the electron transport chain in particular were regulated by tumor-derived AFP. These metabolic changes occurred at mRNA and protein levels, with negative impact on DC stimulatory capacity. Tumor-derived AFP bound significantly more polyunsaturated fatty acids (PUFA) than cord blood-derived AFP. PUFAs bound to AFP increased metabolic skewing and promoted DC functional suppression. PUFAs inhibited DC differentiation in vitro, and ω-6 PUFAs conferred potent immunoregulation when bound to tumor-derived AFP. Together, these findings provide mechanistic insights into how AFP antagonizes the innate immune response to limit antitumor immunity. SIGNIFICANCE: α-Fetoprotein (AFP) is a secreted tumor protein and biomarker with impact on immunity. Fatty acid-bound AFP promotes immune suppression by skewing human dendritic cell metabolism toward glycolysis and reduced immune stimulation.

Immunology and immunotherapy of cholangiocarcinoma.

Cholangiocarcinoma is the second most common primary liver cancer. Its incidence is low in the Western world but is rising globally. Surgery, chemotherapy and radiation therapy have been the only treatment options for decades. Progress in our molecular understanding of the disease and the identification of druggable targets, such as IDH1 mutations and FGFR2 fusions, has provided new treatment options. Immunotherapy has emerged as a potent strategy for many different types of cancer and has shown efficacy in combination with chemotherapy for cholangiocarcinoma. In this Review, we discuss findings related to key immunological aspects of cholangiocarcinoma, including the heterogeneous landscape of immune cells within the tumour microenvironment, the immunomodulatory effect of the microbiota and IDH1 mutations, and the association of immune-related signatures and patient outcomes. We introduce findings from preclinical immunotherapy studies, discuss future immune-mediated treatment options, and provide a summary of results from clinical trials testing immune-based approaches in patients with cholangiocarcinoma. This Review provides a thorough survey of our knowledge on immune signatures and immunotherapy in cholangiocarcinoma.

Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma.

BACKGROUND: Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors. METHODS: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. RESULTS: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment. CONCLUSIONS: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).

What is the gender representation in authorship in later phase systemic clinical trials in biliary tract cancer (BTC)? - a retrospective review of the published literature.

OBJECTIVES: Female physicians in medicine are increasing, but disparities in female authorship exist. The aim of this study was to characterise factors associated with female first (FF) and female senior (SF) authorship in later phase systemic oncological clinical trials in biliary tract cancer (BTC) and identify any changes over time. SETTING: Embase/Medline identified trial publications in BTC (2000-2020) were included. χ2 tests and log regression were used (assessed factors associated with FF and SF authorship, including changes over time (STATA V.16)). PRIMARY OUTCOME MEASURE: FF and SF authorship in later phase systemic oncological clinical trials in BTC. SECONDARY OUTCOME MEASURE: Any changes over time? RESULTS: Of 501 publications, 163 met inclusion criteria. The median percentage of female author representation in publications was 25%; there were no female authors in 13% of publications. Geographic location of the home institution of the first and senior authors was Asia (42%/42%), Europe (29%/29%), USA (24%/22%) and other (4%/6%), respectively. Overall, FF and SF author representation was 20% and 10%, respectively. The median position of the first female author was second in all the publication author lists. The phase of trial, journal-impact factor, industry funding or whether the study met its primary endpoint did not impact FF/SF author representation. More SF authors had home institutions in 'other' geographic locations (40% in 10 trials) (p=0.02) versus Asia (6%), Europe (8%) and USA (14%). There were no significant changes in FF/SF representation over time (p=0.61 and p=0.33 respectively). CONCLUSIONS: FF and SF author representation in later phase systemic clinical trial publications in BTC is low and has not changed significantly over time. The underlying reasons for this imbalance need to be better understood and addressed.

Circulating monocytes associated with anti-PD-1 resistance in human biliary cancer induce T cell paralysis.

Suppressive myeloid cells can contribute to immunotherapy resistance, but their role in response to checkpoint inhibition (CPI) in anti-PD-1 refractory cancers, such as biliary tract cancer (BTC), remains elusive. We use multiplexed single-cell transcriptomic and epitope sequencing to profile greater than 200,000 peripheral blood mononuclear cells from advanced BTC patients (n = 9) and matched healthy donors (n = 8). Following anti-PD-1 treatment, CD14+ monocytes expressing high levels of immunosuppressive cytokines and chemotactic molecules (CD14CTX) increase in the circulation of patients with BTC tumors that are CPI resistant. CD14CTX can directly suppress CD4+ T cells and induce SOCS3 expression in CD4+ T cells, rendering them functionally unresponsive. The CD14CTX gene signature associates with worse survival in patients with BTC as well as in other anti-PD-1 refractory cancers. These results demonstrate that monocytes arising after anti-PD-1 treatment can induce T cell paralysis as a distinct mode of tumor-mediated immunosuppression leading to CPI resistance.

Biliary cancer brain metastases: a multi-institution case series with case reports.

Background: Biliary cancers are rare, and few reported cases of brain metastases from primary biliary cancers exist, especially describing patients in the United States. This report assesses the proportion and incidence of brain metastases arising from primary biliary cancers [cholangiocarcinoma (CCA) and gallbladder cancer] at Stanford University and the University of California, San Francisco, describes clinical characteristics, and provides a case series. Methods: We queried 3 clinical databases at Stanford and the University of California, San Francisco to retrospectively identify and review the charts of 15 patients with brain metastases from primary biliary cancers occurring between 1990 to 2020. Results: Among patients with brain metastases analyzed at Stanford (3,585), 6 had a primary biliary cancer, representing 0.17% of all brain metastases. Among biliary cancer patients at the University of California, San Francisco (1,055), 9 had brain metastases, representing an incidence in biliary cancer of 0.85%. A total of 15 biliary cancer patients with brain metastases were identified at the two institutions. Thirteen out of 15 patients (86.7%, 95% CI: 59.5-98.3) were female. The median overall survival from primary biliary cancer diagnosis was 214 days (95% CI: 71.69-336.82 days) and subsequent OS from the time of brain metastasis diagnosis was 57 days (95% CI: 13.43-120.64 days). Death within 90 days of brain metastasis diagnosis occurred in 66.67% of patients (95% CI: 38.38-88.17). Conclusions: Brain metastases from primary biliary cancers are rare, with limited survival once diagnosed. This report can aid health care providers in caring for patients with brain metastases from primary biliary cancers.

Molecular pathogenesis and systemic therapies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains one of the most prevalent and deadliest cancers. The poor outcome associated with HCC is dramatically changing due to the advent of effective systemic therapies. Here we discuss the molecular pathogenesis of HCC, molecular classes and determinants of heterogeneity. In addition, effective single-agent and combination systemic therapies involving immunotherapies as standard of care are analyzed. Finally, we propose a flowchart of sequential therapies, explore mechanisms of resistance and address the need for predictive biomarkers.

Quality of life assessment of cabozantinib in patients with advanced hepatocellular carcinoma in the CELESTIAL trial.

BACKGROUND: The CELESTIAL trial (NCT01908426) demonstrated overall survival benefit for cabozantinib versus placebo in patients with advanced hepatocellular carcinoma (aHCC) who had received prior sorafenib treatment. This analysis of CELESTIAL compared the impact of cabozantinib versus placebo on health-related quality of life (HRQoL). MATERIALS AND METHODS: Health status was assessed using the EuroQol five-dimension five-level (EQ-5D-5L) questionnaire over the 800-day follow-up period. EQ-5D-5L health states were mapped to health utility scores using reference values for the UK population. Quality-adjusted life years (QALYs) were calculated for each treatment group as the area under the curve for the plot of health utility score over time. The between-treatment group difference in restricted mean QALYs was calculated by generalized linear models and adjusted for baseline differences. A difference of 0.08 in health utility score (or in QALY) was deemed a minimally important difference and to be clinically significant. RESULTS: At week 5, the difference in mean health utility score between cabozantinib and placebo was -0.097 (95% confidence interval [95% CI]: -0.126, -0.067; p ≤ 0.001). Between-group differences in health utility scores diminished over time and were generally non-significant. The cabozantinib group accrued more QALYs than the placebo group over follow-up. Differences in mean QALYs (cabozantinib minus placebo) were statistically and clinically significant, ranging from +0.092 (95% CI: 0.016, 0.169) to +0.185 (95% CI: 0.126, 0.243) in favour of cabozantinib, depending on the reference value set used. CONCLUSIONS: These HRQoL findings support a positive benefit-risk profile for cabozantinib in previously treated patients with aHCC.

Validation and Characterization of FGFR2 Rearrangements in Cholangiocarcinoma with Comprehensive Genomic Profiling.

Cholangiocarcinoma (CCA) is a heterogeneous biliary tract cancer with a poor prognosis. Approximately 30% to 50% of patients harbor actionable alterations, including FGFR2 rearrangements. Pemigatinib, a potent, selective fibroblast growth factor receptor (FGFR) FGFR1-3 inhibitor, is approved for previously treated, unresectable, locally advanced or metastatic CCA harboring FGFR2 fusions/rearrangements, as detected by a US Food and Drug Administration-approved test. The next-generation sequencing (NGS)-based FoundationOneCDx (F1CDx) was US Food and Drug Administration approved for detecting FGFR2 fusions or rearrangements. The precision and reproducibility of F1CDx in detecting FGFR2 rearrangements in CCA were examined. Analytical concordance between F1CDx and an externally validated RNA-based NGS (evNGS) test was performed. Identification of FGFR2 rearrangements in the screening population from the pivotal FIGHT-202 study (NCT02924376) was compared with F1CDx. The reproducibility and repeatability of F1CDx were 90% to 100%. Adjusted positive, negative, and overall percentage agreements were 87.1%, 99.6%, and 98.3%, respectively, between F1CDx and evNGS. Compared with evNGS, F1CDx had a positive predictive value of 96.2% and a negative predictive value of 98.5%. The positive percentage agreement, negative percentage agreement, overall percentage agreement, positive predictive value, and negative predictive value were 100% for F1CDx versus the FIbroblast Growth factor receptor inhibitor in oncology and Hematology Trial-202 (FIGHT-202) clinical trial assay. Of 6802 CCA samples interrogated, 9.2% had FGFR2 rearrangements. Cell lines expressing diverse FGFR2 fusions were sensitive to pemigatinib. F1CDx demonstrated sensitivity, reproducibility, and high concordance with clinical utility in identifying patients with FGFR2 rearrangements who may benefit from pemigatinib treatment.

Discovering dominant tumor immune archetypes in a pan-cancer census.

Cancers display significant heterogeneity with respect to tissue of origin, driver mutations, and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system-here "archetypes"-creating prototypical non-destructive tumor immune microenvironments (TMEs) and modulating tumor-targeting. To discover the dominant immune system archetypes, the University of California, San Francisco (UCSF) Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.

BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update.

There have been major advances in the armamentarium for hepatocellular carcinoma (HCC) since the last official update of the Barcelona Clinic Liver Cancer prognosis and treatment strategy published in 2018. Whilst there have been advances in all areas, we will focus on those that have led to a change in strategy and we will discuss why, despite being encouraging, data for select interventions are still too immature for them to be incorporated into an evidence-based model for clinicians and researchers. Finally, we describe the critical insight and expert knowledge that are required to make clinical decisions for individual patients, considering all of the parameters that must be considered to deliver personalised clinical management.

Characteristics and Growth Rate of Lung Metastases in Patients With Primary Gastrointestinal Malignancies and Lung-dominant Metastatic Disease: A Retrospective Cohort Analysis.

INTRODUCTION: There are no formal guidelines for the management of patients with primary gastrointestinal (GI) cancers who have lung-exclusive or lung-predominant metastases. We performed a retrospective analysis to evaluate host and tumor characteristics of this patient population, model patterns and rates of growth, and describe treatment approaches. MATERIALS AND METHODS: Eligible patients had a GI cancer with either synchronous or metachronous lung metastases but no other visceral or peritoneal sites of involvement. In addition to collecting detailed patient-specific and tumor-specific information, all imaging studies (computed tomography±positron emission tomography scans) were reviewed by an independent radiologist. Up to 5 lung metastases were tracked through each patient's clinical course. Growth rate was estimated using a linear mixed model analysis. RESULTS: Forty patients met eligibility criteria (18 pancreatic, 15 colorectal, 6 hepatobiliary, 1 gastroesophageal; synchronous vs. metachronous, 13 and 27, respectively). Median time from original cancer diagnosis to onset of metachronous lung lesions was 16 months. Interval from first appearance of lung metastases to treatment initiation was 6.2 months. Average growth rate of the largest lesion was 0.21 mm/mo (95% confidence interval, 0.12-0.30), with substantial intrapatient and interpatient variability. Sixty percent of patients underwent locoregional interventions in addition to or in lieu of systemic therapy for their lung metastases. Median survival of the entire study cohort from first appearance of lung metastases was 54 months. CONCLUSIONS: Lung metastases from primary GI cancers have a variable but overall indolent natural history and are generally associated with prolonged survival outcomes. Further efforts to define patterns of growth of lung metastases, informed by size, number, and clinical/molecular features, are needed to guide appropriate timing and selection of therapy as well as surveillance strategies.

Phase II Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma with Tumor Mutation Profiling.

BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is upregulated in nearly half of hepatocellular carcinoma (HCC) tumors and is associated with poor prognosis. In preclinical models of HCC, the combination of mTOR pathway inhibition with the multikinase inhibitor sorafenib improves treatment efficacy. A prior phase I study of the allosteric mTOR inhibitor temsirolimus combined with sorafenib demonstrated acceptable safety at the recommended phase II dose. METHODS: We conducted a single-arm, multicenter phase II trial of the combination of temsirolimus 10 mg intravenously weekly plus sorafenib 200 mg b.i.d. The primary endpoint was time to progression (TTP) with efficacy target of median TTP of at least 6 months; secondary endpoints included overall survival (OS), objective response rate, safety, and alpha-fetoprotein (AFP) tumor marker response. Next-generation tumor sequencing was performed as an exploratory endpoint. RESULTS: Twenty-nine patients were enrolled, including 48% with hepatitis C virus infection and 28% with hepatitis B virus; 86% had Barcelona clinic liver cancer stage C disease. Among 28 patients evaluable for efficacy, the median TTP was 3.7 (95% confidence interval [CI]: 2.2, 5.3) months, with 14% of patients achieving TTP of at least 6 months. The median OS was 8.8 (95% CI: 6.8, 14.8) months. There were no complete or partial responses; 75% of patients had stable disease as best response. AFP decline by at least 50% was associated with prolonged TTP and OS. Serious adverse events occurred in 21%; the most common treatment-related adverse events of CTCAE grade 3 or higher were hypophosphatemia (36%), thrombocytopenia (14%), and rash (11%). There were no grade 5 events attributed to sorafenib or temsirolimus. Tumor next-generation sequencing (NGS) was performed in a subgroup of 24 patients with adequate tumor samples. Tumor mTOR pathway mutations were identified in 42%. There was no association between tumor mutation profile and OS or TTP. CONCLUSIONS: The combination of temsirolimus and sorafenib demonstrated acceptable safety but did not achieve the target threshold for efficacy in this phase II study. Tumor NGS including the presence of mTOR pathway mutations was not associated with treatment response in an exploratory subgroup analysis.

Correction: Biomarkers and overall survival in patients with advanced hepatocellular carcinoma treated with TGF-ßRI inhibitor galunisertib.

[This corrects the article DOI: 10.1371/journal.pone.0222259.].