Atezolizumab plus bevacizumab as first-line systemic therapy for hepatocellular carcinoma: a multi-institutional cohort study.

BACKGROUND: Atezolizumab plus bevacizumab is the standard of care for advanced hepatocellular carcinoma (HCC) in the first-line setting, although was only evaluated in patients with Child-Pugh (CP) A liver function in the IMbrave150 trial. We sought to determine the outcomes of these patients based on CP score and ALBI grade in the US population. METHODS: This multicenter cohort study included patients with HCC who received atezolizumab with bevacizumab as first-line systemic therapy between March 2018 and November 2023. Overall survival (OS) was determined using the Kaplan-Meier method and multivariate analyses were performed using Cox proportional hazard regression method. RESULTS: Among 322 patients, 226, 86, and 10 patients had CP-A, CP-B, and CP-C liver function, respectively. Median age was 66.5 years, 78.6% were male, and 82.6% were White. Median OS (mOS) was 21.6 months for those with CP-A, 9.1 months for those with CP-B7, and 4.7 months for those with CP-B8-C12 (P < .0001). Among patients with CP-A, those with ALBI grade 1 had an mOS of 34.9 months versus 14.2 months in those with grade 2. In multivariate analyses, CP score, ALBI grade, hepatitis B, performance status, and macrovascular invasion were significantly associated with survival. CONCLUSIONS: CP score is an important prognostic tool for patients with HCC receiving atezolizumab plus bevacizumab, and this regimen remains a viable option for patients with CP-B7 with no additional safety concern, although the benefit is significantly less than those with CP-A. ALBI score has independent predictive value in patients with CP-A liver function.

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.

Metabolome-wide association identifies altered metabolites and metabolic pathways in the serum of patients with cholangiocarcinoma.

Background & Aims: Metabolomic and lipidomic analyses provide an opportunity for novel biological insights. Cholangiocarcinoma (CCA) remains a highly lethal cancer with limited response to systemic, targeted, and immunotherapeutic approaches. Using a global metabolomics and lipidomics platform, this study aimed to discover and characterize metabolomic variations and associated pathway derangements in patients with CCA. Methods: Leveraging a biospecimen collection, including samples from patients with digestive diseases and normal controls, global serum metabolomic and lipidomic profiling was performed on 213 patients with CCA and 98 healthy controls. The CCA cohort of patients included representation of intrahepatic, perihilar, and distal CCA tumours. Metabolome-wide association studies utilizing multivariable linear regression were used to perform case-control comparisons, followed by pathway enrichment analysis, CCA subtype analysis, and disease stage analysis. The impact of biliary obstruction was evaluated by repeating analyses in subsets of patients only with normal bilirubin levels. Results: Of the 420 metabolites that discriminated patients with CCA from controls, decreased abundance of cysteine-glutathione disulfide was most closely associated with CCA. Additional conjugated bile acid species were found in increased abundance even in the absence of clinically relevant biliary obstruction denoted by elevated serum bilirubin levels. Pathway enrichment analysis also revealed alterations in caffeine metabolism and mitochondrial redox-associated pathways in the serum of patients with CCA. Conclusions: The presented metabolomic and lipidomic profiling demonstrated multiple alterations in the serum of patients with CCA. These exploratory data highlight novel metabolic pathways in CCA and support future work in therapeutic targeting of these pathways and the development of a precision biomarker panel for diagnosis. Impact and implications: Cholangiocarcinoma (CCA) is a highly lethal hepatobiliary cancer with limited treatment response, highlighting the need for a better understanding of the disease biology. Using a global metabolomics and lipidomics platform, we characterized distinct changes in the serum of 213 patients with CCA compared with healthy controls. The results of this study elucidate novel metabolic pathways in CCA. These findings benefit stakeholders in both the clinical and research realms by providing a foundation for improved disease diagnostics and identifying novel targets for therapeutic design.

Expression of tumor antigens within an oncolytic virus enhances the anti-tumor T cell response.

Although patients benefit from immune checkpoint inhibition (ICI) therapy in a broad variety of tumors, resistance may arise from immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, OVs could potentially restore ICI responsiveness via recruitment, priming, and activation of anti-tumor T cells. Here we find that on the contrary, an oncolytic vesicular stomatitis virus, expressing interferon-ß (VSV-IFNß), antagonizes the effect of anti-PD-L1 therapy in a partially anti-PD-L1-responsive model of HCC. Cytometry by Time of Flight shows that VSV-IFNß expands dominant anti-viral effector CD8 T cells with concomitant relative disappearance of anti-tumor T cell populations, which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, combination OV and anti-PD-L1 therapeutic benefit could be restored. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, through encoding tumor antigens within the virus, oncolytic virotherapy can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.

Bintrafusp alfa and chemotherapy as first-line treatment in biliary tract cancer: A randomized phase 2/3 trial.

BACKGROUND AND AIMS: We compared the safety and efficacy of bintrafusp alfa (BA) in combination with gemcitabine+cisplatin (GemCis), to those of GemCis alone, in patients with biliary tract cancer. APPROACH AND RESULTS: This randomized, double-blind, placebo-controlled, adaptive design phase 2/3 trial (NCT04066491) included adults who are treatment-naive with locally advanced/metastatic biliary tract cancer. Patients (N = 297) were randomized to receive an IV infusion of BA (2400 mg once/3 wk) plus GemCis (gemcitabine 1000 mg/m 2 +cisplatin 25 mg/m 2 on days 1 and 8/3 wk; 8 cycles) (BA group, n = 148) or placebo+GemCis (placebo group, n = 149). The primary end point was overall survival (OS). For adaptation analysis (phase 2-phase 3; data cutoff: May 20, 2021), efficacy was assessed in the first 150 patients who were antibiotic-naive when 80 progression-free survival events had occurred and ≥ 19 weeks of follow-up had been completed (BA, n = 73; placebo, n = 77). Median OS (95% CI) for the BA (11.5 mo [9.3-not estimable]) and placebo (11.5 mo [10.0-not estimable]) groups was comparable (hazard ration 1.23 [95% CI 0.66-2.28]; p = 0.7394); OS data maturity was 27.2% (41 events/151 patients). The most common grade ≥3 treatment-related adverse event was anemia (BA, 26.0%; placebo, 22.8%). Bleeding adverse events were reported more frequently in the BA group (28.8%) versus the placebo group (7.4%). Deaths within 60 days of the first dose were reported in 7.5% and 1.3% of patients in the BA and placebo groups, respectively. CONCLUSIONS: BA+GemCis did not provide a clinically meaningful benefit compared with GemCis alone as first-line treatment for biliary tract cancer, and the study was discontinued early (terminated: August 20, 2021).

PHOCUS: A Phase 3, Randomized, Open-Label Study of Sequential Treatment with Pexa-Vec (JX-594) and Sorafenib in Patients with Advanced Hepatocellular Carcinoma.

Introduction: Intratumoral administration of pexa-vec (pexastimogene devacirepvec), an oncolytic and immunotherapeutic vaccinia virus, given to patients with hepatocellular carcinoma (HCC), is associated with both local and distant tumor responses. We hypothesized subsequent treatment with sorafenib could demonstrate superior efficacy. Methods: This random phase III open-label study evaluated the sequential treatment with pexa-vec followed by sorafenib compared to sorafenib in patients with advanced HCC and no prior systemic treatment. The primary endpoint is overall survival (OS). Key secondary endpoints included time to progression (TTP), progression-free survival, overall response rate (ORR), and disease control rate (DCR). Safety was assessed in all patients who received ≥1 dose of study treatment. Results: The study was conducted at 142 sites in 16 countries. From December 30, 2015, to the interim analysis on August 2, 2019, 459 patients were randomly assigned (pexa-vec plus sorafenib: 234, sorafenib: 225). At the interim analysis, the median OS was 12.7 months (95% CI: 9.89, 14.95) in the pexa-vec plus sorafenib arm and 14.0 months (95% CI: 11.01, 18.00) in the sorafenib arm. This led to the early termination of the study. The median TTP was 2.0 months (95% CI: 1.77, 2.96) and 4.2 months (95% CI: 2.92, 4.63); ORR was 19.2% (45 patients) and 20.9% (47 patients); and DCR was 50.0% (117 patients) and 57.3% (129 patients) in the pexa-vec plus sorafenib and sorafenib arms, respectively. Serious adverse events were reported in 117 (53.7%) patients in the pexa-vec plus sorafenib and 77 (35.5%) patients in the sorafenib arm. Liver failure was the most frequently reported in both groups. Conclusion: Sequential pexa-vec plus sorafenib treatment did not demonstrate increased clinical benefit in advanced HCC and fared worse compared to sorafenib alone. The advent of the added value of checkpoint inhibitors should direct any further development of oncolytic virus therapy strategies.

Second-Line Treatment of Pancreatic Adenocarcinoma: Shedding Light on New Opportunities and Key Talking Points from Clinical Trials.

Despite improvements in overall cancer mortality, deaths related to pancreatic cancer continue to rise. Following first-line treatment, second-line options are significantly limited. Classically, first-line treatment consisted of either gemcitabine or 5-fluorouracil based systemic chemotherapy. Upon progression of disease or recurrence, subsequent second-line treatment is still gemcitabine or 5-fluorouracil based chemotherapy, depending on what was used in the first line and the timing of progression or recurrence. A better understanding of the molecular underpinnings of pancreatic adenocarcinoma (PDAC) has led to new treatment strategies including specifically targeting the desmoplastic stroma, cytokine signaling and actionable mutations. Furthermore, efforts are also directed to enhance the immunogenicity profile of PDAC's well-established immunologically "cold" tumor microenvironment. More recently, the outstanding response rates of chimeric antigen receptor T (CAR-T) cells in hematologic malignancies, have led to clinical trials to evaluate the treatment modality in PDAC. In this review, we summarize recently presented clinical trials for metastatic pancreatic adenocarcinoma with novel treatment approaches in the second line and beyond.

A Phase I Study of KIN-3248, an Irreversible Small-molecule Pan-FGFR Inhibitor, in Patients with Advanced FGFR2/3-driven Solid Tumors.

PURPOSE: Despite efficacy of approved FGFR inhibitors, emergence of polyclonal secondary mutations in the FGFR kinase domain leads to acquired resistance. KIN-3248 is a selective, irreversible, orally bioavailable, small-molecule inhibitor of FGFR1-4 that blocks both primary oncogenic and secondary kinase domain resistance FGFR alterations. EXPERIMENTAL DESIGN: A first-in-human, phase I study of KIN-3248 was conducted in patients with advanced solid tumors harboring FGFR2 and/or FGFR3 gene alterations (NCT05242822). The primary objective was determination of MTD/recommended phase II dose (RP2D). Secondary and exploratory objectives included antitumor activity, pharmacokinetics, pharmacodynamics, and molecular response by circulating tumor DNA (ctDNA) clearance. RESULTS: Fifty-four patients received doses ranging from 5 to 50 mg orally daily across six cohorts. Intrahepatic cholangiocarcinoma (48.1%), gastric (9.3%), and urothelial (7.4%) were the most common tumors. Tumors harbored FGFR2 (68.5%) or FGFR3 (31.5%) alterations-23 (42.6%) received prior FGFR inhibitors. One dose-limiting toxicity (hypersensitivity) occurred in cohort 1 (5 mg). Treatment-related, adverse events included hyperphosphatemia, diarrhea, and stomatitis. The MTD/RP2D was not established. Exposure was dose proportional and concordant with hyperphosphatemia. Five partial responses were observed; 4 in FGFR inhibitor naïve and 1 in FGFR pretreated patients. Pretreatment ctDNA profiling confirmed FGFR2/3 alterations in 63.3% of cases and clearance at cycle 2 associated with radiographic response. CONCLUSION: The trial was terminated early for commercial considerations; therefore, RP2D was not established. Preliminary clinical data suggest that KIN-3248 is a safe, oral FGFR1-4 inhibitor with favorable pharmacokinetic parameters, though further dose escalation was required to nominate the MTD/RP2D. SIGNIFICANCE: KIN-3248 was a rationally designed, next generation selective FGFR inhibitor, that was effective in interfering with both FGFR wild-type and mutant signaling. Clinical data indicate that KIN-3248 is safe with a signal of antitumor activity. Translational science support the mechanism of action in that serum phosphate was proportional with exposure, paired biopsies suggested phospho-ERK inhibition (a downstream target of FGFR2/3), and ctDNA clearance may act as a RECIST response surrogate.

APRI score is not predictive of post-surgical outcomes in cholangiocarcinoma patients.

Background: Cholangiocarcinoma is an epithelial malignancy of the intrahepatic or extrahepatic biliary tree, primarily driven by chronic inflammation and fibrosis. Fibrosis has been shown to correlate with malignancy, and the aminotransferase-platelet ratio index (APRI) score, a marker for hepatic fibrosis, has proved useful in prognosticating hepatocellular carcinoma. This study aimed to assess the utility of APRI score in predicting post-surgical outcomes in cholangiocarcinoma patients. Methods: Clinical data from a total of 152 cholangiocarcinoma patients who underwent surgical resection at the Mayo Clinic were collected. The data were subsequently analyzed to determine if there was a relationship between APRI score and the demographic, laboratory, pathologic and outcome data, including overall survival. To determine the relationship between quantitative and qualitative data and the APRI score, a P-value <0.05 was considered as statistically significant. Results: No relationship between APRI score and demographic factors was identified. There were correlations between APRI score and alanine transaminase, albumin and bilirubin, but the remaining laboratory parameters showed no correlation. APRI score did not prove to be useful as a prognostic tool, as it did not correlate with tumor pathology features (tumor grade t-test P=0.86, N stage ANOVA P=0.94, vascular invasion t-test P=0.59, and perineural invasion t-test P=0.14), or with post-surgical recurrence (t-test P=0.22) and mortality (t-test P=0.39). Conclusion: APRI score is not a prognostic tool for post-surgical outcomes in patients with cholangiocarcinoma.

An overview of up-and-coming immune checkpoint inhibitors for pancreatic cancer.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1/PD-L1) pathway as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have demonstrated substantial potential in several malignancies. Pancreatic adenocarcinoma (PC) still carries a high mortality despite tremendous advances in the anti-cancer arsenal. AREAS COVERED: In this review, we discuss completed and ongoing studies on various ICIs in PC. ICIs have not yielded significant benefits as monotherapy. However, the combination with currently utilized therapies as well as with several other newer forms of therapy has delineated encouraging results. Larger trials are currently underway to definitively characterize the utility of ICIs in the treatment algorithm of PC. ICIs are approved for cancers with mismatch repair deficiency (dMMR) or microsatellite instability-high tumors (MSI-H) as a tumor-agnostic treatment strategy usually referred to as hot tumors. EXPERT OPINION: Studies evaluating different drugs to transform the tumor microenvironment (TME) from 'cold' to 'hot' have not shown promise in PC. There still needs to be more prospective trials evaluating the efficacy of the combination of ICIs with different therapeutic modalities in PC that can augment the immunogenic potential of those 'cold' tumors. Exploratory biomarker analysis may help us identify those subsets of PC patients who may particularly benefit from ICIs.

Phase 1 trial of navitoclax and sorafenib in patients with relapsed or refractory solid tumors with hepatocellular carcinoma expansion cohort.

Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. In this phase 1 study, we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). Maximum tolerated dose (MTD) was determined using the continual reassessment method. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. Ten patients were enrolled in the dose escalation cohort and 15 HCC patients were enrolled in the expansion cohort. Two dose levels were tested, and the MTD was navitoclax 150 mg daily plus sorafenib 400 mg twice daily. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities. Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, and there were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Navitoclax plus sorafenib is tolerable but showed limited efficacy in the HCC expansion cohort. These findings do not support further development of this combination for the treatment of advanced HCC. This phase I trial was conducted under ClinicalTrials.gov registry number NCT01364051.

Chimerization of the Anti-Viral CD8+ T Cell Response with A Broad Anti-Tumor T Cell Response Reverses Inhibition of Checkpoint Blockade Therapy by Oncolytic Virotherapy.

Although immune checkpoint inhibition (ICI) has produced profound survival benefits in a broad variety of tumors, a proportion of patients do not respond. Treatment failure is in part due to immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, we developed a vesicular stomatitis virus expressing interferon-ß (VSV-IFNß) as a viro-immunotherapy against HCC. Since HCC standard of care atezolizumab/bevacizumab incorporates ICI, we tested the hypothesis that pro-inflammatory VSV-IFNß would recruit, prime, and activate anti-tumor T cells, whose activity anti-PD-L1 ICI would potentiate. However, in a partially anti-PD-L1-responsive model of HCC, addition of VSV-IFNß abolished anti-PD-L1 therapy. Cytometry by Time of Flight showed that VSV-IFNß expanded dominant anti-viral effector CD8 T cells with concomitant, relative disappearance of anti-tumor T cell populations which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, the potent anti-viral response became amalgamated with an anti-tumor T cell response generating highly significant cures compared to anti-PD-L1 ICI alone. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, by chimerizing anti-viral and anti-tumor T cell responses through encoding tumor antigens within the virus, oncolytic virotherapy can be purposed for very effective immune driven tumor clearance and can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.

Genome-Wide Association Study of Gallstone Disease Identifies Novel Candidate Genomic Variants in a Latino Community of Southwest USA.

Gallstone disease (GSD) is a prevalent health condition that impacts many adults and is associated with presence of stones in gallbladder cavity that results in inflammation, pain, fever, nausea and vomiting. Several genome-wide association studies (GWAS) in the past have identified genes associated with GSD but only a few were focused on Latino population. To identify genetic risk factors for GSD in Latino population living in the Southwest USA we used self-reported clinical history, physical and lab measurements data in Sangre Por Salud (SPS) cohort and identified participants with and without diagnosis of GSD. We performed a GWAS on this phenotype using GSD cases matched to normal controls based on a tight criterion. We identified several novel loci associated with GSD as well as loci that were previously identified in past GWAS studies. The top 3 loci (MATN2, GPRIN3, GPC6) were strongly associated with GSD phenotype in our combined analysis and a sex stratified analysis results in females were closest to the overall results reflecting a general higher disease prevalence in females. The top identified variants in MATN2, GPRIN3, and GPC6 remain unchanged after local ancestry adjustment in SPS Latino population. Follow-up pathway enrichment analysis suggests enrichment of GO terms that are associated with immunological pathways; enzymatic processes in gallbladder, liver, and gastrointestinal tract; and GSD pathology. Our findings suggest an initial starting point towards better and deeper understanding of differences in gallstone disease pathology, biological mechanisms, and disease progression among Southwest US Latino population.

Targeting KRAS in pancreatic adenocarcinoma: Progress in demystifying the holy grail.

Pancreatic cancer (PC) remains one of the most challenging diseases, with a very poor 5-year overall survival of around 11.5%. Kirsten rat sarcoma virus (KRAS) mutation is seen in 90%-95% of PC patients and plays an important role in cancer cell proliferation, differentiation, metabolism, and survival, making it an essential mutation for targeted therapy. Despite extensive efforts in studying this oncogene, there has been little success in finding a drug to target this pathway, labelling it for decades as "undruggable". In this article we summarize some of the efforts made to target the KRAS pathway in PC, discuss the challenges, and shed light on promising clinical trials.

Clinical Utility of Ivosidenib in the Treatment of IDH1-Mutant Cholangiocarcinoma: Evidence To Date.

Ivosidenib is an isocitrate dehydrogenase 1 (IDH1) inhibitor that is FDA approved for patients with IDH1 mutation and acute myeloid leukemia and previously treated locally advanced or metastatic cholangiocarcinoma. In the Phase III trial ClarIDHy ivosidenib improved progression-free survival, 2.7 months versus 1.4 months (p < 0.0001) and overall survival (OS), median OS was 10.8 months for ivosidenib and 9.7 months for the placebo arm (p = 0.06) for patients with previously treated and IDH1 mutated cholangiocarcinoma. In this review article, we will address the mechanism of action of ivosidenib and data from early trials and safety from the randomized trial in cholangiocarcinoma. As a conclusion, future perspectives of IDH1 inhibition in IDH1 mutated tumors and possible strategies of sequencing and combinations will be reviewed and discussed.

The Cholangiocarcinoma in the Young (CITY) Study: Tumor Biology, Treatment Patterns, and Survival Outcomes in Adolescent Young Adults With Cholangiocarcinoma.

PURPOSE: Increased awareness of the distinct tumor biology for adolescents and young adults (AYAs) with cancer has led to improvement in outcomes for this population. However, in cholangiocarcinoma (CCA), a paucity of data exist on the AYA population. To our knowledge, we present the largest study to date on AYA disease biology, treatment patterns, and survival outcomes in CCA. METHODS: A multi-institutional cohort of patients with CCA diagnosed with intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma (ECC) was used for analysis. Retrospective chart review was conducted on patients who were 50 years old and younger (young; n = 124) and older than 50 years (older; n = 723). RESULTS: Among 1,039 patients screened, 847 patients met eligibility (72% ICC, 28% ECC). Young patients had a larger median tumor size at resection compared with older patients (4.2 v 3.6 cm; P = .048), more commonly had N1 disease (65% v 43%; P = .040), and were more likely to receive adjuvant therapy (odds ratio, 4.0; 95% CI, 1.64 to 9.74). Tumors of young patients were more likely to harbor an FGFR2 fusion, BRAF mutation, or ATM mutation (P < .05 for each). Young patients were more likely to receive palliative systemic therapy (96% v 69%; P < .001), targeted therapy (23% v 8%; P < .001), and treatment on a clinical trial (31% v 19%; P = .004). Among patients who presented with advanced disease, young patients had a higher median overall survival compared with their older counterparts (17.7 v 13.5 months; 95% CI, 12.6 to 22.6 v 11.4 to 14.8; P = .049). CONCLUSION: Young patients with CCA had more advanced disease at resection, more commonly received both adjuvant and palliative therapies, and demonstrated improved survival compared with older patients. Given the low clinical trial enrollment and poor outcomes among some AYA cancer populations, data to the contrary in CCA are highly encouraging.

NCCN Guidelines® Insights: Biliary Tract Cancers, Version 2.2023.

In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.

Futibatinib, an Irreversible FGFR1-4 Inhibitor for the Treatment of FGFR-Aberrant Tumors.

Fibroblast growth factor receptors (FGFR) are emerging as an important therapeutic target for patients with advanced, refractory cancers. Most selective FGFR inhibitors under investigation show reversible binding, and their activity is limited by acquired drug resistance. This review summarizes the preclinical and clinical development of futibatinib, an irreversible FGFR1-4 inhibitor. Futibatinib stands out among FGFR inhibitors because of its covalent binding mechanism and low susceptibility to acquired resistance. Preclinical data indicated robust activity of futibatinib against acquired resistance mutations in the FGFR kinase domain. In early-phase studies, futibatinib showed activity in cholangiocarcinoma, and gastric, urothelial, breast, central nervous system, and head and neck cancers harboring various FGFR aberrations. Exploratory analyses indicated clinical benefit with futibatinib after prior FGFR inhibitor use. In a pivotal phase II trial, futibatinib demonstrated durable objective responses (42% objective response rate) and tolerability in previously treated patients with advanced intrahepatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements. A manageable safety profile was observed across studies, and patient quality of life was maintained with futibatinib treatment in patients with cholangiocarcinoma. Hyperphosphatemia, the most common adverse event with futibatinib, was well managed and did not lead to treatment discontinuation. These data show clinically meaningful benefit with futibatinib in FGFR2-rearrangement-positive cholangiocarcinoma and provide support for further investigation of futibatinib across other indications. Future directions for this agent include elucidating mechanisms of resistance and exploration of combination therapy approaches.

Phase II Trial of Trifluridine/Tipiracil Plus Irinotecan in Patients with Advanced, Refractory Biliary Tract Carcinoma.

BACKGROUND: We sought to determine the safety and efficacy of trifluridine/tipiracil in combination with irinotecan in a phase II trial setting for refractory, advanced unresectable biliary tract carcinoma (BTC). METHODS: A total of 28 patients (27 were evaluable) with advanced BTCs who progressed on at least one prior systemic therapy were enrolled and were treated with trifluridine/tipiracil 25 mg/m2 (days 1-5 of 14-day cycle) and irinotecan 180 mg/m2 (day 1 of the 14-day cycle). The primary endpoint for the study was 16-week progression-free survival (PFS16) rate. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety were pre-specified secondary endpoints. RESULTS: Of 27 patients, PFS16 rate was 37% (10/27; 95% CI: 19%-58%), thereby meeting the criteria for success for the primary endpoint. The median PFS and OS of the entire cohort were 3.9 months (95% CI: 2.5-7.4) and 9.1 months (95% CI: 8.0-14.3), respectively. In the patients evaluable for tumor response (n = 20), the ORR and DCR were 10% and 50%, respectively. Twenty patients (74.1%) had at least one grade 3 or worse adverse event (AE), and 4 patients (14.8%) had grade 4 AEs. A total of 37% (n = 10/27) and 51.9% (n = 14/27) experienced dose reductions in trifluridine/tipiracil and irinotecan, respectively. Delay in therapy was noted in 56% of the patients while 1 patient discontinued the therapy, primarily due to hematologic AEs. CONCLUSION: The combination of trifluridine/tipiracil plus irinotecan is a potential treatment option for patients with advanced, refractory BTCs with good functional status and no targetable mutations. A larger randomized trial is needed to confirm these results. (ClinicalTrials.gov Identifier: NCT04072445).

Dynamics and survival associations of T cell receptor clusters in patients with pleural mesothelioma treated with immunotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are now a first-line treatment option for patients with pleural mesothelioma with the recent approval of ipilimumab and nivolumab. Mesothelioma has a low tumor mutation burden and no robust predictors of survival with ICI. Since ICIs enable adaptive antitumor immune responses, we investigated T-cell receptor (TCR) associations with survival in participants from two clinical trials treated with ICI. METHODS: We included patients with pleural mesothelioma who were treated with nivolumab (NivoMes, NCT02497508) or nivolumab and ipilimumab (INITIATE, NCT03048474) after first-line therapy. TCR sequencing was performed with the ImmunoSEQ assay in 49 and 39 pretreatment and post-treatment patient peripheral blood mononuclear cell (PBMC) samples. These data were integrated with TCR sequences found in bulk RNAseq data by TRUST4 program in 45 and 35 pretreatment and post-treatment tumor biopsy samples and TCR sequences from over 600 healthy controls. The TCR sequences were clustered into groups of shared antigen specificity using GIANA. Associations of TCR clusters with overall survival were determined by cox proportional hazard analysis. RESULTS: We identified 4.2 million and 12 thousand complementarity-determining region 3 (CDR3) sequences from PBMCs and tumors, respectively, in patients treated with ICI. These CDR3 sequences were integrated with 2.1 million publically available CDR3 sequences from healthy controls and clustered. ICI-enhanced T-cell infiltration and expanded T cell diversity in tumors. Cases with TCR clones in the top tertile in the pretreatment tissue or in circulation had significantly better survival than the bottom two tertiles (p<0.04). Furthermore, a high number of shared TCR clones between pretreatment tissue and in circulation was associated with improved survival (p=0.01). To potentially select antitumor clusters, we filtered for clusters that were (1) not found in healthy controls, (2) recurrent in multiple patients with mesothelioma, and (3) more prevalent in post-treatment than pretreatment samples. The detection of two-specific TCR clusters provided significant survival benefit compared with detection of 1 cluster (HR<0.001, p=0.026) or the detection of no TCR clusters (HR=0.10, p=0.002). These two clusters were not found in bulk tissue RNA-seq data and have not been reported in public CDR3 databases. CONCLUSIONS: We identified two unique TCR clusters that were associated with survival on treatment with ICI in patients with pleural mesothelioma. These clusters may enable approaches for antigen discovery and inform future targets for design of adoptive T cell therapies.