Advanced Biliary Tract Cancer Research Articles

Conversion surgery intervention versus continued systemic therapy in patients with a response after PD-1/PD-L1 inhibitor-based combination therapy for initially unresectable biliary tract cancer: a retrospective cohort study.

The role of conversion surgery in patients with unresectable biliary tract cancer (BTC) who responded positively to PD-1/PD-L1 inhibitor-based therapy remains unclear. This study aimed to assess the outcomes in patients with or without conversion surgery. In this cohort study, patients with advanced BTC who received combination therapy with PD-1/PD-L1 inhibitors from July 2019 to January 2023 were retrospectively. Patients who exhibited positive responses and met the criteria for conversion surgery were enrolled, and their surgical and oncological outcomes were analyzed. Out of 475 patients, 34 who met the conversion resection criteria were enrolled. The median follow-up was 40.5 months post-initiation of systemic therapy. Ultimately, 13 patients underwent conversion surgery, while 21 received continuation of systemic treatment alone (non-surgical group). The median interval from the initial antitumor therapy to surgery was 6.7 (interquartile range [IQR] 4.9-9.2) months. Survival with conversion surgery was significantly longer than the non-surgical cohort, with a median progression-free survival (PFS) (unreached vs. 12.4mo; hazard ratio 0.17 [95% CI 0.06-0.48]; P=0.001) and overall survival (OS) (unreached vs. 22.4mo; hazard ratio 0.28 [95% CI 0.09-0.84]; P=0.02), respectively. After a median postoperative follow-up of 32.2 months in the surgical cohort, 8 patients survived without recurrence. The estimated 3-year OS, PFS and recurrence-free survival rate in the surgical cohort were 59.9%, 59.2% and 60.6%, respectively. The R0 resection rate reached 92.3%, with 2 achieving a pathological complete response. One patient experienced a Clavien-Dindo grade 3 complication without surgery-related mortality. No serious adverse events or surgical delays were observed. Multivariate analysis indicated that conversion surgery was independently associated with OS (P=0.03) and PFS survival (P=0.003). Conversion surgery appears safe and offers survival benefits to patients responding to immune checkpoint inhibitors (ICIs)-based combinations. However, further studies are required to validate this strategy in the era of immunotherapy.

Contributions of endoscopic ultrasonography-guided tissue acquisition (EUS-TA) to the diagnostics of biliary stricture and gallbladder lesions.

Endoscopic ultrasonography (EUS) provides high spatial resolution and more detailed images than other diagnostic modalities. Furthermore, EUS-guided tissue acquisition (EUS-TA), such as EUS-guided fine needle aspiration or biopsy (EUS-FNA/FNB), is an indispensable tool in pancreaticobiliary disease diagnostics, supporting a conclusive pathological diagnosis. In this review, we evaluate the current status and the usefulness of EUS-TA for the diagnostics of the following biliary tract diseases: (A) biliary stricture diagnostics, (B) biliary tract cancer (BTC) itself, and (C) staging of advanced BTC. Previous reports have shown that EUS-FNA for biliary lesions is a safe procedure that is useful in differentiating biliary cancer from benign lesions and in the staging of BTC. On the other hand, the diagnostic performance of EUS-TA for bile duct lesions is reported to be similar to that of transpapillary biopsy. Overall, EUS-TA for biliary lesions may be a safe and effective method, but it should be performed with an understanding of the risk of serious adverse events such as bile leakage and peritoneal dissemination of cancer. It is recommended for distal biliary stricture lesions for which endoscopic retrograde cholangiopancreatography cannot confirm the diagnosis or gallbladder lesions if they do not require the needle to pass through the biliary lumen.

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer (TOPAZ-1): patient-reported outcomes from a randomised, double-blind, placebo-controlled, phase 3 trial

In the ongoing, randomised, double-blind phase 3 TOPAZ-1 study, durvalumab, a PD-L1 inhibitor, plus gemcitabine and cisplatin was associated with significant improvements in overall survival compared with placebo, gemcitabine, and cisplatin in people with advanced biliary tract cancer at the pre-planned intermin analysis. In this paper, we present patient-reported outcomes from TOPAZ-1. In TOPAZ-1 (NCT03875235), participants aged 18 years or older with previously untreated, unresectable, locally advanced, or metastatic biliary tract cancer with an Eastern Cooperative Oncology Group performance status of 0 or 1 and one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) were randomly assigned (1:1) to the durvalumab group or the placebo group using a computer-generated randomisation scheme. Participants received 1500 mg durvalumab or matched placebo intravenously every 3 weeks (on day 1 of the cycle) for up to eight cycles in combination with 1000 mg/m2 gemcitabine and 25 mg/m2 cisplatin intravenously on days 1 and 8 every 3 weeks for up to eight cycles. Thereafter, participants received either durvalumab (1500 mg) or placebo monotherapy intravenously every 4 weeks until disease progression or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). Patient-reported outcomes were assessed as a secondary outcome in all participants who completed the European Organisation for Research and Treatment of Cancer's 30-item Quality of Life of Cancer Patients questionnaire (QLQ-C30) and the 21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life Module (QLQ-BIL21). We calculated time to deterioration-ie, time from randomisation to an absolute decrease of at least 10 points in a patient-reported outcome that was confirmed at a subsequent visit or the date of death (by any cause) in the absence of deterioration-and adjusted mean change from baseline in patient-reported outcomes. Between April 16, 2019, and Dec 11, 2020, 685 participants were enrolled and randomly assigned, 341 to the durvalumab group and 344 to the placebo group. Overall, 345 (50%) of participants were male and 340 (50%) were female. Data for the QLQ-C30 were available for 318 participants in the durvalumab group and 328 in the placebo group (median follow-up 9·9 months [IQR 6·7 to 14·1]). Data for the QLQ-BIL21 were available for 305 participants in the durvalumab group and 322 in the placebo group (median follow-up 10·2 months [IQR 6·7 to 14·3]). The proportions of participants in both groups who completed questionnaires were high and baseline scores were mostly similar across treatment groups. For global health status or quality of life, functioning, and symptoms, we noted no difference in time to deterioration or adjusted mean changes from baseline were observed between groups. Median time to deterioration of global health status or quality of life was 7·4 months (95% CI 5·6 to 8·9) in the durvalumab group and 6·7 months (5·6 to 7·9) in the placebo group (hazard ratio 0·87 [95% CI 0·69 to 1·12]). The adjusted mean change from baseline was 1·23 (95% CI -0·71 to 3·16) in the durvalumab group and 0·35 (-1·63 to 2·32) in the placebo group. The addition of durvalumab to gemcitabine and cisplatin did not have a detrimental effect on patient-reported outcomes. These results suggest that durvalumab, gemcitabine, and cisplatin is a tolerable treatment regimen in patients with advanced biliary tract cancer. AstraZeneca.

Durvalumab Plus Gemcitabine and Cisplatin Versus Gemcitabine and Cisplatin in Biliary Tract Cancer: a Real-World Retrospective, Multicenter Study.

The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed cell death ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). The present study investigated for the first time the impact on survival of adding durvalumab to cisplatin/gemcitabine compared with cisplatin/gemcitabine in a real-world setting. The analyzed population included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab in combination with cisplatin/gemcitabine or with cisplatin/gemcitabine alone. The impact of adding durvalumab to chemotherapy in terms of overall survival (OS) and progression free survival (PFS) was investigated with univariate and multivariate analysis. Overall, 563 patients were included in the analysis: 213 received cisplatin/gemcitabine alone, 350 received cisplatin/gemcitabine plus durvalumab. At the univariate analysis, the addition of durvalumab was found to have an impact on survival, with a median OS of 14.8 months versus 11.2 months [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50-0.80, p = 0.0002] in patients who received cisplatin/gemcitabine plus durvalumab compared to those who received cisplatin/gemcitabine alone. At the univariate analysis for PFS, the addition of durvalumab to cisplatin/gemcitabine demonstrated a survival impact, with a median PFS of 8.3 months and 6.0 months (HR 0.57, 95% CI 0.47-0.70, p < 0.0001) in patients who received cisplatin/gemcitabine plus durvalumab and cisplatin/gemcitabine alone, respectively. The multivariate analysis confirmed that adding durvalumab to cisplatin/gemcitabine is an independent prognostic factor for OS and PFS, with patients > 70 years old and those affected by locally advanced disease experiencing the highest survival benefit. Finally, an exploratory analysis of prognostic factors was performed in the cohort of patients who received durvalumab: neutrophil-lymphocyte ratio (NLR) and disease stage were to be independent prognostic factors in terms of OS. The interaction test highlighted NLR ≤ 3, Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0, and locally advanced disease as positive predictive factors for OS on cisplatin/gemcitabine plus durvalumab. In line with the results of the TOPAZ-1 trial, adding durvalumab to cisplatin/gemcitabine has been confirmed to confer a survival benefit in terms of OS and PFS in a real-world setting of patients with advanced BTC.

Comparison of Clinical Trial Results of the Recently Approved Immunotherapeutic Drugs for Advanced Biliary Tract Cancers.

The recently approved immunotherapeutic drugs are Keytruda (pembrolizumab) and Imfinzi (durvalumab) for advanced biliary tract cancers that inhibit PD-1 receptor and PD-L1 ligand, respectively. In this perspective, the results of the two clinical trials, i.e., TOPAZ-1 (NCT03875235) and KEYNOTE-966 (NCT04003636), are critically appraised, compared, and discussed to assess the benefits of these two drugs in the context of the treatment of advanced biliary tract cancers with a focus on PD-L1 status and MIS (microsatellite instability) status and therapy responsiveness in the subgroups. Analyzing the PD-L2 status in biliary tract cancer patients can aid in assessing the prognostic value of PD-L2 expression in determining the clinical response and this may aid in appropriate patient stratification.

DNA Checkpoint Gene Mutation as a Biomarker for Immune Checkpoint Inhibitor Therapy in Advanced Biliary Tract Cancer.

The DNA checkpoint (DNACHK) pathway is engaged in signaling the need for cell cycle arrest. This pathway is being actively researched to assess its role in cancer immunotherapy. A total of 62 patients participated in this study. These patients were treated with immune checkpoint inhibitors (ICIs) for advanced biliary tract cancers (BTCs) from March 2020 to August 2022 at Samsung Medical Center. DNACHK mutated were defined as genomic alterations, such as single nucleotide variants, multi-nucleotide variants, and short insertion and deletions in seven genes; checkpoint kinase 1 (CHEK1), checkpoint kinase 2 (CHEK2), BRCA1, DNA repair-associated (BRCA1), the serine/threonine kinase ATM, the serine/threonine kinase ATR, mediator of DNA damage checkpoint 1 (MDC1) and tumor protein p53 binding protein 1 (TP53BP1). We analyzed the effect of DNACHK mutations on the efficacy of ICIs in advanced BTCs. Patient median age at diagnosis was 68.0 years. 10 patients (16.1%) had GB cancer; the remaining patients (n=52, 83.9%) were diagnosed with cholangiocarcinoma. Thirty-seven (59.7%) patients were categorized into the DNACHK wild-type (WT) group and 25 (40.3%) into the DNACHK mutated (MT) group. The most observed DNA checkpoint mutations were ATM mutations (n=14). Patients in the DNACHK MT group had better disease control rate (DCR) than patients in the DNACHK WT (60.0% vs. 48.6%, p=0.53). Median overall survival (OS) was 8.1 months (95% CI 5.1-22.8) in the MT group and 5.6 months (95%CI 3.1-11.0) in the WT group (p=0.33). The DNACHK pathway is expected to serve as a potential biomarker for ICI treatment.

Efficacy and biomarker analysis of second-line nab-paclitaxel plus sintilimab in patients with advanced biliary tract cancer.

Biliary tract cancer (BTC) is a highly aggressive malignancy with limited second-line therapy. We conducted this phase 2 trial to evaluate the efficacy and safety of second-line nab-paclitaxel plus sintilimab in advanced BTC. Histologically confirmed advanced BTC patients with documented disease progression after first-line chemotherapy were enrolled. Subjects received nab-paclitaxel 125 mg/m2 on days 1 and 8 plus sintilimab 200 mg on day 1, administered every 3 weeks. The primary end point was the objective response rate (ORR). The secondary end points were progression-free survival (PFS), overall survival (OS), and adverse reactions. Simultaneously, next-generation sequencing, programmed cell death ligand 1 immunohistochemistry and multiplex immunofluorescence of tumor-infiltrating lymphocytes were applied to explore potential biomarkers. Twenty-six subjects were consecutively enrolled. The ORR was 26.9% (7/26), including two complete responses and five partial responses, which met the primary end point. The disease control rate was 61.5% (16/26). The median PFS was 169 days (about 5.6 months, 95% confidence interval [CI] 60-278 days). The median OS was 442 days (about 14.7 months, 95% CI 298-586 days). Grade 3 treatment-related adverse events (TRAEs) were mainly anemia (27%), leukopenia (23%), neutropenia (19%), and peripheral sensory neuropathy (8%). No grade 4 or 5 TRAEs occurred. Biomarker analysis suggested that positive PD-L1 and high proportions of CD8+ T-cell infiltration were correlated with improved clinical outcome. Nab-paclitaxel plus sintilimab is a potentially effective and tolerable second-line regimen for advanced BTC that deserves to be studied in large-scale trials. PD-L1 status and CD8+ T cell infiltration might be promising biomarkers for efficacy prediction.

The predictive value of PD-L1 expression in response to anti-PD-1/PD-L1 therapy for biliary tract cancer: a systematic review and meta-analysis.

Recently, anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy offers promising results for advanced biliary tract cancer (BTC). However, patients show highly heterogeneous responses to treatment, and predictive biomarkers are lacking. We performed a systematic review and meta-analysis to assess the potential of PD-L1 expression as a biomarker for treatment response and survival in patients with BTC undergoing anti-PD-1/PD-L1 therapy. We conducted a comprehensive systematic literature search through June 2023, utilizing the PubMed, EMBASE, and Cochrane Library databases. The outcomes of interest included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) according to PD-L1 expression. Subgroup analyses and meta-regression were performed to identify possible sources of heterogeneity. A total of 30 studies was included in the final analysis. Pooled analysis showed no significant differences in ORR (odds ratio [OR], 1.56; 95% confidence intervals [CIs], 0.94-2.56) and DCR (OR, 1.84; 95% CIs, 0.88-3.82) between PD-L1 (+) and PD-L1 (-) patients. In contrast, survival analysis showed improved PFS (hazard ratio [HR], 0.54, 95% CIs, 0.41-0.71) and OS (HR, 0.58; 95% CI, 0.47-0.72) among PD-L1 (+) patients compared to PD-L1 (-) patients. Sensitivity analysis excluding retrospective studies showed no significant differences with the primary results. Furthermore, meta-regression demonstrated that drug target (PD-1 vs. PD-L1), presence of additional intervention (monotherapy vs. combination therapy), and PD-L1 cut-off level (1% vs. ≥5%) significantly affected the predictive value of PD-L1 expression. PD-L1 expression might be a helpful biomarker for predicting PFS and OS in patients with BTC undergoing anti-PD-1/PD-L1 therapy. The predictive value of PD-L1 expression can be significantly influenced by diagnostic or treatment variables. https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023434114.

Efficacy and safety of anlotinib plus anti-PD-1 agents in patients with refractory advanced biliary tract cancers.

Anlotinib has demonstrated promising anti-tumor efficacy in various solid tumors. Additionally, there is evidence suggesting that immune therapy can enhance the systemic responses of anlotinib. This study aimed to assess the effectiveness and safety of combining anlotinib with PD-1 inhibitors compared to fluoropyrimidine-based chemotherapy as a second-line treatment option for advanced biliary tract cancers (BTCs). A total of 242 patients with BTCs were screened at the First Affiliated Hospital of Zhengzhou University from October 2015 to October 2022. Among them, 78 patients who received either anlotinib plus PD-1 inhibitors (AP) or fluoropyrimidine-based chemotherapy (FB) as second-line treatment were included in the study. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), safety, and predictive tumor biomarkers. Among the 78 patients with BTCs, 39 patients received AP, while 39 patients were administered FB. The ORR in the AP group was 20.5%, compared to 5.1% in the FB group. The DCR was 87.2% in the AP group and 66.7% in the FB group. The AP group demonstrated significantly better ORR and DCR compared to the FB group (p=0.042, p=0.032). The median PFS and OS in the AP group were 7.9months (95% CI: 4.35-11.45) and 13.9months (95% CI: 5.39-22.41), respectively. In the FB group, the median PFS and OS were 4.1months (95% CI: 3.17-5.03) and 13.2months (95% CI: 8.72-17.68), respectively. The AP group exhibited significantly better median PFS than the FB group (p=0.027). In the subgroup analysis, patients without liver metastasis had a much longer PFS in the AP group compared to the FB group (14.3 vs. 5.5months, p=0.016). Similarly, patients with CEA≤5μg/L also demonstrated a longer PFS in the AP group compared to the FB group (8.7 vs. 3.9months, p=0.008). The combination of anlotinib and PD-1 inhibitors demonstrated a promising clinical effect compared to fluoropyrimidine-based chemotherapy in the second-line treatment of refractory advanced BTCs. Liver metastases and CEA levels may serve as predictive factors for identifying patients who may benefit from AP therapy.

Abstract 5132: Multi-omics analysis uncovers predictive biomarkers for the efficacy and outcomes of immune checkpoint inhibitor in combination with chemotherapy in advanced unresectable biliary tract cancers

Abstract Background: Biliary tract cancer, typically diagnosed at advanced stages with a poor prognosis, has witnessed a glimmer of hope in the progress of immune checkpoint inhibitors (ICIs). Yet, their limited response rates necessitate the search for effective biomarkers to refine patient selection. Methods: A total of 125 patients with a confirmed histological diagnosis of unresectable advanced or metastatic biliary tract cancers (BTC) who received first-line ICIs in combination with chemotherapy (chemoimmunotherapy) were prospectively enrolled. All baseline samples from 125 patients underwent targeted DNA sequencing, with an additional 62 patients undergoing RNA sequencing, and 85 patients had accessible mIHC data. The associations between molecular characteristics and the response to chemoimmunotherapy, progression-free survival (PFS) and overall survival (OS) were evaluated. Results: The cohort had a median age of 63 years (range from 34 to 82) and 52.8% (66/125) were male, including 54 with gallbladder cancer, 57 with intrahepatic cholangiocarcinoma, and 14 with extrahepatic cholangiocarcinoma. The median duration of follow-up was 14.8 months for the entire cohort, with the median PFS and OS of 6.9 months (95%CI: 6.2-7.9) and 11.8 months (95%CI: 10.3-14.8), respectively. The most mutated genes were TP53 (64/125, 51.2%), KRAS (34/125, 27.2%), ERBB2 (18/125, 14.4%), and ARID1A (17/125, 13.6%). Mutations of TP53 (51.2%, p = 0.042), BRCA2 (4.8%, p = 0.002), cytokine genes (6.4%, p = 0.004), and high tumor mutation burden (p = 0.072) demonstrated significant correlation with chemoimmunotherapy response. KRAS G12D mutations (PFS: P &amp;lt; 0.001; OS: P = 0.034) and ARID1A loss-of-function mutations (PFS: P = 0.009; OS: P = 0.012) were adverse survival factors, while high CXCL9 or CTLA4 expression was associated with response (CXCL9, P = 0.014; CTLA4, P = 0.067), improved PFS (CXCL9, P = 0.018; CTLA4, P = 0.008), and longer OS (CXCL9, P = 0.010; CTLA4, P = 0.008) under chemoimmunotherapy. Patients were classified into three subtypes using the identified survival biomarkers. Among them, Type I patients, characterized by the absence of KRAS G12D or ARID1A mutations but expressing high levels of CTLA4 or CXCL9, demonstrated the best outcomes under chemoimmunotherapy. Interestingly, further RNA analysis suggested that elevated CXCL9 expression correlated with heightened immune checkpoint expressions, including CTLA4, PD-L1, and PD-1 (all P &amp;lt; 0.001), as well as increased tumor microenvironment immune activity, findings validated in two additional independent patient cohorts both internal and external. Conclusions: Our study revealed predictive biomarkers relevant to the response and efficacy of immune checkpoint inhibitors in combination with chemotherapy in advanced biliary tract cancer. Citation Format: Jieer Ying, Qi Xu, Jiaojiao Ni, Hanlin Chen, Chaoqun Li, Yanru Xie, Qinhong Zheng, Jianying Jin, Junrong Yan, Xiaoying Wu, Qiuxiang Ou, Li Yuan, Wei Zhuo, Haimeng Tang. Multi-omics analysis uncovers predictive biomarkers for the efficacy and outcomes of immune checkpoint inhibitor in combination with chemotherapy in advanced unresectable biliary tract cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5132.

Abstract 7624: DNA checkpoint gene mutation as a biomarker of immune checkpoint inhibitor in advanced biliary tract cancer

Abstract Introduction: The DNA checkpoint (DNACHK) pathway is engaged in signaling the need for cell cycle arrest. The G1 and S phase checkpoint allows for repair of damaged DNA, preventing damaged DNA from being copied. The G2 and M phase checkpoint prevents transmission of mutated DNA to the next generation. This pathway, along with mismatch repair (MMR), homologous recombination (HR), and base excision repair (BER), is being actively researched to assess its role in cancer immunotherapy. Methods: Sixty-two patients participated in this study. These patients were treated with immune checkpoint inhibitors (ICIs) for advanced biliary tract cancers (BTCs) from Mar. 2020 to Aug. 2022 at Samsung Medical Center. DNACHK mutations were defined as genomic alterations such as SNVs, MNVs, and short insertion and deletions in seven genes These genes include checkpoint kinase 1 (CHEK1), checkpoint kinase 2 (CHEK2), BRCA1, DNA repair associated (BRCA1), the serine/threonine kinase ATM, the serine/threonine kinase ATR, and mediator of DNA damage checkpoint 1 (MDC1). We analyzed the effect of DNACHK mutations on the efficacy of ICIs in advanced BTCs. Results: Patient median age at diagnosis was 68.0 years. Ten patients (16.1%) had gall bladder (GB) cancer; the remaining patients (n = 52, 83.9%) were diagnosed with cholangiocarcinoma. Among the 62 patients with advanced BTCs treated with ICIs, 37 (59.7%) were categorized into the DNACHK wild-type (WT) group and 25 (40.3%) into the DNACHK mutated (MT) group. The most observed DNA checkpoint mutations were ATM mutations (n=14). MDC1 mutations were found in seven patients, ATR mutations in three, BRCA1 mutations in four, and CHEK2 mutations in three. Patients in the DNACHK MT group had better disease control rates than patients in the DNACHK WT group (60.0% vs. 48.6%, p=0.53). Median overall survival (OS) was 8.1 months (95% CI, 5.1, 22.8) in the MT group and 5.6 months (95% CI, 3.1, 11.0) in the WT group (p=0.33). Conclusions: The results of this study suggest that the DNACHK pathway may be a valuable source of biomarkers for ICI and worthy of further study. Citation Format: Ji Eun Shin, Seung Tae Kim, Dae-Ho Choi, Junho Lee, Jiyeon Hyeon. DNA checkpoint gene mutation as a biomarker of immune checkpoint inhibitor in advanced biliary tract cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7624.

The role of molecular diagnostics in the choice of therapy for biliary tract cancers

The aim of the study was to assess the frequency and clinical significance of various molecular genetic aberrations in biliary tract tumors and to determine the optimal methods of their testing. Material and Methods. We searched the literature sources containing information on predictive molecular markers relevant for the choice of therapy in biliary tract tumors in PubMed and eLibrary databases for the period from 2010 to 2023. data from 60 studies were included in this review. Results. Biliary tract tumors are characterized by poor prognosis and low sensitivity to major systemic therapies. Nevertheless, the emergence of new targeting drugs and prescription of therapy based on the results of molecular genetic analysis can increase the life expectancy and improve the quality of life of a significant proportion of patients. The most frequently detected clinically significant abnormalities in all biliary tract tumors include HER2 gene amplification/hyperexpression (5–20 % of cases), microsatellite instability (1–2 % of cases), BRAF V600E oncogene mutation (1–2 % of cases) and KRAS G12C oncogene mutation (about 1 % of cases). Specific targetable abnormalities unique to intrahepatic cholangiocarcinomas include aberrations in the gene encoding fibroblast growth factor receptor 2, FGFR2 (10–20 % of cases) and mutations in the gene encoding the enzyme isocitrate dehydrogenase 1, IDH1 (5–30 % of cases). Very rare clinically significant molecular markers for biliary tract tumors include translocations involving the receptor tyrosine kinase genes NTRK1-3, RET, ALK and ROS1. Mutations in the genes of the dNA double-strand break repair system by the mechanism of homologous recombination are also potentially significant for the choice of therapy. First of all, these are BRCA1/2 genes, hereditary mutations in which, according to two studies, are characteristic of 5–7 % of patients with biliary cancer. Although a significant part of the above-mentioned disorders can be detected by traditional molecular biological approaches such as PCR, IHC, FISH and Sanger sequencing, a comprehensive analysis of all molecular markers of predictive value in biliary tract tumors is difficult to perform without the help of next-generation sequencing (NGS). Conclusion. To improve treatment outcomes of patients with advanced and metastatic biliary tract cancer by individualizing drug therapy, it is necessary to perform comprehensive molecular genetic analysis of tumour tissue.

Current Status of Targeted Therapy for Biliary Tract Cancer in the Era of Precision Medicine.

First-line chemotherapy has been established for advanced biliary tract cancer (BTC). However, few treatment options are available as second-line treatment. Advances in comprehensive genomic analysis revealed that nearly half of patients with BTC harbor targetable genetic alterations such as fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), BRAF, human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI)-high, neurotrophic tropomyosin receptor kinase (NTRK), rearranged during transfection (RET), and poly (adenosine diphosphate-ribose) polymerase (PARP). This review summarizes currently available options in precision medicine and clinical trials for patients with advanced BTC.

Clinical outcomes for previously treated patients with advanced biliary tract cancer: a meta-analysis.

Aim: A systematic review and meta-analysis were performed to evaluate the efficacy of treatments for previously treated advanced biliary tract cancer (BTC) patients. Materials & methods: Databases were searched for studies evaluating treatments for advanced (unresectable and/or metastatic) BTC patients who progressed on prior therapy. Pooled estimates of objective response rate (ORR), median overall survival (OS)and median progression-free survival(PFS)were calculated using random effects meta-analysis. Results: Across 31 studies evaluating chemotherapy or targeted treatment regimens in an unselected advanced BTC patient population, pooled ORR was 6.9%, median OS was 6.6monthsand median PFS was 3.2months. Conclusion: The efficacy of conventional treatments for previously treated advanced BTC patients is poor and could be improved by novel therapies.

Different Genomic Clusters Impact on Responses in Advanced Biliary Tract Cancer Treated with Cisplatin Plus Gemcitabine Plus Durvalumab.

The results reported in the TOPAZ-1 phase III trial led to the approval of the combination of cisplatin and gemcitabine with durvalumab as the new first-line standard of care for patients with locally advanced or metastatic cholangiocarcinoma. We performed a clustering analysis to classify patients into different groups based on their mutation profile, correlating the results of the analysis with clinical outcomes. We selected 51 patients with cholangiocarcinoma who were treated with the combination of chemotherapy and durvalumab and who were screened usingthe next-generation sequencing-based FoundationOne gene panel. We conducted mutation-based clustering of tumors and a survival analysis. Three main clusters were identified. Cluster 1 is mostly characterized by mutations in genes belonging to the chromatin modification pathway, altered in 100% of patients. Cluster 2 is characterized by the alteration of several pathways, among which DNA damage control, chromatin modification, RTK/RAS, cell-cycle apoptosis, TP53, and PI3K were the most affected. Finally, most altered pathways in cluster 3 were RTK/RAS and cell-cycle apoptosis. Overall response rate was 4/13 (31%), 12/24 (50%), and 0/10 (0%) in cluster 1, cluster 2, and cluster 3, respectively, and the difference between the three clusters was statistically significant (p = 0.0188). By grouping patients into three clusters with distinct molecular and genomic alterations, our analysis showed that patients included in cluster 2 had higher overall response rates, whereas patients included in cluster 3 had no objective response. Further investigations on larger and external cohorts are needed in order to validate our results.

Management of Intrahepatic Cholangiocarcinoma: A Narrative Review.

The management of resectable intrahepatic cholangiocarcinoma remains a challenge due to the high risk of recurrence. Numerous clinical trials have identified effective systemic therapies for advanced biliary tract cancer; however, fewer trials have evaluated systemic therapies in the perioperative period. The objective of this review is to summarize the current recommendations regarding the diagnosis, surgical resection, and systemic therapy for anatomically resectable intrahepatic cholangiocarcinoma. Our review demonstrates that surgical resection with microscopic negative margins and lymphadenectomy remains the cornerstone of treatment. High-level evidence regarding specific systemic therapies for use in resectable intrahepatic cholangiocarcinoma remains sparse, as most of the evidence is extrapolated from trials involving heterogeneous tumor populations. Targeted therapies are an evolving practice for intrahepatic cholangiocarcinoma with most evidence coming from phase II trials. Future research is required to evaluate the use of neoadjuvant therapy for patients with resectable and borderline resectable disease.

Skeletal muscle status and survival among patients with advanced biliary tract cancer

BackgroundStudies have demonstrated a prognostic role of sarcopenia (i.e., loss of skeletal muscle volume and functionality) in patients with various cancer types. In patients with biliary tract cancer, the quantity and quality of skeletal muscles and their serial changes have not been fully investigated in relation to survival outcomes.MethodsWe identified 386 patients with unresectable or recurrent biliary tract cancer and calculated skeletal muscle index (SMI) and skeletal muscle density (SMD) to estimate muscular quantity and quality, respectively, based on computed tomography images. Using the Cox regression model with adjustment for potential confounders, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) according to skeletal muscle status and its serial change.ResultsCompared to patients without sarcopenia, patients with sarcopenia were associated with shorter PFS (multivariable HR, 1.60; 95% CI, 1.15–2.22; P = 0.005), but not with OS (P = 0.027) at the adjusted α level of 0.013. SMD at baseline was associated with OS (multivariable HR comparing the extreme quartiles, 1.52; 95% CI, 1.07–2.14; Ptrend = 0.012), but not with PFS (Ptrend = 0.13). A reduction in SMI rather than that in SMD was associated with OS. Progressive disease was a risk factor for reductions in SMI and SMD.ConclusionsSkeletal muscle quantity and quality and their serial changes were associated with survival outcomes in patients with advanced biliary tract cancer. Our data highlight the importance of designing nutritional and physical interventions for improvements in skeletal muscle status.

Lenvatinib combined with PD-1 inhibitor plus Gemox chemotherapy versus plus HAIC for advanced biliary tract cancer

ObjectiveTo compare the treatment efficacy and safety of lenvatinib and programmed cell death 1 (PD-1) inhibitor combined with oxaliplatin plus gemcitabine (Gemox) chemotherapy or hepatic arterial infusion chemotherapy (HAIC) for patients with advanced biliary tract cancer (BTC). MethodThis study involved 86 patients with advanced BTC receiving PD-1 inhibitor and lenvatinib combined with HAIC (P-L-H group) or Gemox chemothrapy (P-L-G group). Propensity score matching (PSM) (1:1) analysis was used to balance potential bias. The primary endpoints were overall survival (OS) and progression-free survival (PFS), whereas the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and safety. ResultAfter PSM, a total of 60 patients were enrolled with 30 in the P-L-G group and 30 in the P-L-H group. The median PFS was significantly longer with P-L-G group (13.7 versus 6.0 months, p < 0.0001) than with the P-L-H group. The median OS was 23.8 months in the P-L-G group versus 11.6 months in the P-L-H group (p < 0.0001). Patients in the P-L-G group exhibited a better ORR (73.3 % vs 30 %, p = 0.002) compared to the P-L-H group. The DCR was the same in both groups, 96.7 %, respectively. The P-L-G group had a higher incidence of grade 3–4 AEs than the P-L-H group. However, there was no significant difference in the any grade or grade 3–4 of AEs between the two groups. ConclusionPD-1 inhibitor plus lenvatinib and Gemox are promising first-line regimens for the treatment of advanced BTC in the multicenter retrospective real-world study.

Phase II Trial of FOLFIRINOX in Advanced Biliary Tract Cancer.

Biliary tract cancers (BTCs), characterized by poor prognosis and limited treatment options, are increasingly prevalent malignancies with a five-year survival rate of less than 20% for advanced-stage disease. The standard first-line chemotherapy combining gemcitabine and cisplatin offers modest survival benefits, necessitating the exploration of more effective therapies. This study reports the results of a single-arm, open-label, phase 2 trial assessing the efficacy and safety of fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) as a first-line treatment for metastatic or locally advanced unresectable BTC. Patients aged ≥18 with measurable disease and adequate organ function were enrolled, receiving biweekly FOLFIRINOX for up to 12 cycles with follow-up imaging every four cycles. The primary endpoint was the overall response rate (ORR), with progression-free survival (PFS), overall survival (OS), and safety as secondary endpoints. Thirteen patients were enrolled from December 2016 to September 2021 before early termination due to slow accrual and the emergence of immunotherapy. The ORR was 54%, with a disease control rate of 77%. Median PFS and OS were 6.8 and 19.25 months, respectively. Grade 3/4 toxicities were predominantly hematologic, with neutropenia being the most common severe adverse event. The trial suggests that FOLFIRINOX is a potentially effective first-line therapy for unresectable or metastatic BTC with a manageable safety profile. However, the early termination of the study and the introduction of immunotherapy warrant further research to confirm these findings.

A phase II study to evaluate the safety and efficacy of anlotinib combined with penpulimab for advanced refractory biliary tract cancer.

TPS582 Background: Although with modest efficacy, mFOLFOX is recommended as standard second-line chemotherapy for advanced biliary tract cancer (BTC). Several clinical trials are exploring the combination treatment of antiangiogenic drugs and immune checkpoint inhibitors. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor targeting VEGFR1/2/3, FGFR1-4 and PDGFRα/β, which effectively blocks tumor neovascularization and growth. Previous phase I/II clinical trials suggested that anlotinib combined with PD-(L)1 inhibitors as second-line therapy was well tolerated and showed clinical anti-tumor activity in advanced biliary tract cancer (NCT03825705, NCT03996408, ChiCTR1900022003, ChiCTR2000037847). Penpulimab is a novel humanized anti-PD-1 IgG1 antibody with complete removal of Fc receptor mediated effect, and featuring slow antigen binding off-rate and high receptor occupancy. In this study, we explore anlotinib plus penpulimab as a chemo-free combination for second-line and above therapy. Methods: This is a prospective, single-arm, phase II study. BTC patients (pts) failed after the first-line treatment, aged 18-75 and an ECOG PS of 0-1 were recruited.Eligible pts received anlotinib (12mg, po, d1-14, q3w) and penpulimab (200mg, iv, d1, q3w) until disease progression, unacceptable toxicity or up to 2 years. The primary endpoint was Objective Response Rate (ORR). Secondary endpoints included Overall survival (OS), Progression-Free Survival (PFS), Disease Control Rate (DCR) and safety. Based on a two-sided test for one proportion with 5.0% type I error, 80% power to detect an improvement in ORR from 5% to 22%, there will be 27 pts enrolled considering 20% of pts dropping out. Clinical trial information: ChiCTR2300069126 .