Treatment Of Biliary Tract Cancer Research Articles

SY30-5 Current status and future prospects for perioperative treatment of biliary tract cancer

SY30-5 Current status and future prospects for perioperative treatment of biliary tract cancer

Concordance of ctDNA and tissue genomic profiling in advanced biliary tract cancer

Background & AimsRecent advances in molecular profiling enable the identification of potential therapeutic targets for biliary tract cancer (BTC). However, in patients with BTC, molecular profiling is hindered by challenges in obtaining adequate tissue samples. Circulating tumor DNA (ctDNA) may offer an alternative to tissue-based analysis. Here we aimed to assess the concordance between ctDNA and tissue genomic profiling in a large cohort of Asian patients with advanced BTC, and to evaluate the feasibility of liquid biopsy in BTC treatment. MethodsThis study included patients with systemic treatment-naive advanced BTC, treated at CHA Bundang Medical Center between January 2019 and December 2022. We enrolled patients with available baseline tissue-based next-generation sequencing (NGS), and sufficient plasma samples for ctDNA analysis (AlphaLiquid®100 from IMBdx). ResultsAmong 102 enrolled patients, 49.0% had intrahepatic cholangiocarcinoma, 26.5% extrahepatic cholangiocarcinoma, and 24.5% gallbladder cancer. The concordance between intra-patient ctDNA and tumor tissue mutations revealed a sensitivity of 84.8%, and positive predictive value of 79.4%. ctDNA revealed targetable alterations in 34.3% of patients—including FGFR2 fusion, IDH1 mutation, microsatellite instability (MSI)-high, ERBB2 amplification, PIK3CA mutations, BRCA1/2 mutations, and MET amplification. Notably, a novel FGFR2-TNS1 fusion was identified in ctDNA, which was not targeted in the tissue NGS panel. A high maximum somatic variant allele frequency in ctDNA was associated with poor prognosis after gemcitabine/cisplatin-based chemotherapy, in terms of both overall survival (p = 6.9 × 10−6) and progression-free survival (p = 3.8 × 10−7). ConclusionsAmong patients with advanced BTC, ctDNA-based genotyping showed acceptable concordance with tissue genomic profiling. Liquid biopsy using ctDNA could be a valuable complement to tissue-based genomic analysis in BTC. Impact and implicationsOur study is the first large-scale investigation of the clinical utility of liquid biopsy, focusing on ctDNA, as an alternative to conventional tumor tissue analysis, among Asian patients with advanced BTC. The results demonstrated acceptable concordance between analysis of ctDNA versus tissue for identifying therapeutic targets and potentially actionable genetic alterations. This indicates that ctDNA analysis can provide critical insights regarding advanced BTC treatment, particularly in cases where it is challenging to obtain or analyze tumor tissue.

Cost-effectiveness of pembrolizumab plus chemotherapy vs. chemotherapy as first-line treatment for advanced biliary tract cancer in China and the US.

Background: Pembrolizumab is a potentially valuable treatment. However, patients, doctors, and healthcare decision-makers are uncertain about its cost-effectiveness and an appropriate pricing for this new therapy. This study aims to appraise the cost-effectiveness of pembrolizumab as a first-line treatment for advanced biliary tract cancer (BTC) patients in China and the United States (US). Methods: A Markov model was constructed from the perspectives of healthcare systems in both China and the US for pharmacoeconomic evaluation. Patient baseline characteristics and key clinical data were sourced from the KEYNOTE-966 trial (ClinicalTrials.gov, NCT04003636). Costs and utilities were collected from drug cost websites and published literature. Cumulative costs (in USD), life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were measured and compared. Price simulations were conducted under given willingness-to-pay (WTP) thresholds to provide pricing scheme references. The model's robustness was analyzed through one-way sensitivity analysis and probabilistic sensitivity analysis. Results: Basic data analysis illustrates that pembrolizumab ($2662.41/100mg) in combination with chemotherapy regimen was not cost-effective relative to chemotherapy regimens at the WTP threshold of $38,201.19 in China, and the additional cost relative to chemotherapy regimens was $77,114.94 (ICER $556,689.47/QALY) while increasing 0.14 QALYs. Pembrolizumab ($54.71/1mg) also increased efficacy by 0.14 QALYs in the US, but remained also not cost-effective at the US WTP threshold of $229,044, and the total cost increased by $160,425.24 (ICER $1,109,462.92/QALY). Conclusion: Compared with chemotherapy, pembrolizumab plus chemotherapy reduces the disease of burden. However, at its current price, it may not be a cost-effective treatment for advanced BTC in both China and the US. This study can aid decision-makers in making optimal choices.

Nab-paclitaxel plus capecitabine as first-line treatment for advanced biliary tract cancers: An open-label, non-randomized, phase II clinical trial.

Biliary tract cancers (BTCs) are a heterogeneous group of tumors with high malignancy, poor prognosis, and limited treatment options. To explore the efficacy and safety of nab-paclitaxel plus capecitabine as first-line treatment for advanced and metastatic BTCs. This open-label, non-randomized, double-center, phase II clinical trial recruited systemic therapy-naive patients with unresectable or metastatic BTCs between April 2019 and June 2022 at Beijing Cancer Hospital and the First Hospital of China Medical University. Eligible patients were administered nab-paclitaxel (150 mg/m2, day 1) and capecitabine (2000 mg/m2, twice daily, days 1-7) in 14-day cycles until experiencing intolerable toxicity or disease progression. The primary outcome was the objective response rate (ORR). The secondary outcomes included the disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety. A total of 44 patients successfully completed the trial, with a median age of 64.00 years (interquartile range, 35.00-76.00), and 26 (59.09%) were females. Tumor response assessment was impeded for one patient due to premature demise from tumor hemorrhage. Among the remaining 43 patients undergoing at least one imaging assessment, the ORR was 23.26% [95% confidence interval (CI): 11.80%-38.60%], and the DCR was 69.77% (95%CI: 53.90%-82.80%). The median OS was 14.1 months (95%CI: 8.3-19.9), and the median PFS was 4.4 months (95%CI: 2.5-6.3). A total of 41 patients (93.18%) experienced at least one adverse event (AE), with 10 patients (22.73%) encountering grade ≥ 3 AEs, and the most frequent AEs of any grade were alopecia (79.50%), leukopenia (54.55%), neutropenia (52.27%), and liver dysfunction (40.91%), and no treatment-related deaths were documented. Nab-paclitaxel plus capecitabine may be an effective and safe first-line treatment strategy for patients with advanced or metastatic BTCs.

FDA Approval Summary: Durvalumab and Pembrolizumab, Immune Checkpoint Inhibitors for the Treatment of Biliary Tract Cancer.

On September 2, 2022, the Food and Drug Administration (FDA) approved durvalumab in combination with cisplatin and gemcitabine, for the treatment of patients with unresectable or metastatic biliary tract cancers (BTC). On October 31, 2023, the FDA approved pembrolizumab in combination with cisplatin and gemcitabine for the same indication. Approvals were based on two randomized, multiregional, placebo-controlled trials that randomly allocated patients to receive durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966) in combination with chemotherapy or placebo in combination with chemotherapy. Overall survival (OS) was the primary endpoint in both studies. In both studies, a statistically significant and clinically meaningful improvement in OS was demonstrated. In the TOPAZ-1 trial, the median OS of patients receiving durvalumab was 12.8 months [95% confidence interval (CI), 11.1-14.0] and 11.5 months (95% CI, 10.1-12.5) in patients receiving placebo [hazard ratio (HR), 0.80 (95% CI, 0.66-0.97)]. In the KEYNOTE-966 trial, the median OS of patients receiving pembrolizumab was 12.7 months (95% CI, 11.5-13.6) and 10.9 months (95% CI, 9.9-11.6) in patients receiving placebo [HR, 0.83 (95% CI, 0.72-0.95)]. The addition of checkpoint inhibitors to standard of care chemotherapy for this indication did not reveal any new adverse event signals, and the safety profile was generally consistent with the known clinical experience with durvalumab, pembrolizumab, and the backbone chemotherapy regimen. The approvals of durvalumab and pembrolizumab in combination with standard of care cisplatin and gemcitabine for the treatment of unresectable or metastatic BTC add two new therapeutic options for these patients.

Integrating Molecular Insights into Biliary Tract Cancer Management: A Review of Personalized Therapeutic Strategies.

Biliary tract cancers (BTCs) are rare and aggressive malignancies with an increasing incidence and poor prognosis. The standard systemic treatment for BTCs has evolved to include immune checkpoint inhibitors associated with gemcitabine-cisplatin as first-line therapies. However, survival rates remain low, highlighting the critical need for personalized treatment strategies based on molecular profiling. Currently, significant advancements have been made in the molecular characterization of BTCs, where genetic alterations, such as IDH1 mutations and FGFR2 fusions, provide targets for therapy. Molecular profiling is crucial early in the management process to identify potential candidates for clinical trials and guide treatment strategy. The integration of these molecular insights into clinical practice has allowed for the development of targeted therapies, although many of them are still in the phase 2 trial stage without definitive survival benefits demonstrated in phase 3 trials. This integration of comprehensive molecular profile insights with traditional treatment approaches offers a new horizon in the personalized medicine landscape for BTCs, with the aim of significantly improving patient outcomes through precision oncology.

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

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 (BTC). This randomized, double-blind, placebo-controlled, adaptive design phase 2/3 trial (NCT04066491) included treatment-naïve adults with locally advanced/metastatic BTC. Patients (N=297) were randomized to receive an intravenous infusion of BA (2400mg once/3wk) plus GemCis (gemcitabine 1000mg/m2+cisplatin 25mg/m2 on days 1 and 8/3wk; 8 cycles) (BA group, n=148) or placebo+GemCis (placebo group, n=149). The primary endpoint was overall survival (OS). For adaptation analysis (phase 2-phase 3; data cut-off: May 20, 2021), efficacy was assessed in the first 150 patients who were antibiotic-naïve, 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 (11.5mo [9.3-not estimable, NE]) and placebo (11.5mo [10.0-NE]) groups was comparable (hazard ratio 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. BA+GemCis did not provide a clinically meaningful benefit compared to GemCis alone as first-line treatment for BTC and the study was discontinued early (terminated: August 20, 2021).

Nanoliposomal irinotecan and fluorouracil plus leucovorin versus fluorouracil plus leucovorin in patients with cholangiocarcinoma and gallbladder carcinoma previously treated with gemcitabine-based therapies (AIO NALIRICC): a multicentre, open-label, randomised, phase 2 trial

There is an unmet need for effective therapies in pretreated advanced biliary tract cancer. We aimed to evaluate the efficacy of nanoliposomal irinotecan and fluorouracil plus leucovorin compared with fluorouracil plus leucovorin as second-line treatment for biliary tract cancer. NALIRICC was a multicentre, open-label, randomised, phase 2 trial done in 17 German centres for patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0-1, metastatic biliary tract cancer, and progression on gemcitabine-based therapy. Patients were randomly assigned (1:1) to receive intravenous infusions of nanoliposomal irinotecan (70 mg/m2), fluorouracil (2400 mg/m2), and leucovorin (400 mg/m2) every 2 weeks (nanoliposomal irinotecan group) or fluorouracil (2400 mg/m2) plus leucovorin (400 mg/m2) every 2 weeks (control group). Randomisation was by permutated block randomisation in block sizes of four, stratified by primary tumour site. Investigator-assessed progression-free survival was the primary endpoint, which was evaluated in all randomly assigned patients. Secondary efficacy outcomes were overall survival, objective response rate, and quality of life. Safety was assessed in all randomly assigned patients who received at least one dose of the study treatment. Enrolment for this trial has been completed, and it is registered with ClinicalTrials.gov, NCT03043547. Between Dec 4, 2017, and Aug 2, 2021, 49 patients were randomly assigned to the nanoliposomal irinotecan group and 51 patients to the control group. Median age was 65 years (IQR 59-71); 45 (45%) of 100 patients were female. Median progression-free survival was 2·6 months (95% CI 1·7-3·6) in the nanoliposomal irinotecan group and 2·3 months (1·6-3·4) in the control group (hazard ratio [HR] 0·87 [0·56-1·35]). Median overall survival was 6·9 months (95% CI 5·3-10·6) in the nanoliposomal irinotecan group and 8·2 months (5·4-11·9) in the control group (HR 1·08 [0·68-1·72]). The objective response rate was 14% (95% CI 6-27; seven patients) in the nanoliposomal irinotecan group and 4% (1-14; two patients) in the control group. The most common grade 3 or worse adverse events in the nanoliposomal irinotecan group were neutropenia (eight [17%] of 48 vs none in the control group), diarrhoea (seven [15%] vs one [2%]), and nausea (four [8%] vs none). In the control group, the most common grade 3 or worse adverse events were cholangitis (four [8%] patients vs none in the nanoliposomal irinotecan group) and bile duct stenosis (four [8%] vs three [6%]). Treatment-related serious adverse events occurred in 16 (33%) patients in the nanoliposomal irinotecan group (grade 2-3 diarrhoea in five patients; one case each of abdominal infection, acute kidney injury, pancytopenia, increased blood bilirubin, colitis, dehydration, dyspnoea, infectious enterocolitis, ileus, oral mucositis, and nausea). One (2%) treatment-related serious adverse event occurred in the control group (worsening of general condition). Median duration until deterioration of global health status, characterised by the time from randomisation to the initial observation of a score decline exceeding 10 points, was 4·0 months (95% CI 2·2-not reached) in the nanoliposomal irinotecan group and 3·7 months (2·7-not reached) in the control group. The addition of nanoliposomal irinotecan to fluorouracil plus leucovorin did not improve progression-free survival or overall survival and was associated with higher toxicity compared with fluorouracil plus leucovorin. Further research is necessary to define the role of irinotecan-based combinations in second-line treatment of biliary tract cancer. Servier and AIO-Studien.

Nivolumab monotherapy and associations in the treatment of advanced unresectable biliary tract cancer (BTC): A systematic review and meta-analysis.

e16216 Background: Patients with advanced unresectable BTC have a poor prognosis, and treatment options are limited and with variable response rates. Nivolumab (NIVO), a PD-1 inhibitor, has shown its effectiveness against multiple cancer types and has been tested as a therapeutic option in diverse settings and associations. Methods: We performed a systematic review and single arm meta-analysis of clinical trials of NIVO monotherapy or combined therapy in advanced unresectable BTC. PubMed, Embase, and Cochrane database were searched for clinical trials published up to May 1, 2023. Data were extracted from published reports and quality assessment was performed per Cochrane recommendations. The primary endpoints of interest were objective response rate (ORR = CR+PR) and disease control (DC = SD or better response) per RECIST v1.1, at any period of the trial. Results: Out of 80 database results, 6 clinical trials and 358 patients were included, all were using some form of NIVO therapy. Overall, NIVO and associations present an ORR = 13% (95% CI 0.08-0.16, I² = 23%, p = 0.26) and DC = 39% (95% CI 0.27-0.51, I² = 69%, p < 0.05). NIVO monotherapy present an ORR = 6% (95% CI 0.02-0.10, I² = 36%, p = 0.19) and DC = 28% (95% CI 0.04-0.51, I² = 87%, p < 0.001) while NIVO + ipilimumab association show an ORR = 11% (95% CI 0.004-0.22, I² = 76%, p < 0.05) and DC = 37% (95% CI 0.24-0.49, I² = 28%, p = 0.23). NIVO + gencitabine + cisplatin association trials reported an ORR within 13-18% and DC around 32%. This data suggests that associations of NIVO present higher efficacy in the treatment of BTC and should be considered among the first choices of therapy, however drug adverse effects tolerability might play an important part in the individualized patient care. Conclusions: There are marked limitations to the applicability of these findings in clinical practice, therefore a cautionary approach to this data is recommended, given their overall low statistical power, heterogenous study design, and tolerability to adverse effects. New trials of NIVO + associations with better standardized outcomes and comparative arms for different associations and populations will help to better clarify the effects of NIVO in the treatment of advanced unresectable BTC. [Table: see text]

Impact of adjuvant chemotherapy on outcomes after curative-intent surgery for biliary tract cancer: A 10-year retrospective single-center study.

e16273 Background: Surgical resection remains the mainstay of treatment for biliary tract cancers (BTCs). Although adjuvant capecitabine has been shown to reduce recurrence, the best adjuvant chemotherapy remains unclear and numerous practice differences exist. Methods: This study is a retrospective review of patients with BTCs who received curative-intent resection at one institution (Montefiore Medical Center) between 01/2014 and 04/2023. The primary outcome was relapse risk. Kaplan-Meier curves and Cox regression were used to analyze relapse-free and overall survival rates. Results: 146 patients met entry criteria. Median age was 72.2 years (IQR 62.4-77.9 months) and median follow-up time was 20 months (IQR 1-111 months). 35.6% of patients had gallbladder cancer and 64.4% cholangiocarcinoma. 57 patients (39%) relapsed and 30 patients (20.5%) died. 105 patients (71.9%) received adjuvant chemotherapy (41% single agent, 42.9% a double-agent regimen, and 16.2% triple-agent therapy). Examining individual factors (univariate analysis) revealed several linked to higher relapse risk. Patients with advanced cancer stages (III-IV vs I-II) had 2.1 times higher risk. Higher T stages also showed increased risk: 5.6 times greater for T2 and 6.7 times greater for T3 compared to T1. Additionally, positive lymph nodes (N+), elevated post-surgical CA19-9, and presence of lymphovascular or perineural invasion were all significantly associated with 1.88-2.78 times higher relapse risk. Surprisingly, receipt of adjuvant chemotherapy was associated with a higher relapse risk (HR 2.42, 95% CI 1.18, 4.95, p-value 0.015). The association between receipt of adjuvant chemotherapy and relapse remained significant (HR 2.41, 95% CI 1.09-5.35, p = 0.03), after adjusting for age, sex, residual CA19-9, and receipt of adjuvant radiation therapy. Higher overall stage (III-IV vs I-II) was identified as a significant predictor of poorer overall survival (OS) with a hazard ratio of 21.70 (2.94-27.70, p = 0.009). Node-positive disease (HR = 2.25, 1.05-4.80, p = 0.036) and relapse (HR = 3.61, 1.58-8.28, p = 0.002) were also independently associated with worse OS. Conclusions: Adjuvant chemotherapy is commonly given after curative-intent surgery for BTCs at our center. Numerous factors are associated with an increased risk of relapse. Receipt of adjuvant chemotherapy was associated with a higher relapse risk even after adjustment for multiple covariates; the reason for this association remains unclear. More studies are needed to better understand the role and best form of adjuvant chemotherapy in the treatment of BTCs.

Deleterious alterations in homologous recombination repair genes and efficacy of platinum-based chemotherapy in biliary tract cancers.

Platinum-based chemotherapy represents the standard first-line treatment for biliary tract cancers (BTC). Deficits in genes involved in the homologous recombination (HR) and DNA damage response (DDR) may confer higher sensitivity to platinum agents. We retrospectively included patients affected by BTC from 2 Italian institutions. Inclusion criteria consist of the receipt of platinum-based chemotherapy in the metastatic setting and the availability of comprehensive genomic profiling using next-generation sequencing (NGS). Patients were included in the HRD-like group if demonstrated oncogenic or likely oncogenic alterations in HR-/DDR-genes. Clinical endpoints were compared between the HRD-like group and the non-HRD-like group. Seventy-four patients were included, of whom 25 (33%) in the HRD-like group and 49 (66%) in the non-HRD group. With a median follow-up of 26.04 months (interquartile-range [IQR] 9.41-29.27) in the HRD-like group and of 22.48 months (IQR 16.86-40.53) in the non-HRD group, no PFS difference emerged, with a mPFS of 5.18 months in the HRD-like group compared to 6.04 months in the non-HRD group (hazard ratio [HR], 1.017, 95% CI 0.58-1.78; P = .95). No differences were observed in DCR (64% [95 CI 45%-83%] vs 73% [95 CI 61%-86%]; P = .4), and CBR (45% [95% CI 28%-73%] vs 50% [95% CI, 37%-68%]; P = .9) between the HRD-like group and non-HRD groups, respectively. Median OS did not statistically differ between the HRD-like group and non-HRD group (26.7 vs 18.0 months, respectively; HR, 0.670, 0.33 to 1.37, P = .27). HR-/DDR-genes, when assessed with regular tumor-only NGS panels, provide limited clinical validity to identify patients with BTC more likely to benefit from platinum-based chemotherapy.

Therapeutic Outcome of Multidisciplinary Treatment in Unresectable Biliary Tract Cancer: A Multicenter Retrospective Analysis.

There is little established evidence regarding treatment strategies for unresectable biliary tract cancer (BTC). This study aimed to clarify the situation of multidisciplinary treatment for unresectable BTC in the 2000s when there was no international standard first-line therapy. We retrospectively reviewed 315 consecutive patients with unresectable BTC who had been treated at seven tertiary institutions in Kanagawa Prefecture, Japan between 1999 and 2008. The unresectable factors were as follows: locally advanced, 101 cases (32.1%); hematogenous metastases, 80 cases (25.4%); and peritoneal dissemination, 30 cases (9.5%). Chemotherapy or radiation therapy was administered to 218 patients (69.2%). The best supportive care was provided in 97 cases (30.8%). The most common regimen was gemcitabine monotherapy, followed by gemcitabine combination therapy and S-1 monotherapy. The 1- and 2-year survival rates of all patients were 34.6% and 12.2%, respectively. The median survival time (MST) was 8 months in all patients. The 1-year survival rate was 65%, and the MST was 12 months among the locally advanced patients, whereas patients with peritoneal dissemination had the worst outcome; the 1-year survival rate was 7%, and the MST was 5 months. Among treated 90 cases of perihilar cholangiocarcinoma, patients who received chemoradiotherapy (n = 24) had a significantly better outcome than those who received chemotherapy alone (MST: 20 vs. 11 months, P < 0.001). Unresectable BTC has heterogeneous treatment outcomes depending on the mode of tumor extension and location. Multidisciplinary treatment seems useful for patients with locally advanced BTC, whereas patients with metastatic disease still have a poor prognosis.

Envafolimab combined with lenvatinib and gemcitabine plus cisplatin in advanced biliary tract cancer as first-line treatment: A single-arm, open-label, phase II study (ENLIGHTEN study).

e16188 Background: The prognosis of advanced biliary tract cancer (BTC) remains unsatisfactory despite first-line treatment with PD-1/PD-L1 inhibitors in combination with gemcitabine and cisplatin. Lenvatinib (LEN), an anti-angiogenic multi-kinase inhibitor, has recently demonstrated promising antitumor activity in various tumors. This study aimed to determine the efficacy and safety of envafolimab (PD-L1 inhibitor) and LEN in combination with gemcitabine and cisplatin as first-line treatment in advanced BTCs. Methods: This prospective, open-label, single-arm, Simon’s two-stage, phase II study in patients with advanced BTC is ongoing at two centers. All patients received subcutaneous envafolimab (400mg, Q3W) and LEN (8 mg/day, orally once daily) combined with gemcitabine (1000mg/m2, IV, days 1, 8, Q3W) plus cisplatin (25mg/m2, IV, days 1, 8, Q3W) up for 6-8 cycles, followed by maintenance envafolimab and LEN until disease progression (PD) or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). A Simon’s two-stage phase II optimal design was used with following statistical assumptions: If 4 or more patients had partial response (PR) in 10 patients in stage 1, the cohort would expand to a total of 39 patients, and the outcomes would be positive if 15 or more patients achieved PR. The secondary endpoints included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and safety. Results: Between October 2022 and October 2023, 20 patients were enrolled, and included for efficacy and safety analysis. All patients received at least two doses of study medication. Of the first 10 patients enrolled, confirmed responses were noted in 4 patients, and the trial continued to accrual. The ORR and DCR were 45% and 80%, respectively. Nine patients (9/20, 45%) exhibited PR, seven patients (7/20, 35%) showed stable disease (SD), and four patients (4/20, 20%) experienced PD. The most common grade 3/4 treatment-related adverse events (TRAEs) were GGT increased (n = 3, 15%) and platelet decreased (n = 2, 10%). No unacceptable toxicity or treatment-related deaths occurred. Conclusions: Envafolimab and LEN in combination with gemcitabine and cisplatin seems to be an effective and tolerable treatment option in advanced BTC. Survival data is immature and will be updated in the future. Clinical trial information: NCT05410197 .

Three-year follow-up data from KEYNOTE-966: Pembrolizumab (pembro) plus gemcitabine and cisplatin (gem/cis) compared with gem/cis alone for patients (pts) with advanced biliary tract cancer (BTC).

4093 Background: KEYNOTE-966 demonstrated that adding pembro to gem/cis provided a statistically significant, clinically meaningful improvement in OS as first-line therapy for BTC. After a median follow-up (ie, time from randomization to data cutoff) of 25.6 months (mo), median OS was 12.7 mo for pembro + gem/cis vs 10.9 mo with placebo + gem/cis (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.72-0.95; P = 0.0034; data cutoff date December 15, 2022). We present updated efficacy and safety data after 11 mo of additional follow-up. Methods: Key eligibility criteria included age ≥18 years; previously untreated, histologically confirmed metastatic or unresectable locally advanced BTC measurable by RECIST v1.1; and ECOG PS 0 or 1. Pts were randomized 1:1 to pembro 200 mg or placebo Q3W for ≤35 cycles plus gem 1000 mg/m2 on days 1 and 8 Q3W until PD and cis 25 mg/m2 on days 1 and 8 for &lt;8 cycles.Pts were stratified by region (Asia vs non-Asia), stage (locally advanced vs metastatic), and site of origin (gallbladder vs intrahepatic vs extrahepatic). The primary end point was OS; secondary end points were PFS, ORR, and DOR assessed per RECIST v1.1 by blinded independent central review, and safety. The data cutoff date for this analysis was November 14, 2023. Results: 1069 pts were randomized to pembro + gem/cis (n = 533) or placebo + gem/cis (n = 536). At a median follow-up of 36.6 mo (range, 29.2-49.4), the OS benefit of pembro + gem/cis was maintained (HR 0.86, 95% CI 0.75-0.98). Median OS was 12.7 mo (95% CI 11.5-13.6) for the pembro arm vs 10.9 mo (95% CI 9.9-11.6) for the placebo arm. At 24 mo, the OS rate was 24.6% (95% CI 21.0-28.3) in the pembro arm vs 19.2% (95% CI 16.0-22.6) in the placebo arm. OS in key subgroups continued to favor the pembro arm. Median PFS was 6.5 mo (95% CI 5.7-6.9) for the placebo arm vs 5.6 mo (95% CI 4.9-6.5) for the pembro arm (HR 0.85, 95% CI 0.75-0.97). ORR was 28.7% (n = 153) in the pembro arm vs 28.7% (n = 154) in the placebo arm. DOR was 8.3 mo (range: 1.2+ to 44.3+) for the pembro arm vs 6.9 mo (1.1+ to 41.1+) for the placebo arm; at 18 mo, estimates of ongoing response were 24% in the pembro arm vs 14% in the placebo arm. 378 (71.5%) out of 529 treated pts in the pembro arm had grade 3-5 treatment-related adverse events (AEs) vs 370 (69.3%) out of 534 treated pts in the placebo arm. 31 (5.9%) pts in the pembro arm died vs 50 (9.4%) in the placebo arm. There were no additional treatment-related deaths since the final analysis. Conclusions: With a median follow-up of 36.6 mo, the clinically meaningful improvement in OS with pembro + gem/cis was maintained, with no new safety signals, compared with placebo + gem/cis in pts with unresectable or advanced BTC. These data support pembro + gem/cis as first-line treatment for advanced BTC.

Developing behavioral intervention to support molecular testing of patients with biliary tract cancer.

TPS1641 Background: Biliary tract cancer (BTC) represents 7% of gastrointestinal malignancies in the United States, with an incidence of 0.5 to 2.0 cases per 100,000 individuals. Standard care involves systemic chemotherapy, predominantly gemcitabine and cisplatin. Recent advancements in immunotherapy, as evidenced by the TOPAZ-1 trial and KN966, support the use of durvalumab, and pembrolizumab as treatment options. Genetic tumor testing identifies up to 40% of BTC patients with targetable mutations, leading to recent FDA approvals for FGFR2 inhibitors - pemigatinib, infigratinib, futibatinib, and IDH1 inhibitor ivosidenib. The emerging data on inhibitors targeting the BRAF mutation, together with HER2 amplification, underscore the importance of understanding the tumor's molecular profile. Navigating this evolving treatment landscape emphasizes an unmet need for patients to comprehend the pivotal significance of tumor molecular profiling in formulating effective and personalized treatment plans. Identifying knowledge gaps among BTC patients concerning tumor genetic testing and precision medicine, along with strategies to address these gaps, holds promise for improving the management and the outcome of patients with BTC. Methods: This is a behavioral intervention study where participants will undergo two in-person survey interviews before and after an educational intervention. The initial survey aims to establish baseline knowledge about the BTC diagnosis and treatment and ascertain preferences for various educational interventions. Patients’ knowledge gap will be determined by comparing their responses to the initial survey and medical history documented by their treating physicians. They will then be provided with a 10-minute educational video. Participants will have the flexibility to access the video multiple times. Within 6 weeks from enrollment, they will have a post-education survey to determine the effectiveness of the education intervention. Following completion of baseline surveys, collaboration with key stakeholders including medical oncology and community perspectives will be initiated to identify knowledge gaps and inform the design of an educational intervention. The study enrollment will be targeted at BTC patients receiving systemic therapy at Georgetown University Hospital, Fox Chase Cancer Center, and Hackensack Meridian Health. Ten participants are enrolled and have completed the first survey and intervention. This study is currently enrolling participants: GUIRB: STUDY00007119.

Conversion surgery for initially unresectable locally advanced biliary tract cancer: A multicenter collaborative study conducted in Japan and Korea.

Although surgical resection is the only curative treatment for biliary tract cancer, in some cases, the disease is diagnosed as unresectable at initial presentation. There are few reports of conversion surgery after the initial treatment for unresectable locally advanced biliary tract cancer. This study aimed to evaluate the efficacy and safety of conversion surgery in patients with initially unresectable locally advanced biliary tract cancer. We retrospectively collected clinical data from groups of patients in multiple centers belonging to the Japanese Society of Hepato-Biliary-Pancreatic Surgery and Korean Association of Hepato-Biliary-Pancreatic Surgery. We analyzed two groups of prognostic factors (pretreatment and surgical factors) and their relation to the treatment outcomes. A total of 56 patients with initially unresectable locally advanced biliary tract cancer were enrolled in this study of which 55 (98.2%) patients received chemotherapy, and 16 (28.6%) patients received additional radiation therapy. The median time from the start of the initial treatment to resection was 6.4 months. Severe postoperative complications of Clavien-Dindo grade III or higher occurred in 34 patients (60.7%), and postoperative mortality occurred in five patients (8.9%). Postoperative histological results revealed CR in eight patients (14.3%). The median survival time from the start of the initial treatment in all 56 patients who underwent conversion surgery was 37.7 months, the 3-year survival rate was 53.9%, and the 5-year survival rate was 39.1%. Conversion surgery for initially unresectable locally advanced biliary tract cancer may lead to longer survival in selected patients. However, more precise preoperative safety evaluation and careful postoperative management are required.

Insights for clinical management from the real-life data of the centralized West of Scotland biliary cancer clinic.

With the increasing of novel therapeutics for the treatment of Biliary Tract Cancers (BTC), and the need to assess their socio-economic impacts for national licence approvals, it is as important as ever to have real-life data in national populations. We performed an audit of the first 2 year-activity (Sep 2019-Sep 2021) of the centralized West-of-Scotland-BTC clinic. 122 patients accessed the service, including 68% with cholangiocarcinoma (CCA), 27% with gallbladder cancer (GBC), and 5% with ampulla of Vater carcinoma with biliary phenotype (AVC). Median age at diagnosis was 66 (28-84), with 30% of newly diagnosed patients being younger than 60 years-old. Thirty-five cases (29%) underwent surgery, followed by adjuvant-chemotherapy in 66%. 60% had recurrent disease (80% with distant relapse). Sixty-four patients (58%) started first-line Systemic-AntiCancer-Treatment (SACT). Of these, 37% received second line SACT, the majority of which had iCCA and GBC. Thirty-% of those who progressed received third line SACT. About 30% of BTC were eligible for curative surgery. Fifty-eight and twenty% of the overall cohort of advanced BTC patients received first and second line SACT. Our data suggest that reflex genomic profiling may not be cost-effective until molecularly driven strategies are limited to second line setting.

Evaluating the Therapeutic Potential of Durvalumab in Adults with Locally Advanced or Metastatic Biliary Tract Cancer: Evidence to Date.

Advanced biliary tract cancers (BTCs) have historically been managed with chemotherapy but, in recent years, this treatment paradigm has begun to shift with the introduction of immune checkpoint inhibitors in addition to standard of care chemotherapy. The tumor microenvironment of BTC may be enriched with regulatory T lymphocytes and immune checkpoint expression in some patients. Durvalumab, an anti-programmed death ligand-1 (PD-L1) antibody, in combination with gemcitabine and cisplatin, has now received United States Food and Drug Administration approval for treatment of advanced BTC. Regulatory approval was based on the Phase III, randomized TOPAZ-1 trial that demonstrated survival benefit with addition of durvalumab to gemcitabine plus cisplatin compared to chemotherapy alone. The combination of chemotherapy and immunotherapy was well tolerated, and a subset of patients were able to achieve a durable response, with a 2-year overall survival rate of 23.6%. However, limitations remain in identifying which patients are most likely to benefit from immune checkpoint inhibition. Future study should aim to identify biomarkers predictive of substantial benefit, as well as the role of immune checkpoint inhibition in combination with targeted therapies and radiotherapy in the management of advanced BTC.

The efficacy of bile liquid biopsy in the diagnosis and treatment of biliary tract cancer.

Diagnosing biliary tract cancer is difficult because endoscopic retrograde cholangiopancreatography (ERCP) is performed fluoroscopically, and the sensitivity of bile cytology is low. Liquid biopsy of bile using targeted sequencing is expected to improve diagnosis and treatment, but few studies have been conducted. In this study, we examined whether liquid biopsy of bile improves the diagnostic sensitivity of biliary strictures. A total of 72 patients with biliary strictures who underwent ERCP at Chiba University Hospital between April 2018 and March 2021 were examined. Of these, 43 and 29 were clinically and pathologically diagnosed as having malignant and benign biliary strictures, respectively. We performed targeted sequencing of bile obtained from these patients, and the sensitivity of this method was compared with that of bile cytology. Detection of at least one oncogenic mutation was defined as having malignancy. The sensitivity of bile cytology was 27.9%, whereas that of genomic analysis was 46.5%. Comparing bile cytology alone with the combination of cytology and genomic analysis, the latter was more sensitive (53.5%, p < .001). Among the 43 patients with malignant biliary strictures, mutations with FDA-approved drugs were detected in 11 (26%). Liquid biopsy of bile can potentially diagnose malignancy and detect therapeutic targets.

Abstract 2127: Enhancing radiosensitivity in biliary tract cancer: The dual role of surufatinib in tumor suppression and macrophage reprogramming

Abstract Background: Biliary tract cancer (BTC) is notorious for its unfavorable clinical outcomes. Radiotherapy (RT) is a crucial component in BTC treatment. This study explores the radiosensitizing potential and mechanisms of Surufatinib (SF), an oral tyrosine kinase inhibitor, distinguished by its anti-angiogenic and immunomodulatory effects. Methods: In a NOZ mouse xenograft model, tumor growth and expressions of Ki-67, CD31 were analyzed. NOZ and TFK1 BTC cells treated with SF and/or RT underwent assessments for viability, cycle, and apoptosis using CCK8, colony formation, and flow cytometry. Macrophage polarization in SF/RT-treated tumor cell-macrophage co-cultures was studied using Elisa, qRT-PCR, and flow cytometry. Results: In vivo, SF impeded angiogenesis and bolsters the anti-tumor effect of radiotherapy. SF combined with RT significantly reduced subcutaneous tumor growth in nude mice, and diminished Ki-67 and CD31 expressions. In vitro, SF heightened cholangiocarcinoma cells' radio-sensitivity, causing DNA double-strand breaks and apoptosis. SF and radiotherapy combined notably increased γ-H2A expression and apoptosis levels (P&amp;lt;0.05). SF induced inflammatory response changes, favoring M2 to M1 macrophage polarization. In a tumor cell-macrophage co-culture, the SF-radiotherapy group showed increased IL-6 and decreased TGF-β (P&amp;lt;0.05), with upregulated M1 markers (IL-6, CXCL10) and downregulated M2 markers (TGF-β, CCL22, Arg-1) in macrophages (P&amp;lt;0.05). Both in vivo and in vitro, SF significantly reduced CD206+ M2-type macrophages (P&amp;lt;0.05). Conclusion: Surufatinib alters the immune microenvironment in cholangiocarcinoma, reversing the immunosuppressive macrophage polarization induced by radiotherapy and reprogramming M2-type macrophages into M1-type, thereby enhancing the radiosensitivity of cholangiocarcinoma. Citation Format: Ningyu Wang, Hong Ma, Xiangping Mei, Ai Huang, Yong Xiao, Jing Yao. Enhancing radiosensitivity in biliary tract cancer: The dual role of surufatinib in tumor suppression and macrophage reprogramming [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 2127.