Advanced Biliary Tract Cancer Research Articles

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.

Anti-cancer drugs versus supportive care for advanced biliary tract cancers: a systematic review

Introduction Biliary tract cancers (BTCs) have low survival rates in advanced stages. Anticancer drugs (ACDs) are usually recommended, but may be associated with important toxicity and lower quality of life (QoL). Best supportive care (BSC) could represent a valid alternative of treatment. We aim to synthesise evidence regarding the effects of ACDs versus BSC in patients with advanced BTCs. Methods We conducted a systematic review including randomised controlled trials (RCTs) comparing any type of ACD versus BSC, placebo or no active treatment. We searched in five databases. Two reviewers performed selection, risk of bias and data extraction processes. We conducted random-effects meta-analyses and assessed certainty of evidence using GRADE. Results We included eight RCTs. Biological/targeted therapies may result in little to no difference in overall survival (OS) (Mean difference (MD): 1.66 months higher; 95%CI, -0.65 to 3.96; low certainty) and toxicity (Relative risk (RR): 1.38; 95%CI, 0.99 to 1.93; low certainty), with uncertain effects on QoL. Evidence is very uncertain about the effects of chemotherapy on OS (MD: 3.28 months higher; 95%CI, 0.16 to 6.39; very low certainty), and may increase toxicity (RR: 1.33; 95%CI, 1.03 to 1.72; low certainty). We identified insufficient evidence for other prespecified outcomes. Conclusions Compared to BSC, ACDs have poor OS benefit and higher toxicity. Due to overall very low certainty of evidence, the effects of ACDs on critical outcomes are still unclear. Our findings should be used to better inform decision-making processes and future research.

The safety and efficacy of ivonescimab in combination with chemotherapy as first-line treatment for advanced biliary tract cancer.

4095 Background: Despite that PD-1/L1 inhibitors combined with chemotherapy have been approved as first-line(1L) treatment for advanced biliary tract cancer (BTC), the overall survival benefit remains limited, particularly for patients with gallbladder cancer. Ivonescimab, a tetrameric bispecific antibody targeting PD-1 and VEGF, has the potential to produce complementary and synergistic anti-tumor effects through both pathways. This study aimed to evaluate the safety and efficacy of ivonescimab in combination with chemotherapy in advanced BTC. Methods: This was an open-label, multi-center phase II study in patients with unresectable locally advanced and metastatic BTC. Ivonescimab was administered every 3 weeks for up to 8 cycles, along with gemcitabine and cis-platinum. After that, ivonescimab monotherapy was given until disease progression or unacceptable toxicity. The primary endpoints were safety and objective response rate (ORR) by RECIST v1.1. Secondary endpoints included duration of response (DoR), disease control rate (DCR), time-to-response (TTR), progression-free survival (PFS), and overall survival (OS). Results: As of Nov 26, 2023, a total of 22 pts with advanced BTC were enrolled in the study. The median age was 65.0 years (range, 47-75), 81.8% of patients had ECOG of 1. All patients had initially unresectable disease status, 54.5% of patients had intrahepatic cholangiocarcinoma, 4.5% of patients had extrahepatic cholangiocarcinoma and 40.9% of patients had gallbladder cancer at baseline. The median follow-up time was 10.7 months, and the median exposure time of ivonescimab was 7.2 months. A total of 86.4% (19/22) of patients experienced at least one grade 3 or higher treatment-related adverse event (TRAE), but none led to discontinuation treatment or death. The most common grade 3/4 TRAEs with a frequency of at least 10% included white blood cell count decreased (50.0%), neutrophil count decreased (50.0%), anemia (40.9%), platelet count decreased (22.7%), and hypertension (13.6%). The ORR by investigator assessment was 63.6% (14/22) regardless of PD-L1 status, with an ORR of 77.8% (7/9) for gallbladder cancer patients specifically. The DCR was 100% (22/22). The median PFS was 8.5 months (95% CI, 6.8-9.9), with a 6-month PFS rate of 84.2% (95% CI, 58.7-94.6). The median OS was 16.8 months (95% CI, 9.8- NE), with a 9-month OS rate of 81.8% (95% CI, 58.5-92.8). Conclusions: Ivonescimab combined with chemotherapy as 1L treatment demonstrated promising efficacy in pts with advanced BTC. Further trials to validate the efficacy and safety are warranted. Clinical trial information: NCT05214482 .

A phase II study of liposomal irinotecan-based chemotherapy with or without PD-1 inhibitor in patients with unresectable locally advanced or metastatic biliary tract cancer.

e15077 Background: Clinical outcomes for advanced biliary tract cancer (BTC) patients (pt) progressed on first-line therapy remain dismal. Liposomal irinotecan (LI) (HE072) is a formulation encapsulating I in a lipid bilayer vesicle and was approved in China in September 2022. It was used with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic pancreatic cancer progressing on gemcitabine treatment. We conducted an phase II study to investigate HE072 in combination with 5-FU and LV with or without a novel PD-1 inhibitor SG001 in patients with advanced BTC progressed on prior gemcitabine-based chemotherapy. Methods: This is a multi-center, non-randomized, open label phase II study in pts with unresectable locally advanced or metastatic BTC. Key inclusion factors were ECOG PS 0-1, prior gemcitabine-based chemotherapy, evidence of disease progression with at least one measurable lesion and adequate haematological/organ function. Key exclusion factor was brain metastases. Pts were treated with liposomal irinotecan (70 mg/m2) plus LV (400 mg/m2f) and 5-FU (2400 mg/m2) with or without SG001 (240mg) IV every 2 weeks for up to 2 years in absence of disease progression or unacceptable toxicity. Tumor assessments based on RECIST 1.1 were performed every 6 weeks by investigators. Primary endpoint was objective response rate (ORR). Secondary endpoints include progression free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Results: As of April 25, 2023, 17 BTC pts were enrolled into liposomal irinotecan-based chemotherapy arm (n = 7) and liposomal irinotecan-based chemotherapy plus SG001 arm (n = 10). ORR and DCR were 14.3% and 71.4% for chemotherapy arm, 20% and 40% for chemotherapy+ SG001 arm. Median OS and PFS for chemotherapy arm was 11.5(95% CI, 3.9-NE) and 4.2(95% CI, 1.4-NE) months, and for chemotherapy+PD-1 arm was 15.3 (95% CI, 3.6-17.0) and 3.8(95% CI, 1.4-6.9) months. All pts experienced treatment-related adverse events (TRAEs). The incidence of grade≥3 TRAEs was 58.8%(10/17), which occurred in 57% (4/7) of pts treated in chemotherapy arm vs 60% (6/10) in chemotherapy+SG001 arm. Among all patients, the most frequent grade ≥3 TRAEs were fatigue (29.4%), neutropenia (23.5%) and leukopenia (23.5%). One grade 4 TRAE leading to dose reduction in liposomal irinotecan was febrile neutropenia in chemotherapy arm. There were no treatment-related deaths. Conclusions: These preliminary results suggested that liposomal irinotecan plus 5-FU and LV was well-tolerated and showed promising and durable clinical activity in advanced BTC pts progressed on first-line treatment. Combined use of SG001 further improved clinical outcome in these pts without increased toxicity. Combination of liposomal irinotecan, 5-FU, LV and PD-1 inhibitor is a treatment strategy which is worthy of further exploration.

Cadonilimab in combined with gemcitabine and cisplatin in advanced biliary tract cancer (BicureX): A phase II, single-arm clinical trial.

e16158 Background: PD-1 or PD-L1 inhibitors plus chemotherapy as the first-line treatment has been proven to be effective in improving the prognosis of advanced biliary tract cancer (BTC) patients. However, there is still considerable demand for further improvement of BTC patients’ prognosis. This trial aims to evaluate the efficacy and safety of Cadonilimab (PD-1/CTLA-4, a bi-specific antibody) plus gemcitabine and cisplatin for patients with advanced BTC in first -line treatment. Methods: In this phase II, single-arm trial, we will enroll 65 patients with previously untreated, unresectable, locally advanced or metastatic BTC, including intrahepatic or extrahepatic cholangiocarcinoma (ICC/ECC) and gallbladder carcinoma (GBC). Participants received Cadonilimab (10 mg/kg, days 1, every three weeks) plus gemcitabine (1000 mg/m2, days 1, 8, Q3W), and cisplatin (25 mg/m2, days 1, 8, Q3W) for up to eight cycles, followed by Cadonilimab (10 mg/kg, days 1, Q3W) until disease progression or unacceptable toxicity. Treatment response was evaluated with image-based assessment according to response evaluation criteria insolid tumors (RECIST) version 1.1. by two experienced experts and further explored multiple methods, such as 3D visualisation and Spectral computed tomography Scan. The primary endpoint was the objective response rate (ORR); the secondary endpoints are disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Exploratory endpoints included associations between response, molecular characteristics, and the immune microenvironment. Results: Between June 30, and January 31, 2024, a total of 30 patients have undergone at least one imaging evaluation. 66.7% of these patients were diagnosed with ICC, 23.3% with GBC, and 10% with ECC. The mean age was 58.4 years, and 60% of the patients were male. 24 (80%) patients had metastasis. Among them, 1 (3.3%) patient acheived complete response (CR), 15 (50%) patients had partial response (PR) and 8 (26.7%) patients presented with stable disease (SD). The ORR was 53.3% and the DCR was 80%. The most common treatment-related adverse events (TRAEs) of any grade were rash (80%) and anaemia (76.7%). Grade 3 TRAEs were observed in 66.7% of the patients. The most frequent grade 3 TRAEs were anaemia (33.3%), and leukocytopenia (33.3%). No grade 4 or 5 events were observed. All patients were microsatellite stable (MSS), and the median TMB was 2.88 (0-109.44) Muts/Mb. Conclusions: Cadonilimab plus gemcitabine and cisplatin shown a promising efficacy and acceptable safety profile as first-line treatment for advanced BTC patients. Clinical trial information: NCT05978609 .

A randomized phase 2 study of combination atezolizumab and varlilumab (CDX-1127) with or without addition of cobimetinib in previously treated unresectable biliary tract cancer.

4017 Background: Combined MEK inhibition (MEKi) and PD-L1 blockade significantly improved progression-free survival (PFS) versus PD-L1 monotherapy in patients with advanced biliary tract cancer (BTC) following first-line chemotherapy (NCT03201458). Further study has shown MEKi enhances tumor immunogenicity but impairs host T cell activation/priming. The addition of immune agonists, e.g. a CD27 agonist, can rescue T cell function in the setting of systemic MEKi in vivo and may be an effective strategy to optimize MEKi’s immunomodulatory potential when used in combination with checkpoint blockade. Methods: We conducted a randomized ph 2 trial (NCT04941287) evaluating Atezolizumab in combination with the CD27 immune agonist (CDX-1127 [Varlilumab]) with or without the addition of a MEKi (Cobimetinib) in patients with unresectable, previously treated, BTC. Adults with pathologically-confirmed BTC, s/p at least 1 prior line (no more than 2) of systemic therapy, measurable disease, and ECOG PS ≤1 were enrolled. Patients who had received previous PD-[L]1 were eligible. The study was planned for 64 evaluable subjects randomized in a 1:1 ratio, stratified by BTC site, to either AV (Atezolizumab [840mg IV days 1,15])+ Varlilumab [3mg/kg IV days 1, 15]) or CAV (Cobimetinib [60mg oral daily days 1-21, off 22-28] + Atezolizumab + Varlilumab). Overall response rate (ORR) and PFS were co-primary endpoints. The primary correlative outcome was treatment-related changes in CD8+ infiltrating T cells. Results: A preplanned interim analysis based on objective response rates did not meet the threshold for continuance in either treatment arm, so the trial was closed early for futility. In total, 57 patients were enrolled (n = 29 [CAV], n = 28 [AV], 67% had intrahepatic cholangiocarcinoma, and 33% had received previous PD-[L]1. Both CAV and AV regimens were well-tolerated without new safety signals. Adding CDX-1127 did not appear to meaningful increase immunotoxicity beyond established PD-L1 toxicity profiles. ORR was 0% (CAV) and 4% (AV). With a median follow up time of 6.2 months, median PFS was 2.2 (CAV) and 1.8 (AV) months (HR 0.71 [0.40,1.25]). In PD[L]1-experienced patients, median PFS was 3.6 (CAV) and 1.7 (AV) months (HR 0.44 [0.14,1.33]). Median OS was 10.2 (CAV) and 6.1 (AV) months (HR 0.76 [0.37,1.55]). In PD[L]1-experienced patients, median OS was 6.4 (CAV) and 4.4 (AV) months for CAV and AV (HR 0.68 [0.19,2.42]). Primary correlative endpoint and updated survival will be reported at time of meeting. Conclusions: The combination of Atezolizumab and Varlilumab with or without Cobimetinib was safe but did not improve clinical outcomes in advanced stage BTC patients treated in later lines. Though not statistically significant, treatment with CAV demonstrated numerically favorable PFS/OS compared AV among immunotherapy-experienced patients. Clinical trial information: NCT03201458 .

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 .

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]

TOURMALINE: A phase 3b study of durvalumab with gemcitabine-based chemotherapy regimens in advanced biliary tract cancer.

TPS4188 Background: In the Phase 3 TOPAZ-1 study (NCT03875235), durvalumab plus gemcitabine + cisplatin (GC) significantly improved overall survival (OS) versus placebo + GC in participants with advanced biliary tract cancer (aBTC) with a manageable safety profile. To expand on TOPAZ-1, there is a need to further assess the safety and efficacy of durvalumab in combination with other gemcitabine (G)-based chemotherapy regimens used in aBTC, and in a more diverse population to reflect real-world clinical practice. Methods: TOURMALINE (NCT05771480) is a Phase 3b, single-arm, multicenter, international study. Approximately 140 adults with aBTC (intra- or extra-hepatic cholangiocarcinoma, gallbladder or ampulla of Vater carcinoma) will be enrolled. Key inclusion criteria include unresectable disease (advanced, metastatic), WHO/ECOG PS of 0–2, and no prior systemic therapy. Key exclusion criteria include any prior immune-mediated therapy and history of another primary malignancy. Participants will receive durvalumab 1500 mg IV plus an investigator-selected, G-based background chemotherapy; durvalumab will be administered Q3W when combined with a G-based chemotherapy Q3W (8 cycles of durvalumab) except for when combined with GC + S-1 Q2W, in which case durvalumab will be administered Q4W (4 cycles of durvalumab/8 cycles of chemotherapy). G-based chemotherapy will consist of G monotherapy, GC (for WHO/ECOG PS 2 participants only), G + oxaliplatin, G + carboplatin, GC + S-1, G + S-1, and GC + albumin-bound paclitaxel. Following the treatment period, durvalumab Q4W +/- chemotherapy (except for paclitaxel) may continue, at the investigator’s discretion, until discontinuation criteria are met. The primary endpoint is the incidence of Grade 3 or 4 adverse events, assessed by the investigator to be possibly related to any study treatment within 6 months after initiation of durvalumab. Secondary endpoints include OS, objective response rate, progression-free survival, and duration of response. Enrollment is ongoing and planned in France, Germany, United States, Spain, Italy, Japan, South Korea, and Singapore. Clinical trial information: NCT05771480 .

Update results of anlotinib plus TQB2450 (PD-L1 blockade) combined with nab-paclitaxel and cisplatin as first-line treatment for advanced biliary tract cancer: A single-arm, open-label phase II clinical trial.

e16144 Background: Efficacy and prognosis of chemotherapy in first-line setting for patients with advanced biliary tract cancer (BTC) was dismal currently. Recently, PD-1/PD-L1 blockades combined with dual chemotherapy in first-line setting exhibited superior efficacy for patients with BTC. Nevertheless, it's important to highlight that both the TOPAZ-1 and KEYNOTE-966 trials had reported a median OS of less than 13 months. This underscored the necessity for further advancements to meet the demands of clinical practice. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, demonstrated promising therapeutic activity as second-line therapy for patients with BTC. Therefore, this study was designed to explore the efficacy and safety of anlotinib plus TQB2450 (PD-L1 blockade) combined with nab-paclitaxel and cisplatin as first-line therapy in advanced BTC. Preliminary results were presented at the 2024 ASCO-GI Symposium (Abs 498), the consecutively updated results were presented in this report. Methods: Patients with previously untreated metastatic or locally advanced BTC (ICC, ECC, GBC) were recruited and treated with anlotinib (10mg, po, d1~14, q3w) and TQB2450 (1200mg, iv, d1, q3w) plus nab-paclitaxel (200mg/m2, iv, d1, q3w) and cisplatin (60mg/m2, iv, d1, q3w) until disease progression or unacceptable toxicity. The predefined sample size was 20. Primary endpoint was ORR and secondary endpoints included safety, DCR, PFS, OS and biomarker explore. Results: From April 2023 to Oct 2023, a total of 20 patients were enrolled. At the data cut-off date (Jan, 2024), the best overall response indicated that there were 12 PR (60.0%), 6 SD (30.0%) and 2 PD (10.0%). Therefore, the preliminary ORR was 60.0% (95%CI: 36.1%-80.9%), DCR was 90.0% (95%CI: 68.3%-98.8%). At the data cut-off date, the preliminary prognostic result exhibited that the median PFS of the 20 pts was 8.31 months (95%CI: NA~NA). Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-emergent adverse events among the 20 patients with the incidence > 30% were leukopenia (80%), peripheral sensory neuropathy (45%) and fever (35%). Common grade ≥3 treatment-emergent adverse events were leukopenia (30%), fever (5%), decreased platelet count (5%), malaise (5%), nausea (5%), stomachache (5%), oral mucositis (5%), vomit (5%), rash (5%) and hypotension (5%). Conclusions: Preliminary results suggested that anlotinib plus TQB2450 combined with nab-paclitaxel and cisplatin as first-line therapy in advanced BTC exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more patients consecutively. Clinical trial information: NCT05812430 .

QUIC: Phase 2 study of gemcitabine, cisplatin, quemliclustat (AB680), and zimberelimab (AB122) during first-line treatment of advanced biliary tract cancers (BTC)—Big Ten Cancer Research Consortium study BTCRC-GI22-564.

TPS4195 Background: Despite recent approvals of immune checkpoint inhibitors with chemotherapy in the first-line setting, the median overall survival (mOS) for patients with advanced biliary tract cancer (BTC) remains less than 15 months. CD73 is a key enzyme responsible for the conversion of extracellular adenosine 5’-monophosphate into adenosine and may play an important role in creating an immunosuppressed tumor microenvironment. High expression of CD73 in BTC is associated with decreased OS. Quemliclustat (Q) is a potent, selective, reversible inhibitor of CD73. Q in combination with chemotherapy has demonstrated promising activity in patients with advanced pancreatic cancer without significant increase in adverse events. The BTCRC-GI22-564 study evaluates safety and preliminary efficacy of Q in combination with zimberelimab (Z), a monoclonal antibody targeting human PD-1, with gemcitabine and cisplatin (GC) as first-line therapy for patients with advanced BTC, QUIC (Q and Immunotherapy in Cholangiocarcinoma). Methods: This is an open label, single arm, phase II multi-site trial, evaluating Q and Z in combination with GC in patients with advanced BTC who have not received systemic treatment for advanced disease or who completed adjuvant therapy > 6 months prior to development of recurrent disease. Chemotherapy is given on days 1, 8, 22 and 29 of each 42-day cycle as per local standards. Z is administered at a fixed dose of 360 mg via IV infusion every 3 weeks. Q is administered via IV infusion on days 1, 15, and 29. A safety run-in portion built into the study is planned to enroll 6 subjects to ensure there are no dose limiting toxicities (DLT). If a study defined DLT is observed, Q, gemcitabine and cisplatin will be reduced by 1 dose level, and an additional 6 subjects will be enrolled in the safety run-in portion. The primary efficacy endpoint is median progression free survival (mPFS) with null and alternative survival of 6.0 and 10.0 months, respectively. Based on an accrual rate of 3 patients per month, we expect to accrue 33-39 patients which will provide at least 83% power with a one-sided alpha of 0.1. Secondary endpoints include mOS, disease control rate, overall response rate, and duration of response. Correlative endpoints will assess clinical outcomes with immune infiltration within tumor microenvironment, CD73 and PD-L1 expression. The QUIC study is currently open to enrollment through BTCRC. Clinical trial information: NCT06048133 .

A retrospective analysis of efficacy and safety of lenvatinib combined with PD-1 inhibitor and chemotherapy in advanced biliary tract cancer (BTC).

e16173 Background: Lenvatinib combined with PD-1 inhibitor and chemotherapy has showed a relatively high antitumor activity for ICC in phase 2 clinical trials. This study retrospectively analyzes the efficacy and safety of real-world lenvatinib combined with PD-1 inhibitor and chemotherapy in BTC. Methods: Patients with advanced BTC who received lenvatinib combined with PD-1 inhibitor plus oxaliplatin and gemcitabine (Gemox) chemotherapy were retrospectively screened. The overall survival, progression-free survival, objective response rate, disease control rate and safety were evaluated. Results: From Jan 2021 to Apr 2023, 27 pathologically-confirmed advanced BTC pts were enrolled. The median age is 61 (range, 39-74) years, 18 (66.7%) were male. Fourteen patients had TNM stage Ⅳdisease, and 7 patients had stage III. Twenty-six (96.3%) patients had an ECOG performance status of 1. All patients were child-pugh A. Fourteen patients had metastasis, 8 patients with lymph node metastasis, 4 with bone metastasis. 11 (40.7%) had positive PD-L1 expression. At baseline, 18 (66.7%) patients had a CA19-9 level > 200 U/mL. The median CEA level was 3.56 ng/mL; 48.1% of the patients had a level > 5 ng/mL. At the date cut off (Dec 15, 2023), the median follow-up time was 10.4 months (range: 4.8-25.7). ORR was 70.4% (19/27), and disease control rate (DCR) was 85.2% (23/27). Three pts with locally advanced disease were down-staged and then underwent resection. They remained disease-free survival at the end of last follow-up. The median PFS was 9.0 months (95% CI: 4.0-14.0) and median duration of response (DOR) was 9.8 months. The median OS was 20.4 months (95% CI: 13.6-27.2). 12-months OS rate was 73.3% (95% CI: 57.5%-89.2%).20/27 pts experienced treatment-related adverse events (AE). No grade 5 AE was observed. The most common AE was fatigue 66.7% (18/27), headache 7.4% (2/27). Grade 3 fatigue and grade 3 kidney injury occurred in 1 patient separately. Conclusions: Lenvatinib combined with PD-1 inhibitor and Gemox chemotherapy provided remarkable efficacy with reasonable tolerability in advanced BTC patients.

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 <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.

Safety and efficacy of IBI343 (anti-claudin18.2 antibody-drug conjugate) in patients with advanced pancreatic ductal adenocarcinoma or biliary tract cancer: Preliminary results from a phase 1 study.

3037 Background: Prognosis for advanced pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancer (BTC) remains poor, with limited treatment options available. Expression of claudin18.2 (CLDN18.2) has emerged as a potential target for anti-cancer treatment. Herein, we report preliminary safety and efficacy results of IBI343, an antibody-drug conjugate (ADC) consisting of anti-CLDN18.2 monoclonal antibody conjugated to exatecan (topoisomerase I inhibitor), in patients (pts) with advanced PDAC or BTC in a phase 1 study. Methods: Eligible pts who failed or were intolerant to standard treatment were enrolled. IBI343 were intravenously administered at 6 mg/kg or 8 mg/kg Q3W. In dose escalation, pts were enrolled regardless of CLDN18.2 expression. In dose expansion, pts were required to have CLDN18.2 expression ≥40% (1+/2+/3+ staining intensity by immunohistochemistry). Primary endpoint was safety. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and progression free survival (PFS) assessed by investigator per RECIST v1.1. Results: As of December 19, 2023, 35 pts (1 pt in dose escalation and 34 pts in dose expansion) were enrolled from China and Australia (males: 57.1%, median age: 58.0 years, ECOG PS 1: 71.4%, stage IV: 91.4%, median lines of prior treatment: 2) including 28 PDAC pts and 7 BTC pts. Pts received IBI343 at 6 mg/kg (n=17) or 8 mg/kg (n=18). Median duration of treatment was 7.0 weeks (range: 3.0-23.6) with 23 (65.7%) pts still on treatment. In all pts, treatment-related adverse events (TRAEs) occurred in 28 (80.0%) pts including grade ≥3 TRAEs in 9 (25.7%) pts. Common TRAEs (≥20%) were anemia (42.9%), neutrophil count decreased (28.6%), nausea (25.7%), vomiting (25.7%) and white blood cell count decreased (22.9%). Serious TRAEs occurred in 4 (11.4%) pts. TRAEs leading to dose interruption and treatment discontinuation occurred in 7 (20.0%) pts and 1 (2.9%) pt respectively. No TRAE led to death. Safety profiles of IBI343 in PDAC and BTC were comparable with the whole study cohort and no new safety signal was observed. As of January 15, 2024, 25 pts at 6 mg/kg and 8 mg/kg were efficacy evaluable. Partial response (PR) was observed in 7 pts (5 PDAC and 2 BTC). The ORR was 28.0% (95%CI: 12.1-49.4) and DCR was 80.0% (95%CI: 59.3-93.2). In evaluable pts at 6 mg/kg with CLDN18.2 expression ≥60% (1+/2+/3+, n=13), 5 pts had PR with ORR of 38.5% (95%CI: 13.9-68.4) and DCR of 84.6% (95%CI: 54.6-98.1). Among 10 PDAC pts in this subgroup, ORR was 40% (95%CI: 12.2-73.8). DoR and PFS data were immature. More updated data on safety and efficacy will be presented at the meeting. Conclusions: IBI343 was well tolerated with favorable safety profiles and encouraging efficacy in CLDN18.2-positive PDAC and BTC. Clinical trial information: NCT05458219 .

300P Prognostic and predictive role of FGFR2 and IDH1 targetable alterations in advanced biliary tract cancer (aBTC): Data from the Italian ANITA dataset

300P Prognostic and predictive role of FGFR2 and IDH1 targetable alterations in advanced biliary tract cancer (aBTC): Data from the Italian ANITA dataset

Alliance EAY191-A6: FOLFOX in combination with binimetinib as second-line therapy for patients with advanced biliary tract cancers (BTCs) with MAPK pathway alterations: A ComboMATCH treatment trial.

TPS4196 Background: Advanced BTC patients have poor prognosis. Up to 40% of BTCs have KRAS mutations and are associated with worse overall survival (OS). With a median OS of 7.7 months in KRAS wild-type compared to 1.7 months in KRAS mutated disease, these alterations are independent poor prognostic factors in BTC. Gemcitabine and cisplatin (GC) with or without immunotherapy are often used as 1st-line therapies. However, there is a lack of data on best 2nd-line regimens. mFOLFOX6 (5-fluorouracil [5-FU], leucovorin [LV], oxaliplatin) or liposomal irinotecan+5-FU+LV are options when no biomarkers are found (e.g., MSI-H, BRAFV600E, FGFR-fusions, IDH1-mutation, HER2-overexpression). Prior studies do not demonstrate benefit with MEK inhibitors (MEKi), but none of the studies had biomarker selection. Pre-clinical studies in BTC cell lines suggest synergy between MEKi and 5-FU. Thymidylate synthase (TS )levels induced by 5-FU are downregulated by addition of binimetinib. Early clinical studies show safety and tolerance of this combination. In this study, we will evaluate if the combination of mFOLFOX6+binimetinib improves OS for patients with BTC and MAPK mutations compared to mFOLFOX6 alone in 2nd-line therapy. Methods: EAY191-A6 is a treatment study arm of the NCI ComboMATCH master registration trial EAY191. The A6 trial has a randomized phase II design, enrolling a maximum of 66 patients. Patients with any MAPK pathway mutations except those with available therapies will be eligible. Patient must first enroll to the EAY191 master trial. Local molecular results may be used for enrollment. Submission of tissue at baseline is mandatory. Eligible patients will be randomized 1:1 to mFOLFOX6 vs mFOLFOX6 + binimetinib (45 mg oral twice a day every 14 days). Stratification factors include location and stage of disease. Primary efficacy analysis will compare OS in the intent-to-treat population. If the observed hazard ratio (HR) of experimental arm vs standard of care is < 0.545 (corresponding to an observed increase in OS by 5 months or longer), experimental treatment will be considered superior. An interim futility analysis at 50% of expected events will be conducted. If the observed HR is ≥ 1, experimental treatment will not be considered superior, and accrual maybe suspended. Secondary endpoints include progression-free survival, objective response rate, duration of response, disease control rate and toxicity of treatments. Exploratory objectives include prognostic modeling, correlations of genomic alterations with response or resistance and use of machine learning for outcome prediction. This study is active and open to accrual. Clinical trial information: NCT05564403 .

314P Real-world experience of carboplatin and gemcitabine combination chemotherapy in advanced biliary tract cancer: A single centre experience from Nottingham University Hospitals (UK)

314P Real-world experience of carboplatin and gemcitabine combination chemotherapy in advanced biliary tract cancer: A single centre experience from Nottingham University Hospitals (UK)

Genomic and transcriptomic biomarkers of nab-paclitaxel plus gemcitabine-cisplatin in patients with advanced biliary tract cancer.

Genomic and transcriptomic biomarkers of nab-paclitaxel plus gemcitabine-cisplatin in patients with advanced biliary tract cancer.

287P Association of progression-free survival (PFS) with overall survival (OS) in advanced biliary tract cancer (BTC): A trial- and patient-level analysis

287P Association of progression-free survival (PFS) with overall survival (OS) in advanced biliary tract cancer (BTC): A trial- and patient-level analysis

Effect of triplet regimen (single-agent chemotherapy plus anti-PD-1 antibody and tyrosine kinase inhibitors) on survival compared to chemotherapy in the second-line treatment of advanced biliary tract cancer: A retrospective analysis.

e16132 Background: TOPAZ-1 and KEYNOTE-966 trials have demonstrated the survival benefit of immune checkpoint inhibitors (ICIs) plus chemotherapy in advanced biliary tract cancer (BTC). Although the ABC‐06 study proved the benefits of FOLFOX in 2nd line therapies, the efficacy is limited. There is no consensus regarding the optimal therapy regimen, and more effective therapeutic options are needed. This retrospective analysis aims to evaluate the efficacy of a triplet regimen compared to standard chemotherapy in 2nd line BTC. Methods: Pts > 18 years, with ECOG PS 0/1, histologically confirmed metastatic BTC and progression on 1st line Gemcitabine-based therapy were eligible. A triple regimen was referred as Cohort A: tislelizumab and other anti-PD-1 antibody, capecitabine or S-1 plus tyrosine kinase inhibitors (TKIs, lenvatinib or anlotinib). Standard chemotherapy was Cohort B: mFOLFOX or irinotecan plus capecitabine. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), overall response rates (ORR), disease control rate (DCR) and safety. Results: This study retrospectively collected and analyzed treatment and clinical information from 121 pretreated BTC pts from Oct. 2021 to Oct. 2023, with a median age of 60 (range 36-82) years and 48% (58) of the pts were female. Among them, 86 patients received the triple regimen, while 35 patients received standard chemotherapy. Pts’characteristics were well balanced between the two groups in terms of gender, age, ECOG score, primary site, CEA, CA199, or presence of distant metastasis. According to the RECIST1.1 criteria, 1 pt achieved CR and 31 pts had PR in the triple treatment cohort, ORR reached 37.2% (95%CI 27.0-48.3%), which was significantly higher than the 2.8% (95%CI 0.1-14.9%) in the standard chemotherapy cohort (p < 0.0001). Accordingly, the DCR of the two groups were 89.5% (95%CI 81.1-95.1%) and 71.4% (95%CI 53.7-85.4%) respectively. As of Oct 31, 2023, all patients developed progression, and the median PFS in cohort A was 6 months, compared to 2.0 months in cohort B (HR, 0.29, 95%CI 0.16-0.52, p < 0.0001). 64 patients of cohort A and 28 patients of cohort B developed death. The median OS in cohort A was 16.0 months, compared to 6.0 months in cohort B (HR 0.35, 95%CI 0.19~0.64, p < 0.0001). Any grade TRAEs occurred in 54.7% pts of cohort A and 42.9% of cohort B. Most common grade 3 TRAEs were hypohepatia (19.8%), hand-foot syndrome (11.6%), gastrointestinal reaction (1.2%) in cohort A, and hypohepatia (8.6%), hand-foot syndrome (2.9%) in cohort B. Conclusions: The retrospective analysis suggests that the triple regimen as second-line treatment for advanced BTC pts may help improve the efficacy and survival, and is worthy of further prospective exploration.