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The goal of this observational study is to evaluate the clinical efficacy and safety of lenvatinib plus pembrolizumab combination therapy in patients with advanced biliary tract cancer (BTC). This study aims to identify potential biomarkers that may predict treatment response by analyzing genetic data from blood and tissue samples. The study will focus on real-world clinical outcomes and the exploratory discovery of biomarkers associated with the efficacy of this treatment regimen.
Biliary tract cancers (BTCs) have a higher prevalence in Asia compared to Western countries, with South Korea ranking second globally in BTC incidence. According to data from the Central Cancer Registry in 2023, the 5-year survival rate for BTC from 2017 to 2021 was 28.9%, significantly lower than other cancers such as gastric cancer (77.9%), colorectal cancer (74.3%), and breast cancer (93.8%).
Surgery is the primary treatment for BTC, but only 40-50% of patients are eligible for curative resection. For patients with unresectable, advanced, or metastatic BTC, the standard first-line treatment has been gemcitabine plus cisplatin (GP) since the results of the ABC-02 Phase 3 trial in 2010. Recently, two Phase 3 trials-TOPAZ-1 in 2022 and KEYNOTE-966 in 2023-demonstrated significant survival benefits with the addition of immune checkpoint inhibitors (durvalumab or pembrolizumab) to GP therapy, establishing these combination regimens as the new first-line standard treatment for advanced BTC. These combinations have been approved for use in South Korea.
However, for patients who fail first-line GP therapy, the most commonly selected second-line treatment, FOLFOX (5-FU + leucovorin + oxaliplatin), offers only a modest survival extension of about one month compared to supportive care. This highlights the clinical unmet need for more effective second-line treatments. A multicenter Phase 2 trial has demonstrated the efficacy of lenvatinib plus pembrolizumab as a promising treatment option for these patients.
This prospective observational study aims to evaluate the clinical efficacy and safety of lenvatinib plus pembrolizumab combination therapy in real-world clinical practice for advanced BTC. Additionally, the study seeks to explore potential predictive biomarkers through genetic analyses of blood and tissue samples to better understand which patients are most likely to benefit from this treatment.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Len/Pemb | lenvatinib plus pembrolizumab combination therapy. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| lenvatinib plus pembrolizumab | Drug |
If the patient undergoes surgery or additional biopsy related to treatment (collected from preserved specimens). |
| Measure | Description | Time Frame |
|---|---|---|
| collected tumor samples | Tumor samples will be collected from patients with advanced biliary tract cancer. The incidence of genetic alterations in these samples will be analyzed using H&E staining, immunohistochemistry (IHC), and RNA sequencing. The data will be reported as the percentage of patients with detectable genetic alterations and correlated with treatment response and survival duration. | through study competition, an average of 2 years |
| Collected Blood Samples | Blood samples will be collected from patients with advanced biliary tract cancer.These samples will undergo flow cytometry, ELISA, and ctDNA analysis, and the results will be correlated with treatment response and survival outcomes. (PFS, OS). | Through study completion, an average of 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| Multi-Omics Analysis for Therapeutic Target Identification | Multi-omics analysis, including DNA, RNA, and protein analysis, will be conducted to identify potential therapeutic targets and subtypes of biliary tract cancer. The analysis will integrate molecular data to identify actionable genetic alterations and protein expression levels, which will be summarized and correlated with clinical outcomes (e.g., PFS, OS). |
| Measure | Description | Time Frame |
|---|---|---|
| Progression-Free Survival (PFS) | This outcome measures the time from the start of treatment to the first occurrence of disease progression or death. PFS will be analyzed using Kaplan-Meier survival curves, and the median PFS will be reported. | Through study completion, an average of 2 years. |
| Overall Survival (OS) |
Inclusion Criteria:
Exclusion Criteria:
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Patients with Advenced Biliary Tract Cancer will be recruited at CHA Bundang Medical Center
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Hong Jae Chon, MD. PhD | Contact | 82-31-780-3928 | minidoctor@cha.ac.kr |
| Name | Affiliation | Role |
|---|---|---|
| Hong Jae Chon, MD. PhD | CHA University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Bundang CHA Medical Center | Recruiting | Seongnam-si | Gyeonggi-do | 13496 | South Korea |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20375404 | Result | Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1273-81. doi: 10.1056/NEJMoa0908721. | |
| 38319896 | Result |
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| ID | Term |
|---|---|
| D001661 | Biliary Tract Neoplasms |
| D018281 | Cholangiocarcinoma |
| ID | Term |
|---|---|
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001660 | Biliary Tract Diseases |
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| ID | Term |
|---|---|
| C531958 | lenvatinib |
| C582435 | pembrolizumab |
| D000073890 | Liquid Biopsy |
| D001483 | Base Sequence |
| ID | Term |
|---|---|
| D001706 | Biopsy |
| D003581 | Cytodiagnosis |
| D003584 | Cytological Techniques |
| D019411 | Clinical Laboratory Techniques |
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Tissue, Blood
|
|
| Through study completion, an average of 2 years. |
| Biomarkers on the Efficacy of Lenvatinib and Pembrolizumab for Advanced Biliary Tract Cancer | his outcome will investigate the correlation between molecular biomarkers and the efficacy of lenvatinib and pembrolizumab in patients with advanced biliary tract cancer. Biomarkers will be evaluated for their association with overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). The outcome will report which biomarkers predict better therapeutic response. | Through study completion, an average of 2 years. |
This outcome measures the time from the start of treatment to death from any cause. OS will be evaluated and reported using Kaplan-Meier survival analysis, and median OS will be calculated. |
| Through study completion, an average of 2 years. |
| Objective Response Rate (ORR) | ORR is defined as the percentage of patients who achieve a complete or partial response based on RECIST 1.1 criteria. This outcome will report the proportion of patients who show a measurable response to treatment. | Through study completion, an average of 2 years. |
| Incidence of Adverse Events (AEs) | The safety and tolerability of lenvatinib and pembrolizumab will be assessed by monitoring the occurrence and severity of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. | Through study completion, an average of 2 years. |
| Oh DY, Ruth He A, Qin S, Chen LT, Okusaka T, Vogel A, Kim JW, Suksombooncharoen T, Ah Lee M, Kitano M, Burris H, Bouattour M, Tanasanvimon S, McNamara MG, Zaucha R, Avallone A, Tan B, Cundom J, Lee CK, Takahashi H, Ikeda M, Chen JS, Wang J, Makowsky M, Rokutanda N, He P, Kurland JF, Cohen G, Valle JW. Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer. NEJM Evid. 2022 Aug;1(8):EVIDoa2200015. doi: 10.1056/EVIDoa2200015. Epub 2022 Jun 1. |
| 37075781 | Result | Kelley RK, Ueno M, Yoo C, Finn RS, Furuse J, Ren Z, Yau T, Klumpen HJ, Chan SL, Ozaka M, Verslype C, Bouattour M, Park JO, Barajas O, Pelzer U, Valle JW, Yu L, Malhotra U, Siegel AB, Edeline J, Vogel A; KEYNOTE-966 Investigators. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 Jun 3;401(10391):1853-1865. doi: 10.1016/S0140-6736(23)00727-4. Epub 2023 Apr 16. |
| 33798493 | Result | Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, Falk S, Gillmore R, Wadsley J, Patel K, Anthoney A, Maraveyas A, Iveson T, Waters JS, Hobbs C, Barber S, Ryder WD, Ramage J, Davies LM, Bridgewater JA, Valle JW; Advanced Biliary Cancer Working Group. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021 May;22(5):690-701. doi: 10.1016/S1470-2045(21)00027-9. Epub 2021 Mar 30. |
| 35967452 | Result | Shi C, Li Y, Yang C, Qiao L, Tang L, Zheng Y, Chen X, Qian Y, Yang J, Wu D, Xie F. Lenvatinib Plus Programmed Cell Death Protein-1 Inhibitor Beyond First-Line Systemic Therapy in Refractory Advanced Biliary Tract Cancer: A Real-World Retrospective Study in China. Front Immunol. 2022 Jul 27;13:946861. doi: 10.3389/fimmu.2022.946861. eCollection 2022. |
| 32832493 | Result | Lin J, Yang X, Long J, Zhao S, Mao J, Wang D, Bai Y, Bian J, Zhang L, Yang X, Wang A, Xie F, Shi W, Yang H, Pan J, Hu K, Guan M, Zhao L, Huo L, Mao Y, Sang X, Wang K, Zhao H. Pembrolizumab combined with lenvatinib as non-first-line therapy in patients with refractory biliary tract carcinoma. Hepatobiliary Surg Nutr. 2020 Aug;9(4):414-424. doi: 10.21037/hbsn-20-338. |
| 38650446 | Result | Li L, Yu D, Yang J, Zhang F, Zhang D, Lin Z, Zhai M, Wang J, Zhang T, Zhao L. Significant response to pembrolizumab plus lenvatinib in Epstein-Barr-virus-associated intrahepatic cholangiocarcinoma: a case report. Cancer Biol Ther. 2024 Dec 31;25(1):2338644. doi: 10.1080/15384047.2024.2338644. Epub 2024 Apr 22. |
| D004066 |
| Digestive System Diseases |
| D000230 | Adenocarcinoma |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
| D019937 |
| Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D013048 | Specimen Handling |
| D008919 | Investigative Techniques |
| D015394 | Molecular Structure |
| D001669 | Biochemical Phenomena |
| D055598 | Chemical Phenomena |
| D040342 | Genetic Structures |
| D055614 | Genetic Phenomena |