담도암 면역치료 및 표적치료의 최신 지견과 전망 = Recent Advances in Immunotherapy and Targeted Therapy for Biliary Tract Cancer

국문 초록 (Abstract)

담도암은 지난 20년간 유병률이 꾸준히 증가함에 따라 사망률 또한 상승하고 있다[1,2]. 담도암은 간내 담도암, 간문부 담도암, 간외 담도암, 담낭암으로 분류되며, 다른 암과 달리 고유한 해부학적 및 분자 생물학적 특성을 가진다. 대부분의 환자가 진단 시 수술이 불가능한 진행성 단계에서 발견되어 치료의 한계가 크고 예후가 불량한 암으로 분류된다[1-3]. 그러나 최근 몇 년간 유전자 분석 연구를 포함한 다양한 연구 성과를 통해 담도암의 분자적기초가 밝혀지고, 면역학적 및 분자적 접근법이 발전하면서 진단과 치료에 있어 큰 변화를 맞이하고 있다[1]. 특히 담도암의 면역학적 특징이 밝혀지고 분자 생물학적 연구가 발전하면서 담도암 또한 특징적인 면역 미세 환경을 가진 종양으로 재평가되고 있으며 면역치료의 개발에 있어서 면역 미세 환경 고려의 중요성이 커지고 있다[2]. 또한, 담도암 관련 섬유아세포의 다양성과 기능에 대한 연구가 진전되고, 순환 유리 종양 DNA (circulating tumor DNA) 분석 기술이 발달하면서 담도암 진단 및 치료반응 평가의 유용성이 부각되고 있다[2]. 담도암에 대한 분자 표적치료는 섬유아세포 성장인자 수용체 2 (fibroblast growth factor receptor 2, FGFR2) 융합과 이소시트로산 탈수소 효소 1 (isocitrate dehydrogenase 1, IDH1) 돌연변이를 표적으로 하는 약제를 중심으로 임상에서 사용되고 있으며, 사용 범위가 점차 확대되고 있다. 더불어 durvalumab 또는 pembrolizumab 같은 면역 관문 억제제와 gemcitabine-cisplatin의 병용 요법이 생존율 개선 효과를 보이며 진행성 담도암 1차 치료의 패러다임이 변화하고 있다. 본 종설에서는 최근 담도암의 면역치료와 표적치료에 대한 최신 지견을 검토하고, 이를 국내 임상 환경에 적용하여 담도암 치료에 실질적인 도움을 제공하고자 한다.

다국어 초록 (Multilingual Abstract)

Biliary tract cancer (BTC) is a rare malignancy with increasing incidence and mortality over the past two decades. Despite its unique anatomical and molecular features, BTC is typically diagnosed at advanced stages, thereby limiting treatment options and resulting in poor prognosis. Recent advances in molecular profiling and immunotherapy have revolutionized the BTC management, illustrating its molecular and immunologic underpinnings. Immune checkpoint inhibitors such as durvalumab and pembrolizumab, when combined with gemcitabine/cisplatin, provide considerable survival benefits, with phase 3 trials such as TOPAZ-1 and KEYNOTE-966 demonstrating improved overall and progression-free survivals with immune checkpoint inhibitors compared to the conventional gemcitabine/cisplatin therapy. Therapies targeting FGFR2 fusions, IDH1 mutations, and HER2 overexpression have further expanded the therapeutic landscape, offering precision medicine opportunities for patients with actionable mutations. However, challenges persist owing to the rarity of BTC and inherent limitations of small cohort studies. Future research should focus on large, multicenter, prospective trials, establish new treatment paradigms, and expand therapeutic applications. In addition, integrating next-generation sequencing into routine practice will enhance molecular-based treatment approaches. This review explores the latest advancements in BTC immunotherapy and targeted therapies, emphasizing their clinical applicability in improving patient outcomes.

참고문헌 (Reference)

• 1 Harding JJ, "Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study" 24 : 772-782, 2023
• 2 Subbiah V, "Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours(LIBRETTO-001) : a phase 1/2, open-label, basket trial" 23 : 1261-1273, 2022
• 3 Lee CK, "Trastuzumab plus FOLFOX for HER2-positive biliary tract cancer refractory to gemcitabine and cisplatin : a multi-institutional phase 2 trial of the Korean Cancer Study Group(KCSGHB19-14)" 8 : 56-65, 2023
• 4 Cho SM, "Timeline of FDA-approved targeted therapy for cholangiocarcinoma" 14 : 2641-, 2022
• 5 Loeuillard E, "Targeting tumorassociated macrophages and granulocytic myeloidderived suppressor cells augments PD-1 blockade in cholangiocarcinoma" 130 : 5380-5396, 2020
• 6 Normanno N, "Role of molecular genetics in the clinical management of cholangiocarcinoma" 7 : 100505-, 2022
• 7 Zhou G, "Reduction of immunosuppressive tumor microenvironment in cholangiocarcinoma by ex vivo targeting immune checkpoint molecules" 71 : 753-762, 2019
• 8 Lee SH, "Recent advancement in diagnosis of biliary tract cancer through pathological and molecular classifications" 16 : 1761-, 2024
• 9 Doleschal B, "Real world evidence reveals improved survival outcomes in biliary tract cancer through molecular matched targeted treatment" 13 : 15421-, 2023
• 10 Meric-Bernstam F, "Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer(MyPathway) : an updated report from a multicentre, open-label, phase 2a, multiple basket study" 20 : 518-530, 2019
• 11 Abou-Alfa GK, "Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma : a multicentre, open-label, phase 2study" 21 : 671-684, 2020
• 12 Maio M, "Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers : updated analysis from the phase II KEYNOTE-158 study" 33 : 929-938, 2022
• 13 Kelley RK, "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" 401 : 1853-1865, 2023
• 14 Lin J, "Pembrolizumab combined with lenvatinib as non-first-line therapy in patients with refractory biliary tract carcinoma" 9 : 414-424, 2020
• 15 Subbiah V, "Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial" 28 : 1640-1645, 2022
• 16 Demols A, "NTRK gene fusions in biliary tract cancers [abstract]" 574-, 2020
• 17 Lu C, "Metabolic regulation of epigenetics" 16 : 9-17, 2012
• 18 Villanueva L, "Lenvatinib plus pembrolizumab for patients with previously treated biliary tract cancers in the multicohort phase II LEAP-005study [abstract]" 321-, 2021
• 19 Abou-Alfa GK, "Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma(ClarIDHy) : a multicentre, randomised, double-blind, placebo-controlled, phase 3 study" 21 : 796-807, 2020
• 20 Parimi V, "Genomic landscape of 891 RET fusions detected across diverse solid tumor types" 7 : 10-, 2023
• 21 Goyal L, "Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma" 388 : 228-239, 2023
• 22 Doebele RC, "Entrectinib in patients with advanced or metastatic NTRK fusionpositive solid tumours : integrated analysis of three phase 1-2 trials" 21 : 271-282, 2020
• 23 Drilon A, "Efficacy of larotrectinib in TRK fusion-positive cancers in adults and Children" 378 : 731-739, 2018
• 24 Javle MM, "Efficacy and safety results of FGFR1-3 inhibitor, tinengotinib, as monotherapy in patients with advanced, metastatic cholangiocarcinoma: results from phase II clinical trial [abstract]" 434-, 2024
• 25 Oh DY, "Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer(TOPAZ-1) : updated overall survival from a randomised phase 3 study" 9 : 694-704, 2024
• 26 Subbiah V, "Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer(ROAR) : a phase 2, open-label, single-arm, multicentre basket trial" 21 : 1234-1243, 2020
• 27 Valle J, "Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer" 362 : 1273-1281, 2010
• 28 Ilyas SI, "Cholangiocarcinoma-novel biological insights and therapeutic strategies" 20 : 470-486, 2023
• 29 Tsang ES, "A phase II study of olaparib and durvalumab in patients with IDHmutated cholangiocarcinoma [abstract]" 4099-, 2023
• 30 Oh DY, "279MO Three-year survival, safety and extended long-term survivor(eLTS)analysis from the phase III TOPAZ-1 study of durvalumab(D)plus chemotherapy in biliary tract cancer(BTC)" 35 : S117-, 2024