Background Biliary tract cancers (BTC) represent an uncommon and heterogeneous group of tumors of bile duct and the patients (pts) have poor prognosis. The TOPAZ-1 study led the approval of front-line durvalumab (D) in combination (GCD) with cisplatin and gemcitabine (GC) in advanced BTC.1 2 Modest durable responses with immune checkpoint inhibitor monotherapy (ICI) have also been reported in a subgroup among refractory BTC.3 To date, traditional ICI biomarkers (high tumor mutational burden [TMB], and PD-L1) have not shown a strong association with the response or outcomes.4 A paucity of comprehensive datasets with clinically annotated biospecimens has limited our ability to understand the impact of heterogenous biology (e.g. different etiology, driver mutations, and anatomic location) BTC outcomes on ICI.5 Herein, we report the initial analysis of comprehensive clinical, pathologic, genomic, and spatial transcriptomic analyses from large real-world and clinical trial datasets to describe the immunogenic BTC subgroup (iBTC).
Methods Pts with BTC treated at Memorial Sloan Kettering (MSK) and Moffitt, who received an ICI (> 2 cycles), GCD, GC between July 2017 and June 2023, were identified (IRB 19–006). Progression Free Survival (PFS) comparison was analyzed by the Kaplan Meier method. We included genomics using targeted gene sequencing and pathologic analyses of available tissues. Further bulk and spatial transcriptomic and exome analyses are ongoing.
Results N=208 pts with BTCs who received either GCD (N=35), GC (N=128) and ICI (N=45) were identified at MSK. Across the whole group (N=208), median age 63 years (32–81), female 95 (45%), intrahepatic cholangiocarcinoma (IHCC) 144 (69%), extrahepatic cholangiocarcinoma (EHCC) 40 (19%), GBC 24 (12%) (table 1). Hematoxylin and eosin (H&E) stains of N=45 samples were evaluated by a pathologist for tumor infiltrating (TI) and peritumoral (PT) lymphocytes (Lym), macrophages (Mac), and polymorphonuclear cells (PMN). No statistically significant differences were observed but numerically higher peritumoral infiltration of lymphocytes and macrophages were observed in PT-Lym (p=0.13) and PT-Mac (p=0.16) when groups of PFS <6m and PFS>6m were compared. (figures 1 and 2) Deeper evaluation of the tumor immune contexture and their gene programming using spatial and bulk transcriptomic and genomic analyses (N=29 ICI, N=16 GCD) together with N=11 ICI from Moffitt are ongoing.
Conclusions Durable responses (PFS>6M) to immunotherapy were seen in a subgroup of BTC. Currently available biomarkers have not predicted the response, but ongoing deeper analysis of spatial immune, tumor, and stromal microenvironment analysis will be presented.
Acknowledgements Funded by Society of MSK
Oh D, He A, Qin S. Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer, NEJM Evid 2022;1(8)
Kelley R, Ueno M, Yoo C. 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.
Kim R, Chuang V, Alese O. A Phase 2 Multi-institutional Study of Nivolumab for Patients With Advanced Refractory Biliary Tract Cancer. JAMA Oncol. 2020;6(6):888–894.
Kim D, Kim Y, Kovari K. Biomarker analysis from a phase II multi-institutional study of nivolumab in patients with advanced refractory biliary tract cancer. Eur J Cancer. 2022 Nov;176:171–180
Mody K, Jain P, El-Refai S. Clinical, Genomic, and Transcriptomic Data Profiling of Biliary Tract Cancer Reveals Subtype-Specific Immune Signatures. JCO Precis Oncol. 2022 Jun;6:e2100510
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.