Session I: Systemic Therapies

December 2023, Vol 4, No 4

Left to right: Gregory Lesinski, PhD, MPH, Jennifer Knox, MD, MSc, FRCPC(C), Milind Javle, MD, Cassian Yee, MD, Nilofer Azad, MD, Laura Goff, MD, MSCI, MMHC

At the 5th annual CCA Summit, panelists discussed advances in systemic therapies including traditional chemotherapy as well as immunotherapy and novel targets in the first session. Milind Javle, MD, MPH, University of Texas MD Anderson Cancer Center, first presented on novel targets and combination strategies for the treatment of cholangiocarcinoma (CCA) in his presentation titled “Novel Targets and Combinations in Cholangiocarcinoma.” He discussed methylthioadenosine phosphorylase (MTAP), a tumor suppressor, as a therapeutic target whose loss is associated with poor survival.1 It has been suggested that PRMT5 is a synthetic lethal target for MTAP-deleted tumors as high levels of methylthioadenosine from MTAP loss partially inhibit PRMT5, and PRMT5 inhibitors require methylthioadenosine in the pocket for binding. PRMT5, methylthioadenosine, and MAT2A inhibitors are a promising area of development with many ongoing phase 1/2 studies. Another target of interest discussed by Dr Javle is the dual blockade of vascular endothelial growth factor (VEGF) and DLL4, which are responsible for vascularized tumor growth. CTX-009 is a novel DLL4 and VEGF-A bispecific antibody that has been shown to overcome VEGF resistance and reduce tumor growth.1 Early trials have suggested a benefit of CTX-009 in patients with biliary tract cancer (BTC), and there is a phase 2/3 randomized, controlled trial in progress of CTX-009 in combination with paclitaxel versus paclitaxel alone in patients with advanced BTC.1 Early data have suggested that BAP1 is another promising target for CCA because mutations in this gene are associated with aggressive disease and somatic mutations.2 Cancers harboring mutations in BAP1 can be treated with histone deacetylase inhibitors, poly (ADP-ribose) polymerase inhibitors, and EZH2 inhibitors, which are currently being studied in a variety of tumor types. Finally, Dr Javle discussed novel immunotherapy combinations with existing approved treatments, including IDH inhibitors and FGFR inhibitors. Currently, there is an ongoing study of the IDH inhibitor ivosidenib in combination with PD-L1 inhibitor nivolumab and CTLA-4 inhibitor ipilimumab in patients with IDH1-mutated CCA, and a phase 2 study of the FGFR inhibitor pemigatinib in combination with PD-L1 inhibitor atezolizumab and VEGF inhibitor bevacizumab in FGFR-altered CCA.

The presentation by Midhun Malla, MD, MS, University of Alabama, was titled “Systemic chemotherapy in biliary tract cancers: can the needle be moved further,” and it focused on the current and future role of systemic therapy in metastatic, adjuvant, and neoadjuvant settings in patients with BTC. In patients with advanced BTC, clinical trial results using gemcitabine/cisplatin (GemCis)-based regimens have plateaued over the past decade, as regimens that include GemCis with additional agents have similar outcomes to GemCis alone.3 For example, results of the recently published SWOG-1815 trial concluded that GemCis plus nab-paclitaxel did not confer a survival benefit over GemCis alone.4 The addition of immune checkpoint inhibitors to chemotherapy in patients with advanced BTC has improved overall survival (OS) by 1 to 2 months, but the role of chemotherapy in the second-line setting is still unknown; therefore, further second-line prospective clinical trials are needed.3 Adjuvant chemotherapy may be beneficial in patients with BTC, as adjuvant capecitabine improved relapse-free survival (RFS) and OS compared with surveillance in the BILCAP trial,5 and adjuvant S-1 demonstrated significantly longer RFS and OS compared with surveillance in the JCOG1202 study in patients with curatively resected BTC.6 Dr Malla noted, however, that adjuvant therapy may not be beneficial in elderly patients >70 years of age; a national cancer database analysis of adjuvant therapy in the elderly (median age, 78 years) showed that adjuvant therapy was associated with a high hazard of death (hazard ratio, 1.2).3 The phase 2 single-arm prospective feasibility study, NEO-GAP, examined neoadjuvant GemCis plus nab-paclitaxel in patients with resectable high-risk intrahepatic CCA.7 Results indicated that 23% of patients achieved a partial response, 67% had stable disease, and 10% had progressive disease.7 Guidelines currently recommend chemotherapy combinations as preferred therapies for neoadjuvant treatment; however, the decision to use neoadjuvant therapy needs to be individualized by a multidisciplinary team.3

Cassian Yee, MD, University of Texas MD Anderson Cancer Center, presented on T-cell receptor (TCR) targets in BTC. TCRs have the potential to be successful therapeutic targets in solid tumors as there are thousands of potential targets, they are human leukocyte–antigen restricted, and are less likely to experience antigen loss.8 The immunopeptidome is the set of peptides presented by major histocompatibility complex molecules on the surface of antigen-presenting cells9 that can be used to identify potential TCR targets for rare and ultra-rare cancers, such as CCA, using RNA sequence data sets. TCR targets can be identified and used to create TCR-based therapies, including adoptive-cell therapies and bispecific antibodies or T-cell engagers, and vaccines.

Nilofer Azad, MD, Johns Hopkins Medicine, presented on “The future of cancer vaccines in BTC: it’s our time!” Although there have been significant advancements in the treatment of advanced BTC over the past 5 years, these patients still have poor survival. Immunotherapy is a promising therapeutic area that has the potential to improve outcomes; however, a key challenge in patients with BTC is that these tumors are considered “cold” in that they have a low number of infiltrating T-effector cells and are less likely to respond to checkpoint inhibitor therapy. In preclinical studies, a 2-step approach is being investigated to magnify the response of checkpoint inhibitor therapy in patients with BTC using cancer vaccines.10 The first step is to use a vaccine to trigger neoepitope-specific T-cell infiltration into the tumor, and then adding one or more checkpoint modulators to optimize T-cell quality within the tumor microenvironment.10 Efforts focused on using this combinatorial approach in patients with immunologically “cold” tumors are ongoing.

Laura Goff, MD, MSCI, MMHC, Vanderbilt-Ingram Cancer Center, presented on combination strategies and downstaging for localized CCA. Conversion to resectability is dependent on tumor selection factors and the effectiveness of therapy; historically, the reported rate of conversion to resection has ranged from 7% to 27% using chemotherapy with or without locoregional therapy.11 The NEO-GAP phase 2 study of GemCis and nab-paclitaxel for resectable intrahepatic CCA demonstrated an overall response rate of 45%, and 12 (20%) patients were converted from unresectable to resectable disease undergoing curative surgery.12 Dr Goff explained that in order to be successful, combination trials should define the population of interest, use therapies with high response rates, and validate the correlation of response rates with OS. Current ongoing studies include high-risk neoadjuvant studies, locoregional combination studies, conversion studies, and studies with systemic therapy combinations.

Gregory B. Lesinski, PhD, MPH, Winship Cancer Institute of Emory University, presented on several novel and alternative immunotherapy targets in BTC. Several immunotherapy approaches are currently being investigated, including immune checkpoint inhibitors that block immune-suppressing signals, immune-stimulating agonists (eg, CD27), adoptive T-cell therapy that consists of modified T cells that target tumor components (chimeric antigen receptor T-cell therapy), and cancer vaccines.13 CD27 is a therapeutic target of increasing interest as it is selectively upregulated by MEK inhibitor in tumor-infiltrating lymphocytes and may rescue T-cell activation from MEK inhibition because it is expressed in all stages of T-cell maturation.14 In early trials, CD27 agonists have been shown to enhance the efficacy of dual MEK and PD-L1 blockade. This led to the development of a randomized phase 2 study of CDX-1127 (varlilumab), a CD27 agonist, in combination with atezolizumab with or without cobimetinib in previously treated, unresectable BTC.


  1. Javle, M. Novel Targets and Combinations in Cholangiocarcinoma. Presented at: 5th Anniversary Cholangiocarcinoma Summit, October 19-21, 2023; Scottsdale, Arizona.
  2. Al-Shamsi HO, Anand D, Shroff RT, et al. BRCA-associated protein 1 mutant cholangiocarcinoma: an aggressive disease subtype. J Gastrointest Oncol. 2016;7(4):556-561.
  3. Malla, M. Systemic Chemotherapy in Biliary Tract Cancers: Can the Needle Be Moved Further? Presented at: 5th Anniversary Cholangiocarcinoma Summit, October 19-21, 2023; Scottsdale, Arizona.
  4. Shroff RT, Guthrie KA, Scott AJ, et al. SWOG 1815: a phase III randomized trial of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin in newly diagnosed, advanced biliary tract cancers. 2023 ASCO Gastrointestinal Cancers Symposium. Abstract LBA490.
  5. Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20(5):663-673.
  6. Ikeda M, Nakachi K, Konishi M, et al. Adjuvant S-1 versus observation in curatively resected biliary tract cancer: a phase III trial (JCOG1202: ASCOT). 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 382.
  7. Maithel SK, Javle MM, Mahipal A, et al. NEO-GAP: a phase II single-arm prospective feasibility study of neoadjuvant gemcitabine/cisplatin/nab-paclitaxel for resectable high-risk intrahepatic cholangiocarcinoma. J Clin Oncol. 2022; 40(16 suppl):4097-4097.
  8. Yee C. TCRs and T cells first things first. Presented at: 5th Anniversary Cholangiocarcinoma Summit, October 19-21, 2023; Scottsdale, Arizona.
  9. Yewdell JW. MHC class I immunopeptidome: past, present, and future. Mol Cell Proteomics. 2022;21(7):100230.
  10. Azad N. The future of cancer vaccines in BTC: it’s our time! Presented at: 5th Anniversary Cholangiocarcinoma Summit, October 19-21, 2023; Scottsdale, Arizona.
  11. Goff L. The role of combinations: downsizing for localized cholangiocarcinoma. Presented at: 5th Anniversary Cholangiocarcinoma Summit, October 19-21, 2023; Scottsdale, Arizona.
  12. Maithel SK, Keilson JM, Cao HST, et al. NEO-GAP: a single-arm, phase II feasibility trial of neoadjuvant gemcitabine, cisplatin, and nab-paclitaxel for resectable, high-risk intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2023;30(11):6558-6566.
  13. Greten TF, Schwabe R, Bardeesy N, et al. Immunology and immunotherapy of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol. 2023;20(6):349-365.
  14. Ebert PJR, Cheung J, Yang Y, et al. MAP kinase inhibition promotes t cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity. 2016;44(3):609-621.

Related Items

Session II: Surgical Approaches to BTC
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Presentations cover the history of surgical approaches to biliary tract cancers, neoadjuvant and adjuvant perioperative therapies, transplantation, and advances in surgery technology.
5th Annual CCA Summit: Keynote Address
December 2023, Vol 4, No 4
This year’s Keynote Address touched on wide-ranging topics in the management of cholangiocarcinoma, from recent advances to emerging management strategies.
Session IV: Radiation Therapy to the Liver
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Expert panelists discussed the benefits and limitations of various radiation regimens.
Session V: New Molecular Targets/Pathways in CCA
December 2023, Vol 4, No 4
Session V included a series of presentations on new molecular targets and pathways in cholangiocarcinoma.
Session VII: Biomarkers
December 2023, Vol 4, No 4
The tumor microenvironment, the various types of biomarkers, and the many applications for biomarkers were discussed in this series of presentations.
CCA Summit Poster Walk
December 2023, Vol 4, No 4
Many informative and interesting posters covering clinical trials were presented at the CCA Summit. The session featured 3 posters that examined the chemotherapy/immunotherapy landscape, including “Gemcitabine plus cisplatin versus non-gemcitabine and cisplatin regimens as neoadjuvant treatment for cholangiocarcinoma patients prior to liver transplantation: an institution experience.”

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