The 5th Annual Cholangiocarcinoma (CCA) Summit, held October 19 to 21, 2023, in Scottsdale, AZ, brought together experts from around the world to discuss the latest research and clinical data pertaining to the diagnosis and treatment of patients with CCA and other biliary tract cancers (BTCs). During the first session, panelists discussed advances in systemic therapies including traditional chemotherapy as well as immunotherapy and novel targets.
Milind Javle, MD, MPH, Hubert L. and Olive Stringer Professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, opened the session with a presentation titled “Novel Targets and Combinations in Cholangiocarcinoma.” He began by discussing methylthioadenosine phosphorylase (MTAP), a tumor suppressor, as a therapeutic target, the loss of which 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 several 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 VEGFA bispecific antibody that has been shown to overcome VEGF resistance and reduce tumor growth.1 Early trials have suggested a benefit with this agent in patients with BTC, and there is a phase 2/3 randomized, controlled trial in progress assessing CTX-009 in combination with paclitaxel versus paclitaxel alone in patients with advanced BTC.1 Preliminary data have suggested that BAP1 is another promising target in 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 (Tibsovo) in combination with the PD-L1 inhibitor nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy) in IDH1-mutated CCA, and a phase 2 study of the FGFR inhibitor pemigatinib (Pemazyre) in combination with the PD-L1 inhibitor atezolizumab (Tecentriq) and the VEGF inhibitor bevacizumab (Avastin) in FGFR-altered CCA.
Midhun Malla, MD, MS, Associate Professor, Hematology & Oncology, University of Alabama, Birmingham, focused on the current and future role of systemic therapy in metastatic, adjuvant, and neoadjuvant settings in patients with BTC. In patients with advanced disease, 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 (Abraxane) 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 (Xeloda) improved relapse-free survival and OS compared with surveillance in the BILCAP trial,5 and adjuvant S-1 demonstrated significantly longer relapse-free survival 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 aged >70 years; a national cancer database analysis of adjuvant therapy in elderly patients (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 Findings 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, Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, presented on the use of T-cell receptor (TCR) targets in patients with 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 they 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, Co-Director, Cancer Genetics and Epigenetics, and Professor, Oncology, Johns Hopkins Medicine, Baltimore, MD, gave a presentation titled “The Future of Cancer Vaccines in BTC: It’s Our Time!” Although there have been significant advancements in the treatment of patients with advanced BTC over the past 5 years, these individuals still have poor survival. Immunotherapy is a promising therapeutic area that has the potential to improve outcomes; however, a key challenge in 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 This entails using 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, Executive Medical Director, Vanderbilt-Ingram Cancer Center Cancer Patient Care Center, and Professor of Medicine, Hematology-Oncology, Vanderbilt-Ingram Cancer Center, Nashville, TN, discussed 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 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 investigations include high-risk neoadjuvant studies, locoregional combination studies, conversion studies, and studies with systemic therapy combinations.
Gregory B. Lesinski, PhD, MPH, Professor, Department of Hematology and Medical Oncology, and Vice Chair for Basic Research, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, presented on several novel and alternative immunotherapy targets in BTC. Numerous immunotherapy approaches are currently being investigated, including immune checkpoint inhibitors that block immune-suppressing signals, immune-stimulating agonists (eg, CD27), adoptive T-cell therapy consisting 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 (Tecentriq) with or without cobimetinib (Cotellic) in previously treated, unresectable BTC.
