Systemic control has always been the mainstay in the treatment of advanced biliary tract cancer (BTC), with several first- and second-line therapies approved by the US Food and Drug Administration. In addition, molecularly targeted therapy can offer a treatment approach in many patients with cholangiocarcinoma (CCA) who have potentially targetable genomic alterations.
Sunyoung Lee, MD, PhD, of the University of Texas MD Anderson Cancer Center, highlighted the importance of a multidisciplinary approach to CCA treatment. Systemic control has always been essential to the treatment of advanced BTC, and several first- and second-line therapies are available. In addition to systemic chemotherapy, molecularly targeted therapy can offer a personalized approach to treatment in the 35% to 45% of patients with CCA who have potentially targetable genomic changes.
In CCA, 5 subgroups of mutations are recognized, including fibroblast growth factor receptor (FGFR), cell cycle–related genes, IDH1/2 alterations, MAPK pathway aberrations, and chromatin-modifying mutations. Several therapies have been approved by the US Food and Drug Administration or are being investigated in clinical trials targeting many of these mutations. In addition, many inoperable patients may benefit from local control with liver-directed therapy, including external beam radiation therapy, percutaneous ablation, radioembolization, and transarterial chemoembolization. Patients treated with chemotherapy alone have a higher mortality rate from tumor-related liver failure due to inadequate control of primary or satellite lesions. Internal data from MD Anderson comparing clinical outcomes in patients who received liver radiation therapy plus chemotherapy versus chemotherapy alone found that patients who received combination therapy had decreased death rates from hepatic failure. Overall, a multidisciplinary approach to the treatment of CCA is important to improve survival and offer personalization of treatment in patients with targetable mutations.
Chemotherapy remains the mainstay of frontline treatment in patients with advanced BTC. Recently, results from the TOPAZ-1 trial supported the addition of the immune checkpoint inhibitor (ICI) durvalumab to chemotherapy as a new first-line standard of care. Because of this approval, researchers have speculated that dual ICI therapy could be beneficial in the frontline treatment of CCA.
IMMUCHEC was a phase 2 trial comprised of 5 treatment arms comparing various combinations of durvalumab, tremelimumab, gemcitabine, and cisplatin. The greatest objective response rate was seen with chemotherapy alone; however, overall survival (OS) was longest in patients who received chemotherapy plus tremelimumab and durvalumab, suggesting potential benefit with ICI combinations.1 The most efficacious second-line treatment option remains to be established; historically, clinical outcomes in this setting have been modest. The ABC-06 trial showed an improvement in OS with FOLFOX (folinic acid, fluorouracil, and oxaliplatin) after progression on gemcitabine/cisplatin (GemCis), and the NIFTY and NALIRICC trials demonstrated efficacy of fluorouracil and leucovorin plus liposomal irinotecan.2 The efficacy of ICI monotherapy in the second line has shown mixed results, and combination ICI plus chemotherapy in the refractory setting has also failed to demonstrate any meaningful clinical activity. Targeted therapies have gained traction in the second-line setting, and several therapies have been studied targeting FGFR2, IDH1/2, BRAF, and NRTK.
Daniel Ahn, DO, MS, from the Mayo Clinic, described several ongoing studies that could change the frontline treatment paradigm if they yield positive results. The FIGHT-302 trial is investigating pemigatinib versus GemCis as frontline therapy in patients with advanced intrahepatic CCA with FGFR2 rearrangements. Chemotherapy intensification may also play a role in frontline treatment: SWOG 1815 is investigating GemCis plus nab-paclitaxel versus GemCis alone. Finally, KEYNOTE-966 is evaluating pembrolizumab plus GemCis versus GemCis alone, and the findings are expected to be crucial in understanding the role of maintenance therapy. Although chemotherapy remains the first-line treatment option in patients with advanced BTC, future studies may impact the frontline treatment paradigm.
Therapeutic advances in targeted therapy remain critical in improving outcomes in patients with targetable mutations. However, with response rates at <50%, half of patients will have disease progression or die within 9 months. The challenge for researchers is to understand the mechanisms that result in these outcomes and to determine whether response rates can be improved through combination therapy or sequencing.
James Harding, MD, of Memorial Sloan Kettering Cancer Center, described intrinsic and acquired mechanisms of resistance to targeted therapy in his presentation. Intrinsic resistance can be mediated in part by the heterogeneity of the genome, transcriptome, and epigenome. A subset of BTCs harbor co-occurring mutations in TP53, CDKN2A, and RAS, which are associated with worse outcomes and can influence response to targeted therapies. In addition, in cells that are intrinsically resistant, reactivation of signaling pathways can occur with inhibitor therapy, as seen with FGFR inhibitors. A recent study showed that epidermal growth factor receptor (EGFR) signaling limits the effectiveness of FGFR inhibitor therapy and suggested that patients may benefit from combination therapy with FGFR and EGFR inhibitors.
Acquired resistance includes patients who have an initial response or extended stabilization of disease, but then have disease progression. Genetic mechanisms to explain acquired resistance include alterations in oncogenic drivers, alterations in downstream pathways, existence of parallel or alternative pathways, and loss of oncogenic drivers; less understood nongenetic mechanisms remain to be investigated. Efforts to overcome acquired resistance may include more potent and/or selective inhibitors of molecular targets and combination therapy, which has been studied in FGFR mutations, where 67% of patients will develop secondary mutations. Research at Memorial Sloan Kettering has suggested that the class of inhibitor and how it binds in the binding pocket of the target molecule may influence the type of resistance. Other models of acquired resistance can include Lamarckian induction, an epigenetic mechanism of resistance, and dynamic fluctuation, both of which are less well described in BTC.
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