Recent genomic profiling studies revealed that approximately 40% of patients with biliary tract cancers harbor actionable genomic mutations.
The advances in the understanding and characterization of biliary tract cancers (BTCs), particularly intrahepatic cholangiocarcinoma (iCCA), and genomic profiling over the past decade have led to a rapid expansion of available treatment options.
“Historically, [iCCA] was a poorly understood, underappreciated, and ill-defined disease....years ago, [iCCA] was among the commonly defined unknown primary cancers, as we did not know better,” Ghassan K. Abou-Alfa, MD, MBA, professor of medicine at Weill Cornell Medical College and medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, said in an interview with Targeted Therapies in Oncology™. Due to this limited and poor understanding of advanced cholangiocarcinoma, treatment options were limited to chemotherapy, primarily using gemcitabine-based regimens to treat pancreatic cancer.1,2
BTCs are a well-defined family of tumors subclassified based on their anatomical site into distinct subtypes, including iCCA, extrahepatic cholangiocarcinoma (eCCA), and gallbladder cancer (GBC).3,4 BTCs are the second most common primary liver cancer, accounting for 3% of all gastrointestinal tumors.5 When most patients with BTCs, including iCCA, receive a diagnosis, it is at an advanced stage and typically treated with chemotherapy. The commonly used chemotherapy regimens, cisplatin and gemcitabine, are associated with a median overall survival (OS) of less than 12 months.1,2,6
Recent genomic profiling studies revealed that approximately 40% of patients with BTC harbor actionable genomic mutations, including fibroblast growth factor receptor (FGFR) fusions (approximately 5% to 10%), isocitrate dehydrogenase (IDH) 1/2 mutations (approximately 10% to 15%), HER2 amplifications/mutations (approximately 10% to 15%), BRAF V600E mutation (3%), BRCA2 mutations (3%), and microsatellite instability (1%).7,8
The genomic characterization of BTCs has paved the way for developing targeted therapies and opened the door to apply personalized treatment strategies to treat patients with CCA (FIGURE9). In addition, the detection of actionable mutations among patients with BTCs highlights the importance of early genomic testing. “Genetic testing of patients with cholangiocarcinoma is a must; a tumor genomic profile should be an integral part of patients’ medical reports,” Abou-Alfa said.
In 2021, several landmark approvals of targeted cancer therapies for CCA have been achieved, including the approval of IDH1 and FGFR2 inhibitors.
IDH 1 and 2 (IDH1/2) are essential enzymes that play a critical role in various cellular functions, including cellular metabolism, epigenetic regulation, redox functions, and DNA repair mechanisms.3 IDH1 and IDH2 catalyze the NADP-positive–dependent oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) and CO2. Mutations in IDH1/2 result in dysregulation of the catalytic functions of IDH1/2, leading to increased conversion of α-KG to D-2-hydroxyglutarate, an oncogenic metabolite that promotes tumor proliferation metastasis, and malignant transformation through several mechanisms, including DNA methylation.10 Mutations in IDH1/2 have been detected in various cancers, including low-grade gliomas and secondary gliomas, chondrosarcoma, acute myeloid leukemia, and iCCA. In iCCA, IDH1/2 mutations were identified in 15% to 20% of cases, which led to an interest in investigating the activity of IDH1/2 inhibitors in this patient population.11
The results of the ClarIDHy trial (NCT02989857) led to the approval of ivosidenib (Tibsovo), a first-in-class, oral, small-molecule inhibitor of mutant IDH1, for patients with previously treated, locally advanced, or metastatic CCA with an IDH1 mutation.12 The trial enrolled 187 patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation. Ivosidenib treatment resulted in an overall survival (OS) of 10.3 months (95% CI, 7.8-12.4) compared with 7.5 months for the placebo (95% CI, 0.56-1.12; P = .09).12 Serious ivosidenib-related treatment-emergent adverse events (TEAEs) were reported in 3 patients (2%) and included grade 4 hyperbilirubinemia, grade 3 cholestatic jaundice, grade 2 prolonged QT interval, and grade 3 pleural effusion. Ivosidenib treatment resulted in 63% reduction in the risk of progression or death (HR, 0.37 [95% CI, 0.25-0.54]; 1-sided P < .001) compared with placebo.12
“Since IDH mutations are seen in [approximately] 20% of patients and ivosidenib is FDA approved, this drug is an important oral option that delayed the risk of progression by 63%. That makes it a wonderful second- and third-line treatment for these patients,” Rachna T. Shroff, MD, MS, associate professor of medicine, medical director of the clinical trials office, chief of gastrointestinal medical oncology, and director of Arizona Clinical Trials Network at University of Arizona College of Medicine in Tucson, said during an interview with Targeted Therapies in Oncology™.
FGFs and their associated fibroblast growth factor receptors (FGFRs) play critical roles in intracellular survival and proliferative pathways.13 Alterations in FGFR genes, including activating mutations, chromosomal translocations, gene fusions, and gene amplification, can lead to ligand-independent signaling and constitutive receptor activation.13 Consequently, activating key downstream signaling pathways induces oncogenesis by activating the Ras-Raf-MEK-ERK pathway, the PI3K-AKT-mTOR pathway, and the JAKSTAT pathway.13
In an analysis of 4853 solid tumors, FGFR genetic aberrations were identified in 7.1% of all cancers. Among the CCA tumors included in the study (N = 115), 7% harbored FGFR aberrations.14 These aberrations were mainly in the gene encoding for FGFR2 (6.1%), 14 which led to the development and approval of several FGFR2-targeted drugs to treat iCCR.
The FDA approved pemigatinib (Pemazyre), a selective, potent, oral inhibitor of FGFR1- 3 in April 2020 as the first targeted drug for patients with advanced refractory CCA with an FGFR2 fusion or rearrangement.15 In the FIGHT-202 (NCT02924376) trial, a multicenter study that included a total of 147 patients with locally advanced or metastatic CCA with or without FGFR2 fusions, the objective response was observed in 38 patients (26%) with FGFR2 fusions or rearrangements, including 3 complete responses and 35 partial responses.10 In the trial, the most frequent grade 3 or worse adverse events were hypophosphatemia (18 [12%]), arthralgia (9 [6.1%]), stomatitis (8 [5.4%]), hyponatremia (8 [5.4%]), abdominal pain (7 [4.8%]), and fatigue (7 [4.8%]). Hyperphosphatemia occurred early after treatment initiation (median time to onset 15 days [95% CI, 8-47]) and was managed with a low-phosphate diet, concomitant phosphate binders, diuretics, dose reduction, and dose interruption.10
Infigratinib (Truseltiq), a selective, ATP-competitive inhibitor of FGFRs, also was granted accelerated approval by the FDA for metastatic CCA.16 In a phase 2, single-arm trial of patients with advanced CCA harboring FGFR2 alterations, infigratinib treatment resulted in an overall response rate (ORR) of 23.1% (95% CI, 15.6%-32.2%; 25 of 108 patients). The most common treatment-emergent adverse events of any grade were hyperphosphatemia (n = 83), stomatitis (n = 59), fatigue (n = 43), and alopecia (n = 41). The most common ocular toxicity was dry eyes (n = 37). Central serous retinopathy and retinal pigment epithelial detachment events occurred in 18 (17%) patients, of which 10 (9%) were grade 1, 7 (6%) were grade 2, and 1 (1%) was grade 3.17
Futibatinib, a highly selective irreversible FGFR1-4, also was granted FDA breakthrough therapy designation for patients with CCA positive for FGFR2 gene fusions and rearrangements. The approval was based on the results of FOENIX-CCA2 (NCT02052778), a single-arm, multicenter phase 2 study.18 The trial included 103 patients with locally advanced or metastatic unresectable harboring FGFR2 gene fusions or other rearrangements following disease progression after greater than or equal to 1 line of systemic therapy, including gemcitabine plus platinum-based chemotherapy. Futibatinib treatment resulted in an ORR of 41.7% and disease control rate (DCR) of 82.1%. Responses were durable, with a median duration of response of 9.7 months and 72% of responses that were 6 months or more. DCR was 82.5%, median progression-free survival was 9.0 months, and median overall survival was 21.7 months, with a 12-month OS rate of 72%. The most common treatment-related adverse events (TRAEs) of any grade were hyperphosphatemia (85%), alopecia (33%), and dry mouth (30%).18
Gunagratinib (ICP-192) is a novel pan-FGFR inhibitor that irreversibly inhibits FGFR signaling through covalent interaction.19 In a phase 1 study that included 30 patients, among the 12 patients with FGF/FGFR gene aberrations who had completed at least 1 tumor assessment, the ORR was 33.3%, including 1 patient (8.3%) with complete response (CR) and 3 patients (25%) with partial response (PR).19 The DCR was 91.7% (11 of 12 patients).19
Derazantinib is an oral, potent, ATP-competitive, pan-FGFR inhibitor with strong activity against FGFR1-3 kinases.13 Derazantinib also inhibits several other kinases, including RET, DDR2, VEGFR1, and KIT. In a phase 1/2, open-label study (NCT01752920) that included 29 patients with unresectable iCCA with an FGFR2 fusion who progressed on were intolerant to or were not eligible for first-line chemotherapy, treatment with derazantinib 300 mg once daily resulted in an ORR of 20.7% and DCR of 82.8%.20 The pivotal, open-label, single-arm, phase 2 FIDES-01 trial (NCT03230318) is evaluating derazantinib in previously treated patients with iCCA with 1 cohort for patients with FGFR2 gene fusions and another for patients with FGFR2 mutations or amplifications.21
Collectively, FGFR inhibitors represent valuable treatment options for patients with iCCA with FGFR fusions and rearrangement. Although “FGFR fusions are only seen in [approximately] 10% to 15% of patients, infigratinib, pemigatinib, and futibatinib have all demonstrated impressive overall response rates, making this a relevant target. Having these drugs available will impact survival simply by giving patients more treatment options beyond gemcitabine and cisplatin,” Shroff said.
“Identification of new drivers and targetable alterations, such as NTRK, RNF43, and BRAF, is needed to expand opportunities for developing precision treatments for this deadly disease,” Luca Fabris, MD, PhD, associate professor of gastroenterology in the Department of Molecular Medicine, University of Padua School of Medicine in Italy, and adjunct associate professor of medicine at Yale Liver Center in New Haven, Connecticut, said in an email. Molecular profiling studies of patients with CCA revealed additional actionable targets. A recent mutation profiling of 75 CCA specimens identified ERBB2 genetic aberrations in 20% of patients with perihilar and distal CCAs and only 1.8% of iCCAs.22 Activation of this pathway leads to downstream oncogenic pathway activation, including the MAPK pathway.9
The ongoing MyPathway study (NCT02091141) is evaluating the efficacy of FDA-approved therapies in nonindicated tumors with potentially actionable molecular alterations. Among patients enrolled in the study, 39 had HER2-positive biliary tract cancer treated with a dual anti-HER2 regimen, pertuzumab (Perjeta) plus trastuzumab (Herceptin). Nine of 39 patients achieved a partial response (objective response rate 23% [95% CI 11-39]).23
Mutations in the BRAF gene also were identified in 5% of patients with biliary tract tumors.24 Based on these findings, the combination of dabrafenib (Tafinlar) and trametinib (Mekinist), which demonstrated efficacy in BRAF V600E–mutated cancers, was evaluated in the ROAR basket trial (NCT02034110). Among 43 patients with biliary tract cancers, the combination of dabrafenib and trametinib resulted in an ORR of 51% (95% CI, 36%-67%) at a median follow-up of 10 months. In addition, 17 patients experienced TRAEs, including pyrexia (19%). These findings demonstrate the importance of routine testing for BRAF V600E mutation for all patients with biliary tract cancer.24
Immune checkpoint inhibitors have advanced the treatment of many types of cancer. In CCA, molecular profiling studies that included 260 biliary tumors showed that 45.2% of the cases had increased expression of key immune checkpoints.25 Additionally, enhanced expression in PD-1 and PD-L1 was reported in surgically resected iCCA compared with adjacent tissue.26 Several clinical trials are ongoing, including TOPAZ-1 (NCT03875235), a randomized, double-blind placebo-controlled, multiregional, international study of 757 patients with unresectable advanced or metastatic biliary tract cancer, which is investigating the combination of durvalumab, an anti– PD-L1 monoclonal antibody, with gemcitabine and cisplatin.27
“No doubt, immunotherapy will bring good news for the patients with cholangiocarcinoma and will emerge as an important treatment option,” Abou-Alfa said. However, new challenges in sequencing therapeutic strategies that involve chemotherapy and targeted therapies may arise soon as clinical trials of immune checkpoint inhibitors continue to progress. “The potential use of checkpoint inhibitors in first-line treatment will present challenges in terms of therapeutic sequencing of chemotherapy and targeted therapies,” Abou-Alfa said.
With the changing treatment landscape of CCA, several challenges are emerging. Among these is the integration of molecular testing in routine clinical practice, which will require access to molecular testing resources. Additionally, community oncologists need to learn about the currently available testing platform.
“The new world of targeted therapy options in cholangiocarcinoma presents significant challenges to oncologists, primarily in terms of the technical aspects of assays and education around the multiple complexities of targeted therapy,” John Bridgewater, MD, PhD, a professor and medical oncologist at University College London Hospitals in England, said in an email.
Furthermore, Shroff said, “with the advent of targeted therapies, we need to improve options for biomarker testing. Tissue-based next-generation sequencing is currently the standard approach, but this often fails due to inadequate tissue or poor quality. Circulating tumor DNA [ctDNA] is an ideal tool to understand the genomic profi le of CCAs quickly in a way that accounts for tumor heterogeneity. Thus, improving the concordance and breadth of ctDNA will have a tremendous impact.”
Identifying resistance mechanisms to targeted therapies will continue to drive the development of next-generation inhibitors with improved efficacy. Several reports demonstrated the emergence of acquired resistance to FGFR2 inhibitors.28 Targeted sequencing of tumor DNA after disease progression following treatment with infigratinib identified a mutation in the FGFR2 kinase domain associated with upregulation of the PI3K/AKT/ mTOR signaling pathway.28 Additionally, acquired resistance mechanisms to ivosidenib were also described. Mutations in the receptor tyrosine kinase pathway have been associated with primary resistance.
Isoform switching has also been described as a mechanism of acquired resistance to selective IDH inhibitors.29 The emergence of an oncogenic IDH2 mutation in cholangiocarcinoma was identified as a resistance mechanism to selective mutant IDH1 inhibition.29
Additional studies are needed to reveal resistance mechanisms. According to Fabris, “translational studies to improve our understanding of how to overcome resistance to targeted therapies will be pursued.” Additionally, since not all patients respond to treatment, the “identification of new diagnostic and prognostic biomarkers may enable early diagnosis and predict treatment response,” he said.
Novel combination strategies may be investigated to overcome resistance mechanisms and improve treatment outcomes.
“Potential strategies harnessing FGFR inhibition in the neoadjuvant and adjuvant setting, as well as in combination with chemotherapy, are worthy of consideration by future studies,” Fabris said. Additionally, advances in understanding the role of the tumor microenvironment may reveal novel druggable targets in the near future to overcome resistance mechanisms and improve treatment outcomes. “Better understanding of the multifaceted actions played by the tumor microenvironment, which is particularly abundant in CCAs, may lead to the discovery of new druggable targets,” Fabris said.
Collectively, the rapid advances in the treatment of patients with CCA will continue to improve treatment outcomes. However, with the expanding treatment landscape of CCA, several challenges will arise, including the integration of routine molecular testing in clinical practice and therapeutic sequencing decisions. Additionally, personalized targeted therapies will continue to offer hope for patients with CCA.
“We will need to do upfront genomic profiling, align this with patients’ wishes and goals of care, and strategically provide treatments. This has and will continue to improve outcomes for these patients, which is truly exciting,” Shroff said.
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28. Krook MA, Lenyo A, Wilberding M, et al. Efficacy of FGFR inhibitors and combination therapies for acquired resistance in FGFR2-fusion cholangiocarcinoma. Mol Cancer Ther. 2020;19(3):847-857. doi:10.1158/1535-7163.MCT-19-0631
29. Harding JJ, Lowery MA, Shih AH, et al. Isoform switching as a mechanism of acquired resistance to mutant isocitrate dehydrogenase inhibition. Cancer Discov. 2018;8(12):1540-1547. doi:10.1158/2159-8290.CD-18-0877