Abstract
The prognosis of patients affected by cholangiocarcinoma is classically poor. Until recently, chemotherapeutic drugs were the only systemic treatment option available, leading to an overall survival lower than 1 year. In recent decades, different genetic alterations have been identified as playing a key role in the oncogenic signaling. A subgroup of intrahepatic cholangiocarcinoma is characterized by FGFR family mutations, more frequently represented by gene fusions of FGFR2. Based on the results of FIGHT-202 trial, in April 2020 the US FDA approved the FGFR inhibitor pemigatinib in advanced previously treated cholangiocarcinoma patients with FGFR2 rearrangements, opening the way to targeted therapy in this disease. This review summarizes the body of evidence about the efficacy of pemigatinib in cholangiocarcinoma.
Lay abstract
Cholangiocarcinoma is cancer that forms in the slender tubes bile ducts that carry the digestive fluid bile. This condition, also known as bile duct cancer, is a type of tumor that is very difficult to treat with common chemotherapy. Intrahepatic cholangiocarcinoma, those tumors occurring in the parts of the bile ducts within the liver, are frequently caused by alterations of a gene called FGFR2. Pemigatinib is a novel potent drug that selectively inhibits the function of altered FGFR2 and recently demonstrated to be a valid treatment for patients affected by intrahepatic cholangiocarcinoma. Here, we present results about the efficacy of pemigatinib in this disease.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2, 10 (2002).
- 2. . Cholangiocarcinoma of the extrahepatic bile ducts. Semin. Surg. Oncol. 19(2), 156–176 (2000).
- 3. . Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology 128(3), 620–626 (2005).
- 4. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 362(14), 1273–1281 (2010).
- 5. . New horizons for precision medicine in biliary tract cancers. Cancer Discov. 7(9), 943–962 (2017). • An overview about precision oncology in biliary tract cancers.
- 6. . Clinical and translational research challenges in biliary tract cancers. Curr. Med. Chem.
doi:10.2174/0929867327666200123090153 (2020) (Epub ahead of print). - 7. . Fibroblast growth factor signalling: from development to cancer. Nat. Rev. Cancer 10(2), 116–129 (2010). • A comprehensive review about FGFR signalling in cancer.
- 8. . Roles of fibroblast growth factor receptors in carcinogenesis. Mol. Cancer Res. 8(11), 1439–1452 (2010).
- 9. . Fibroblast growth factor regulation of neovascularization. Curr. Opin. Hematol. 15(3), 215–220 (2008).
- 10. . Advances and challenges in targeting FGFR signalling in cancer. Nat. Rev. Cancer 17(5), 318–332 (2017).
- 11. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist 19(3), 235–242 (2014).
- 12. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum. Pathol. 45(8), 1630–1638 (2014).
- 13. Genomic spectra of biliary tract cancer. Nat. Genet. 47(9), 1003–1010 (2015). •• Large molecular characterization of biliary tract cancers.
- 14. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology 59(4), 1427–1434 (2014).
- 15. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J. Clin. Oncol. 36(3), 276–282 (2018).
- 16. Infigratinib in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: the PROOF 301 trial. Future Oncol.
doi:10.2217/fon-2020-0299 (2020) (Epub ahead of print). - 17. Preclinical activity of ARQ 087, a novel inhibitor targeting FGFR dysregulation. PLoS ONE 11(9), e0162594 (2016).
- 18. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br. J. Cancer 120(2), 165–171 (2019).
- 19. Updated results of a Phase IIa study to evaluate the clinical efficacy and safety of erdafitinib in Asian advanced cholangiocarcinoma (CCA) patients with FGFR alterations. J. Clin. Oncol. 37(Suppl. 15), 4117–4117 (2019).
- 20. Safety and efficacy of the selective FGFR inhibitor debio 1347 in Phase I study patients with FGFR genomically activated advanced biliary tract cancer (BTC). J. Clin. Oncol. 36(Suppl. 4), 447–447 (2018).
- 21. Phase II Study of AZD4547 in patients with tumors harboring aberrations in the FGFR pathway: results from the NCI-MATCH trial (EAY131) subprotocol W. J. Clin. Oncol. 38(21), 2407–2417 (2020).
- 22. . Antibodies directed against receptor tyrosine kinases: current and future strategies to fight cancer. MAbs 6(4), 838–851 (2014).
- 23. . Antibody drug conjugates: lessons from 20 years of clinical experience. Ann. Oncol. 27(12), 2168–2172 (2016).
- 24. . HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 5(10), 761–772 (2005).
- 25. mTOR inhibition potentiates HSP90 inhibitor activity via cessation of HSP synthesis. Mol. Cancer Res. 12(5), 703–713 (2014).
- 26. Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS ONE 6(1), e15640 (2011).
- 27. . Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review. J. Gastrointestinal Oncol. 10(4), 751–765 (2019).
- 28. Comprehensive molecular profiling of IDH1/2 mutant biliary cancers (BC). J. Clin. Oncol. 38(Suppl. 4), 479–479 (2020).
- 29. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three Phase I-II trials. Lancet Oncol. 21(2), 271–282 (2020).
- 30. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three Phase I/II clinical trials. Lancet Oncol. 21(4), 531–540 (2020).
- 31. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 373(8), 726–736 (2015).
- 32. Efficacy and safety of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E-mutated biliary tract cancer (BTC): a cohort of the ROAR basket trial. J. Clin. Oncol. 37(Suppl. 4), 187–187 (2019).
- 33. Multi-institutional Phase II study of selumetinib in patients with metastatic biliary cancers. J. Clin. Oncol. 29(17), 2357–2363 (2011).
- 34. A Phase Ib study of Selumetinib in combination with cisplatin and gemcitabine in advanced or metastatic biliary tract cancer: the ABC-04 study. BMC Cancer 16, 153 (2016).
- 35. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 144(4), 829–840 (2013).
- 36. A Phase I dose escalation study of oral c-MET inhibitor tivantinib (ARQ 197) in combination with gemcitabine in patients with solid tumors. Ann. Oncol. 25(7), 1416–1421 (2014).
- 37. A Phase II and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma. Cancer 123(11), 1979–1988 (2017).
- 38. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 19(13), 2878–2880 (2017).
- 39. Palbociclib in patients with pancreatic and biliary cancer with CDKN2A alterations: results from the targeted agent and profiling utilization registry study. JCO Precision Oncol.
doi:10.1200/po.19.00124(3) , 1–8 (2019) (Epub ahead of print). - 40. Overall survival and clinical characteristics of BRCA-associated cholangiocarcinoma: a multicenter retrospective study. Oncologist 22(7), 804–810 (2017).
- 41. HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target? Cancer Metastasis Rev. 36(1), 141–157 (2017).
- 42. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357(6349), 409–413 (2017).
- 43. Program death 1 immune checkpoint and tumor microenvironment: implications for patients with intrahepatic cholangiocarcinoma. Ann. Surg. Oncol. 23(8), 2610–2617 (2016).
- 44. PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma. Oncotarget 8(15), 24644–24651 (2017).
- 45. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the Phase II KEYNOTE-158 study. J. Clin. Oncol. 38(1), 1–10 (2020).
- 46. INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2 and 3, displays activity against genetically defined tumor models. PLoS ONE 15(4), e0231877 (2020).
- 47. Preliminary results from a Phase I/II study of INCB054828, a highly selective fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced malignancies. Presented at: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics. Philadelphia, PA, USA, 26–30 October 2017.
- 48. ABC-06 | A randomised Phase III, multi-centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin / 5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced / metastatic biliary tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy. J. Clin. Oncol. 37(Suppl. 15), 4003–4003 (2019).
- 49. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, Phase II study. Lancet Oncol. 21(5), 671–684 (2020). •• First reporting of the Phase II FIGHT-202 trial showing activity of pemigatinib in FGFR altered advanced cholangiocarcinoma patients.
- 50. . Combination versus mono-therapy as salvage treatment for advanced biliary tract cancer: a comprehensive meta-analysis of published data. Crit. Rev. Oncol. Hematol. 139, 134–142 (2019).
- 51. Second-line chemotherapy in advanced biliary cancers: a retrospective, multicenter analysis of outcomes. Cancer 125(24), 4426–4434 (2019).
- 52. Advanced intrahepatic cholangiocarcinoma: post hoc analysis of the ABC-01, -02 and -03 clinical trials. J. Natl Cancer Inst. 112(2), 200–210 (2020).
- 53. Cholangiocarcinoma with FGFR genetic aberrations: a unique clinical phenotype. JCO Precision Oncol.
doi:10.1200/po.17.00080(2) , 1–12 (2018) (Epub ahead of print). - 54. . Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat. Rev. Drug Discov. 15(1), 51–69 (2016).
- 55. Frequent subclinical macular changes in combined BRAF/MEK inhibition with high-dose hydroxychloroquine as treatment for advanced metastatic BRAF mutant melanoma: preliminary results from a Phase I/II clinical treatment trial. Retina 39(3), 502–513 (2019).
- 56. Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy. Oncogenesis 5(7), e241 (2016).
- 57. . Upregulation of EphB3 in gastric cancer with acquired resistance to a FGFR inhibitor. Int. J. Biochem. Cell Biol. 102, 128–137 (2018).
- 58. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma. Cancer Discov. 7(3), 252–263 (2017). •• Identification of mechanisms of acquired resistance to FGFR inhibitors.
- 59. Akt activation mediates acquired resistance to fibroblast growth factor receptor inhibitor BGJ398. Mol. Cancer Ther. 16(4), 614–624 (2017).
- 60. RAS-MAPK reactivation facilitates acquired resistance in FGFR1-amplified lung cancer and underlies a rationale for upfront FGFR-MEK blockade. Mol. Cancer Ther. 17(7), 1526–1539 (2018).
- 61. The secretome engages STAT3 to favor a cytokine-rich microenvironment in mediating acquired resistance to FGFR inhibitors. Mol. Cancer Ther. 18(3), 667–679 (2019).
- 62. Epithelial-mesenchymal transition confers resistance to selective FGFR inhibitors in SNU-16 gastric cancer cells. Gastric Cancer 19(1), 53–62 (2016).
- 63. . TAS-120 cancer target binding: defining reactivity and revealing the first fibroblast growth factor receptor 1 (FGFR1) irreversible structure. Chem. Med. Chem. 14(4), 494–500 (2019).