Most Read Articles
Prof. Corinne Faivre-Finn, 30 Nov 2020
Consolidation therapy with the PD-L1 inhibitor durvalumab (Imfinzi®, AstraZeneca) following chemoradiation therapy (CRT) has become the standard of care in patients with unresectable stage III non-small-cell lung cancer (NSCLC), based on primary results of the PACIFIC study. The 4-year update of the study, presented recently at the European Society for Medical Oncology Virtual Congress 2020 (ESMO 2020), demonstrated durable and sustained survival benefits that were consistent with those reported in the primary analyses.
Dr. Roy Herbst, Dr. David Spigel, 09 Jul 2020
The third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) osimertinib is a standard of care in patients with EGFR-positive advanced non-small-cell lung cancer (NSCLC). Results of the ADAURA study, presented at the American Society of Clinical Oncology 2020 Virtual Scientific Programme (ASCO 2020), support earlier use of osimertinib in the adjuvant setting, with superior disease-free survival (DFS) in patients who underwent complete resection of stage IB/II/IIIA EGFR-positive NSCLC. 
Prof. Mark Shackleton, 01 Apr 2020
In recent years, the focus on immuno-oncology has generated a wealth of compelling evidence supporting the use of immune checkpoint inhibitors – in particular those targeting the programmed death-ligand 1 (PD-L1) or PD-1 pathway. At the 8th Oncology Summit organized by the Hong Kong Society of Clinical Oncology, Professor Mark Shackleton of Alfred Health and Monash University, Australia, discussed recent advances in immunotherapy for the management of metastatic Merkel cell carcinoma (MCC) with a focus on the role of the PD-L1 inhibitor avelumab.  
Pearl Toh, 08 Jan 2021
Combining the anti-PD-1 antibody sintilimab and a bevacizumab biosimilar significantly improves survival compared with the standard treatment of sorafenib in the first-line setting for patients with advanced, unresectable hepatocellular carcinoma (HCC), according to the ORIENT-32 study presented at ESMO Asia 2020.

Role of pemigatinib in management of previously-treated, locally advanced or metastatic cholangiocarcinoma

30 Nov 2020
Cholangiocarcinomas (CCAs) are a group of rare and often difficult-to-diagnose cancers that arise from epithelial cells of bile ducts. While the standard first-line treatment for locally advanced or metastatic CCAs is chemotherapy, targeted therapy developed in recent years has expanded the armamentarium of second-line treatment options for patients failing first-line chemotherapy. This article summarizes key challenges in the management of CCAs and the promising data from the FIGHT-202 trial (Fibroblast Growth Factor Receptor Inhibitor in Oncology and Hematology Trial), which investigated the safety and antitumour activity of pemigatinib in patients with previously treated intrahepatic CCA (iCCA) with fibroblast growth factor receptor (FGFR) 2 gene alterations.  

Current challenges in management of CCAs

CCAs, which account for less than 3 percent of all malignant tumours, are classified as intrahepatic or extrahepatic based on tumour location in the biliary tract. [Nat Rev Gastroenterol Hepatol 2011;8:189-200]

CCAs are generally challenging to manage as patients usually present at late stages of disease with nonspecific symptoms such as painless jaundice, weight loss or cholangitis, which complicates the diagnosis. [Nat Rev Gastroenterol Hepatol 2011;8:189-200] When diagnosed, most patients have locally advanced or metastatic disease. [Expert Rev Gastroenterol Hepatol 2018;12:671-681] It is estimated that half of untreated patients will die within 3–4 months of presentation due to the indirect effects of local tumour progression, bile duct obstruction, liver failure or sepsis from cholangitis and abscesses. [Nat Rev Gastroenterol Hepatol 2011;8:189-200]

While surgical resection is currently the only potentially curative treatment for CCAs, the large size and aggressive behaviour of these tumours present a challenges for curative resection. [Expert Rev Gastroenterol Hepatol 2018;12:671-681] Surgery is an option for only about 35 percent of patients with CCAs, and of those who do undergo potentially curative resection, an estimated 35 percent will relapse within 2 years. [Lancet Oncol 2020, doi: S1470-2045(20)30109-1]   

For patients with surgically unresectable disease, the current standard-of-care (SoC) first-line treatment for locally advanced or metastatic CCA is gemcitabine plus cisplatin. However, chemotherapy is associated with modest response rates and poor overall survival rates. [N Engl J Med 2010;362:1273-1281] Until recently, there has been no established SoC after failure of first-line chemotherapy, and the efficacy of second-line chemotherapy regimens for advanced biliary cancer has remained low. [Lancet Oncol 2020, doi: S1470-2045(20)30109-1]

Pemigatinib targets FGFR alterations in iCCA 

FGFR fusions are estimated to be present in 10–20 percent of patients with iCCA, and have been identified as an early driver of oncogenic events. [Mol Cancer Ther 2020;19:847-857; Nat Genet 2015;47:1003-1010]

Pemigatinib is a selective, potent, oral, competitive inhibitor of FGFR1, FGFR2 and FGFR3. [Cancer Res 2015;75(Suppl 15):771] Its IC50 is lower than that of other erdafitinib, another FGFR inhibitor approved by the US FDA for treatment of metastatic or unresectable urothelial carcinoma, with an IC50 for FGFR2 of 0.5 nM (compared with 2.5 nM for erdafitinib). [Cells 2019, doi:10.3390/cells8060614]

The phase I/II dose-finding FIGHT-101 study had previously demonstrated preliminary efficacy and manageable toxicities of pemigatinib (both as monotherapy and in combination with pembrolizumab) in the treatment of a subpopulation of patients with advanced CCA with FGFR alterations. [Mol Cancer Ther 2019;18(Suppl 12):A078; J Clin Oncol 2020;38(Suppl 15):3606] The promising results of FIGHT-101 prompted the phase II FIGHT-202 study, which evaluated the safety and antitumour activity of pemigatinib in patients with locally advanced or metastatic CCA who had progressed after at least one prior systemic therapy. [Lancet Oncol 2020, doi: S1470-2045(20)30109-1]

FIGHT-202: Therapeutic potential of pemigatinib in CCA

Patients eligible for the FIGHT-202 trial were assigned to one of three cohorts: FGFR2 fusions or rearrangements (n=107), FGFR alterations (n=20), or no FGFR alterations (n=18). All patients self-administered oral pemigatinib at a starting dose of 13.5 mg once daily irrespective of cohort assignment until radiological disease progression, unacceptable toxicity, withdrawal of consent or physician choice. [Lancet Oncol 2020, doi: S1470-2045(20)30109-1]

The primary efficacy outcome of overall response rate in patients with FGFR2 fusions or rearrangements was 35.5 percent, of which 2.8 percent (n=3) were complete responses and 32.7 percent (n=35) were partial responses. Among patients with FGFR2 fusions or rearrangements, the median duration of response was 7.5 months, with response maintained at 6 months in 68 percent of responding patients and at 12 months in 37 percent of the patients. Disease control was achieved in 82 percent of patients (n=88). (Figure 1)

“Ninety-one [88 percent] of 103 patients with FGFR2 fusions or rearrangements who had post-baseline measurements had reductions in centrally assessed best percentage change from baseline in target lesion size,” the researchers noted. (Figure 1)

HK-INN-001_01

In patients with FGFR2 fusions or rearrangements, median progression-free survival (PFS) was 6.9 months and median overall survival (OS) was 21.1 months with daily pemigatinib. In comparison, in patients without FGFR alterations, median PFS was 1.7 months and median OS was 4.0 months. (Figures 2 and 3) [Lancet Oncol 2020, doi: S1470-2045(20)30109-1]

HK-INN-001_02

HK-INN-001_03

Pemigatinib a viable option for CCA patients with FGFR2 alterations

Based on the promising results of the FIGHT-202 trial, the US FDA granted accelerated approval to pemigatinib in April 2020 for the treatment of adults with previously treated, unresectable locally advanced or metastatic CCA with a FGFR2 fusion or alteration, making it the first targeted therapy approved for the treatment of CCA patients with an FGFR2 alteration. [www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pemigatinib-cholangiocarcinoma-fgfr2-rearrangement-or-fusion; US FDA NDA/BLA Multi-disciplinary Review and Evaluation NDA 213736, 2 April 2 2018] Subsequently, the US National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Hepatobiliary Cancers were updated to recommend pemigatinib in patients with CCA with FGFR2 fusions or rearrangements. [https://www.nccn.org/about/news/ebulletin/ebulletindetail.aspx?ebulletinid=3679 ]

Currently, the only SoC second-line chemotherapy option for patients with CCA that is supported by evidence from a phase III clinical trial is the combination of fluorouracil/leucovorin and mFOLFOX (modified leucovorin, fluorouracil and oxaliplatin). The trial (Study ABC-06) demonstrated a median OS of 6.2 months with the combination chemotherapy regimen, as compared with 5.3 months with best supportive care, in patients with locally advanced or metastatic biliary tract cancers who had progressed on first-line gemcitabine plus cisplatin. [J Clin Oncol 2019;37(Suppl 15):4003]

Manageable toxicity with pemigatinib

The most common adverse event (AE) observed across all three cohorts of FIGHT-202 was hyperphosphataemia, which normally occurred early after treatment initiation and was manageable with a low-phosphate diet, concomitant phosphate binders, diuretics and dose reductions or interruptions. [Lancet Oncol 2020, doi: S1470-2045(20)30109-1] Other common AEs associated with pemigatinib treatment include ocular toxicity, alopecia, diarrhoea, fatigue and dysgeusia, which are manageable and largely reversible with dosage modification and supportive care. [US FDA NDA/BLA Multi-disciplinary Review and Evaluation NDA 213736, 2 April 2018]

Conclusion

There is encouraging data to support the role of pemigatinib as a therapeutic option in previously treated patients with iCCA who have FGFR2 alterations. [Lancet Oncol 2020, doi: S1470-2045(20)30109-1] AEs associated with pemigatinib are toxicities that oncologists are familiar with and would generally expect in patients with a serious and life-threatening condition. [US FDA NDA/BLA Multi-disciplinary Review and Evaluation NDA 213736, 2 April 2018] 

Digital Edition
Asia's trusted medical magazine for healthcare professionals. Get your MIMS Oncology - Hong Kong digital copy today!
Sign In To Download
Editor's Recommendations
Most Read Articles
Prof. Corinne Faivre-Finn, 30 Nov 2020
Consolidation therapy with the PD-L1 inhibitor durvalumab (Imfinzi®, AstraZeneca) following chemoradiation therapy (CRT) has become the standard of care in patients with unresectable stage III non-small-cell lung cancer (NSCLC), based on primary results of the PACIFIC study. The 4-year update of the study, presented recently at the European Society for Medical Oncology Virtual Congress 2020 (ESMO 2020), demonstrated durable and sustained survival benefits that were consistent with those reported in the primary analyses.
Dr. Roy Herbst, Dr. David Spigel, 09 Jul 2020
The third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) osimertinib is a standard of care in patients with EGFR-positive advanced non-small-cell lung cancer (NSCLC). Results of the ADAURA study, presented at the American Society of Clinical Oncology 2020 Virtual Scientific Programme (ASCO 2020), support earlier use of osimertinib in the adjuvant setting, with superior disease-free survival (DFS) in patients who underwent complete resection of stage IB/II/IIIA EGFR-positive NSCLC. 
Prof. Mark Shackleton, 01 Apr 2020
In recent years, the focus on immuno-oncology has generated a wealth of compelling evidence supporting the use of immune checkpoint inhibitors – in particular those targeting the programmed death-ligand 1 (PD-L1) or PD-1 pathway. At the 8th Oncology Summit organized by the Hong Kong Society of Clinical Oncology, Professor Mark Shackleton of Alfred Health and Monash University, Australia, discussed recent advances in immunotherapy for the management of metastatic Merkel cell carcinoma (MCC) with a focus on the role of the PD-L1 inhibitor avelumab.  
Pearl Toh, 08 Jan 2021
Combining the anti-PD-1 antibody sintilimab and a bevacizumab biosimilar significantly improves survival compared with the standard treatment of sorafenib in the first-line setting for patients with advanced, unresectable hepatocellular carcinoma (HCC), according to the ORIENT-32 study presented at ESMO Asia 2020.