Pemigatinib, a potent inhibitor of FGFRs for the treatment of cholangiocarcinoma
Valeria Merz1,2 , Camilla Zecchetto1,3 & Davide Melisi*,1,3
1Digestive Molecular Clinical Oncology Research Unit, Universit`a degli Studi di Verona, Verona, Italy
2Medical Oncology Unit, Santa Chiara Hospital, Trento, Italy
3Experimental Cancer Medicine Unit, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy *Author for correspondence: Tel.: +39 045 812 8148; [email protected]
The prognosis of patients affected by cholangiocarcinoma is classically poor. Until recently, chemothera- peutic 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 mu- tations, 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 cholan- giocarcinoma 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 di- gestive 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.
First draft submitted: 17 July 2020; Accepted for publication: 15 September 2020; Published online: 9 October 2020
Keywords: biliary tract cancer • cholangiocarcinoma • FGFR • FGFR inhibitor • FIGHT-202 • pemigatinib
Background
Biliary tract cancers are a group of anatomically different and genetically heterogenous tumors. The traditional classification identifies intrahepatic cholangiocarcinoma (iCCA), arising above the second-order bile ducts, perihilar and distal cholangiocarcinoma (extrahepatic), gallbladder cancer and ampulla of Vater cancer.
Intrahepatic disease accounts approximately for 10% of cholangiocarcinoma cases and is the second most common liver tumor after hepatocellular carcinoma. In recent decades, incidence of iCCA has been rising in Europe, North America, Japan and Australia [1]. This increasing incidence might partially be explained with the introduction of novel techniques that led to an increase in diagnostic accuracy [2]. Furthermore, it has been suggested that it could be related to the increase of risk factors, as obesity, cirrhosis and chronic viral hepatitis [3].
Systemic treatment with the chemotherapeutic combination of gemcitabine plus cisplatin remains the standard of care for patient newly diagnosed with a cholangiocarcinoma and offers a median overall survival (OS) lower than 1 year [4]. Nonetheless, evidence supporting the implementation also in pancreaticobiliary tumors of precision oncology, defined as identification and targeting of tumor driver alterations, is rapidly increasing.
Actionable targets for precision medicine in iCCA
Different anatomical types of cholangiocarcinoma reflect peculiar molecular landscapes. In particular, iCCA is frequently characterized by alterations of protoncogenes and oncosuppressors that could become possible target for tailored therapies [5,6].
The FGFR family consists of transmembrane receptor tyrosine kinases composed of three extracellular immunoglobulin-like domains and one intracellular tyrosine kinase domain [7]. Four different FGFR members (FGFR1-4) have been identified while their ligands FGFs are more than 20. The binding of a ligand to a FGFR
10.2217/fon-2020-0726 C⃝ 2020 Future Medicine Ltd Future Oncol. (Epub ahead of print) ISSN 1479-6694
causes receptor dimerization and transphosphorylation of tyrosine kinase domains, leading to the activation of downstream transduction pathways [8]. FGFR signaling is constitutively involved in angiogenesis, tissue repair and inflammation [9]. Alterations in genes encoding FGFR have been identified in cholangiocarcinoma as tar- getable genetic driver alterations. FGFR2 rearrangements are responsible for a ligand-independent activation of this receptor-tyrosine kinase, resulting in upregulation of FGFR pathway. This aberrant signaling enhances cellular pro- liferation, migration, survival and angiogenesis, promoting carcinogenesis [10]. FGFR2 fusions are typically found in iCCA and are present in about 10–16% of patients [11,12]. Chromosomal fusions represent the most common alterations and consist of FGFR2 exons 1–17, encoding the extracellular and kinase domains, fused in-frame to a 3′ partner, that has a protein dimerization domain, resulting a chimeric FGFR2 protein constitutively active [13,14].
Many FGFR inhibitors are being tested in clinical trials in patients with cholangiocarcinoma harboring FGFR pathway alterations. The first generation of multikinase inhibitors with anti-FGFR activity, as dovitinib and ponatinib, lacked sufficient specificity and potency to be active in FGFR-driven tumors. A pilot study with the nonselective tyrosine-kinase inhibitor ponatinib is currently ongoing in patients with advanced iCCA with FGFR2 fusions (ClinicalTrials.gov: NCT02265341).
Many second-generation inhibitors have shown promising results (Table 1). Pemigatinib will be discussed further in the text. Infigratinib (BGJ398, BBP-831, Novartis) is an ATP-competitive pan-FGFR kinase inhibitor. In a Phase II trial, infigratinib in second or later lines showed an overall response rate (ORR) of 14.8%, a disease control rate (DCR) of 75.4% and a median progression free survival (PFS) of 5.8 months in patients with FGFR alterations [15]. Updated results reported at ESMO 2018 showed an investigator-assessed confirmed ORR of 26.9% and a DCR of 83.6% and median PFS and OS were 6.8 and 12.5 months, respectively. Infigratinib is currently being investigated in the PROOF 301 trial (ClinicalTrials.gov: NCT03773302) as first line compared with gemcitabine plus cisplatin in advanced cholangiocarcinoma patients with FGFR2 gene fusions or translocations [16].
Tumor activity has also been demonstrated by the orally bioavailable, potent, ATP-competitive, multikinase inhibitor derazantinib (ARQ 087, MSD) that strongly inhibits FGFR2, FGFR1 and FGFR3 kinases [17]. In a Phase I/II study enrolling patients with unresectable iCCA with FGFR2 fusion derazantinib showed an ORR of 20.7%, a DCR of 82.8% and a median PFS of 5.7 months and a manageable safety profile [18]. The ongoing pivotal single-arm Phase II FIDES-01 trial is investigating tumor activity of derazantinib in patients with advanced cholangiocarcinoma with FGFR gene fusions, mutations or amplifications (ClinicalTrials.gov: NCT03230318).
The oral pan-FGFR inhibitor erdafitinib (JNJ-42756493; Janssen, Beerse, Belgium) demonstrated encouraging efficacy in a Phase II study, that reported 50% of ORR and 83.3% of DCR in Asian patients with FGFR alterations [19]. The safety profile was acceptable and similar to experience in other tumor types and populations.
Data from a Phase I study suggested signals of activity also for the selective FGFR inhibitor Debio 1347 (CH5183284; Debiopharm, Lausanne, Switzerland) [20]. The Phase II FUZE trial in patients with advanced solid tumors harboring FGFR fusions treated with Debio 1347 includes a cohort for patients with cholangiocarcinoma (ClinicalTrials.gov: NCT03834220).
Preliminary signals of activity in tumors harboring FGFR fusions have been recently reported with the oral, ATP-competitive small molecule, FGFR1-3 inhibitor AZD4547 (AstraZeneca, Cambridge, UK) in the histology- agnostic Phase II NCI-MATCH trial, in which one of the two patients with cholangiocarcinoma showed a partial response (PR) [21].
FGFR1, -2 and -3 inhibitor E7090 (Eisai, Tokyo, Japan) is being tested in advanced cholangiocarcinoma with FGFR2 fusion in a Phase II trial (ClinicalTrials.gov: NCT04238715). In the expansion part of the first-in-human Phase I study, E7090 showed a DCR of 100% in six patients with cholangiocarcinoma harboring FGFR2 gene fusion and 83% of PRs.
A Phase I trial is investigating the oral FGFR inhibitor CPL304110 (Celon Pharma, Kielpin, Poland) in patients with advanced solid tumors (ClinicalTrials.gov: NCT04149691).
HMPL-453 is an orally bioavailable inhibitor of FGFR1, -2 and -3. A Phase II trial is recruiting advanced iCCA patients with FGFR2 fusion, that receive HMPL-453 Tartrate after at least one systemic therapy (ClinicalTrials.gov: NCT04353375).
In the Phase III trial FOENIX-CCA3, the third-generation irreversible FGFR inhibitor futibatinib (TAS- 120; Tahio Oncology, Tokyo, Japan) is being tested as first-line therapy in patients with iCCA harboring FGFR2 gene rearrangements (ClinicalTrials.gov: NCT04093362).
Several monoclonal antibodies against the FGF-FGFR axis have been developed but they have been scarcely investigated in cholangiocarcinoma. They can block the ligand binding or can prevent the receptor dimerization.
MFGR1877S (Genentech, CA, USA) and FP-1039 (GSK, London, UK) showed poor results in early phase clinical trials [22,23].
In order to inhibit the FGFR kinase in FGFR2 fusion-positive tumors, the inhibition of HSP90 has also been ex- plored. HSP90 is a chaperone molecule involved in protein folding and post-translational protein modifications [24]. The HSP90 inhibitor ganetespib demonstrated to inhibit the oncogenic signaling in FGFR fusion-positive bladder cancer [25]. In vivo, ganetespib showed a synergistic effect with infigratinib in terms of tumor reduction [26].
In iCCA a high prevalence of mutations in IDH1 and IDH2, encoding for cytoplasmic and mitochondrial isocitrate dehydrogenase (NADP) respectively, has been described. IDH1 mutation has been reported in about 13.1% of iCCA compared with 0.8% of eCCA [27]. IDH2 mutations have a lower frequency and were found in 4% of iCCA [28]. IDH mutant biliary cancers showed less frequent mutations in p53 (13 vs 43%), KRAS (8 vs 19%), CDKN2A (1 vs 9%) and SMAD4 (0 vs 9%) compared with IDH wild-type tumors, respectively. Compared with IDH wild-type biliary tract cancers, in IDH mutant ones lower human EGFR2 (HER2) expression (3 vs 0.5%) and amplification (6 vs 0%) rates and FGFR2 fusions (7 vs 2%) were detected. Furthermore, IDH mutant biliary cancers showed a lower tumor mutational burden (0.7 vs 3.7%) and a trend for lower MSI rates (0.6 vs 3%). The Phase III, multicentre, randomised, ClarIDHy trial recently showed an improvement in median PFS in patients with advanced IDH1-mutant cholangiocarcinoma treated with ivosidenib [27].
NTRK genes encode for the neurotrophin receptors TRKA, TRKB and TRKC and gene fusions are oncogenic drivers in various tumor types. In sequencing studies NTRK gene fusions have been identified in about 1–3.5% of patients with iCCA [11]. Encouraging response rates have been reported in patients with NTRK fusion-positive cholangiocarcinoma treated with entrectinib and larotrectinib [29,30]. The Phase II basket STARTRK-2 trial is evaluating the activity of entrectinib in patients with solid tumors harboring NTRK1/2/3, ROS1 or ALK gene rearrangements (ClinicalTrials.gov: NCT02568267).
BRAF mutations, most commonly V600E, occur in about 3–7.1% of iCCA [5]. Among eight patients with BRAFV600-mutated cholangiocarcinoma, one showed PR and four stable disease (SD) [31]. In a preliminary report of the ROAR basket trial the combination of dabrafenib and trametinib showed activity in the BRAF V600E biliary cancer cohort [32].
In a Phase II study, the treatment with the MEK 1/2 inhibitor selumetinib in not molecularly selected metastatic biliary cancer patients led to 12% objective responses and 68% of SD [33]. A Phase Ib study in patients with advanced biliary tract cancer showed a median PFS of 6.4 months with the combination of selumetinib [34].
In an integrative molecular analysis, more than half of iCCAs were characterized by activation of MET, EGFR and MAPK signaling [35]. However, early phase studies with tivantinib or cabozantinib did not show any promising results [36,37].
The Cancer Genome Atlas investigators found alterations of CDKN2A, a gene encoding the negative regulators of cell-cycle progression p16INK4A and p14ARF, in 47% of predominantly iCCA cases [38]. However, the TAPUR study failed to demonstrate palbociclib activity in patients with advanced biliary or pancreatic cancers with CDKN2A loss or mutation [39].
BRCA 1 and BRCA2 mutations have been identified in about 1–4% of iCCA [13]. In a retrospective series, one out of four patients with BRCA mutated cholangiocarcinoma receiving PARP inhibitors showed a PFS of 42.6 months [39,40]. A prospective Phase II study will evaluate activity of olaparib in advanced biliary tract cancer patients with mutations DNA repair genes (ClinicalTrials.gov: NCT04042831).
HER2 overexpression rate is lower in iCCA compared with eCCA and gallbladder cancer [41]. Various ongoing trials are testing the targeting of this pathway, including MyPathway (ClinicalTrials.gov: NCT02091141) and KAMALEON trial (ClinicalTrials.gov: NCT02999672).
The frequency of mismatch repair deficiency has been reported in up to 10% of iCCA, but it was lower when the analysis was limited to the advanced disease [42]. In previous series, PD-L1 expression has been reported in 9–72% of cholangiocarcinoma samples and on 46–63% of immune cells in the tumour microenvironment [43,44]. It could represent a a biomarker for anti-PD-1 and anti-PD-L1 therapies and further studies are needed. The Phase II KEYNOTE-158 study showed an ORR of 41% in mismatch repair deficient advanced cholangiocar- cinoma [45]. Several trials are currently testing checkpoint inhibitors alone (ClinicalTrials.gov: NCT03110328, NCT02829918, NCT03260712, NCT03101566) or combined with chemotherapy or other molecules (Clinical- Trials.gov: NCT03101566, NCT03875235, NCT03046862, NCT03111732, NCT03101566, NCT02982720).
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Figure 1. Molecular structure of pemigatinib.
Pemigatinib
Pemigatinib (INCB054828, Pemazyre) is a potent and selective oral inhibitor of FGFR1, 2 and 3.
The chemical name of this drug is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4- ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′ ,2′ :5,6]pyrido[4,3d]pyrimidin-2-one. The molecular formula is C24H27F2N5O4 and its molecular weight is 487.50 (Figure 1).
Pharmacology & pharmacokinetics
Pemigatinib is an ATP-competitive inhibitor of the FGFR tyrosine kinase domain. Pemigatinib showed a potent inhibition of FGFR1, FGFR2 and FGFR3, with half maximal inhibitory concentration (IC50 ) values of 0.4, 0.5 and 1 nmol/l, respectively, and a weaker activity on FGFR4. Pemigatinib selectivity was tested using a panel of 56 different tyrosine and serine-threonine kinases with a fixed ATP concentration of 1 mM for all reactions. Pemigatinib exhibited a high selectivity for FGFRs, showing IC50 values less than 1 nM only for VEGFR2/KDR and c-KIT. The 80-fold selective activity of pemigatinib against VEGFR showed in cell-based assays led to avoiding the toxicities observed with first-generation multikinase FGFR inhibitors [46]. Pemigatinib is formulated as immediate release tablets in strenghts of 0.5, 2 and 4.5 mg.
Clinical development of pemigatinib in solid tumors
FGFR inhibitor in oncology and Hematology Trial (FIGHT)-101 (INCB54828-101, ClinicalTrials.gov: NCT02393248) is a Phase I/II, three-part, open-label, dose-escalation trial in patients with advanced pretreated solid tumors with (parts 2 and 3) or without (parts 1 and 3) FGF/FGFR alterations treated with pemigatinib alone (parts 1 and 2) or in combination with other agents (part 3) (Table 2). Preliminary reports of this ongoing trial have been presented at AACR-NCI-EORTC International Conference. No dose-limiting toxicities were observed with monotherapy and the maximum tolerated dose was not reached. The pharmacologically active dose was 9 mg QD and the maximum safely administered dose was 20 mg. In part 1, no patients had a response, while in part 2, three patients showed a PR [47].
Various studies are ongoing in urothelial carcinoma in different stages. FIGHT-201 (ClinicalTrials.gov: NCT02872714) is an ongoing Phase II, open-label, multicenter study enrolling patients with metastatic or unresectable urothelial carcinoma harboring FGFR3 mutations/fusions (cohort A) or other FGF/FGFR alterations (cohort B) who failed at least one line of therapy or that are platinum ineligible. Interim results reported an ORR of 25% in cohort A, including patients with unconfirmed PRs. In cohort B, one patient with FGF10 amplification showed an unconfirmed PR. FIGHT-205 (ClinicalTrials.gov: NCT04003610) is an ongoing Phase II study testing pemigatinib plus pembrolizumab versus pemigatinib versus gemcitabine plus carboplatin as first line in patients with metastatic or unresectable cisplatin ineligible urothelial carcinoma and FGFR3 gene alterations. Recently, the Phase II, open-label, single-arm PEGASUS trial started in the adjuvant setting (ClinicalTrials.gov: NCT04294277). PEGASUS trial aims at assessing safety and efficacy of pemigatinib in high-risk urothelial carcinoma patients with FGFR alterations who underwent radical surgery. In a Phase II study (ClinicalTrials.gov: NCT03914794) pemi- gatinib is being tested in nonmuscle invasive bladder cancer patients with recurrent tumors and a prior history of low- or intermediate-risk non-muscle invasive bladder cancer tumors. Patients receive pemigatinib for 4–6 weeks prior to transurethral resection of bladder tumor.
FIGHT-203 is a Phase II study evaluating the efficacy and safety of pemigatinib in patients with myeloid or lymphoid neoplasms with FGFR1 rearrangements. Interim analysis reported that 80% of patients had a major cytogenetic response.
Two tumor-agnostic studies are evaluating pemigatinib in solid tumors with FGFR alterations. FIGHT-207 (ClinicalTrials.gov: NCT03822117) is a Phase II, open-label, single-arm, aiming to assess the efficacy and safety
of pemigatinib in patients with advanced solid tumor malignancies with activating FGFR mutations, fusions or rearrangements progressed at least on one prior line of therapy and without other effective treatment options. Patients are divided in three cohorts based on their FGFR status: FGFR1-3 in-frame fusions or FGFR2 intron 17 rearrangements (cohort A), known/predicted activating point mutations in FGFR1-3 (cohort B), any other FGFR1- 3 point mutations and variants of unknown significance or FGFR1/FGFR3 rearrangements without an identified partner gene (cohort C). Rearrangements involving FGFR2 are classified as fusions if the genomic breakpoint is within the intron 17/exon 18 hotspot and the gene partner is known or is predicted to be in-frame with FGFR2. Other FGFR2 rearrangements include those with genomic breakpoint in the FGFR2 intron 17/exon 18 hotspot, but with a novel partner gene that is predicted to be out-of-frame or out-of-strand, or no partner gene (designated as partner N/A or intron 17 rearrangement). The primary end point is ORR in cohorts A and B. FIGHT-208 is a Phase II, open-label, single-arm, multicenter study that evaluates the efficacy and safety of pemigatinib in patients with advanced solid tumors harboring activating FGFR mutations or translocations. The primary end point is ORR.
Pemigatinib is being tested also in metastatic or unresectable colorectal cancer with activating FGFR alterations in a Phase II trial (ClinicalTrials.gov: NCT04096417).
Clinical development of pemigatinib in cholangiocarcinoma
The current standard treatment for second-line therapy of cholangiocarcinoma has been recently defined by the Advanced Biliary Tract Cancer (ABC)-06 trial, which demonstrated a significant improvement in median OS by using the chemotherapeutic regimen mFOLFOX (modified fluorouracil, leucovorin and oxaliplatin) if compared with active symptom control (6.2 vs 5.3 months, HR: 0.69, p = 0.03) [48].
FIGHT-202 was an open-label, single-arm, multicenter, Phase II trial that evaluated the safety and the activity of pemigatinib in patients with locally advanced or metastatic cholangiocarcinoma who received at least one previous systemic cancer therapy (Table 1) [49]. Before the enrollment, patient samples were centrally evaluated by using an NGS DNA sequencing test. The study included three cohorts of patients: A, patients with FGFR2 fusions or rearrangements; B, patients with other FGF/FGFR alterations; C, patients with no FGF/FGFR alterations. Pemigatinib was administered orally at the dose of 13.5 mg once daily in a 21-day cycle (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary end point of the study was the proportion of patients in cohort A who achieved an objective response.
Across all cohorts, 86% of patients had metastatic disease and 39% had received two or more previous systemic therapies. A total 98% of patients with FGFR2 fusions or rearrangements had intrahepatic cholangiocarcinoma and were more frequently women, aged younger than 65 years and with disease confined to the liver. A total 9% of prescreened patients had FGFR2 fusions or rearrangements and this is consistent with the available scientific literature [11]. Most of partners were unique to individual patients and the most common FGFR2 partner was BICC1. In cohort A, 35.5% of patients achieved an objective response, with 2.8% of complete responses and 32.7% of partial responses. DCR was 82%. A total 88% of patients experienced a reduction in target lesion size. Median time to response and median duration of response were 2.7 and 7.5 months, respectively. Median PFS was 6.9 months, median OS was 21.1 months but survival data were not mature at the data cutoff. Objective responses were similar across different subgroups. The FGFR2 rearrangement partner did not seem to impact the probability of response. Patients of cohorts B and C had no responses and achieved 40.0 and 22.2% of SD, respectively.
Although overall survival data were not mature and comparing data across studies is not formally acceptable, activity results of pemigatinib in FIGHT-202 trial seem promising. A recent meta-analysis evaluating studies of second-line therapies reported an ORR of 9.5%, median PFS and OS were 2.6 and 6.5 months, respectively [50]. Median OS was 11 months in a retrospective multicenter study of advanced biliary tract cancer patients receiving a second-line therapy [51].
The most relevant weakness of this study is that it does not take in account a possible prognostic role of FGFR2 fusions or rearrangements. Recently, a post hoc analysis of individual data from patients with advanced iCCA treated with first-line cisplatin-gemcitabine chemotherapy suggested that patients with advanced iCCA or with liver-only iCCA have longer OS compared with those with other biliary tract cancers [52]. A retrospective analysis reported a possible positive prognostic role of FGFR genetic aberrations in patients with cholangiocarcinoma compared with FGFR wild-type counterparts [53]. The lack of a control arm precluded a comparison with standard chemotherapy.
Based on the positive results of FIGHT-202 trial, the Phase III FIGHT-302 (NCT03656536) has recently started. This is a randomized, open-label, multicenter study, that will evaluate the efficacy of pemigatinib compared
Table 3. Rules for pemigatinib dose interruption and restarting (reused and modified from the FIGHT-202 study protocol in the Supplementary Appendix).
Adverse event Action taken
AST and/or ALT is ti5.0× ULN
Step 1: Interrupt pemigatinib up to 2 weeks (14 days) until the toxicity has resolved to Grade 1
Step 2: Restart pemigatinib at same dose. If assessed as related to pemigatinib, restart pemigatinib at next lower dose; monitor as clinically indicated
Any Grade 1 or Grade 2 toxicity Continue pemigatinib treatment and treat the toxicity; monitor as clinically indicated.
Any Grade 3 toxicity, if clinically significant and not manageable by supportive care
Step 1: Interrupt pemigatinib up to 2 weeks (14 days), until toxicity resolves to Grade 1
Step 2: Restart pemigatinib at same dose. If assessed as related to pemigatinib, restart pemigatinib at next lower dose; monitor as clinically indicated
Any recurrent Grade 3 toxicity after two dose reductions
Discontinue pemigatinib administration
Any other Grade 4 toxicity
QT/QTc to ti500 milliseconds or to ti60 milliseconds over baseline
Discontinue pemigatinib administration
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ULN: Upper limit normal
with gemcitabine plus cisplatin chemotherapy as first-line therapy for patients with unresectable or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements. Primary end point is PFS. It is allowed the enrollment of patients that have received adjuvant or neo-adjuvant treatment completed at least 6 months before.
Based on the results of FIGHT-202 trial, in April 2020 the US FDA approved pemigatinib in patients with advanced or metastatic FGFR2-positive cholangiocarcinoma progressed during or after at least one other treatment. Pemigatinib approval by the EMA is currently under evaluation.
Safety & tolerability of pemigatinib
In the Phase I FIGHT-101 trial no dose-limiting toxicities were observed with monotherapy. When pemigatinib was administered as single agent with the intermitting schedule, the most common adverse events were hyperphos- phatemia (74%) and fatigue (40%) for 9 and 13.5 mg doses and hyperphosphatemia (67%) and stomatitis (50%) for 20 mg dose (Table 3) [49]. The most frequent grade 3 or higher adverse events were hyponatremia (7%) and pneumonia (7%).
Considering patients enrolled in all three cohorts of FIGHT-202, the most common adverse events were repre- sented by hyperphosphatemia (60%), alopecia, diarrhea, fatigue, dysgeusia and nail toxicities (≥40% incidence)
(Table 4) [49]. Grade 3 or worse adverse events occurred in 64% of patients and were hypophosphatemia (12%), arthralgia (6%), stomatitis (5%), hyponatremia (5%), abdominal pain (5%) and fatigue (5%). Hyperphosphatemia is an expected on-target pharmacologic effect of FGFR inhibition, blocking the FGF23–FGFR1 signaling in the renal tubule [10]. FGFR1 is of primary importance in phosphate homoeostasis through feedback mechanisms also involving FGF23, 1,25(OH)2D3 and parathyroid hormone [54]. It is seen to occur early after the start of pemiga- tinib (after about 2 weeks). In FIGHT-202 trial, hyperphosphatemia was of mild and could be managed with diet
modifications taking low-phosphate foods if serum phosphate level >5.5 and ≤7 mg/dl, with the use of phosphate binders and diuretics if serum phosphate level was >7 mg/dl, or with a pemigatinib dose reduction (Table 5). Serum phosphate monitoring was continued for at least twice a week until it returned into normal range. The phosphate concentration has been suggested to be a surrogate for exposure. Indeed, post hoc analyses of FIGHT-202 showed that the increase in serum phosphate concentration correlated with exposure with a sigmoidal relationship. Furthermore, it has been observed a bell-shaped association between change in phosphate levels and patients with an objective response, suggesting 13.5 mg as an optimal starting dose.
Mean phosphate, 1,25(OH)2D3 and parathyroid hormone concentrations decreased from baseline after day 15 of cycle 1. Similarly, the proportion of patients with reduced 1,25(OH)2D3 and parathyroid hormone levels increased, respectively, from 15 and 11% at baseline to 79 and 22% on day 1 of cycle 5. Hypophosphatemia might have been caused by an excessive correction of hyperphosphatemia during the off-treatment week or from negative feedback mechanisms on phosphate homoeostasis.
In FIGHT-202 trial, 4% of patients had serous retinal detachment, mostly grade 1 or 2 events. Serous retinal detachment is caused by the accumulation of subretinal fluid that might reflect an altered function of the outer retinal barrier or of the retinal pigment epithelium resulting from FGFR inhibition and subsequent downstream downregulation of the mitogen activated protein kinase pathway [55]. The protocol required comprehensive eye
Table 4. Treatment-related adverse events occurring in ≥10% of patients in FIGHT-202 study.
Adverse event Grade 1–2 (%) Grade 3 (%)
Grade 4 (%)
Hyperphosphatemia 81 (55) 0 0
Alopecia 67 (46) 0 0
Dysgeusia 55 (38) 0 0
Diarrhea 49 (34) 4 (3) 0
Fatigue 45 (31) 2 (1) 0
Stomatitis 39 (27) 8 (5) 0
Dry mouth 42 (29) 0 0
Nausea 34 (23) 2 (1) 0
Decreased appetite 34 (23) 1 (1) 0
Dry eye 30 (21) 1 (1) 0
Dry skin 22 (15) 1 (1) 0
Arthralgia 16 (11) 6 (4) 0
Palmar-plantar erythrodysesthesia 16 (11) 6 (4) 0
Constipation 20 (14) 0 0
Hypophosphatemia 8 (5) 10 (7) 0
Pain in extremity 15 (10) 0 0
Vomiting 13 (9) 1 (1) 0
Weight decreased 13 (9) 1 (1) 0
Myalgia 10 (7) 1 (1) 0
Nail discolouration 10 (7) 1 (1) 0
Abdominal pain 8 (5) 1 (1) 0
Anemia 8 (5) 1 (1) 0
Onychoclasis 8 (5) 1 (1) 0
Paronychia 8 (5) 1 (1) 0
Hyponatremia 4 (3) 3 (2) 1 (1)
Urinary tract infection 7 (5) 1 (1) 0
Hypercalcemia 5 (3) 1 (1) 0
Skin exfoliation 5 (3) 1 (1) 0
Blood alkaline phosphatase increased 2 (1) 2 (1) 0
Acute kidney injury 3 (2) 1 (1) 0
Erythema 3 (2) 1 (1) 0
Nail disorder 3 (2) 1 (1) 0
Aspartate aminotransferase increased 1 (1) 2 (1) 0
Alanine aminotransferase increased 2 (1) 1 (1) 0
Dysphagia 2 (1) 1 (1) 0
Keratitis 2 (1) 1 (1) 0
Rash pruritic 1 (1) 1 (1) 0
Hyperbilirubinemia 0 1 (1) 0
Hypokalemia 0 1 (1) 0
Proteinuria 0 1 (1) 0
Skin toxicity 0 1 (1) 0
Thrombosis 0 1 (1) 0
examination at screening and every three cycles. Patients with corneal or retinal disorder at baseline were excluded from the study.
In FIGHT-202 trial, 42% of patients had dose interruptions caused by adverse events and 14% had adverse events leading to dose reductions. In 9% of patients, adverse events were responsible for treatment discontinuation. Overall, 45% of patients experienced a serious adverse event. No treatment-related deaths were reported.
Table 5. Guidance for hyperphosphatemia management.
Serum phosphate level Supportive care
Interruption/discontinuation of pemigatinib
Restarting pemigatinib
ti5.5 and ≤7 mg/dl Initiate a low-phosphate diet No action Not applicable
ti7 and ≤10 mg/dl
Initiate/continue a low-phosphate diet and initiate phosphate binding therapy. Monitor serum phosphate approximately twice a week and adjust the dose of binders as needed; continue to monitor serum phosphate at least twice a week until return to ≤7 mg/dl
If serum phosphate level continues to be ti7 and ≤10 mg/dl with concomitant phosphate-binding therapy for 2 weeks, or if there is recurrence of serum phosphate level in this range, interrupt pemigatinib for up to 2 weeks
Restart at the same dose when serum phosphate is ti7 mg/dl. If serum phosphate level recurs at ti7 mg/dl, restart pemigatinib with dose reduction
ti10 mg/dl
Continue to maintain a low-phosphate diet, adjust phosphate-binding therapy and start/continue phosphaturic agent. Continue to monitor serum phosphate approximately twice a week until return to ≤7 mg/dl
If serum phosphate level is ti10 mg/dl for 1 week following phosphate-binding therapy and low-phosphate diet,
interrupt pemigatinib. If there is recurrence of serum phosphate level in this range following two dose reductions, permanently discontinue pemigatinib
Restart pemigatinib at reduced dose with phosphate binders when serum phosphate is ti7 mg/dl
Mechanisms of resistance to pemigatinib in cholangiocarcinoma
In order to identify mechanisms of resistance for FGFR inhibitors, several preclinical studies have been conducted, mostly in urothelial, lung and gastric cancer. In a clinical scenario the collection of post-progression plasma and tumor sampling becomes essential in detecting mechanisms of resistance.
Different mechanisms of acquired resistance to FGFR inhibitors have been demonstrated. It can occur through activation of alternate receptor tyrosine kinases, such as MET, Ephrin 3B (Eph3B) or EGFR family [56,57]. Ac- quired FGFR gatekeeper mutations, preventing the drug binding, are another mechanism of resistance to FGFR inhibitors [58]. In this case, dependence of the tumor on FGFR pathway is maintained. Also the activation of intracellular signaling pathways can be responsible for resistance to FGFR inhibition. In particular, it has been reported an increased signaling of PI3K/AKT/mTOR [59], MAPK [60] and STAT3 [61] pathways. Another possible mechanism of resistance is represented by the emergence of epithelial-mesenchymal transition [62].
The first attempt to determine mechanisms underlying acquired resistance to FGFR inhibitor therapy in cholangiocarcinoma in a clinical setting was reported in patients treated with infigratinib. Rapid onset of acquired resistance was observed in infigratinib trial that reported a median PFS of 5.8 months [15]. It has been reported the genomic characterization of cell-free circulating tumor DNA, primary and metastatic tumor biopsies in three patients with FGFR2 fusion-positive cholangiocarcinoma progressed on infigratinib. Serial analysis of cell-free circulating tumor DNA demonstrated FGFR2 kinase domain point mutations at progression. All three patients developed the FGFR2 V564F gatekeeper mutation and two patients developed additional FGFR2 kinase domain mutations. Marked inter- and intralesional heterogeneity was revealed in post-progression biopsies and rapid autopsy and different FGFR2 mutations in resistant clones were reported. In one patient rapid autopsy revealed three different FGFR2 kinase domain mutations in spatially distinct metastases. Thus, the interlesional heterogeneity represents a big challenge in addressing acquired resistance in patients treated with FGFR inhibitors.
FGFR inhibitors that covalently bind the ATP-binding pocket of FGFR could represent an intriguing strategy to overcome resistance caused by gatekeeper mutation of FGFR. Futibatinib (TAS-120) is a third-generation, irreversible FGFR inhibitor that covalently binds to a highly conserved P-loop cysteine residue in the ATP pocket of FGFR [63]. It showed in vitro potency at low nanomolar concentrations and high specificity against wild-type FGFR1–4 and some FGFR2 kinase domain mutations. In a Phase I basket trial futibatinib determined tumor shrinkage in 71% of patients with previously treated iCCA harbouring FGFR2 gene fusions, with an ORR of 25%. Three out of 17 patients with other FGF/FGFR aberrations had PRs. Futibatinib proved to be able in overcoming acquired resistance to second-generation FGFR inhibitors. It was designed to improve specificity by binding FGFR in a covalent mode and a different orientation in the ATP-binding pocket. A recent study demonstrated the efficacy of futibatinib in four patients previously treated with infigratinib or Debio 1347. Tumor biopsies and ctDNA were collected prior to futibatinib and after progression. From in vitro experiments with iCCA lines and from ctDNA analyses, futibatinib resulted to be active against all mutations except V565F.
Conclusion
Cholangiocarcinoma is characterized by several targetable genetic alterations and different drug classes are being investigated. Pemigatinib opened the targeted therapy era in biliary tract cancer and represents the first target agent FDA approved. Pemigatinib is currently under investigation in previously untreated patients in order to increase the number of patients that could benefit from it. Great efforts are being made with the aim of bypassing acquired resistance to this FGFR inhibitor. Other FGFR inhibitors and other molecules targeting different pathways are being studied. Even if every single genetically altered tumor is essentially rare, many different drugs could target a big proportion of cholangiocarcinomas with targetable mutations. Hypothetically, every patient with a diagnosis of cholangiocarcinoma should be nowadays screened with a genomic profiling test and possibly be addressed to a tailored treatment.
Future perspective
Genomic sequencing led to the identification of molecular alterations in different intracellular pathways in cholan- giocarcinoma. FGFR pathway inhibition represented the first targeted therapeutic strategy approved in cholangio- carcinoma. Many drugs targeting FGFR fusions have yielded promising results demonstrating high response rates and considerable disease control. Adding chemotherapeutic agents or checkpoint inhibitors to FGFR inhibitors could improve their efficacy. However, the mutational landscape of cholangiocarcinoma suggests that many different altered pathways could be targeted by specific agents.
Furthermore, a tailored approach will probably become of major importance also after disease progression. A central role in identifying mechanisms of escape to second-generation FGFR inhibitors could be played by performing and studying solid and liquid biopsies at the disease progression. Irreversible FGFR inhibitors are currently under investigation and have already demonstrated signals of activity in some cases of acquired resistance to first- and second-generation FGFR inhibitors.
In a near future, tailored therapy could become the standard of care in cholangiocarcinoma patients since the first line.
Executive summary
Background
•Chemotherapy has been the standard of care in advanced cholangiocarcinoma patients, that have a prognosis lower than 1 year from the diagnosis.
•FGFR alterations, in particular FGFR2 rearrangements, are the oncogenic drivers in a subset of intrahepatic cholangiocarcinoma.
Pemigatinib in cholangiocarcinoma
•Pemigatinib is an oral ATP-competitive inhibitor of FGFR1, 2 and 3.
•The US FDA recently approved pemigatinib previously treated advanced cholangiocarcinoma patients. Activity in cholangiocarcinoma
•FIGHT-202 is a single-arm, multicenter, Phase II trial that evaluated activity and safety of pemigatinib in previously treated advanced cholangiocarcinoma patients with FGFR2 fusions or rearrangements.
•Pemigatinib was administered per os at the dose of 13.5 mg q.d. in a 21-day cycle (2 weeks on, 1 week off).
•A total 35.5% of patients with FGFR2 fusions or rearrangements achieved an objective response, which was the primary end point. Disease control rate was 82%. Median progression free survival was 6.9 months. Median overall survival was 21.1 months (survival data not mature).
•FIGHT-302 is an ongoing Phase III, randomized, multicenter trial that aims at comparing pemigatinib with gemcitabine plus cisplatin in first-line setting in advanced cholangiocarcinoma patients with FGFR2 fusions or rearrangements.
Safety
•Hyperphosphatemia was the most common adverse event in FIGHT-202 and represents an on-target effect.
•Grade 3 or worse adverse events occurred in 64% of patients and were hypophosphatemia, arthralgia, stomatitis, hyponatremia, abdominal pain and fatigue.
Conclusion
•Pemigatinib is the first targeted therapy approved in cholangiocarcinoma.
•A targeted approach is endeavoured in patients who become resistant to pemigatinib.
•Other selective agents are expected to be effective in targeting different molecular alterations.
Author contributions
V Merz, C Zecchetto and D Melisi wrote, read and approved the manuscript.
Acknowledgments
Work in the unit of D Melisi is supported by the Investigator Grants Nos. 19111 and 23719 and 5×1000 Grant No. 12182 through the Associazione Italiana per la Ricerca sul Cancro (AIRC), by the Ricerca Finalizzata 2016 grant GR-2016-02361134 through the Italian Ministry of Health and by the ‘Nastro Viola’ and ‘Voglio il Massimo’ associations of patients’ donations to D Melisi.
Financial & competing interests disclosure
D Melisi receives research funding and had consulting role with Incyte Co. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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Papers of special note have been highlighted as: • of interest; •• of considerable interest
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