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953293 TAM0010.1177/1758835920953293Therapeutic Advances in Medical OncologyA Saborowski, U Lehmann research-article20202020 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol FGFR inhibitors in cholangiocarcinoma: 2020, Vol. 12: 1 –12 https://doi.org/10.1177/1758835920953293 DOI: 10.1177/ https://doi.org/10.1177/1758835920953293 what’s now and what’s next? © The Author(s), 2020. Article reuse guidelines: sagepub.com/journals- Anna Saborowski, Ulrich Lehmann and Arndt Vogel permissions Abstract: Patients with intrahepatic cholangiocarcinoma (iCCA) face a highly dismal prognosis, due to late stage diagnosis, the relative chemoresistance of the disease, and an overall limited portfolio of established therapeutic concepts. In recent years, a number of next generation sequencing studies have provided detailed information on the molecular landscape of biliary malignancies, and have laid the groundwork for the evaluation of novel, targeted therapeutic opportunities. Although nearly 40% of patients harbor genetic alterations for which targeted options exist, rapid translation into clinical trials is hampered by the overall low patient numbers. One of the most frequent genetic events in patients with iCCAs are fusions that involve the fibroblast growth factor receptor 2 (FGFR2). Impressive results from pivotal phase II studies in pre-treated patients have confirmed that FGFR-inhibitors are a promising therapeutic option for this genetic subgroup, and the rapid pace with which these inhibitors are being clinically developed is clearly justified by the imminent benefit for the patients. However, the success of these agents should not blind us to key challenges that need to be addressed to optimize FGFR-directed therapies in the future. A better understanding of mechanisms that convey primary and secondary resistance will be crucial to improve up-front patient stratification, to prolong the duration of response, and to implement reasonable co- treatment approaches. In this review, we provide background information on the pathobiology of oncogenic FGFR fusions and selected genetic testing strategies, summarize the latest clinical data, and discuss future directions of FGFR-directed therapies in patients with iCCA. Keywords: biliary tract cancer, genetic rearrangement, next generation sequencing, precision oncology, translational medicine Received: 11 April 2020; revised manuscript accepted: 6 August 2020. Correspondence to: Cholangiocarcinoma diagnosed at early stages. However, due to late Arndt Vogel Cholangiocarcinomas (CCAs) are highly aggres- manifestation of clinical symptoms, most patients Department of Gastroenterology, sive tumors that display features of biliary differen- present with locally advanced or metastatic dis- Hepatology and tiation. CCAs can arise either within the liver, ease, and, even after complete resection, the major- Endocrinology, Hannover Medical School, Carl- termed intrahepatic cholangiocarcinoma (iCCA), ity experience rapid recurrence. Therefore, Neuberg Str. 1, Hannover, or in the perihilar or distal portions of the draining palliative treatments are the mainstay of CCA 30625, Germany vogel.arndt@mh- bile ducts (perihilar or distal CCA, respectively). therapy. Unfortunately, CCAs are highly chemo- hannover.de In most countries, CCAs are considered “rare” therapy refractory malignancies, with a median Anna Saborowski cancers with incidence rates below 6/100,000. overall survival (mOS) of 11–13 months under Department of Gastroenterology, However, reflecting the distribution of different first-line palliative treatment with gemcitabine and Hepatology & 3,4 risk factors, and likely also different ethnic back- cisplatin. Except for initial data from the United Endokrinologie, Medizinische Hochschule grounds, CCA incidence ranges from 0.1/100,000 Kingdom (UK) in favor of second-line therapy Hannover, Hannover, in Australia to more than 110/100,000 in Northeast with 5-FU and oxaliplatin, no established second Germany 1,2 5 Thailand. line therapeutic concepts exist (ABC-06 trial). Ulrich Lehmann Institute of Pathology, Medizinische Hochschule Surgical resection is the only potentially curative In recent years, sequencing studies have addressed Hannover, Hannover, Germany option and should be offered to patients that are the genetic underpinnings of CCA. Overall, journals.sagepub.com/home/tam 1 Creative Commons CC BY: This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Medical Oncology 12 CCAs are genetically heterogeneous, and the subsequent transphosphorylation of the tyrosine molecular profiles segregate with the anatomical kinase domains. Key downstream substrates location (intrahepatic versus perihilar or distal include PLC-y-mediated activation of PKC, as CCA), the histological subtype, as well as with well as pFRS2-induced activation of PI3K and the putative pathogenic risk factors, thus adding MAPK, but, depending on the (cellular) con- to the complexity of the disease. Despite the text, several other pathways may as well be genetic diversity, a recurrent repertoire of driver affected, such as c-JUN and STAT-signaling. genes and potentially targetable lesions exists: Activation of FGFR2 is subject to especially indeed, several studies suggest that about 40% of complex control mechanisms, that involve the patients harbor targetable alterations, indicating receptor being “held” in a dimeric state by bind- precision oncology has the potential to comple- ing of a Grb2 dimer, leading on the one hand to 6–10 ment existing therapies. Recently, the first a partial phosphorylation of the receptor, but on randomized phase III study that investigated a the other hand inhibiting the phosphorylation of precision oncology-based concept in a genetically additional residues that are crucial for recruit- selected CCA patient cohort was completed and ment of downstream signaling proteins. Only in reported positive data for the IDH-inhibitor ivo- the presence of FGF ligands, upregulation of the sidenib in IDH1 mutant patients. kinase activity releases Grb2 through phospho- rylation, permitting active signal transduction 18–20 An emerging “class” of drug targets in oncology through FGFR2. are fusion oncogenes, and, specifically in CCA, fusions that involve the fibroblast growth factor FGFR2 fusions typically result from chromo- receptor 2 (FGFR2). These fusions are detected somal events that lead to an in frame fusion in 10–15% of patients with iCCA. Of note, they between the 5′ portion of the FGFR2 gene, and a are found nearly exclusively in intrahepatic, but partner gene. FGFR2 is located on chromosome not in perihilar or extrahepatic CCA, or hepato- 10, and around 50% of FGFR2-fusions evolve 9,10,12 21 cellular carcinoma. Fusions that involve through intrachromosomal events. On a struc- other members of the FGFR family are rare in tural level, the FGFR2 portion of the fusion gene biliary tract cancers, with an incidence below retains the extracellular domain, as well as the 0.5%. Although there is initial evidence that kinase-domain, whereas the fusion partner con- FGFR2 genetic alterations occur more fre- tributes a dimerization signal, leading to constitu- quently in younger patients and are associated tive, ligand-independent, pathway activation. with a more indolent disease progression, it remains enigmatic whether FGFR2 fusion posi- In light of the therapeutic relevance, which we will tive patients represent a distinct prognostic discuss later in this review, a reliable identification subgroup. of fusion positive iCCA patients is crucial. Therefore, it is important to be aware that not all diagnostic strategies are equally suited, and that FGFR signaling detection of FGFR2 fusions as well as other fusion The fibroblast growth factor receptor (FGFR) oncogenes is highly dependent on the selection of family consists of four subtypes of transmem- an appropriate testing strategy. A diagnostic brane tyrosine kinase receptors, FGFR1–4. In advantage is that the location of the breakpoint in addition, a structurally related protein that lacks the FGFR2 gene appears to be nearly universal the tyrosine kinase domain – FGFR5 – has within intron 17 or exon 18 (INCYTE, personal recently been suggested to function as a co-receptor communication A. Vogel). However, with respect for FGFR1. While physiological FGFR signal- to potential partner genes, more than 150 fusion ing plays an important role in several cellular pro- partners have been described until now, albeit cesses such as proliferation, survival, migration, with variable frequency. and angiogenesis, dysregulated FGFR activity can set the stage for malignant transformation. In addition, increased FGF/FGFR signaling has Methodological considerations for the been described as a secondary resistance mecha- detection of therapeutically relevant fusion nism to targeted therapies. transcripts Promoter activation or loss of negative regulatory The binding of FGF ligands to their respective elements can result in highly active transcription receptors results in receptor dimerization and of oncogenic fusion DNA and frequently leads to 2 journals.sagepub.com/home/tam A Saborowski, U Lehmann et al. overexpression of the corresponding fusion pro- validated test to detect FGFR2 fusions via break- teins. This overexpression can be detected by tra- apart FISH is widely available. ditional immunohistochemistry and serve as a surrogate marker for the presence of a fusion The most comprehensive protocols for the identi- gene. Immunohistochemistry is readily available fication of fusion transcripts are based on next in most laboratories, relatively cost-effective, generation sequencing (NGS) technologies, and requires only a single tissue section, and has a gene fusions can be detected by sequencing very short turnaround time. However, specificity, genomic DNA or RNA (via cDNA). NGS-based reproducibility, and comparability of staining fusion detection employs two distinct approaches: results between different laboratories are often the regions of interest can either be enriched for difficult issues. In addition, robust and highly the sequencing reaction by so-called hybrid cap- specific antibodies are not necessarily available ture probes or by amplification using flanking for all targets of interests. The fusion partner primers (amplicon-approach). might also compromise the staining quality by interfering with proper binding to the target pro- Some of the clinically most frequently used panel tein. In CCA, wildtype FGFR2 is frequently sequencing assays employ a hybrid capture-based expressed on tumor cells, as well as on normal method to generate target-enriched DNA librar- cholangiocytes, thereby preventing reliable detec- ies from FFPE tumor tissue (e.g. Foundation- ® 23 tion of the fusion protein. Therefore, although OneCDx ) (Figure 1). Chromosomal immunohistochemistry is under many circum- translocations resulting in FGFR2 fusions nearly stances a useful and easily implemented screening always occur in intron 17 or exon 18, which allows tool, it is not suitable for the detection of FGFR2 the design of highly specific hybrid capture probes fusions in iCCA patients. close to the fusion breakpoints. After isolation, tumor DNA is randomly sheared into smaller A second cost-effective, sensitive and fast approach fragments, sequencing adapters are attached, and to detect specific fusion transcripts is conventional the capture probes hybridize to the target DNA multiplex polymerase chain reaction (PCR). sequences. Captured DNA is then purified, However, with a growing number of fusion part- amplified and sequenced, thereby allowing for the ners, to screen for FGFR2 fusions would require identification of FGFR2 fusions without prior designing and using a high number of different knowledge of the fusion partner identity. Of note, primer pairs in a single assay. Importantly, this whereas highly reliable for the detection of approach would not be comprehensive as it would FGFR2 fusions, the sensitivity of hybrid capture fail to identify patients harboring novel FGFR2 assays may vary depending on the fusion; for fusions. For instance, it would have missed instance, detection of some NTRK3 fusions can approximately 50% of the FGFR2 fusions seen in be technically challenging, since the breakpoints the recent FIGHT-202 study. occur in intronic regions with reduced sequence complexity (repetitive sequences) or high propor- Fluorescence in situ hybridization (FISH) is also a tion of the DNA bases adenine and thymine well-established and widely used technique that is (“AT-rich”) that are so large that they cannot be available in most laboratories for the analysis of faithfully covered by capture probes. chromosomal alterations. Fusions can be conven- iently detected by an adaptation of the FISH Other NGS-based approaches that are applied technique, called break-apart FISH, which uses frequently in daily clinical practice use DNA and two fluorescent (e.g., red and green) DNA probes cDNA from FFPE tissues that are converted into that are designed to target sequences flanking the amplicon libraries, which target the variants and gene of interest. Due to the proximity of the gene fusions of interest (e.g., ONCOMINE probes, a yellow signal is observed under the assays). Of note, amplicon-based approaches microscope, whereas, in the event of a chromo- can detect only known fusion transcripts for somal rearrangement, the probes become sepa- which validated primer pairs have been designed rated, resulting in distinct red and green signals. and included in the panel, and thus cannot be Therefore, break-apart FISH is suitable to detect considered an unbiased approach for detection of both known and novel gene fusions, but does not novel or less common rearrangements (including allow identification of the fusion partner. In addi- several FGFR2 fusions). However, the advantage tion, this method is generally limited to one of the amplicon approach is its superior sensitiv- genetic alteration per slide, and currently no ity compared with the hybrid capture or the journals.sagepub.com/home/tam 3 Therapeutic Advances in Medical Oncology 12 Figure 1. Hybrid capture-based method to generate target-enriched DNA libraries from FFPE tumor tissue ® 25 (e.g., FoundationOneCDx ) adapted from Jennings et al. anchored multiplex PCR protocols described in results for immune oncology (IO) concepts in the following. iCCA patients, FGFR2 fusions are promising tar- gets for precision oncology: indeed, thus far, a Archer FusionPlex is a third NGS-based number of phase II studies have been published approach and utilizes target-enriched cDNA that report a clinically meaningful benefit for libraries (Figure 2). Unlike conventional multi- FGFR2-directed therapies. Two larger single-arm plex PCR that uses pairs of gene-specific primers, phase II trials reported strikingly similar results in the assay enables detection of all fusions associ- fusion-positive patients treated with different oral ated with the genes of interest in a single sequenc- ATP-competitive FGFR inhibitors: objective ing assay, even without prior knowledge of fusion responses were 31% (22/71) with an estimated partners or breakpoints. Adaptors that harbor a mPFS of 5.8 months for infigratinib [ClinicalTrials. 28,29 universal primer binding site are ligated to cDNA gov identifier: NCT02150967], and 35.5% fragments, and targets are amplified using a gene- (38/107) with a mPFS of 6.9 months in patients specific and one universal primer. The exon level treated with pemigatinib (Fight-202) detection by the Archer assay and the amplicon- [ClinicalTrials.gov identifier: NCT02924376]. based assays targeting cDNA provide direct evi- A phase I/II study with derazantinib, limited to 29 dence of expression of a functional in-frame patients, reached an ORR of 21% (6/29) with a 30,31 fusion transcript, and allow easier primer/probe mPFS of 5.7 months. Disease control rates design because low complexity or repetitive were highly comparable across all trials (82– sequences are less frequent in coding sequences 83%). Survival data of these trials are still imma- within exons. ture and must be interpreted with caution due to their single-arm design and the unknown prog- nostic impact of FGFR2 fusions in the second Clinical studies with FGFR inhibitors in CCA line setting in biliary tract cancers. Of note, no Considering the relatively small benefit of first- responses were seen in iCCA patients with non- line chemotherapy, the lack of efficient second- fusion FGFR2 alterations (i.e., mutations/ampli- line regimens, and thus far rather disappointing fications), but disease stabilization with a mPFS 4 journals.sagepub.com/home/tam A Saborowski, U Lehmann et al. Figure 2. Amplicon-based method to generate target-enriched cDNA libraries from FFPE tumor tissue mRNA ® 25 (e.g. Archer FusionPlex ) adapted from Jennings et al. comparable with that of patients with FGFR2 approved for therapy-resistant urothelial cancers fusions of 6.7 months was observed in some harboring FGFR2/3 genetic alterations. In patients with FGFR2 mutations treated with CCA, a phase I as well as a phase IIa study in derazantinib (4/6). An additional phase II study, Asian patients showed promising results for the FUZE trial, has recently finished recruit- erdafitinib, but due to the low patient numbers ment, and results are pending. In this basket the clinical data available thus far cannot be con- trial, the FGFR1-3 inhibitor debio 1347 was not sidered fully conclusive yet [ClinicalTrials.gov only administered to iCCA patients with FGFR2 identifier: NCT01703481] and [ClinicalTrials. 37–39 fusions, but also to patients with other solid can- gov identifier: NCT02699606]. Clinical cers with FGFR1-3-fusion/re-arrangements trial data on FGFR inhibitors in iCCA are sum- [ClinicalTrials.gov identifier: NCT03834220]. marized in Table 1. In a recently published phase I study with debio 1347, RECIST responses were seen across FGFR-inhibitor associated toxicity profiles are tumor types and mechanisms of FGFR activa- comparable between the compounds and appear tion, that is, FGFR1-3 amplification, mutation to be overall manageable, although dose reduc- 33–35 and fusions. Currently, two FGFR inhibi- tions or interruptions are frequent (~ 60%). The tors have gained FDA approval: pemigatinib was most common adverse event (AE) reported across approved in April 2020 for the treatment of all trials was hyperphosphatemia due to the physi- advanced iCCA, whereas erdafitinib was ological involvement of the FGF23/FGFR journals.sagepub.com/home/tam 5 Therapeutic Advances in Medical Oncology 12 6 journals.sagepub.com/home/tam Table 1. Clinical trial data on FGFR inhibitors. Compound Clinical trial Study population ORR (95% CI) DCR (95% CI) mDOR, mPFS, months mOS, months Current development Reference months (95% CI) (95% CI) (95% CI) Pemigatinib FIGHT-202 Pre-treated Cohort A: 35.5% Cohort A: 82% Cohort Cohort A: 6.9 Cohort A: 21.1 Phase III, 1st line, against Abou-Alfa Selective phase II A: FGFR2 fusions/ (26.50–45.35) (74–89) A: 7.5 (6.2–9.6) (14.8– NE) Gemcitabine/Cisplatin et al. FGFR1-3 [ClinicalTrials. rearrangements: 107 CR: 2.8% Cohort B: 40% (5.7–14.5) Cohort B: 2.1 Cohort B: 6.7 (Fight-302) [ClinicalTrials. inhibitor gov identifier: B: other FGF/FGFR PR: 32.7% (19–64) (1.2–4.9) (2.1–16.6) gov identifier: NCT02924376] alterations: 20 Cohort B: 0% Cohort C: 22% Cohort C: 1.7 Cohort C: 4.0 NCT03656536] C: no FGF/FGFR Cohort C: 0% (6–48) (1.3–1.8) (2.3–6.5) recruiting alterations: 18 Infigratinib Phase II Pre-treated Fusions: 31% Fusions: 5.4 6.8 (5.3–7.6) 12.5 Phase III, 1st line against Javle et al. ; [ClinicalTrials. FGFR2 fusions: 71 (20.5–43.1) 83.6% (3.7– 7.4) (9.9–16.6) Gemcitabine/Cisplatin Javle et al. (BGJ 398) ATP competitive gov identifier: FGFR2 mutations: 8 Mutations: 0% (72.5–91.5) (PROOF) [ClinicalTrials.gov NCT02150967] FGFR2 amplifications: 3 Amplifications: identifier: NCT03773302] FGFR1-3 inhibitor 0% recruiting Derazantinib Phase I/II FGFR2 fusions: 29 (27 Fusions: 20.7% Fusions: Fusions: 5.7 Phase II Mazzaferro (ARQ 087) [ClinicalTrials. pre-treated) Mutations: 0% 82.8% (4.04–9.2) FGFR2 fusions, mutations et al. ; Multi-kinase gov identifier: FGFR2 Mutations: 6 Wildtype: 0% Mutations: Mutations: 6.7 and amplifications, Busset inhibitor with NCT01752920] FGFR wildtype: 9 67% (1.0–14.7) pretreated et al. potent pan- Wildtype: 0% Wildtype: 1.4 (FIDES-01) [ClinicalTrials. FGFR activity (0.7–NA) gov identifier: NCT03230318], recruiting Debio1347 Phase I iCCA cohort: 9 patients iCCA cohort: iCCA cohort: iCCA cohort: Phase II, basket design, Voss et al. ; Selective [ClinicalTrials. FGFR2 translocations: 5 PR 22% (2/9, 1 66% median time on FGFR1-3 fusion positive Ng et al. FGFR1-3 gov identifier: FGFR1 translocation:1 FGFR2 fusion, 1 treatment: 24 weeks solid malignancies, inhibitor NCT1948297] FGFR2 mutation: 1 FGFR2 activating (4–57 weeks) pretreated FGFR2 activating deletion) (FUZE) [ClinicalTrials.gov deletion:1 identifier: NCT03834220] FGFR3 mutation: 1 Futibatinib Phase I Total: 45 pretreated Fusions: 25% Fusions: 79% Median treatment Phase III, 1st line Meric- [ClinicalTrials. CCA (41 iCCA) (7/28) time: against Gemcitabine/ Bernstam (TAS 120) Selective gov identifier: FGFR2 fusions: 28 Other: FGFR2 fusions: 7.4 Cisplatin et al. ; NCT02052778] Other FGF/FGFR cPR: 17.6% (3/17) (4.8–NC) (FOENIX-CCA3) Tran et al. irreversible FGFR1-4 aberrations: 17 Prior FGFR Other: 6.8 (1.9–NC) [ClinicalTrials.gov identifier: Prior FGFR-inhibitor –inhibitors: NCT04093362] inhibitor therapy: 13 cPR: 30.7% (4/13) Not yet recruiting (3 with FGFR2 fusions, 1 FGFR2 amplification) Phase I pretreated CCA CCA cohort: CCA cohort: CCA CCA cohort: 5.1 Bahleda Erdafitinib (JNJ-42756493) [ClinicalTrials. subgroup with FGFR 3/11, all PR 55% cohort: (1.6–16.4) et al. ; gov identifier: aberrations: 11 (27.3%; 6–61) 12.9 All patients: 2.9 Soria et al. Pan FGFR inhibitor NCT01703481] Fusions: 8/11 All patients: 9 Erdafitinib LUC2001 Only Asian patients 12 evaluable: 83.3% (10/12) 6.83 Treatment duration: Park et al. (JNJ-42756493) phase IIa Pretreated CCA with PR: 50% (6/12) FGFR2 (3.65–12.16) 4.83 (0.5–20.3) Pan FGFR [ClinicalTrials. FGFR alterations FGFR2 alterations: 10 mPFS 5.59 inhibitor gov identifier: FGFR2 fusions: 8 alterations: 10 evaluable (1.87–13.67) NCT02699606] FGFR2 mutations: 3 evaluable 100% (10/10) FGFR2 alterations: FGFR3 fusions: 1 ORR: 60% (6/10) 10 evaluable FGFR3 mutations:2 mPFS 12.35 (3.15–19.38) CCA, cholangiocarcinoma; iCCA, intrahepatic CCA; CI, confidence interval; DCR, ; FGFR, fibroblast growth factor receptor; mDOR, median duration of response; mOS, median overall survival; mPFS, median progression-free survival; ORR, overall response rate; DCR, disease control rate. A Saborowski, U Lehmann et al. signaling axis in phosphate homeostasis. Further extended panel diagnostics (e.g., via the frequent AEs included fatigue, alopecia, FoundationOne CDx panel in the FIGHT GI-toxicity (diarrhea or constipation), nail toxici- Study). The availability of such data is highly ties (onychodystrophy and nail loss), as well as advantageous because it accelerates the clinical stomatitis and dry eye. annotation of therapy-relevant cause-effect rela- tionships on the basis of the co-mutational spec- The positive results from the already completed trum. Initial analyses from the FIGHT-202 study phase II trials can legitimately be considered a ther- already revealed that the mutational landscape of apeutic breakthrough in a cancer with such limited patients with FGFR2 fusion differs from patients treatment options, especially in second- or higher without fusions. BAP1 alterations were enriched lines of therapy. Currently, three randomized con- in fusion positive patients (38.7% versus 8.2%), trolled phase III trials are recruiting patients with whereas all other recurrent alterations occurred FGFR2-fusions/re-arrangements that compare less frequently in patients with FGFR2 fusions, standard of care (gemcitabine + cisplatin) with including TP53 as well as oncogenic drivers such infigratinib (PROOF) [ClinicalTrials.gov identi- as KRAS, and ERBB2. Notably, FGFR2 and fier: NCT03773302], pemigatinib (Fight-302) IDH1 mutations were not mutually exclusive [ClinicalTrials.gov identifier: NCT03656536], (5/107; 5.1%) raising the question: which of both or futibatinib (FOENIX-CCA3) [ClinicalTrials. druggable alterations is the main driver and gov identifier: NCT04093362], in first-line set- should be targeted first. In respect to the question ting with the designated primary endpoint progres- of to what extent the co-mutational spectrum sion-free survival (PFS). Despite the promising affects the efficacy of FGFR2 inhibitors, initial data from the phase II studies in pre-treated genetic subgroup analysis of patients that received patients, the trial designs nevertheless appear pemigatinib in the FIGHT-202 trial suggest a ambitious: a positive outcome would require that negative predictive value of TP53 mutations; no the targeted agents, which previously achieved a responses were observed in patients with p53 mPFS of 6.9 months (pemigatinib, 95% CI 6.2– mutations (zero of nine) and mPFS was signifi- 9.6) or 6.8 months (infigratinib, 95% CI 5.3–7.6) cantly shorter in p53 mutant patients compared in second or higher line, outperform the mPFS of with p53 wildtype patients (p = 0.0003). With the 8 months reached under gemcitabine and cisplatin increasing availability of genetic and clinical in the first line (ABC02 trial) in a head-to-head patient data from clinical trials, as well as real-life comparison. However, in contrast to previous “all data, such integrative analysis will shed light on comer” trials, these studies will recruit a geneti- the molecular underpinnings of primary resist- cally more homogenous group of exclusively iCCA ance, and will ultimately help to improve up-front patients, and will help to determine the prognostic patient stratification. and predictive value of FGFR2 fusions in biliary tract cancer. Of note, the presence of FGFR2 Beyond the observation that only one out of three fusions might not only be of value as a positive pre- patients responds to the targeted inhibitors, the dictive biomarker for FGFR-inhibitors, but may long-term benefit is frequently limited, and the also serve as a negative predictive indicator for the longest median duration of response (mDOR) in use of chemotherapy. a phase II setting was 7.5 months for pemigatinib. Paralleling findings in other solid malignancies, both on- and off-target resistance can emerge Primary and secondary resistance to FGFR2 under the continuous selective pressure of the directed therapies tyrosine-kinase inhibitors. On-target resistance to Critical assessment of the existing data reveals FGFR inhibitors is defined as resistance despite that only a subset of patients with FGFR2 fusions the continued reliance on FGFR-fusion signaling. achieves a clinically meaningful response. This Generally, on target resistance results from de observation indicates that the presence of a fusion novo mutations within the FGFR2-kinase domain does not necessarily guarantee sensitivity to tar- of the chimeric protein that interfere with the geted inhibitors, and points towards the existence binding of the small molecule inhibitor. Treatment of strong molecular networks that are capable of with a second FGFR-targeted inhibitor can be conferring primary resistance. Conveniently, a considered in some cases. However, the complex- pre-requisite for trial inclusion was (and is) the ity of secondary resistance mutations is high- genetic proof of the FGFR2 chromosomal altera- lighted by initial data from liquid biopsies that tion, which is usually conducted by performing confirm the frequent presence of not only a single journals.sagepub.com/home/tam 7 Therapeutic Advances in Medical Oncology 12 but multiple different mutations in the FGFR2 genomic regions coding for the secondary resist- 45,46 kinase domain. Investigations using pre-clini- ance mutations. cal models provided convincing evidence that FGFR inhibitors exhibit distinct activity profiles Another opponent of long-lasting responses to against secondary FGFR mutations, thus indicat- FGFR inhibitors is off target resistance. Off target ing that the genetic alterations can (and, in the resistance bypasses oncogene addiction through future, should) guide selection of the most appro- the acquisition of novel (epi-) genomic alterations priate compound. For instance, the irreversible that converge on the activation of alternative FGFR inhibitor futibatinib (TAS-120), soon be pathways. Specifically, in CCA patients under entering a phase III trial against gemcitabine and treatment with FGFR inhibitors, the PI3K/AKT cisplatin in first line in FGFR2 gene rearranged pathway has been reported to convey secondary iCCA (FOENIX-CCA3), may not only be an resistance. This is in line with pre-clinical data option for first-line treatment but also as rescue from other tumor entities that harbored genetic treatment, because it remains active against a FGFR1, FGFR2 or FGFR3 alterations, and subset of secondary mutations that may emerge developed AKT-mediated resistance after ini- 49–51 under prior treatment with ATP-competitive tially responding to FGFR inhibitors. It is inhibitors, such as infigratinib or debio 1347. The well conceivable that a considerable overlap exists translational significance of these findings has between mechanisms that lead to off-target resist- been clinically confirmed in a subset of patients ance and those that cause primary resistance. A that progressed under FGFR-inhibitor therapy, more global understanding of mechanisms that but responded to an FGFR inhibitor re-challenge convey off-target resistance will aid in the identi- 40,41,46 with futibatinib. fication of viable co-treatment strategies that delay time to progression or re-establish disease The Achilles heel of most FGFR inhibitors is that control. their activity depends on binding to the ATP binding pocket of the tyrosine kinase. So-called gatekeeper mutations frequently affect residue Outlook: FGFR-directed combination V564 (V565 annotated according to FGFR2 iso- therapies form IIIb), and can inhibit the drug from access- After completion of the currently recruiting trials ing the hydrophobic pocket due to steric that address the role of FGFR-targeted mono- hindrance. Futibatinib appears to retain limited therapy, the field will likely move towards combi- potency against selected mutations at the gate- nation approaches. One potential future concept keeper residue, such as V565I, but not V565F, that is currently under discussion will be the com- which was still relatively sensitive towards debio bination of immune-oncology (IO) and FGFR 1347 in an in vitro assay. The most promising inhibition. Highly promising results for the com- activity profile in that regard, however, has been bination of IO and targeted therapies have already attributed to a compound that was developed as been reported for other solid malignancies, such an ATP-competitive pan-FGFR inhibitor, as in ERBB2/HER-2 positive gastric cancer LY2874455. Wu et al. provided in vitro evidence [ClinicalTrials.gov identifier: NCT02954536]. that LY2874455 has the potential to overcome Thus far, only pre-clinical data exist for dual tar- drug resistance driven by FGFR gatekeeper geting of the FGF receptors and immune check- mutations. However, although LY2874455 points. Initial data in murine model systems demonstrated good tolerability in patients with implicate that FGFR-inhibition can alter the solid organ malignancies, the clinical develop- immune microenvironment of tumors and ment of LY2874455 has been discontinued. enhance the anti-tumor T-cell responses. In addition, some FGFR inhibitory compounds also In the near future, longitudinal liquid biopsy exhibit activity against other receptor tyrosine diagnostics starting prior to the initiation of tar- kinases: for instance, derazantinib inhibits the geted therapies will likely become an important Colony Stimulating Factor 1 Receptor (CSF1R) tool to track the evolution of secondary resistance in vitro at similar concentrations as required for mutations that mediate treatment failure and to the inhibition of FGF-receptors. Tumor mac- guide selection of adequate second line therapy. rophage modulation through CSF1R blockade Of note, not all NGS panels used for the diagno- may render tumors more responsive to T-cell 54,55 sis of FGFR2 fusions necessarily cover all the checkpoint inhibition. 8 journals.sagepub.com/home/tam A Saborowski, U Lehmann et al. Summary and to develop experimentally informed co-treat- During the last 4 years, the portfolio of available ment as well as sequential-treatment strategies. FGFR-inhibitory compounds quickly expanded. The growing interest in FGFR inhibitors as tar- Conflict of interest statement geted therapy for FGFR2-fusion positive iCCA is AV: honoraria from Roche, BMS, MSD, and fueled by exceptionally encouraging results from Incyte. AS: honoraria from BMS and Roche. UL: clinical phase II trials in pre-treated patients, honoraria from AstraZeneca, BMS, Novartis, which resulted in the recent United States Food Roche, and ThermoFisher and Drug Administration (FDA) approval of pemigatinib for the treatment of advanced iCCA Funding patients with FGFR2 fusions. Ongoing phase III The authors disclosed receipt of the following trials are comparing the efficacy of the targeted financial support for the research, authorship, agents with gemcitabine and cisplatin in the first and/or publication of this article: AS and AV are therapeutic line. funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - SFB/ The number of identified possible FGFR2 fusion TRR 209 - 314905040, and Vo959/9-1 (to AV), partners is steadily growing and currently already as well as the Else Kröner-Fresenius Foundation exceeds 150 different genes. 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Therapeutic Advances in Medical Oncology – SAGE
Published: Sep 16, 2020
Keywords: biliary tract cancer; genetic rearrangement; next generation sequencing; precision oncology; translational medicine
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