Alberto D’Angelo , Stefan Bagby , Ilaria Camilla Galli , Carlotta Bortoletti & Giandomenico Roviello
Abstract
Introduction: Erdafitinib is the first orally administered pan-fibroblast growth factor receptor (FGFR) kinase inhibitor approved by the Food and Drug Administration (FDA).Areas covered: Specifically binding to FGFR family (FGFR-1 to FGFR-4), erdafitinib leads to reduced cell signaling and cellular apoptosis. Coupled with the ability to bind to vascular endothelial Pathologic complete remission growth factor 2 (VEGFR-2), KIT, Fms-related tyrosine kinase 4 (FLT4), platelet-derived growth factor receptor α and β (PDGFR-α and PDGFR- β), RET and colony-stimulating factor 1 receptor (CSF-1R), erdafitinib has further reported antitumor features causing cell killing.Expert opinion: In this review, we provide a comprehensive overview of erdafitinib chemical structure, pharmacologic properties and current knowledge of clinical efficacy in the treatment of locally advanced or metastatic urothelial carcinoma. This treatment, recently approved in the U.S., is available for adult patients harboring FGFR2/FGFR3 genetic alterations who progressed within 12 months of an adjuvant or neoadjuvant chemotherapy regimen including platinum or progressed during or after prior a chemotherapy regimen including platinum.
Keywords: Urothelial carcinoma; solid tumors; genitourinary cancer therapy; erdafitinib; toxicity; Pan-FGFR inhibitors; bladder cancer therapy, FGFR mutations.
1.Background
Second-line chemotherapy regimens with vinflunine or taxanes have shown a median overall survival (OS) of 7 up to 9 months with an objective response rate (ORR) of nearly 10% for patients diagnosed with locally advanced or metastatic urothelial carcinoma [1,2]. A substantial clinical benefit has been recently provided by novel drugs of the immune checkpoint inhibitors (ICI) family [3–6] which reported an increased OS of 10.3 months with an ORR ranging from 13 to 21% in one clinical trial [7].
2.Introduction
Bladder cancer is the 9th most common cancer worldwide. Urothelial carcinoma (UC), previously known as transitional cell carcinoma, is the most prevalent histotype, accounting for 90% of the events in Europe and the USA [8,9]. Unfortunately, nearly 25% of patients are locally advanced or metastatic at the time of diagnosis. Systemic platinum-based chemotherapy is the standard treatment for fit patients, leading to a five-year OS of 13-15% [10]. Overall, regardless of the specific treatment administered, a drop of up to 5% in terms of five-year OS has been reported for metastatic UC (mUC) patients [11]. Recently, the FDA approved checkpoint immunotherapy for those who progressed after prior treatment or are not eligible for standard chemotherapy regimens. Standard first-line regimens generally include either cisplatin-based combination chemotherapy for cisplatin-eligible patients or immune checkpoint inhibitors (ICIs) for platinum- ineligible patients, regardless of programmed death-ligand 1 (PD-L1) expression. Not all patients benefit from immunotherapy [12].
According to gene expression profiles, urothelial carcinoma (UC) has been classified into several molecular subtypes – correlated with alterations in DNA damage response genes, PD-L1 status and mutations in the fibroblast growth factor receptor (FGFR) – resulting in different treatment rates [13– 16]. It is noteworthy that the luminal I subtype has shown a poor response to immunotherapy [17], with a decreased immune signature and expression of PD-L1 compared to other subtypes. With an increased rate of mutation in FGFR genes, FGFR inhibition may be a valid option for the luminal I subtype of UC [18].Erdafitinib (JNJ-42756493), also known as Balversa, was discovered by Janssen Group in partnership with Astex Pharmaceuticals and approved by the Food and Drug Administration (FDA) in April 2019. Erdafitinib is a potent pan-tyrosine kinase inhibitor of fibroblast growth factor receptor (FGFR) 1-4 approved for patients diagnosed with locally advanced or metastatic UC who progressed after platinum-based chemotherapy and actionable FGFR2 or FGFR3 genetic alterations [19]. Here we review the pharmaceutical features, the clinical efficacy and the adverse events of erdafitinib, with a final discussion of ongoing trials.
3.Erdafitinib and the FGFR inhibition pathway
The potent in vitro selective inhibition by erdafitinib of FGFR1, FGFR2, FGFR3 and FGFR4 activity was demonstrated at the University of Newcastle in 2006 [20]. Its antitumor activity was then reported in FGFR-expressing cell lines [21]. FGFRs are transmembrane proteins physiologically associated with vitamin D homeostasis and the control of phosphate [22]; thus, when activated, FGFRs induce survival, cell proliferation, migration and differentiation through several downstream signaling molecules such as phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) (Figure 1) [23–25]. FGFR genetic alterations, including mutations and fusions, have been shown to play a pivotal role in the neoplastic progression of various tumors such as liver, lung, gastric and breast cancer, and they are common in patients with urothelial carcinoma [26–28].
Approximately 20% of local advanced or metastatic UC patients harbor FGFR mutations [29] – normally those with luminal I histotype – and nearly 37% of these mutations are found in patients with upper tract UC (UTUC) [30]. The most common activating FGFR3 point mutations are S249C, R248C and Y373C in exons 7,10 and 15 respectively; less commonly, gene fusion involving FGFR3 such as FGFR3-JAKMIP1, FGFR3-BAIAP2L1 and FGFR3-TACC3 have also been reported [31]. Given this scenario, it seems possible that FGFR inhibition would show clinical benefit for UC patients with luminal I histotype, where immunotherapy treatment might be less efficient.Following the accelerated approval of erdafitinib in April 2019, the FDA also approved the therascreen FGFR RGQ RT-PCR kit developed by Qiagen for the detection of FGFR2/3 fusions or FGFR3 mutations, interrogating the RNA from formalin-fixed paraffin-embedded tumor samples [32].
4. Pharmacokinetic and Pharmacodynamic properties
Erdafitinib(chemical name N-(3,5 dimethoxyphenyl)-N’-(1-methylethyl)-N-[3-(1-methyl-1H- pyrazol-4-yl) quinoxalin-6-yl] ethane-1,2 diamine, molecular formula C25H30N6O2) (Figure 1) shows dose-dependent inhibition of FGFR1, FGFR2, FGFR3 and FGFR4 with IC50 of 1.2, 2.5, 3 and 5.7 nM, respectively [21]. Erdafitinib also inhibits vascular endothelial growth factor receptor (VEGFR) 2 kinasein vitro with IC50 of 36.8 nM [21].Erdafitinib is normally supplied as oral tablets of 3 mg, 4 mg or 5 mg leading to inhibition of the FGF23-Kloto axis and renal tubular FGFR, both involved in the homeostasis of serum phosphate, resulting in hyperphosphatemia first-time diagnosed in patients administered with 9mg daily [25,33]. No notable alterations of soluble FGF23, vitamin D, calcium or parathyroid hormone (PTH) levels were reported except for a slight fallin PTH and slight rise in vitamin D at 5 mg and 2 mg Erdafitinib doses, respectively [34]. Erdafitinibis rapidly absorbed with a median Tmax of 2.5 hours and a half-life of 50 to 60 hours. The rapid oral absorption is time-independent and linear according to either the tested dose range of 0.5 to 12 mg per day or 10 or 12 mg once per day [34].
Distribution volume is somewhat low (26L) according to the data from the phase I clinical trial, with an oral clearance of 0.26 L/h; once absorbed, 99% of erdafitinibis bound to plasma protein, specifically to alpha-1-acid glycoprotein [32,34]. Erdafitinib is metabolised by CYP2C9 (39%) and CYP3A4 (20%) although individuals carrying the CYP2C9*3/*3 alteration are poor erdafitinib metabolizers and are exposed to higher toxicity due to the 50% increase in drug availability [32]. The drug is mainly excreted in faeces (69%) and urine (19%) after a single oral dose; the pharmacokinetics of erdafitinibis poorly understood inpatients with liver and renal deficiency [32]. According to the phase II trial, the initial recommended erdafitinib dose was agreed at 9 mg daily on a continuous setting; however, due to the overall tolerability and hyperphosphatemia side effect shown by the intermitting setting, the protocol was thereafter modified to an 8 mg daily dose continuously administered on a 28-cycle setting [34].
5.Clinical efficacy of erdafitinib
The first exploratory phase I study of erdafitinib included 65 adult patients with advanced solid tumors – urothelial cancer included – with no standard antineoplastic treatment available [34]. Among the 59 patients evaluable for clinical activity, 23 presented with FGFR1-4 or FGF3/FGF4 alterations and 16 of these patients had stable disease (SD) while four showed partial response (PR) – three confirmed and one unconfirmed. The three patients who reported a confirmed partial response were those diagnosed with UC; by contrast, no responses were demonstrated in the 36 patients without evidence of FGFR alterations [34].More recently, a phase II study enrolled 99 patients with locally advanced and unresectable or metastatic UC with at least one FGFR3 mutation (n=74) or FGFR2/3 fusion (n=25) who progressed after prior chemotherapy treatment or within 12 months of neoadjuvant or adjuvant chemotherapy [35]. Of these, 22 were previously treated with ICIs. Objective response rate (ORR) was the agreed primary endpoint.
Enrolled patients were randomized 1:1 to receive either an intermittent regimen (10 mg per day, 7 days on and 7 days off) or a continuous regimen (6 mg per day). Subsequently, based on interim analysis data, the groups were unified on a dosage of 8 mg per day in a continuous regimen, potentially escalating further to 9 mg per day on day 14 in case of no side effects and serum phosphate level inferior to 5.5 mg/dl. The confirmed ORR was 40% (95% CI, 31-50), with 37% of PR and 3% of complete response (CR) and a median duration of response of 5.6 months (95% CI, 4.2-7.2) [35]. Participants harboring FGFR mutations showed a better response rate (49%) when compared to patients with FGFR fusions (16%) [36]. As second endpoints, overall survival (OS) and progression-free survival (PFS) had a median duration of 13.8 and 5.5 months, respectively [36]. Among the 22 patients who had previously received immunotherapy, although partial, the confirmed response rate to erdafitinib was 59% [35]. The objective response rate of erdafitinib (40%) is comparable to other targeted therapy molecules such as the antibody-drug conjugate enfortumab vedotin (ORR 42%), sacituzumab govitecan (ORR 31%) and FGFR1-3 inhibitor INCB054828 (ORR 25%), while slightly superior to immune checkpoint inhibitors (ORR of 13-21%) [35][37][38][39].Overall, phase I and phase II studies have shown a clinical benefit of erdafitinib in locally advance or metastatic UC patients carrying FGFR gene alterations. As a consequence, in April 2019,the FDA approved erdafitinib with an ORR of 32.2% (95% CI, 22.4-42.0) on a blinded independent review committee assessment [40].
6.Adverse events and ocular toxicity
In phase I and II studies, nearly all patients showed toxicity during treatment with the most common any grade adverse events (AE) being hyperphosphatemia (65%), asthenia (55%), mouth dryness (45%), toxicity of nails (35%), constipation (34%) and anorexia (32%) [35]. 67% of patients experienced grade 3 and/or grade 4 AEs in phase II clinical study with hyponatremia (11%), stomatitis (10%) and asthenia (7%) the most common AEs, which led to dose reduction and dose interruption for 55 patients (56%) and 13 patients (14%), respectively [35]. However, the percentages and the type of adverse events in the 9 mg per day group were similar to those in the overall population. One patient died from acute myocardial infarction whilst not evaluated as related to the treatment [35][41]. Hyperphosphatemia, a well-known pharmacodynamic effect of erdafitinib, was reported in 77% of participants [36]. The median onset was 20 days after initiating the treatment although the frequency subsequently decreased with no additional complications, perhaps as a result of compensatory mechanisms of phosphorus homeostasis [42]. Only 2% of patients experienced grade 3 or 4 hyperphosphatemia. The rise in phosphate level needs strict monitoring and may require dose modification of erdafitinib [35][41].
Ocular toxicity, including dry eye, xerophthalmia, keratitis, foreign body sensation, and corneal erosion was reported to be frequent during erdafitinib therapy and occurred in 28% of patients, with grade 3 AE in 6% of patients [35]. Central serous retinopathy or retinal pigment epithelial detachment was described in 25% of patients and were classified as grade 3 in 3% of patients. Most ocular adverse events were low grade and resolved with dose interruption or reduction. Ocular toxicity is another well-established side effect of erdafitinib and, consequently, patients should receive dry eye prophylaxis and monthly eye examinations for the first four months of therapy and every three months afterwards [43], as advised by the FDA [44][35][40][41].
7.Other second-line regimen options and ongoing trials
Currently, two separate second-line treatment options are available for patients diagnosed with locally advanced or metastatic urothelial cancer, including ICIs and FGFR-inhibitors. UC patients have benefited from ICIs such as anti-programmed cell death-1 (anti-PD-1) and anti-programmed death-ligand 1 (anti-PD-L1) agents which showed durable responses and improvements of quality of life in nearly 20% of patients [4,6,7,45,46]. According to the clinical trials KEYNOTE-361, IMvigor130, KEYNOTE-052 and IMvigor210 (for cisplatin-unfit patients), the UC patients that benefitted most from ICIs in a first-line setting were those with high expression of PD-L1, whereas a decreased survival was reported for those with low PD-L1 expression when compared to the standard care (platinum-based regimens) [5,47–50]. Unfortunately, only a small proportion of patients are good responders to ICI therapies.
In addition to the recent FDA approval of erdafitinib for treatment of mUC with actionable FGFR2/FGFR3 alterations in a second-line regimen, other FGFR inhibitors such as pemigatinib, infigratiniband rogaratinib have been investigated in different phase I and II clinical trials, showing an encouraging overall ORR of 25% [37,51–54]. Additionally, the anti-FGFR3 monoclonal antibody vofatamab has also been explored alone or in combination with pembrolizumab (PD-1 inhibitor), with an interim analysis response rate ranging from 10% to 33% [55]. Different FGFR inhibitors are being investigated in separate ongoing trials – alone or in combination with other agents – for the treatment of UC (Table 1). The FGFR inhibitors under clinical investigation include pemigatinib (NCT03914794,NCT02872714,NCT042942777),infigratinib (NCT04228042,NCT04197986), rogaratinib (NCT02608125, NCT04125693) and debio 1347 (NCT03834220) (Table 1). In addition, two new agents are under evaluation for patients diagnosed with UC: PRN1371, a new FGFR1-4 inhibitor, is being administered in a single group assignment clinical trial (NCT02608125) to evaluate its safety and tolerability profile in nine UC patients [56]; and derazantinib, another FGFR 1-3 inhibitor that is under assessment in 303 UC patients alone or in combination with atezolizumab (PD-L1 inhibitor) for the evaluation of the objective response rate as the primary outcome (NCT04045613) (Table 1).
Another approach involves antibody-drug conjugate (ADC) agents, including enfortumab-vedotin (EV) and sacituzumab govitecan (SG). EV consists of anti-nectin-4 antibody bound to monomethyl auristatin E (MMAE), a microtubule disrupting agent, that showed a positive ORR of 44% and a CR of 12% in a phase II trial (EV-201) for locally advanced or metastatic UC patients [38]. SG is instead bound to an active metabolite of irinotecan (SN38), targeting the highly expressed urothelial cancer protein Trop-2 [57]. A recent phase I/II trial reported a promising response rate (RR) of 31% in advance UR patients who progressed following both ICIs and platinum-based chemotherapy [39].
8.Suggested treatment sequence
Before any systemic treatment, recurrent or metastatic UC patients must be evaluated for different aspects: age is most important (elderly patients normally experience more frequent and severe toxicities), followed by comorbidities (including autoimmune disease, diabetes mellitus and chronic kidney disease), and socioeconomic status which might affect CT administration. In terms of the first-line regimen, cisplatin-based combination CT is currently the gold standard treatment for cisplatin-fit patients, whereas ICIs – regardless of PD-L1 expression – can be used for platinum- unfit patients [58]. Alternatively, when ICIs are not available or the patient reported a health condition which advises against ICI use, single-agent gemcitabine can be administered – albeit evidence supporting this approach is lacking. As far as second-line treatment is concerned, ICIs are the gold standard option for patients who progressed after platinum-based CT, with pembrolizumab the preferred agent according to KEYNOTE-045 [7,59]. For those patients harbouring FGFR2/FGFR3 alterations, erdafitinib can be administered at this stage. In the case of patients who progressed after first-line ICI, cytotoxic CT can be administered, according to cisplatin eligibility. For those who failed both ICI and platinum regimens, either EV (which has shown clinical benefit) or erdafitinib (according to FGFR susceptibility) can be administered [31,38]. High quality supportive care should be considered at any stage for patients who do not tolerate the systemic treatment or show deterioration of performance status.
9.Expert opinion
Erdafitinib fills un unmet need for a targeted therapy in patients affected by urothelial cancer harboring FGFR genetic alterations, specifically those with locally advanced or metastatic stage disease who progressed following a first line cisplatinum-based systemic regimen or are not eligible for a cisplatinum-based regimen. Erdafitinibis currently under investigation for additional FGFR alteration-harboring neoplasms including esophageal, prostate, liver, and non-small lung carcinoma, lymphoma and cholangiocarcinoma [60]. Erdafitinib is the first oral therapy approved for metastatic UC and, coupled with the concurrent FDA approval of the therascreen FGFR RT-PCR kit [40] as a companion diagnostic test developed by Qiagen, is marking a new era of biomarker- driven drug discovery for UC. Although only approximately 20% of patients are eligible for erdafitinib and no one will be eligible without testing, the number of biopsies (liquid or/and metastatic) is predicted to rise for the identification of these actionable FGFR mutations. UC patients who progressed following a PD-1/PD-L1 immunotherapeutic ICI regimen reported better outcomes (59%) when LDN212854 administered with erdafitinib whereas the confirmed response rates for patients medial congruent who progressed following CT and for those with no prior CT were 40% and 42%, respectively [35]; it is still unclear, however, how FGFR mutational status should be considered in deciding between targeted therapy or immune checkpoint inhibitor.
In terms of first-line therapies, the NCT04197986 (Table 1) clinical trial is noteworthy; this is a phase III, randomized and place- controlled study to evaluate the efficacy of infigratinib (FGFR1-3 inhibitor) following surgery in patients with invasive UC. This study is at the “recruitment” stage with an estimated enrollment of 218 patients and disease-free survival (DFS) as the primary endpoint. Unfortunately, no preliminary data have been reported.On the other hand,a recent retrospective study evaluating data from Imvigor 210 and CheckMate275, both studies of ICI in mUC patients, showed that patients harbouring FGFR3 alteration responded to ICI similarly to those with no alteration and, therefore, FGFR3 alteration cannot be considered an ICI-resistance biomarker [61]. It is noteworthy that the phase II EV study reported comparable response rates among patients with a previous response to ICI therapies [38]. Separate approaches to optimize combined treatment strategies of immunotherapy plus erdafitinib and to overcome potential resistance mechanisms to ICIs are being considered.
In support of this, erdafitinib plus PD-1 ICI agent showed improved survival and tumor shrinkage in the FGFR2K660N /p53mut murine lung cancer model, when compared to ICI alone [62]; an additional study on the biology of upper tract UC observed T cell depletion in the tumor microenvironment, likely due to increased expression of FGFR3 via activating fusions and mutations; this T cell effect was reversible upon erdafitinib treatment [53]. Erdafitinib is under assessment in combination with cetrelimab (anti-PD-1 agent) in two separate groups of mUC patients (NCT03473743) (Table 1): a dose-expansion group which is enrolling patients ineligible for cisplatinum therapy, and a dose-escalating group which is enrolling patients who have been administered with previous chemotherapy regimens. Preliminary data suggest a safe combination of both drugs plus an observed promising initial efficacy [63]. The last significant benefit of erdafitinib is its efficacy in patients with visceral metastasis and limited response to ICIs. To address this further, the phase II THOR trial (NCT03390504) (Table 1) is currently recruiting UC patients with visceral metastasis and comparing standard chemotherapy with two combination therapies: vinflunine (or docetaxel) plus erdafitinib, and pembrolizumab plus erdafitinib.
Erdafitinib offers an additional promising option for advanced UC and potential route towards a precision medicine approach in UC management. Several novel combinations including erdafitinib are currently being investigated in clinical studies and will potentially get approval in the foreseeable future. Full approval for erdafitinib use in urothelial cancer is conditional upon successful completion of confirmatory trials. It is predicted that molecular profiling of urothelial cancer will move to the frontline over the next decade. This should lead to better understanding of tumor behavior and to new predictive markers towards the goal of significantly improved outcomes for UC patients.