Erdafitinib for the treatment of metastatic bladder cancer
ABSTRACT
Introduction: Since the approval of immune checkpoint inhibitors (ICIs), there has been continuing and significant progress in urothelial cancer (UC) treatment. However, only about one fifth of UC patients respond to ICI. Recently, erdafitinib was developed for treating locally advanced or metastatic UC (mUC) with FGFR3 or FGFR2 alterations, accounting for 15-20% of patients. Erdafitinib is the first targeted therapy ever approved for mUC.Areas covered: This review summarizes the preclinical and clinical data on erdafitinib for UC. PubMed search and relevant articles presented at international conferences were used for the literature search.Expert opinion: The FDA approval of erdafitinib provided a new treatment option for FGFR- altered UC progressing on platinum-based chemotherapy. It is not clear whether FGFR inhibitor is a preferred second-line treatment choice to ICI. Compared to ICI, erdafitinib has a better response rate in patients with visceral metastases. However, shorter duration of response and toxicity profile of erdafitinib, particularly ocular toxicity, is an important consideration. Regular eye exams are recommended by the FDA. Tumor profiling during upfront therapy may help identify those who benefit at time of progression. In summary, a high unmet need remains for new drugs in chemotherapy- and ICI-refractory UC.
1.Introduction
Bladder cancer is the 6th most common cancer in the United States and the 9th most common cancer worldwide. Urothelial carcinoma (UC), formerly known as transitional cell carcinoma, is the most common type of bladder cancer, accounting for 90% of the cases in the United States and Europe [1,2]. About 25% of the patients with bladder cancer present with metastatic disease or will develop metastasis eventually [3]. The five-year survival rate drops dramatically from 70% in patients with non-muscle invasive stage to 35% and 5% in locally advanced and metastatic UC (mUC) patients, respectively [3]. The standard choice of treatment in fit patients with locally advanced or metastatic disease is systemic platinum- based chemotherapy, with five-year overall survival (OS) of 13%-15% [4].In recent years, checkpoint immunotherapy has been approved for patients who are not eligible for or have progressed through chemotherapy [5]. However, despite durable responses in some, many will not benefit from immunotherapy [6]. Several groups have classified bladder cancer into different molecular subtypes suggesting an association between treatment response and molecular alterations in bladder cancer, including PD-L1 status, FGFR alterations, and DNA damage response gene alterations [7-13]. Various subtypes of UC have been defined based on gene expression profiling [9]. The luminal papillary subtype has been shown to have a lower PD-L1 expression and poorer response to immune checkpoint inhibitors (ICI) [14]. This subtype was found to have a higher FGFR3 alteration rate, particularly FGFR3 mutations and FGFR2/3 fusions [14]. Therefore, FGFR inhibition seems to be an interesting treatment option for this subtype of UC.In April 2019, FDA (Food and Drug Administration) granted accelerated approval of erdafitinib (Balversa), a pan-fibroblast growth factor receptor (FGFR) inhibitor, for patients with locally advanced or metastatic UC with susceptible FGFR3 or FGFR2 genetic alterations after progression on platinum-based chemotherapy [15]. In this review, we summarize the pharmacology, and clinical trials evaluating the efficacy and tolerability of erdafitinib in locally advanced or metastatic UC patients.
2.Overview of second-line therapeutic options
Treatment options for locally advanced and mUC patients have changed significantly since the approval of ICI. During one year’s period, FDA approved five different ICI, including anti PD-1 (programmed cell death-1) and anti PD-L1 (programmed death-ligand 1) antibodies in this setting. Immune check point inhibition has shown improvement in quality of life as well as durable responses in about 15-20% of patients [16-22]. However, a significant proportion of patients do not respond to ICI.Based on some correlative data, patients with high PD-L1 expression seemed to respond better to ICI [17,18]. In both KEYNOTE-361 (NCT02853305) and IMvigor130 (NCT02807636) studies, decreased survival was observed among PD-L1-low patients in the monotherapy arm, as compared to platinum-based chemotherapy [18,23]. Therefore, the frontline use of ICI with pembrolizumab and atezolizumab was limited to mUC with PD-L1 expression in those ineligible for cisplatin-based chemotherapy, as per FDA and European Medicines Agency (EMA) recommendations.There is an area of unmet need for patients with poor or no response to ICI. This includes still a large proportion of mUC patients. Based on that, the development of targeted therapies in the treatment of UC patients has been g rowing and expanding.
Recently, FDA gave approval to erdafitinib, a selective, potent inhibitor of FGFR1-4, as the first targeted agent for the treatment of mUC patients with actionable FGFR3/FGFR2 alterations [11]. In addition to erdafitinib, other FGFR inhibitors including rogaratinib, infigratinib and pemigatinib have been explored in separate phase I and II trials, with an objective response rate (ORR) of around 25% [24-29] . Results from interim analyses of trials of the anti-FGFR3 monoclonal antibody vofatamab (B-701) as monotherapy and in combination with the PD-1 inhibitor pembrolizumab have been recently reported, with confirmed response rates of 10% and 33%, respectively [30]. Currently, there are several ongoing trials using FGFR inhibitors as either monotherapy or in combination with other agents for UC. Some of these are listed in Table 1.Enfortumab-vedotin (EV), an antibody-drug conjugate (ADC) composed of an anti-nectin-4 antibody bound to a microtubule disrupting agent, monomethyl auristatin E (MMAE), was given a breakthrough designation in locally advanced or mUC patients with recent progression on ICI. The phase II trial of EV (EV-201) reported an approximate ORR of 44%, including complete response (CR) in 12% of the patients [31] . Other ADCs beyond EV have been studied in phase 1/2 trials in previously treated advanced UC patients. Sacituzumab govitecan is an ADC bound to SN38 (the active metabolite of irinotecan) and targets Trop-2, which is highly expressed in UC. Confirmed RR of 31% has been reported in advanced UC patients who have progressed after both platinum chemotherapy and ICIs [32].
3.Development of erdafitinib
Fibroblast growth factor receptors are transmembrane proteins physiologically involved in controlling phosphate and vitamin D homeostasis [33,34]. Activation of the FGFR results in cell proliferation, survival and migration [35]. This happens through activation of the downstream pathways, including mitogen-activated protein kinase (MAPK) and the phosphoinositide 3-kinase (PI3K), which play roles in cell proliferation, migration and cell survival [33,36] . FGF/FGFR signaling pathway alterations have been reported to be involved in neoplastic progression of several tumors, including gastric cancer, lung cancer, liver cancer, breast cancer and UC [37-40]. FGFR3 alterations have been reported in approximately 20% of mUC cases [41] and 37% of the upper tract UC patients [28,42].Erdafitinib is a potent small-molecule selective pan-FGFR kinase inhibitor. It was first discovered through a partnership between Astrex Pharmaceuticals and University of Newcastle in 2006 and then was licensed to Janssen in 2008 [43,44]. In vitro, erdafitinib was shown to bind and inhibit the activity of FGFR1, FGFR2, FGFR3, and FGFR4 [45].Evidence of antitumor activity was demonstrated in several FGFR-expressing cell lines and tumors using xenograft mouse models [45].The first-in-human trial, showed clinical activity with an acceptable safety profile in 2015 [46]. In March 2018, FDA granted Breakthrough Therapy designation for erdafitinib for adults with locally advanced or mUC. In April 2019, erdafitinib received accelerated FDA approval for the treatment of adult patients with locally advanced or mUC with susceptible FGFR2 or FGFR3 alterations, including mutation, amplification or fusion, who have progressed after at least one prior line of platinum-based chemotherapy. FDA also granted simultaneous approval to a companion diagnostic test, the therascreen FGFR RGQ RT-PCR Kit, which is a reverse-transcriptase-polymerase-chain-reaction assay developed by Qiagen that tests for specific FGFR3 mutations or FGFR2/3 fusions using RNA derived from formalin-fixed paraffin-embedded tumor tissue samples [47].
4.Pharmacodynamics, pharmacokinetics & metabolism
Erdafitinib is a kinase inhibitor with the chemical name N-(3,5 dimethoxyphenyl)-N’-(1- methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl] ethane-1,2 diamine and molecular formula of C25H30N6O2 [Figure 1]. It is supplied as 3 mg, 4 mg or 5 mg film- coated tablets.Erdafitinib was shown to be a potent inhibitor of FGFR1, FGFR2, FGFR3 and FGFR4 (IC50 1.2, 2.5, 3 and 5.7 nM, respectively), but a weaker inhibitor of vascular endothelial growth factor receptor (VEGFR) 2 kinase (IC50 36.8 nM) in the in vitro assays [45]. In various preclinical studies using xenograft mouse models, erdafitinib demonstrated antitumor activity in a dose-dependent fashion [45]. Increase in serum phosphate levels is a result of inhibition of the renal tubular FGFR and the FGF23-Klotho axis, which are involved in serum phosphate homeostasis [34,41]. In the phase 1 trial (NCT01703481), hyperphosphatemia was first noted at a daily dose of 4 mg, and peak phosphate values were reached in patients dosed with the 9-mg daily dose. No significant changes were observed in calcium levels. No dose-dependent changes in the levels of vitamin D, parathyroid hormone (PTH) or soluble FGF23 were noticed. Increase in vitamin D was noted at erdafitinib doses ≥ 2 mg daily, and decrease in PTH was seen at doses above 4 mg, with likely a plateau effect at higher erdafitinib doses [46].Erdafitinib is orally bioavailable and has a rapid oral absorption (median Tmax 2.5 h). It has a half-life of about 50 to 60 hours. No significant changes were observed in the pharmacokinetics of the medication with high-fat or high-calorie food.
Along the tested dose range of 0.5 to 12 mg daily (continuously daily dosing schedule with 21-day cycles) or 10 or 12 mg once daily (7 days-on/7 days- off intermittently with 28-day cycles), the plasma PK of erdafitinib is linear and time-independent [46].The phase 1 trial reported low distribution volume and rapid oral clearance of 26 L and 0.26 L/h, respectively [46]. Over 99% of Erdafitinib is bound to plasma protein, particularly to alpha-1-acid glycoprotein. After a single oral dose or erdafitinib, the majority of it was excreted in feces (69%) and in the urine (19%) [47]. The pharmacokinetics of erdafitinib in severe renal or liver failure is not known [47]. The primary metabolism of erdafitinib is through CYP2C9 (39%) and CYP3A4 (20%) [47]. Patients with CYP2C9*3/*3 genotype (present in 0.4% to 3% of the population) are poor metabolizers of erdafitinib, expected to have 50% higher exposure and higher toxicity [47].From the safety perspective, the most commonly reported toxicities were hyperphosphatemia (65%), asthenia (55%), dry mouth (45%), nail toxicity (35%), constipation (34%), anorexia (32%), and dysgeusia (31%). 42% of patients experienced grade 3 or higher side effects.
The dose-limiting-toxicity (DLT) was defined as treatment interruption due to drug-related toxicities over 10 days (in the continuous scheduling), and over 5 days (in the 7-day-on/7- day-off dosing schedule), grade 4 hematologic toxicities, grade 3 nonhematologic toxicities (excluding nausea, vomiting, and treatment-responsive diarrhea), as well as hyperphosphatemia resulting in 2 weeks or more of treatment interruption [30]. Maximum- tolerated dose (MTD) was defined as the maximum dose with less than 33% of the patients having DLT during cycle 1 of the treatment [46].The initial recommended phase 2 dose (RP2D) was 9 mg daily on a continuous schedule. Improvement in the side effects, particularly hyperphosphatemia, and overall tolerability was reported with intermittent scheduling. Therefore, 10 mg daily-dose with a 7-day-on/7-day-off dosing schedule was considered as the final RP2D; however, based on the data of an interim analysis on pharmacokinetic and pharmacodynamic modeling of phosphate levels, as a surrogate for clinical efficacy, the protocol was amended in August 2016 to increase erdafitinib dose to 8 mg daily continuously throughout a 28-day cycle, changing the study to a single-arm trial [46].
5.Clinical efficacy
5.1.Phase I trial
The first-in-human, multicenter, phase I study of erdafitinib, JNJ-42756493, enrolled a total of 65 adult patients with advanced solid-tumor malignancies, including urothelial cancer with no standard treatment options. The study was conducted at six different centers in the United States and Europe [46]. 59 patients were evaluable for clinical activity, including 23 patients with FGFR alterations. Of these 59, the 36 patients with unknown or no FGFR alterations did not show any responses. Amongst the 23 patients with FGFR alterations, 16 had stable disease, and 4 had partial responses (PR), one unconfirmed and three confirmed responses.Three of the PR cases were patients with UC who had received more than four previous lines of treatment. Two of these three patients stayed on treatment for 10 and 12 months, respectively [46].
5.2.Phase II trial
The results of the phase II study of erdafitinib were published in June 2019. This open-label, multicenter trial studied locally advanced or mUC patients with prespecified FGFR alterations who had progressed after at least one prior line of chemotherapy or within 12 months of adjuvant or neoadjuvant chemotherapy (n=99). The primary end point of the study was ORR [48].All the patients were required to have one or more FGFR3 mutations (n=74) or FGFR2/3 fusion (n=25), diagnosed by a central laboratory. Of these patients, 53% had a creatinine clearance of less than 60 ml/min; 66% had visceral metastases; 22% of the patients (n=22) had an ICI as their previous line of treatment [48]. The participants were initially randomized 1:1 to receive either an intermittent 10-mg-daily dose (with 7-days-on/7-days-off dosing schedule) or a continuous 6-mg-daily dose; however, as previously mentioned, based on the interim analysis data, the protocol was amended to increase erdafitinib dose to continuous 8- mg-daily dosing [48]. The dose of erdafitinib could be increased further to 9 mg per day on day 14, in case of no side effects, and if the patient’s serum phosphate level had not reached to 5.5 mg/dl, based on the association of serum phosphate level of above 5.5 mg/dl and improved response rate reported in the phase I trial [29].
The ORR in the phase II study was 40% (95% CI, 31-50), including 37% PR and 3% CR. The response rates were not affected by the number of previous lines of treatment or presence of visceral metastases. The median duration of response was 5.6 months (95% CI, 4.2-7.2). The median duration of progression-free survival and OS were 5.5 and 13.8 months, respectively. Patients with FGFR3 mutation were noted to have a better ORR (49%) as compared with that of FGFR2/3 fusion patients (16%). Of the 22 patients with previous immunotherapy, 21 had not responded to ICI. Of these, 59% showed some response to erdafitinib [48]. The FDA approval was associated with a confirmed ORR of 32.2% (95% CI, 22.4-42.0) [15].Grade 3 or 4 toxicities occurred in 67% of the participants of the phase II trial of erdafitinib, of which 46% were deemed to be treatment related. The most common grade 3/4 adverse events (AEs) were hyponatremia (11%), stomatitis (10%), asthenia (7%), nail dystrophy (6%), urinary tract infection (5%) and palmar-plantar erythrodysesthesia syndrome (5%). The frequency of hyperphosphatemia of all grades was 77%, with grade 3/4 hyperphosphatemia reported only in 2% of patients [48]. Ocular toxicities, including central serous retinopathy or retinal pigment epithelial detachment were frequent, with grade 3 or higher toxicity reported in 10% of patients [15].
6.Post-marketing surveillance
All the patients treated with erdafitinib reported some toxicity, including nearly 50% treatment-related grade 3 or higher AEs. Dose interruption and dose reduction were required due to AEs in 68% and 53% of the patients, respectively. AEs resulted in treatment discontinuation in 13% of patients. There was one death report related to AEs. Phosphate level needs to be monitored, which can guide dose modification of erdafitinib if necessary. As mentioned earlier, erdafitinib has risk of serious ocular toxicities, which was the most common reason for permanent discontinuation of treatment. Regular eye exam has been required by the FDA, including monthly ophthalmological examinations during the first four months of treatment, every 3 months afterwards, and in case of any concerning visual symptoms [15].
7.Regulatory affairs
Erdafitinib monotherapy has been currently approved in the US for the treatment of locally advanced or metastatic urothelial cancer patients with FGFR3 or FGFR2 genetic alterations following progression on platinum-based chemotherapy. Patients need to be tested by a, now FDA-approved, companion diagnostic test (Qiagen), which uses a reverse-transcriptase- polymerase-chain-reaction (RT-PCR) assay to assess for FGFR3 mutation or FGFR2/3 fusion [15].
8.Conclusion
About 20% of mUC patients have FGFR gene alterations. The phase I and II trials of erdafitinib have demonstrated benefit in this group of locally advanced or mUC patients with these gene mutations and fusions. Patients with FGFR3 mutations had the best ORR (49%) vs, those with FGFR2/3 fusion (ORR 16%). The response rate of erdafitinib (40%) is comparable to other targeted therapy agents, including a FGFR1-3 inhibitor, INCB054828, (ORR 25%), antibody-drug conjugates enfortumab-vedotin (ORR 44%), and sacituzumab govitecan (ORR 31%), and ICIs (ORR 15-20%) [17-22,31,32,48,49]. With grade 3 or more AEs noted in about half of the patients, caution needs to be taken [48]. Toxicity can be a limiting factor for the treatment of mUC patients with lower performance status.
9.Expert opinion
Erdafitinib is the first targeted therapy agent for the treatment of mUC and the first FGFR inhibitor that has received FDA approval [50]. There are now two second-line treatment options for UC patients who progress through chemotherapy; i.e. ICI and FGFR inhibition. A recent study, using the data from two ICI trials in mUC, showed that the response rates to ICI were not different in patients with FGFR3 mutations than in those with wild-type cancer; therefore, FGFR3 mutation is not an ICI-resistance biomarker and patients with FGFR3 mutation respond to ICI similarly to those without mutation [51]. Unlike immune checkpoint inhibition, patients with visceral metastases had a good response rate to erdafitinib, with evidence of response in those with high tumor burden [17,48,52]. Thus, erdafitinib may be a better second-line therapy option for FGFR3-mutated patients with visceral metastases and bulky disease. However, in choosing the treatment option, patient’s performance status and toxicity profile of erdafitinib may be limiting factors. Moreover, while about 40% of the patients showed some response in the phase 2 trial, the median duration of response was 5.6 months (95% CI, 4.2 to 7.2). The median OS (mOS) with erdafitinib (13.8 months) was similar to ICIs (14.8 months with atezolizumab [IMvigor 210], 10.3 months with pembrolizumab [Keynote 045]). However, FGFR3 mutations are more common in the subtype of bladder cancer that has the best prognosis (luminal papillary subtype); therefore, the comparison between these treatments would be difficult.
Randomized trials could address this better. The results of Thor trial, the phase III study comparing erdafitinib with chemotherapy vs. immunotherapy, may be helpful for answering this question. Overall, erdafitinib may be a reasonable choice as a second-line treatment for FGFR-altered patients with visceral metastases and good performance status. Given evidence of response to both FGFR inhibition and ICI in FGFR3 mutated mUC, combination of ICI and FGFR inhibitor may be a potential treatment option for this population in the near future. There are ongoing trials investigating these combinations, including a phase Ib/II study of erdafitinib plus anti- PD-1 cetrelimab (JNJ-63723283 ), and a phase 1b/II trial of FGFR3 inhibitor vofatamab plus anti-PD-1pembrolizumab (FIERCE-22), [NCT03473743, NCT03123055]. The preliminary data from the FIERCE-22 trial was presented at ASCO 2019 [30]. In five years’ time, it is expected that molecular profiling of UC will move to the frontline, in light of the emerging development of new targeted therapies in order to better predict effective regimens upfront. There are multiple novel combinations that are currently being tested in clinical trials, which will potentially get approval in the near future. Recent increasing advances in understanding of tumor biology and predictive markers in UC have shined hope of finding novel effective treatments for this devastating disease.