Fibroblast growth factor receptors as therapeutic targets in clear-cell renal cell carcinoma.

Review

Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by University of Laval on 06/27/14 For personal use only.

Fibroblast growth factor receptors as therapeutic targets in clear-cell renal cell carcinoma 1.

Introduction

2.

Treatment

3.

The FGF pathway

4.

Conclusions

5.

Expert opinion

Guru Sonpavde†, Christopher D Willey & Sunil Sudarshan †

University of Alabama at Birmingham Comprehensive Cancer Center, Division of Hematology and Oncology, Birmingham, AL, USA

Introduction: Metastatic clear-cell renal cell carcinoma (RCC) is a highly vascularized tumor type that is often associated with inactivating mutations in the von Hippel-Lindau gene that ultimately drives pro-angiogenic signaling pathways, including the VEGF pathway. As such, new therapies indicated for RCC have largely focused on blocking angiogenesis by inhibiting this pathway. Despite the contribution of these agents to clinical outcomes in RCC, acquired resistance that stimulates tumor regrowth and revascularization quickly emerges. Resistance to VEGF inhibition appears to largely result from activation of compensatory angiogenesis pathways (including the fibroblast growth factor [FGF] pathway), providing a rationale to investigate their inhibition. Areas covered: This review explores the role of the FGF pathway in resistance to VEGF-targeted therapy and rationale for targeting in RCC. PubMed, as well as ASCO and ESMO congress abstracts, were searched for preclinical and clinical data for FGF inhibitors in RCC. Expert opinion: The FGF pathway presents a logical target in RCC and trials of the FGF receptor inhibitors regorafenib, dovitinib, nintedanib, lenvatinib and cediranib demonstrated clinical activity. Clinical development should focus on optimizing the use of this therapy by improving patient selection and evaluating combined therapy. Keywords: angiogenesis, cediranib, dovitinib, drug resistance, fibroblast growth factor pathway, lenvatinib, nintedanib, regorafenib, renal cell carcinoma Expert Opin. Investig. Drugs (2014) 23(3):305-315

1.

Introduction

Cancers of the kidney and renal pelvis are expected to affect » 65,150 new patients and cause 13,680 deaths in the US in 2013 [1]. Nearly 90% of these cancers will be renal cell carcinomas (RCC). About one-quarter of patients with RCC are diagnosed with metastatic disease [2,3], which is characterized by highly vascularized tumors [4-7]. In particular, the clear-cell histological subtype exhibits extensive vascularization frequently associated with inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase, which normally functions to promote proteasomal degradation of the transcription factor, hypoxia-inducible factor (HIF) [8]. Inactivation of VHL stabilizes, and thus, upregulates HIF, resulting in downstream expression of pro-angiogenic factors, including VEGF, platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) [4-7]. Activation of the mammalian target of rapamycin (mTOR) pathway can also lead to HIF accumulation, and is another important factor contributing to angiogenesis in RCC [9]. In addition to VHL inactivation and mTOR activation, other genes have been associated with RCC in recent analyses [10-13]. These findings are preliminary and as such, HIF-stimulated angiogenesis remains the most well-characterized oncogenic mechanism in RCC. 10.1517/13543784.2014.871259 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted

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Clear-cell renal cell carcinomas are highly vascularized, resulting from inactivation of the von Hippel--Lindau (VHL) gene. Loss of VHL induces upregulation of the HIF and downstream activation of multiple angiogenesis pathways, including the VEGF axis and the FGF axis. Currently, VEGF inhibitors, including the monoclonal antibody bevacizumab and the multitargeted tyrosine kinase inhibitors sunitinib, sorafenib, pazopanib and axitinib, as well as the mTOR inhibitors everolimus and temsirolimus are indicated for clear-cell RCC. Unfortunately, patients eventually progress due to acquired drug resistance, which is postulated to occur as a result of bypass activation of tumor growth and angiogenesis pathways. The FGF pathway plays a role in resistance to VEGF pathway inhibition in preclinical models, providing a rationale for clinical investigation of FGF inhibitors in RCC. To this end, tyrosine kinase inhibitors that simultaneously target FGFR, VEGFR and other angiogenic targets are currently in clinical development, of which dovitinib is the most advanced. These agents have the potential to improve clinical outcomes for patients with VEGF pathway inhibitor refractory RCC. Given that nintedanib and dovitinib did not improve outcomes in unselected patients in the first-line or third-line settings, respectively, the establishment of biomarker-based patient selection and development of combination regimens could potentially further optimize FGF pathway inhibitor therapy.

This box summarizes key points contained in the article.

2.

Treatment

Until the advent of targeted agents, cytokine-based therapy, using interleukin-2 or interferon-a, was the primary treatment for metastatic RCC, and would yield median progression-free survival (PFS) of 3 -- 5 months and median overall survival (OS) of 13 months in previously untreated patients [14-18]. The development of VEGF pathway-targeted inhibitors, including bevacizumab, a monoclonal antibody targeting the VEGF ligand, and the VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, pazopanib and axitinib, which also inhibit several other kinases, has resulted in substantial improvements in treatment outcomes for patients with metastatic RCC [16,19]. With these agents, patients who are initially naive to targeted therapy demonstrate a median PFS of 5 -- 12 months and median OS of 11 -- 26 months [15,16,20-22]. However, despite these advances, nearly all patients will eventually progress on VEGF pathway inhibitors. The mTOR inhibitor everolimus has activity in the second-line (post-VEGF inhibitor) setting, with a median PFS of 4.9 versus 1.9 months when compared with placebo [23]. In addition, the mTOR inhibitor temsirolimus is approved by the US FDA for RCC based on a study in previously untreated 306

patients with poor prognosis [24]. Although second-line everolimus is efficacious, an unmet need remains to further improve treatment outcomes. Attempts to understand the mechanisms of resistance to VEGF pathway-targeted agents may facilitate the development of novel agents that can further improve clinical benefit. Drug resistance Resistance to VEGF pathway-targeted agents is characterized by tumor regrowth and revascularization despite continued effective VEGFR inhibition [25]. Resistance does not appear to involve VEGFR resistance mutations in endothelial cells (ECs), which line the surface of blood vessels and are key components in angiogenesis, because unlike tumor cells, ECs do not replicate clonally. Consequently, VEGFR resistance mutations would have to hypothetically occur in multiple ECs to drive tumor progression. Rather, resistance to VEGF inhibitors has been proposed to occur via expression of alternative pro-angiogenic molecules, such as interleukin-8, ephrin and angiopoietin, as well as through pathways that promote tumor cell survival, proliferation, invasion and metastasis, including epidermal growth factor, hepatocyte growth factor receptor c-MET, insulin-like growth factor and phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR [26,27]. Furthermore, activation of HIF via mTOR complex 2 (mTORC2, which is normally inhibited when mTORC1 is active), or upregulation of HIF via alternate signaling pathways drives angiogenesis and tumor growth independently of VEGF/VEGFR. Indeed, VEGF pathway inhibition that blocks angiogenesis can trigger tumor hypoxia, resulting in activation of HIF-1a, and increased expression of pro-angiogenic factors, including FGF ligands in models of pancreatic islet tumors [28]. Thus, the activation of compensatory angiogenesis pathways constitutes an important mechanism of resistance via tumor revascularization after VEGFR inhibition. 2.1

3.

The FGF pathway

The FGF pathway is expressed in many tissues and is involved in multiple biological processes, including wound healing, embryogenesis, organogenesis and carcinogenesis (Figure 1). Cellular processes regulated by FGF pathway activation include differentiation, mitogenesis, motility, invasiveness, survival and angiogenesis [29]. These processes are controlled by 18 FGF ligands (FGF1-10, and FGF16-23) and 4 functional type 1 transmembrane receptors (FGFR1-4) that signal through the PI3K/Akt, Ras/Raf, protein kinase C, and signal transducers and activators of transcription (STAT) pathways to stimulate proliferation of ECs and tumor cells and resistance to apoptosis-inducing chemotherapeutic agents [30-32]. Given its roles in angiogenesis and tumor resistance, the FGF pathway has been explored as a target for highly vascularized tumors, including RCC and hepatocellular carcinoma. In addition, genetic abnormalities that lead to an activated FGF pathway have been detected in a variety of cancers. For

Expert Opin. Investig. Drugs (2014) 23(3)

Fibroblast growth factor receptors as therapeutic targets in clear-cell renal cell carcinoma

Endothelial cell mTOR Akt

MAPK MEK STAT Raf

PI3K

Receptor tyrosine kinases

Ras

JAK

FGFR


Ras PI3K

FGF

Raf Akt MEK

MAPK

HIF mTOR

Hypoxia HIF accumulation

Target genes

Tumor cell

Figure 1. FGF Pathway. In tumor cells, activation of receptor tyrosine kinases can induce signaling cascades through the Ras/ Raf/MEK/MAPK and PI3K/Akt/mTOR pathways to stimulate transcription of target genes in the nucleus. HIF accumulation via hypoxia, VHL inactivation or mTOR activation can also lead to increased levels of pro-angiogenic target gene transcription. Secretion of these pro-angiogenic factors, including FGFs, can lead to activation of endothelial cells and subsequent angiogenesis.

example, activating point mutations of FGFR3 have been detected in » 40% of bladder cancers [33] and » 10% of endometrial carcinomas have activating mutations of FGFR2 [34,35]. Gene amplification of FGF pathway components has also been associated with cancer. For example, FGFR2 gene amplification is observed in 10% of gastric cancers [36], and amplification of 8p11-12 (which encompasses the FGFR1 gene) is observed in 10% of breast cancers that are predominantly estrogen receptor positive [37,38]. Furthermore, amplification of 11q12-14, which contains FGF3, FGF4, FGF19 and the cyclin D1 gene, is detected in » 30% of breast tumor samples [39]. Gene overexpression has also been observed -- 15% of patients with multiple myeloma have a t(4;14) translocation that leads to overexpression of FGFR3, without a change in gene copy number [40,41]. FGF ligands stimulate all phases of angiogenesis to create a favorable environment for tumor growth [42,43]. For example, FGF1 and FGF2 (also known as basic FGF) ligands are potent mitogens that stimulate EC proliferation predominantly through FGFR1, which is the principal FGF receptor expressed on ECs. FGF ligands, including FGF1, FGF2, FGF4, FGF8b and FGF10, stimulate various steps in angiogenesis. For

example, FGFs increase protease production to degrade basement membranes, enabling EC invasion into the surrounding extracellular matrix, and upregulate integrin and cadherin expression to promote EC migration to the site of angiogenesis. FGF2 may also be involved in blood vessel maturation by promoting deposition of the extracellular matrix, a key structural component of the new blood vessel, and recruiting pericytes, which modulate the function of ECs to regulate vascular function and structure. FGF1 and FGF2 have also been shown to directly stimulate tumor growth [44,45]. The role of FGF2 in RCC has been explored. FGF2 is expressed by 75 -- 80% of RCC [46,47] and hypoxia has been shown to increase FGF2 levels. In addition, hypoxia can increase EC responsiveness to FGF2 [28,48]. It has also been shown that high FGF2 expression is associated with a worse prognosis in RCC [49]. Thus, the FGF pathway appears to play an important role in RCC tumor growth and progression. Role of FGF pathway in VEGF pathway-inhibitor resistance

3.1

As described above, tumors that initially respond to VEGFR inhibition by developing hypoxia may acquire resistance


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through the upregulation of alternative angiogenic pathways, including the FGF pathway [25]. Therefore, inhibition of the FGF pathway may decrease angiogenesis and reduce tumor growth associated with resistance to VEGFR-targeted therapies. Indeed, the FGF pathway has been shown to play a role in VEGF pathway resistance, using a mouse pancreatic tumor model [28]. In the model, inhibiting VEGFR2 signaling reduced tumor growth and angiogenesis at 10 days compared with controls. However, despite sustained VEGFR2 inhibition, tumors regrew and intratumoral vessel density increased by 4 weeks. The resistant tumors showed increases of pro-angiogenic factors, including FGF1 and FGF2. When FGF signaling was also inhibited via the addition of an FGF trap (soluble FGFR2 that acts as a decoy for FGF ligand to prevent it from activating FGFR receptors on the cell surface) starting at Day 10, tumor regrowth and intratumoral vessel density was diminished at 4 weeks compared with the VEGFR2-inhibited, non-FGF-inhibited control. Thus, targeting the FGF pathway maintained angiogenic inhibition and counteracted a mechanism of resistance to VEGF pathway inhibition. Elevated FGF2 levels have also been observed in patients with RCC treated with VEGF pathway inhibitors. For example, a significant rise in FGF2 levels was detected in patients with metastatic RCC who progressed while receiving the VEGFR and PDGF receptor (PDGFR) inhibitor sunitinib [50]. Similarly, FGF2 levels tended to increase and remained high prior to progression on sunitinib [51]. In another study, high baseline plasma levels of FGF2 were observed in patients who were previously treated with VEGF pathway inhibitors [52]. Combined, these results suggest that increased expression of FGF2 could be a mechanism of resistance of VEGF pathway-targeted treatment of RCC.

in combination with the VEGF and PDGF pathways for the treatment of RCC.

Preclinical activity of FGFR inhibitors in RCC FGF pathway inhibitors have been tested in preclinical models of RCC. In one experiment, regorafenib, an inhibitor of FGFR1/2, as well as VEGFR1-3, PDGFRa/b, TIE2, c-KIT, RET and Raf, exhibited tumor shrinkage in RCC (786-O) xenografts [53]. The 786-O cell model is particularly useful for testing agents that target the VEGF and FGF pathways, since its homozygous deletion of VHL causes increased VEGF synthesis and surface accumulation and abnormal activation of FGFR1. Another TKI, dovitinib, inhibits FGFR1-3, VEGFR1-3, PDGFRb, c-KIT, FLT3 and, less potently, PDGFRa [54,55]. When tested in a 786-O xenograft model, dovitinib also reduced tumor volume [52]. In this study, dovitinib showed a greater reduction of tumor volume than did sunitinib or sorafenib (agents that primarily inhibit the VEGF and PDGF pathways). Similarly, dovitinib demonstrated greater antitumor activity in the RCC xenograft models Caki-1 and TG206 compared with other anti-angiogenic agents [52,56]. Overall, these results suggest that there may be an advantage to simultaneously targeting the FGF pathway

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Clinical activity of FGFR inhibitors in RCC Multiple FGF pathway inhibitors have been explored in clinical trials (Table 1). Here, we summarize the available data from studies in patients with RCC. 3.3

Regorafenib In a single-arm, international, multicenter Phase II study, 49 previously untreated patients with favorable or intermediate-risk RCC, according to Memorial Sloan-Kettering Cancer Center scoring, were treated with single-agent regorafenib [57]. Nineteen patients (39.6%) achieved a partial response (PR), with a median duration of response of 14.1 months. Ten patients maintained responses for longer than 12 months, and five for longer than 18 months. The disease control rate was 63% (n = 30), with a median duration of stable disease of 3.9 months. The median PFS and time to progression (TTP) were both 11.0 months. The median OS could not be calculated at the time of data cutoff because of censored patients. Common drug-related adverse events (AEs) of any grade included hand and foot skin reaction (71%), fatigue (53%), hypertension (49%), diarrhea (45%) and mucositis (43%). Common grade 3 AEs included hand and foot skin reaction (33%), diarrhea (10%), renal failure (10%), fatigue (8%) and hypertension (6%). Grade 4 AEs were observed in two patients: cardiac ischemia or infarction (4%), hypomagnesemia (2%) and pain in the chest or thorax (2%). Here, regorafenib demonstrated activity that was similar to historical data with other targeted first-line therapies, so the authors suggested that further investigation in RCC should focus on biomarker-defined subsets of patients, including those with evidence of angiopoietin/TIE or FGF pathway upregulation. 3.3.1

Nintedanib Nintedanib is a TKI that inhibits VEGFR1-3, FGFR1-3, PDGFRa/b, FLT3 and Src. In a Phase II study conducted in European countries, previously untreated patients with RCC were randomized 2:1 to receive nintedanib (n = 64) or sunitinib (n = 32) [58]. Confirmed objective response rate (ORR) was 18.8% with nintedanib, but trended higher in the sunitinib arm (31.3%; odds ratio, 0.53; p = 0.193), although the disease control rate was similar between the arms (77 and 78% for nintedanib and sunitinib, respectively). Median PFS was 8.4 months in both arms (hazard ratio [HR], 1.16; p = 0.561), and median TTP was 8.5 months in both arms (HR, 1.19; p = 0.515). The median OS was not statistically different at 20.4 and 21.2 months in the nintedanib and sorafenib arms, respectively (HR, 0.86; p = 0.631). AEs were generally similar between the nintedanib versus sunitinib arms and included diarrhea (61 vs 50%), nausea (38 vs 34%), fatigue (both 25%) and vomiting (16 vs 22%), respectively. Of note, dermatologic AEs were less frequent (8 vs 47%) in the nintedanib arm, including no cases of hand--foot



Table 1. FGF pathway inhibitors in clinical investigation. Compound

Company


FGFR small-molecule inhibitors studied in RCC Dovitinib (TKI258) Novartis

Regorafenib (BAY 73-4506; Stivarga) Lenvatinib (E7080)

Nintedanib (BIBF 1120; Vargatef) Cediranib (AZD2171)

Bayer

Eisai

Target(s) FGFR1-3; VEGFR1-3; PDGFRa/b; c-KIT, FLT3

FGFR1/2; VEGFR1-3; PDGFRa/b; TIE2, c-KIT, RET, Raf VEGFR1-3; PDGFRa/b; FGFR1-4; c-KIT

Boehringer Ingelheim

FGFR1-3; VEGFR1-3; PDGFRa/b; FLT3; Src

AstraZeneca

VEGFR1-3; PDGFRa/b; FGFR1; c-KIT

FGFR small-molecule inhibitors studied in other indications Brivanib (BMS Bristol-Myers Squibb VEGFR2/3; FGFR3; Raf; 582664) c-KIT; FLT3 Masitinib (AB1010)

AB Science

Orantinib (TSU-68) AZD4547

Taiho Pharmaceuticals AstraZeneca

BGJ398 Novartis Ponatinib ARIAD (Iclusig, AP24534) E-3810 Ethical Oncology Science ACTB-1003 ACT Biotech Antibody-based FGF pathway inhibitors MFGR1877S Genentech (R3MAb) GSK3052230 Human Genome Sciences (HGS1036; (GSK; Five Prime FP-1039) Therapeutics)

c-KIT, PDGFRa/b, Lyn, FGFR3 VEGFR2; PDGFRb; FGFR1 FGFR1-3; VEGFR2

Phase/indication 3: RCC 2: GIST, bladder, breast, scirrhous gastric carcinoma, HCC, endometrial 1: Pancreatic 3: Colorectal, HCC, GIST 2: RCC 1: SCLC 3: Thyroid, HCC 2: Melanoma, NSCLC, RCC (1/2), glioma, endometrial 3: Ovarian, NSCLC 2: Prostate, RCC, HCC, colorectal 3: Glioblastoma 2: Colorectal, RCC, GIST, breast 1: NSCLC, AML, prostate 3: HCC, colorectal 1: Gastrointestinal

FGFR1-3 FGFR1-4; PDGFRa; RET; BCR-ABL VEGFR1-3; FGFR1/2 FGFR1-4; PI3K (RSK, S6K)

3: Pancreatic, GIST, MM, melanoma 3: HCC 2: Gastric 1/2: Breast 2: Melanoma 2: Lung, GIST 1: AML 1: AST 1: AST (planned)

FGFR3

1: MM

FGFR1 ligands

1: AST

Notes

FDA approved for colorectal, GIST

No longer in clinical development

No longer in clinical development

FDA approved for CML and ALL

ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; AST: Advanced solid tumors; CML: Chronic myelogenous leukemia; FGFR: Fibroblast growth factor receptor; GIST: Gastrointestinal stromal tumor; HCC: Hepatocellular carcinoma; MM: Multiple myeloma; NSCLC: Non-small cell lung cancer; PDGFR: Platelet-derived growth factor receptor; RCC: Renal cell carcinoma; SCLC: Small cell lung cancer.

syndrome with nintedanib compared with 31.3% of patients in the sunitinib arm experiencing an event. Due to the similar efficacy compared with sunitinib in molecularly unselected patients, investigators suggest that further development of nintedanib be considered for patients with RCC showing an activated FGF pathway. Cediranib The TKI cediranib inhibits VEGFR1-3, FGFR1, PDGFRa/b and c-KIT. In a single-arm Phase II study in 44 previously untreated patients with RCC, 38% achieved a PR and 85% achieved disease control [59]. The median PFS 3.3.3

and OS were 8.9 and 28.6 months, respectively. The most common grade ‡ 3 treatment-related AEs included hypertension (36%), fatigue (30%), hand--foot syndrome (16%), diarrhea (11%) and dyspnea (11%). A second Phase II study randomized patients with no prior anti-VEGF therapy 3:1 to receive cediranib (n = 53) or placebo (n = 18) [60]. Baseline characteristics were well balanced between arms, including prior therapy received. Forty-seven percent and 50% of patients in the cediranib and placebo arms, respectively, received prior immuno/hormonal therapy. The primary endpoint, percentage change from baseline in tumor size at 12 weeks, showed a mean 20% decrease for cediranib and


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20% increase for placebo (p = 0.0001). In the cediranib arm, 18 patients (34%) achieved a PR and 25 (47%) had stable disease, compared with 0 PRs and 4 disease stabilizations (22%) in the placebo arm. Of the patients who responded to cediranib, 11 (61%) had durable responses ‡ 1 year. Median PFS was 12.1 and 2.8 months for cediranib and placebo, respectively (HR 0.45; p = 0.017). Common AEs of any grade in the cediranib arm included diarrhea (74%), hypertension (64%), fatigue (58%) and dysphonia (58%). Grade 3/4 AEs in the cediranib arm included hypertension (grade 3, 19%) and fatigue (grade 3, 17%; grade 4, 2%). Pharmacodynamic analyses demonstrated notable changes from baseline for plasma VEGF (increase) and soluble VEGFR2 (decrease) in the cediranib arm but not in the placebo arm; however, no relationship between these markers and change in tumor size was observed. In addition, no trends in FGF2 levels were detected for either arm. Taken together, these studies demonstrated clinical activity of cediranib in RCC that appears to be similar to monotherapy with approved VEGFR inhibitors. Lenvatinib The above studies examined the TKIs in single-agent regimens. Combinations of TKIs with mTOR inhibitors may allow for a multitargeted approach, but have often led to higher toxicities. The TKI lenvatinib, which inhibits VEGFR1-3, PDGFRa/b, FGFR1-4 and c-KIT [61,62], was combined with everolimus in a Phase Ib/II study in patients with advanced or metastatic RCC [63]. Of the 20 patients enrolled in the Phase Ib portion, 85% received prior VEGF inhibitor therapy and 35% received a prior mTOR inhibitor. At doses below or at the maximum tolerated dose, 6 of 18 patients achieved a PR and the PFS was 7.2 months. Nausea, vomiting, mucositis, elevated creatine phosphokinase and abdominal pain were the dose-limiting toxicities (DLTs). The most common treatment-related AEs (any grade) were fatigue (45%), mucosal inflammation (40%), proteinuria (35%), diarrhea (30%), rash (30%), hypertension (25%), nausea (25%), vomiting (25%), constipation (20%), decreased appetite (20%) and epistaxis (20%). Overall, the combination of lenvatinib and everolimus appeared to be safe in the Phase Ib portion of this trial. A Phase II expansion of this study is ongoing and will evaluate lenvatinib and everolimus both alone and in combination in patients who received one prior VEGF-targeted therapy (clinicaltrials.gov: NCT01136733). The primary endpoint for the Phase II expansion is PFS. Estimated enrollment was 180 patients, and the estimated primary completion date was December 2013. 3.3.4

Dovitinib The TKI dovitinib targets FLT3, c-KIT, FGFR1-3, VEGFR1-3, PDGFRb and, less potently, PDGFRa, as previously mentioned [54,55]. Dovitinib has been studied in a Phase I/II trial in patients with previously treated RCC. In the Phase I dose-escalation portion of the trial, 80% of patients had received at least one prior VEGF pathway-targeted therapy and 55% of patients received at least one prior mTOR 3.3.5

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inhibitor [52]. In the 15 patients who were treated at the recommended Phase II dose, the ORR was 13.3%, and the median PFS and OS were 8.1 and 13.3 months, respectively. Stable disease was 60%, and disease control lasted for at least 2 and 4 months in 73 and 60% of patients in this dose cohort. Sinus bradycardia, hypertensive crisis, asthenia, nausea and vomiting were DLTs. The most common AEs (any grade) related to dovitinib were nausea (75%), diarrhea (70%), vomiting (70%) and asthenia (50%). AEs were generally mild; grade 3 events were £ 5% with the exception of asthenia (15%) and there was only one grade 4 event (5%; hypertensive crisis). A pharmacodynamic analysis showed inhibition of VEGFR (as determined via increases in placental growth factor and decreases in soluble VEGFR2 serum levels) and FGFR (as determined via increases in FGF23 serum levels) between baseline and day 15. Interim analysis of the Phase II dose expansion part of the study shows a median PFS and OS of 5.5 and 11.8 months, respectively, and nearly half (49.2%) of patients had stable disease for at least 2 months [64]. Grade 3/4 AEs were most commonly asthenia (13.6%), fatigue (13.6%), hypertriglyceridemia (11.9%), diarrhea (10.2%) and hypertension (10.2%). Of the above agents, dovitinib is the only FGF pathway inhibitor to enter Phase III trials in RCC. The Phase III trial compared dovitinib (n = 284) with sorafenib (n = 286) in patients previously treated with one VEGF pathway inhibitor and one mTOR inhibitor [65]. Both arms had similar activity. Median PFS by central review (the primary endpoint) was 3.7 and 3.6 months (HR, 0.86; 95% CI, 0.72 -- 1.04; p = 0.063) and interim analysis of OS demonstrated median values of 11.1 and 11.0 months (HR, 0.96; 95% CI, 0.75 -- 1.22; p = 0.357) in the dovitinib and sorafenib arms, respectively. AEs more common in the dovitinib arm were diarrhea (68 vs 45%), nausea (53 vs 29%) and vomiting (44 vs 16%), whereas AEs more common in the sorafenib arm were palmar-plantar erythrodysesthesia (40 vs 11%), hypertension (28 vs 19%) and alopecia (21 vs 1%). Although dovitinib did not demonstrate superior efficacy compared with sorafenib, the results provide landmark PFS and OS data for future studies of third-line agents. FGF inhibitors appear active in a molecularly unselected population, but their efficacy may be further optimized with the identification of predictive biomarkers. Thus far, predictive biomarkers for FGF inhibitors and other molecularly targeted agents in RCC have been elusive [66-68]. However, in order to improve and personalize therapy for RCC, tumor-, plasmaand host genetics-based predictive biomarkers need to be aggressively developed. For example, the promising activity of foretinib, a MET- and VEGFR2-inhibiting TKI, in patients with advanced papillary RCC and germ line MET mutations provides a rationale for continued investigation in this area [69]. 4.

Conclusions

RCC is a highly vascularized tumor type, and therefore relies heavily on angiogenesis mechanisms for survival. Although




targeted inhibition of the VEGF pathway induces tumor response, patients often relapse due to acquired drug resistance that appears to be largely associated with hypoxia-triggered activation of other angiogenesis and growth pathways. The FGF pathway is one such angiogenesis pathway, and preclinical data in RCC models indicate that its pharmacological inhibition may help overcome anti-angiogenesis escape. Furthermore, FGF-targeted agents that also target additional angiogenesis pathways may provide greater tumor control than agents with more limited angiogenesis inhibition. This provides a rationale for the investigation of dovitinib, lenvatinib, cediranib, regorafenib and nintedanib, FGFR TKIs with additional angiogenic targets, for the treatment of RCC. Overall, these agents have demonstrated clinical activity in both treatment-naive and pretreated patients with RCC. However, it largely remains to be determined whether they can further improve outcomes, particularly PFS and OS, over currently available targeted therapies, and if so, what is the optimal sequence of therapy. A significant amount of research is seeking to identify and validate new molecular targets, including the FGF pathway, as therapeutic options. The results of ongoing and future clinical trials offer hope to patients with RCC. 5.

Expert opinion

Molecularly targeted therapy has drastically improved clinical outcomes for metastatic RCC -- the use of VEGF pathway inhibitors appears to prolong both PFS and OS compared with cytokine therapy, and mTOR inhibitors are efficacious in both the first line (temsirolimus; poor prognosis) and second line (everolimus). However, despite the overwhelming clinical benefit attained with VEGF pathway and mTOR inhibitors, nearly all patients will progress due to acquired drug resistance. Because inhibition is sustained during relapse, it is thought that acquired drug resistance is mediated by escape mechanisms that activate other angiogenic and tumor growth pathways. Thus, these pathways may represent therapeutic targets for concurrent or salvage inhibition. The FGF pathway is notable because it has both angiogenic and growth functions and its activation is implicated in VEGF pathway resistance. Agents that simultaneously target VEGFR and FGFR have been investigated in RCC as a means of providing broad-based angiogenesis inhibition, and of these, dovitinib proceeded to Phase III development in patients who received both a prior VEGF inhibitor and an mTOR inhibitor. Completed trials of FGFR inhibitors demonstrated antitumor activity, although a randomized Phase II trial in the first line did not show that nintedanib was more efficacious than the approved therapy sunitinib. Additionally, recently presented results from the Phase III study of dovitinib versus sorafenib in patients who previously received one VEGF pathway inhibitor and one mTOR inhibitor did not demonstrate an extension of PFS with dovitinib in an unselected population. Taken together, these results show that

although FGFR inhibitors have potential as therapies for refractory RCC, their use must be further optimized. For example, patient selection may be improved. Given the spectrum of VEGF resistance pathways in RCC, FGF pathway inhibition may not be active against refractory tumors exhibiting activation of escape pathways other than FGF. Therefore, developing predictive biomarkers to identify patients who are likely to respond to FGF inhibition could help optimize the use of FGF-targeted agents. However, it is currently unknown which biomarkers would predict FGF pathway inhibitor activity, or whether this strategy would be effective at all given the multiple angiogenic escape pathways that could be activated. In addition to the need to develop biomarkers for FGF pathway inhibitors, there is a general unmet need for identification and validation of predictive biomarkers for approved targeted therapies in RCC as well, because not all patients respond to VEGF pathway or mTOR inhibition. Investigation into candidate biomarkers for VEGF therapies is ongoing, but has not yet yielded successful results [66-68]. However, in order to improve outcomes and personalize therapy in RCC, biomarkers and companion diagnostics must be developed, ideally for all targeted therapies. Therefore, the necessity of continued investigation into predictive factors for approved therapies, as well as for FGF inhibitors, is emphasized. Another strategy to optimize the use of FGF inhibitors may be through the use of combination therapy to inhibit tumor growth and/or angiogenesis via multiple mechanisms of action. As previously mentioned, investigation of dual inhibition of FGFR and mTOR is ongoing. Targeting alternative pathways is another option, and the VEGF and MET inhibitor cabozantinib is currently being investigated in a Phase III trial (NCT01865747). If effective, combinations with FGF inhibitors could be considered to determine if targeting a wider array of selected pathways would be beneficial. Since RCC is an immunogenic disease that appears to possess immune evasion mechanisms [70], a combination of FGFR inhibition and immunotherapy may have clinical activity. Inhibition of programmed death-1 (PD-1), a negative regulator of T-cell activation, or one of its ligands (PD-L1) has demonstrated activity in patients with pretreated RCC [71-73], and a Phase III trial comparing the PD-1 inhibitor nivolumab with second-line everolimus is ongoing [74]. Another strategy combines VEGFR/PDGFR inhibition with immunotherapy [75]. Results from these ongoing trials could offer clinical validation for these targets and combinations, as well as guidance for future trials pairing PD-1 inhibitors with FGFR inhibitors. Going beyond VHL, detailed molecular characterization of RCC has elicited additional candidate genes that may or may not play a role in the standard angiogenesis mechanism. High-throughput sequencing has identified inactivating mutations in genes encoding histone methylases and demethylases (SETD2, JARID1C, UTX ), a chromatin remodeling complex gene, polybromo 1 (PBRM1), genes implicated in deubiquitination (BAP1) and components of the ubiquitin-mediated


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proteolysis pathway (UMPP) [10-13]. Of note, mutations in components of the UMPP have been shown to induce HIF and may contribute to tumorigenesis via VHL-independent angiogenesis. PBRM1 and BAP1 mutations appeared to be mutually exclusive, with BAP1-mutant tumors exhibiting aggressive pathological features and poorer survival compared with PBRM1-mutant tumors. Although these data are preliminary and the clinical impact is currently unknown, therapies personalized for patients with tumors that harbor these mutations may eventually be developed. Despite the efficacy gained with VEGF pathway and mTOR inhibitors, continued investigation into targeting additional molecular mechanisms has the potential to provide improved outcomes to patients with RCC. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Acknowledgments The authors thank PJ Simon and M Vishnu from Articulate Science for their medical editorial assistance with this manuscript.

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Affiliation

Guru Sonpavde†1 MD, Christopher D Willey2 MD PhD & Sunil Sudarshan3 MD † Author for correspondence 1 Associate Professor, University of Alabama at Birmingham Comprehensive Cancer Center, Division of Hematology and Oncology, 1720 2nd Avenue South, WTI 5, Birmingham, AL 35294-3300, USA Tel: +1 205 975 3742; Fax: +1 205 934 9511; E-mail: [email protected] 2 Associate Professor, University of Alabama at Birmingham Comprehensive Cancer Center, Department of Radiation Oncology, Birmingham, AL, USA 3 Associate Professor, University of Alabama at Birmingham Comprehensive Cancer Center, Department of Urology, Birmingham, AL, USA


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