Systemic treatment of renal cell cancer: A comprehensive review

Cancer Treatment Reviews 60 (2017) 77–89

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Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv

Anti-Tumour Treatment

Systemic treatment of renal cell cancer: A comprehensive review Amparo Sánchez-Gastaldo a,1, Emmanuelle Kempf b,1, Aránzazu González del Alba c, Ignacio Duran d,⇑ a

Medical Oncology Department, Hospital Universitario ‘‘Virgen del Rocio”, Seville, Spain Medical Oncology Department, Hôpital Universitaire Henri Mondor – Albert Chenevier, AP-HP, Créteil, France c Medical Oncology Department, Hospital Universitario ‘‘Son Espasses”, Palma de Mallorca, Spain d Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain b

a r t i c l e

i n f o

Article history: Received 29 April 2017 Received in revised form 26 August 2017 Accepted 26 August 2017

Keywords: Renal cell cancer Targeted therapy Angiogenesis Monoclonal antibody Tyrosine-kinase inhibitor mTOR inhibitor Immunotherapy

a b s t r a c t Kidney cancer represents about 5% of all new cancer diagnoses. The most common form of kidney cancer arises from renal epithelium, named renal cell carcinoma (RCC). This entity comprises different histological and molecular subtypes. Unraveling the molecular biology and cytogenetic of RCC has enabled the development of several targeted agents that have improved treatment outcomes of these patients. This article reviews all the agents currently approved for the treatment of RCC, and discuss upcoming molecules. Mechanism of action, preclinical and clinical development and ongoing trials, are presented for each agent, providing a broad vision of the current state of targeted therapy in RCC and possible future developments. Ó 2017 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction Each year, around 64.000 and 115.000 patients are diagnosed with kidney cancer in the United States (US) and in Europe, respectively. This disease represents about 5% of all new cancer diagnosis and leads nearly to 15.000 and 49.000 deaths yearly in US and in Europe, respectively [1]. The most common form of kidney cancer arises from renal epithelium and is named renal cell carcinoma (RCC). Recently, the pathology classification of tumors of the kidney has been updated. The most frequent RCC subtypes include clear cell, papillary [types I and II] and chromophobe tumors [2]. Around 25–30% of RCC patients are diagnosed at a locally advanced or metastatic stage. An additional third of the RCCs will recur after a successful treatment for a localized tumor. The historical therapeutic strategy for advanced RCC relied on cytokines. Those drugs led to a response rate in the range of 10–15% and to a median overall survival (OS) of 10–12 months, while they were associated with substantial side effects [3]. The last decade witnessed important advances in the understanding of RCC molecular biology leading to a parallel development of several targeted agents and a remark⇑ Corresponding author at: Medical Oncology Department, Hospital Universitario Virgen del Rocio, Avenida Manuel Siurot s/n, 41013 Seville, Spain. E-mail address: [email protected] (I. Duran). 1 Amparo Sanchez-Gastaldo and Emmanuelle Kempf contributed equally to this work.

able improvement in treatment outcomes. Nowadays, half of the patients who are diagnosed with an advanced RCC are likely to survive more than two years.

Molecular biology Clear cell renal cell carcinoma Clear cell RCC (ccRCC) is more likely to occur sporadically than within a hereditary familial syndrome (95% and 5% of the cases, respectively) [4]. The Von Hippel-Lindau (VHL) syndrome is due to mutations occurring in the homonymous gene. This condition is associated with an increased risk of medical disorders like retinal angiomas, hemangioblastomas, and ccRCC (40–60% of the cases). Up to 90% of sporadic ccRCCs are related to an abnormal function of the VHL gene either through mutations or post transcriptional changes [5]. The understanding of this molecular pathway has provided the rationale for the further development of targeted therapies in ccRCC patients. The VHL gene encodes for a protein [pVHL] that regulates the level of expression of a transcription factor named hypoxia-inducible factor (HIF). HIF modulates the cellular response according to oxygen availability. In the situation of a normoxic environment, HIF interacts with pVHL and is therefore eliminated by ubiquitinization. Conversely, conditions of low oxygen or of deficiency in pVHL lead to an accumulation of HIF

http://dx.doi.org/10.1016/j.ctrv.2017.08.010 0305-7372/Ó 2017 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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and transcription of genes related to the cellular adaptation to hypoxia. The transcription of those genes promote angiogenesis, cell growth and glycolysis through the activation of vascular endothelial growth factor (VEGF), transforming growth factor (TGF) alpha and beta and platelet derived growth factor (PDGF) [6]. Most of the innovative targeted therapies approved in advanced ccRCC target those proteins and their cognate receptors. Analysis of more than 400 ccRCC samples by The Cancer Genome Atlas (TCGA) project showed data in the same direction. The most relevant genetic alterations in this tumor subtype were related to cellular oxygen sensing and include VHL and its related pathway members. Moreover a set of genes involved in chromatin modulation such as SETD2, KDM5C, PBRM1 and BAP1 appeared frequently mutated. Also, tumors more aggressive had an up-regulation of genes involved in fatty acid synthesis and glycolysis and down regulation of genes involved in Krebs cycle and almost a third of cases had mutations in the PI3K/AKT/mTOR signaling pathway. These results in combination with the data from gene expression will most likely serve as the basis for a future classification that will probably help in matching tumors and best treatment options [7,8]. Papillary tumours A recent characterization of 161 primary papillary RCC (pRCC) in the TCGA project confirmed that type 1 and type 2 pRCC are not only clinically and pathologically diverse but also represent biologically different entities [9]. MET pathway alterations are more characteristic of type 1 pRCC. Conversely, activation of the NRF2–antioxidant response elements (ARE) pathway, CDKN2A silencing, SETD2 mutations and TFE3 fusions are characteristics of type 2 pRCC. A subgroup of these tumors with a particular poor prognosis and an association with fumarate hydratase (FH) mutations presented a CpG island methylator phenotype (CIMP). Based on these TCGA findings type 2 pRCC could be subdivided in at least three subtypes based on molecular and phenotypic features: IIa, IIb and CIMP profile. Papillary type I renal cell carcinoma The hereditary papillary RCC (HPRC) syndrome is an inherited condition that is associated with an increased risk of bilateral type I papillary RCC. The HPRC is due to an activating mutation occurring in the gene MET and located on the chromosome 7. As previously mentioned, recent characterization of the genomics of papillary RCC type I (pRCC) [9] has shown how even in the sporadic forms up to 81% of patients harbor alteration in MET either through mutation, splice variants, gene fusion or high copy number of chromosome 7. MET encodes for a transmembranal receptor of the hepatocyte growth factor (HGF). When binding to its receptor, HGF activates cellular pathways for proliferation through second messenger molecules like GRB2, GAB1 or PI3K. The activating mutation of MET leads to a permanent stimulation of its related receptor, independently of the binding of HGF. Yet, the development of papillary RCC tumors requires additional oncogenic events within the cell [10]. Here is the rationale for a therapeutic strategy targeting MET and its regulators in RCC, especially in papillary type I tumors [11].

and decreases the intracellular levels of fumarate. Conversely, when the fumarate hydratase is inactivated, the accumulation of fumarate prevents the degradation of HIF through hydroxylation. Moreover, the data obtained from the genomic analysis of sporadic forms of this tumor subtype trough the TCGA has shown its complexity. As commented above, type II pRCC could be divided in three subtypes with different genomics and clinical behavior known as: IIa, IIb and CIMP profile. These tumors are characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2–ARE. The CIMP tumors, that have a particularly poor prognosis and early onset, are characterized by genome-wide hypermethylation, FH mutations or low expression, and a shift to a Warburg-like metabolism. Chromophobe renal cell carcinoma The familial syndrome called Birt-Hogg-Dube (BHD) is due to an inherited and inactivating mutation of the homonymous gene, localized on the short arm of the chromosome 17. This condition is associated with an increased risk for different types of renal tumors, like hybrid oncocytic neoplasm (50%), chromophobe RCC [chRCC] (33%), ccRCC (10%) or oncocytoma (7%) [13]. Fibrofolliculomas are benign hair follicle tumors which are found in this syndrome in 85% of the cases. Pulmonary cysts are likely to be associated with spontaneous pneumothorax, and are diagnosed in more than 85% of the patients with BHD syndrome. The underlying germline mutation of the gene BHD occurs in around 90% of family members of a BHD patient [14]. The genomic analysis of sporadic chRCC cases published recently has revealed particular features for this subtype. chRCC typically presents with aneuploidy and massive elimination of chromosomal material. It harbors frequently TP53 mutations that are largely inactivating and appear combined with deletions on chromosome 17 (where BHD gene is located]. Also the loss of PTEN in association with deletions on chromosome 10 are common findings in this tumor type along with a high frequency of gene fusions involving the TERT promoter and an APOBEC-type mutational spectrum in a subset of tumours [15]. The gene BHD encodes for a protein named folliculin. This protein binds AMPH, and interacts with FNIP1 and FNIP2. This complex downregulates the activity of the mechanistic target of rapamycin (mTOR). The deficiency of folliculin increases the activity of mTOR pathway, leading to an upregulation of HIF [16]. Based on the previous data both mTOR and HIF pathways are seen as potential therapeutic targets. Therapies in RCC Approved drugs Targeting VEGF/VEGFR Angiogenesis is a key-target for the treatment of metastatic RCC (mRCC). Therapeutic strategies include the inhibition of the receptor of the vascular endothelial growth factor (VEGFR) by tyrosine kinase inhibitors and the blockade of the ligand itself (VEGF) by monoclonal antibodies (Fig. 1). Some anticancer drugs combining both effects have been developed recently.

Papillary type II renal cell carcinoma The Hereditary Leiomyomatosis RCC (HLRCC) syndrome leads to the frequent development of papillary type II RCC. This familial syndrome is characterized by an aggressive type of kidney cancer, and by cutaneous and uterine leiomyomas [12]. The HLRCC condition is due to an inactivating mutation of the gene which encodes for the fumarate hydratase. This enzyme is part of the Krebs cycle

Bevacizumab. Bevacizumab is an endovenous recombinant human monoclonal antibody that binds and neutralizes all the isoforms of VEGF which are biologically active [17]. Bevacizumab was the first antiangiogenic treatment to show clinical efficacy in advanced RCC. In a phase II trial, 116 patients with relapsing mRCC were randomized into three arms: placebo, low-dose (3 mg/kg), or highdose of bevacizumab (10 mg/kg) every 2 weeks. The study findings

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Fig. 1. Angiogenesis pathway and targeted therapies in RCC.

demonstrated the superiority of Bevacizumab and the clinical relevance of antiangiogenics regarding the treatment of mRCC patients [18]. One American and one European phase III clinical trials, (CALGB 90206 and AVOREN trials, respectively), compared bevacizumab in combination with interferon alfa-2a (IFN) to IFN, in the first line of treatment [19,20]. Both assessed the same dosages of bevacizumab and of IFN alfa-2a (10 mg/kg every 2 weeks i.v. and 9 MU three times weekly subcutaneous, respectively). The patient populations differed slightly such as the use of placebo which was given in the European trial. For example, the CALGB 90206 clinical trial allowed inclusion of patients without cytoreductive nephrectomy. In both trials, the median progression-free survival (PFS) was significantly longer in the arm with bevacizumab than in the arm with the monotherapy. No differences in overall survival (OS) were shown between both arms despite a possible trend towards it. These results could be due to the crossover in the European trial and to the high rate of administration of subsequent therapy in both arms (>50%). In the American study, there was no crossover but the patients could received subsequent therapy after IFN. Both studies revealed a significantly higher objective response rate (RR) increase in the experimental arm (25.5 vs. 13.1%, p < 0.0001 and 194 31 vs. 13%, p < 0.0001 in the American and European trials, respectively. The main side effects related to the combination included anorexia, asthenia, fatigue, proteinuria and hypertension. Bevacizumab plus IFN was registered in November 2007 and in August 2009 by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), respectively, for untreated patients with a mRCC of good or intermediate risk (Memorial Sloan Kettering Cancer Center (MSKCC) classification (Table 1). More recently, bevacizumab was assessed in combination with mTOR inhibitors (everolimus and temsirolimus) with no clinical benefit and toxicity as a limiting factor [21–24].

In advanced RCC, the clinical efficacy of sorafenib was shown in the phase III TARGET study [25,26]. This international phase III trial randomized 905 cytokine-refractory mRCC patients with favorable or intermediate MSKCC risk into two double blind arms: 400 mg of sorafenib twice a day versus placebo. Despite few objective responses (OR) (10% vs. 2%, p < 0.001), the median PFS was longer in the experimental arm at the time of the interim analysis (5.5 vs. 2.8 months; Hazard Ratio (HR) 0.44; p < 0.01) allowing further crossover. In the intent-to-treat analysis, the primary endpoint being the OS did not differ from a statistical point of view. The most common grade 3 or 4 adverse events (AEs) sorafenib was associated with were as follows: hand-foot-syndrome (86%), fatigue (5%), dyspnea (4%) and hypertension (4%). Sorafenib was approved by the FDA and the EMA in December 2005 and July 2006, respectively, for cytokine-refractory advanced RCC patients (Table 1). In second line, sorafenib was also investigated after progression to a previous tyrosine kinase inhibitor (TKI). The phase III trial INTORSECT randomized 512 mRCC patients with progressive disease after sunitinib in two groups: temsirolimus or sorafenib [27]. The median PFS did not differ statistically (4.2 vs. 3.9 months, respectively) but the secondary endpoint, the OS, favoured sorafenib (12.3 vs. 16.6 months; HR 1.31; 95% Confidence Interval, 1.05– 1.63). Sorafenib has been evaluated in the adjuvant setting in the ASSURE trial, but was not associated with any clinical benefit both in terms of PFS and OS compared to placebo [28]. The CROSS-J-RCC trial compared sunitinib to sorafenib in untreated mRCC patients. No significant difference in terms of PFS was shown [29]. In the adjuvant setting, the SORCE trial compares sorafenib to placebo for 1 or 3 years after surgery [NCT00492258]. The RESORT trial is assessing the clinical value of sorafenib for 1 year after radical resection of the metastases [NCT01444807] [30].

Sorafenib. Sorafenib is an oral multitarget kinase inhibitor, which inhibits VEGFR 1-3, platelet-derived growth factor receptor (PDGFR), c-Kit, the serine-threonine Kinase Raf-1 and the stem cell factor receptor.

Sunitinib. Sunitinib is an oral multikinase inhibitor that neutralizes VEGFR 1-3, c-Kit, PDGFR and FMS-like tyrosine kinase-3 (Flt3). A pivotal randomized phase III trial compared sunitinib vs. IFN in 750 untreated patients with mRCC [31]. Patients received oral sunitinib, 50 mg once daily during 4 weeks in 6-week cycles or

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Table 1 Drugs approved for first- and second-line treatment of mRCC. Drugs

Target

ORR

PFS

OS

Approval first-line treatment mRCC

Dosage

Bevacizumab (mAB)

Circulating VEGF

10.2 m vs 5.4 m, HR 0.68** (IFN + BV vs IFN + placebo) [19] 8.5 m vs 5.2 m, HR 0.71** (IFN + BV vs IFN) [20]

No statistically significant difference [19,20]

BV + IFN (good or intermediate prognosis): FDA (Aug 2009), EMA (Nov 2007)

Sunitinib (TKI)

VEGFR 1-23, PDGFR, c-Kit, Fit3

31% vs 13% (IFN + BV vs IFN + placebo) [19] 25.5% vs 13% (IFN + BV vs IFN) [20] 39% vs 8% (SUNITINIB vs IFN) [31]

11 m vs 5 m, HR 0.54** (SUNITINIB vs IFN) [31]

No statistically significant difference [31]

Pazopanib (TKI)

VEGFR 1-23, PDGFR, c-Kit.

30% vs 3% (PAZOPANIB vs placebo) [33]

9.2 m vs 4.2 m, HR 0.46** (PAZOPANIB vs placebo) [33]

No statistically significant difference [33]

Temsirolimus (mTOR inhibitor)

mTOR

8.6% vs 4.8% vs 8.1% (TEMSIROLIMUS vs IFN vs IFN + TEMSIROLIMUS) [54]

5.5 m vs 3.1 m vs 4.7 m, (TEMSIROLIMUS vs IFN vs IFN + TEMSIROLIMUS [54]

10.9 m vs 7.3 m vs 8.4 m (TEMSIROLIMUS vs IFN vs IFN + TEMSIROLIMUS) [54] HR 0.73, *** (TEMSIROLIMUS vs IFN)

SUNITINIB (good or intermediate prognosis)): FDA (Jan 2006) and EMA (Feb 2007) PAZOPANIB (good or intermediate prognosis), also in cytokine-pretreated: FDA (Feb 2007), EMA (Feb 2007) TEMSIROLIMUS (poor prognosis, non-clear cell RCC included): FDA (May 2007), EMA (Nov 2007)

BV 10 mg/kg iv every 2 weeks + IFN 9 MU 3 times per week for 1 year SUNITINIB 50 mg oral daily, 4 week ON, 2 weeks OFF PAZOPANIB 800 mg oral daily

Drugs

Target

ORR

PFS

OS

APPROVAL second-line treatment mRCC

DOSAGE

Sorafenib (TKI)

VEGFR 1-23, PDGFR, c-Kit, kinase Raf1. mTOR

10% vs 2% (SORAFENIB vs placebo) [25]

5.5 m vs 2.8 m, HR 0.44, * (SORAFENIB vs placebo) [25]

No statistically significant difference [25]

SORAFENIB (citokinerefractory mRCC): FDA (Dec 2005), EMA (Jul 2006)

SORAFENIB 400 mg oral twice daily

ORR 1.8% vs 0%, SD 63% vs 32% (EVEROLIMUS vs placebo) [57,58] ORR 19.4% vs 9.4% (AXITINIB vs SORAFENIB) [42,43] ORR 25% VS 5% (NIVOLUMAB vs EVEROLIMUS) [63]

PFS 4.9 m vs 1.9 m, HR 0.33** (EVEROLIMUS vs placebo) [57,58]

OS no statistically significant difference [57,58]

EVEROLIMUS 10 mg oral daily

PFS 6.7 m vs 4.7 m, HR 0.67** (AXITINIB vs SORAFENIB) [42,43]

No statistically significant difference [42,43]

EVEROLIMUS (previously treated with VEGF targeted therapies): FDA (Mar 2009), EMA (Aug 2009) AXITINIB: FDA (Jan 2012), EMA (Sep 2007)

AXITINIB 10 mg oral twice daily

PFS 4.6 vs 4.4 mHR 0.88, 95%CI 0.75–1.03(NIVOLUMAB vs EVEROLIMUS)

OS 25 m vs 19 m, HR 0.73 p = 0.002 (NIVOLUMAB vs EVEROLIMUS) [63]

NIVOLUMAB (after progression to TKI therapy): FDA (Nov 2015)

NIVOLUMAB 3 mg/kg i.v. every 2 weeks

ORR 57% VS 11% (CABOZANTINIB vs EVEROLIMUS) [47] ORR (LENVATINIB with EVEROLIMUS, EVEROLIMUS, LENVATINIB alone) [51]

PFS 7.4 vs 3.9 m, HR 0
51, 95% CI 0
41-0
62 [47]

OS 21.4 vs 16.5 m, HR 0.66, 95%CI 0.53–0.83 [47]

CABOZANTINIB 60 mg oral daily

PFS 14.6 vs 5.5 vs 7.4 HR 0.4; 95% CI 0.24–0.68; 0.66; 95%CI 0.3–1.1 (LENVATINIB with EVEROLIMUS, EVEROLIMUS, LENVATINIB alone) [51]

OS no statistically significant difference [51]

CABOZANTINIB (after antiangiogenic therapy): FDA April 2016, EMA July 2016 LENVATINIB with EVEROLIMUS (after antiangiogenic therapy): FDA March 2016, EMA July 2016 under conditional approval

Everolimus (mTOR inhibitor) Axitinib (TKI)

VEGFR 1-23

Nivolumab (mAB)

Fully human IgG4 antibody against PD1. MET, VEGFR2, RET

Cabozantinib (TKI)

Lenvatinib (TKI)

VEGFR1-3, FGFR1-4, PDGFRb, RET, KIT

TEMSIROLIMUS 25 mg iv weekly

LENVATINIB: 18 mg oral daily with EVEROLIMUS 5 mg oral daily

mAb: monoclonal antibody; TKI: tyrosine-kinase inhibitor; ORR: Overall response rate; OS: Overall survival; PFS: progression-free survival; IFN: Interferon; HR: Hazard Ratio. * p < 0.001. ** p < 0.01. *** p = 0.008.

subcutaneous IFN three times weekly, with an increasing dosage from 3 MU to 9 MU. This trial showed a statistically significant benefit in both objective RR (ORR) (39% vs. 8%; p < 0.001) and median PFS (11 vs. 5 months; HR 0.54; p < 0.001) for patients treated with the experimental treatment. No difference in median OS was seen, maybe because of a crossover occurring in more than 50% of placebo-assigned patients. An exploratory analysis of patients who did not receive any post-study anticancer drug revealed that the median OS related to sunitinib was twice longer than with IFN (28.1 months vs. 14.1 months, respectively; HR 0.64; p = 0.003). The most common grade 3 AEs reported were hypothyroidism (14%), hypertension (12%), fatigue (11%), hand foot

syndrome (9%) and diarrhea (9%). Sunitinib was registered by the FDA in January 2006 for patients with mRCC refractory to cytokine therapy. The drug received full approval in February 2007 from both the FDA and the EMA due to the study findings in untreated patients with advanced RCC (Table 1). Sunitinib has become one of the standard therapeutic options for patients with untreated mRCC. In the adjuvant setting, the STRAC trial showed that sunitinib for 1 year after resection of a high-risk RCC was associated with a longer median disease-free survival (DFS) than placebo: 6.8 vs 5.6 months (HR 0.76; p = 0.03), respectively. Data related to OS were not mature at the date of the analysis and serious AEs did not seem to differ

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significantly in terms of incidence (21.9% vs 17.1%) [32]. Those results are contradictory with the ASSURE study findings which showed no benefit in terms of PFS and OS in this indication. Pazopanib. Pazopanib is an oral second-generation multikinase inhibitor targeting the effects of VEGFR1- 3, c-kit and PDGFR. A pivotal, double blind, placebo-controlled phase III trial included both cytokine-pretreated and treatment-naïve locally advanced and/or mRCC [33]. Among the 435 patients who were randomized 1:1 either to pazopanib 800 mg daily either to placebo, most of them had tumors of good or intermediate risk according to the MSKCC classification. Crossover after placebo was permitted. Pazopanib was significantly associated with a longer median PFS compared to placebo in the overall population, in the cytokine-pretreated patients and in the treatment-naïve subpopulation: 9.2 vs. 4.2 months, HR 0.46, p < 0.0001; 7.4 months vs. 4.2 months; HR 0.54; p < 0.001 and 11.1 months vs. 2.8 months, HR 0.40, p < 0.0001, respectively. In a further survival analysis, no difference in median OS between pazopanib and placebo groups was observed (22.9 vs. 20.5 months; HR 0.91; p = 0.22) [34]. Pazopanib was approved by the FDA in October 2009 in the first line of treatment for patients with advanced RCC (Table 1). The phase III COMPARZ trial compared randomly pazopanib to sunitinib as first-line therapy for advanced RCC [35]. This first face-to-face comparison of two approved VEGF-targeted therapy in this setting was a non-inferiority trial, the PFS being the primary endpoint. The predefined criterion for noninferiority was reached with a median PFS of 8.4 and 9.5 months (HR 1.05, 95% CI, 0.90– 1.22), respectively. This trial emphasized a different safety profile between both drugs: diarrhea and hepatotoxicity being more frequent with pazopanib, while fatigue and hand-foot syndrome were most seen with sunitinib. An interesting double-blind cross-over study performed by Escudier et al. [PISCES study] demonstrated that patients were more likely to prefer pazopanib over sunitinib, because of health-related quality of life (HRQoL) and safety issues [36]. Because of these improvements in both objective and subjective clinical endpoints, pazopanib is a standard of care for untreated patients diagnosed with mRCC. A single arm phase II trial showed that pazopanib was associated with an ORR of 27% (95%CI 17–40) and a median PFS of 7.5 months (95%CI 5.4–9.4) in the second-line setting, after a previous treatment by antiangiogenics (NCT00731211) [37]. The phase III PROTECT study (NCT01235962) assessed the efficacy and safety of pazopanib compared with placebo in patients who had a locally advanced RCC after nephrectomy. Over 1500 patients with pT2 (high grade), pT3 or greater cc RCC received pazopanib or placebo during 1 year. After the first 403 patients were treated the pazopanib dose was changed to 600 mg to improve tolerability and the endpoint of the study modified to DFS with that dosing. The results were presented at the 2017 ASCO meeting showing that the study did not meet the primary DFS endpoint. Elevated ALT and AST were the most frecuent AEs leading to treatment discontinuation in both the 600 and 800 mg groups with the PAZ 600 (ALT 16% and AST 5%) and PAZ 800 (ALT 18% and AST 7%) groups. Yet, a 31% decrease in the risk of recurrence was observed for those patients who received 800 mg [38]. Axitinib. Axitinib is a selective and second-generation multitarget TKI that inhibits the receptors VEGFR1-3. Some preclinical and clinical data suggested that axitinib might have an increased efficacy when compared with first-line VEGFR inhibitors [39]. Two phase II trials evaluated axitinib in patients with cytokinerefractory mRCC and after sorafenib. The ORR reached 44% and 22.6%, respectively [40,41]. The phase III AXIS trial compared axitinib 5 mg twice daily to sorafenib at standard dose in 723 mRCC

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patients as a second-line option [42]. Patients had progressed after an initial systemic therapy including sunitinib (54%), cytokines (35%) and bevacizumab-IFN or temsirolimus (11%). A dose escalation of axitinib was predefined to reach up to 10 mg twice daily according to the toxicity profile of each patient. PFS, which was the primary endpoint, was significantly longer in the axitinib group than in the sorafenib group (6.7 vs. 4.7 months, HR 0.67, p < 0.001). The type of prior treatment did not impact those study findings: the HR related to PFS for the subgroup of patients pretreated by sunitinib and for the group of patients pretreated by cytokine were: 0.74 (95%CI 0.57–0.96) and 0.46 (95%CI 0.32–0.68), respectively. The ORR differed significantly in both arms (19.4% vs. 9.4%, p < 0.001). Axitinib induced some side effects such as hypertension, diarrhea and fatigue. In January 2012, the FDA registered axitinib for the treatment of mRCC patients in the second-line setting (Table 1). The last survival analysis of the AXIS trial showed no difference in terms of OS between the two groups: 20.1 months versus 19.2 months for axitinib and sorafenib (p = 0.3744), respectively [43]. In a phase III study when compared with sorafenib in the firstline setting, axitinib was associated with improvements in both median PFS and ORR: 6.5 versus 10.1 months (HR 0.767; p = 0.0377), and 14.6% versus 32.3% (p = 0.0006), respectively. Nevertheless these results were inferior to those of sunitinib or pazopanib, therefore axitinib remain an option in second line [44]. Axitinib is being also evaluated in the adjuvant setting in the ATLAS trial (NCT01599754). This study is a prospective, randomized, double blind placebo controlled phase 3 trial of oral axitinib starting at 5 mg twice daily given 3 years vs. placebo. The primary endpoint is to demonstrate an improvement in DFS in patients at high risk of recurrent. The study has completed recruitment and results are awaited. Cabozantinib. Cabozantinib is an oral TKI of MET, VEGFR2, AXL and RET with promising antitumor activity evidenced in preclinical studies. Data from phase I and II studies revealed encouraging activity with PR of 28% and median PFS around 15 months [45]. The main AEs were hyponatremia, hypophosphatemia, fatigue, diarrhea and hypertension [46]. The clinical development of cabozantinib focused in patients who had already progressed to previous treatment. Thus, the METEOR phase III clinical trial randomized RCC patients refractory to antiangiogenics to two arms: cabozantinib at a dose of 60 mg daily and everolimus at a dose of 10 mg daily. Median PFS was longer and ORR was better in the experimental arm: 7.4 versus 3.8 months (HR 0.58; 95%CI 0.45– 0.75), and 21% versus 5%, respectively. An interim analysis showed that median OS was increased in the cabozantinib arm (HR 0.67; 95%CI 0.51–0.89). Side effects were manageable [47]. In April and July 2016, the FDA and the EMA approved cabozantinib at a dose of 60 mg daily for the treatment of patients with an advanced RCC refractory to antiangiogenics, respectively. More recently the CABOSUN phase II trial showed in a population of patients with intermediate or poor prognosis mRCC that cabozantinib was associated with a better median PFS than sunitinib in the first line setting: 8.2 versus 5.6 months (adjusted hazard ratio, 0.66; 95% CI, 0.46–0.95; one-sided P = 0.012). Also cabozantinib was superior in terms of ORR [46% (95%CI, 34–57) versus 18% (95%CI, 10–28]. Grade 3–4 AEs of all causality were 67% for cabozantinib and 68% for sunitinib and comprised fatigue, hypertension, diarrhea palmar-plantar erythrodysesthesia and hematological toxicity. These data open an option of this compound moving to the first line setting in the future [48] (Table 1). Lenvatinib. Lenvatinib is an oral multitargeted TKI of VEGFR1-3, FGFR1-4, PDGFRb, RET and KIT. In a phase I clinical trial, promising results were shown in 9 advanced RCC patients at a dose up to

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25 mg qd [49]. A further phase Ib clinical trial evidenced that the daily combination of lenvatinib at a dose of 18 mg with everolimus at a dose of 5 mg was a potential therapeutic option for mRCC patients refractory to antiangiogenics: the response rate was 30% and the median PFS reached 10.9 months (95%CI 5.15–14.6) [50]. Those results were confirmed in a multicenter phase 2 trial that randomized 153 patients with mRCC progressing after a first-line treatment of antiangiogenics. Patients treated with the combination experienced better PFS than patients treated by everolimus alone (HR 0.4; 95%CI 0.24–0.68) but not compared to the group of lenvatinib in monotherapy (HR 0.66; 95%CI 0.3–1.1). The median PFS in the three groups reached 14.6, 5.5 and 7.4 and months, respectively. Grade 3–4 AEs occurred in 71%, 50% and 79% of the patients, respectively with 2 deaths related to the experimental drug [51]. In March 2016, the FDA approved the combination of lenvatinib with everolimus for the treatment of patients with advanced RCC following one prior antiangiogenic therapy, as a ‘‘breakthrough therapy designation”. The EMA registered the combination in July 2016 under accelerated assessment program, and requested post-authorization studies. There is an international randomized phase III study currently recruiting patients that test the combination of Lenvatinib-Everolimus vs Lenvatinib/Pembrolizumab versus Sunitinib alone in first line advanced RCC (NCT02811861) (Table 1). Targeting the mTOR pathway TORC1 and TORC2 are two distinct multiprotein complexes which include a serine-threonine kinase called ‘‘mechanistic target of rapamycin” (mTOR). Both complexes regulate many aspects of protein expression associated with cell proliferation making both attractive as therapeutic targets in RCC (Fig. 2). Temsirolimus. Temsirolimus is an intravenous mTOR inhibitor that is converted into its active metabolite sirolimus. Sirolimus inhibits the TORC1 complex by binding FKBP12 protein. In early phase clinical trials, temsirolimus showed promising activity in patients with mRCC and its recommended dose was defined as 25 mg in a weekly basis [52,53]. A phase III, open-label, clinical trial randomized untreated mRCC patients with at least three of six protocolspecified poor prognosis factors [54]. The three arms of treatment

were IFN, temsirolimus or IFN plus temsirolimus. Overall survival was the primary endpoint. Patients allocated to the temsirolimus arm experienced the best clinical outcome, with a median OS reaching 10.9 months (p = 0.008 versus IFN) while the toxicity profile was acceptable. About 20% of the patients included in this trial had a non-clear cell RCC and they also benefited from temsirolimus. In 2007, this drug was approved by both the FDA and the EMA for the treatment of untreated mRCC with poor prognosis criteria, being an acceptable alternative in patients with non-clear cell RCC (Table 1). Everolimus. Everolimus is an mTOR inhibitor administered orally at 10 mg daily, as established by phase I clinical trials [55]. In an uncontrolled phase II study, everolimus showed promising antitumor activity in patients with advanced RCC previously treated with cytokines [56]. Based on those results, a randomized, double-blind phase III trial was designed (RECORD-1), to assess the clinical efficacy and toxicity of everolimus versus placebo for the treatment of mRCC patients following VEGFR inhibitors (sorafenib, sunitinib or both) [57]. The primary endpoint was PFS and secondary endpoints included OS and safety. In the second interim analysis which was confirmed later in an update of this trial, the everolimus arm was associated with better results than the placebo arm in terms of median PFS (4.9 versus 1.9 months; HR 0.33; p < 0.001) [58]. However, differences in median OS between both arms were not statistically significant (14.8 versus 14.4 months; HR 0.87; p = 0.162). The main AEs observed in the everolimus treatment arm were rash, fatigue and stomatitis. Everolimus caused pneumonitis in 8% of the patients treated, 8 of them reaching a grade 3 of severity. In 2009, everolimus was approved by both the FDA and the EMA for the treatment of mRCC after antiangiogenics (Table 1). Subsequently other studies such as RECORD-2 and RECORD-3 have tested everolimus in other settings. RECORD-2 tested everolimus in combination with bevacizumab versus IFN-bevacizumab in a randomized phase II first line study in mRCC. The study could not demonstrate additional benefit for the everolimus arm [59]. In RECORD-3 the value of the sequence everolimus-sunitinib was tested against the opposite (sunitinib-everolimus) in a randomized phase II study with a non-inferiority design in a population of mRCC untreated patients. The study failed to conclude that the lat-

Fig. 2. PI3K-AKT-mTOR pathway and targeted therapies in RCC.

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ter was superior reinforcing the sequence of TKI-mTOR inhibitor that was the already established standard of care [60]. Additionally, everolimus as a monotherapy agent is currently being assessed in a phase II trial for rare kidney cancers: Birt-HoggDube syndrome and chromophobe renal cancer [NCT02504892]. Lastly, alternating antiangiogenics with mTOR inhibitors is being tested in two phase II studies in first line treatment as follows: sunitinib with temsirolimus [NCT01517243], pazopanib with everolimus [NCT01408004]. A phase II study combines everolimus with imatinib in kidney cancer patients previously treated [NCT00331409]. Everolimus is also associated with panobistat, an HDAC inhibitor, in a phase I/II trial including refractory kidney cancer patients [NCT01582009]. The potential synergetic cancer inhibition of sirolimus and metformin will be assessed in a phase I study of solid tumors including kidney cancers [NCT02145559]. The combination of everolimus with other compounds such as lenvatinib has been previously reviewed. Immunotherapy Active immunotherapy: anti-PD1, anti-PDL1 and anti-CTLA4. Despite the notable development of targeted therapies in RCC in the last decade that has changed treatment paradigm in this setting, VEGF/VEGFR and mTOR inhibitors do not benefit all patients, do not always produce durable responses and resistance emerge to these agents both as primary refractory and after an initial benefit. In this context, stimulating the immune system through drugs targeting the so-called checkpoint pathways through the blockage of programmed cell death 1 (PD1) and its ligand, programmed cell death ligand 1 (PDL1) have been tested in RCC with success [61]. Nivolumab (BMS-936558). Nivolumab is a fully human IgG4 antibody against PD1. In a phase I clinical trial, one RCC patient previously treated experienced a partial response that lasted more than 18 months after only 3 infusions of nivolumab. Grade 3–4 toxicities occurred in 14% of the patients and included respiratory disorders as pneumonitis, which were fatal in 3 patients [62]. These findings prompted the clinical development of this compound in

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mRCC. The CheckMate 025 phase III trial randomized 821 patients with mRCC previously treated by one or two lines of antiangiogenic therapy to receive nivolumab 3 mg/kg i.v. every 2 weeks or everolimus 10 mg orally daily [63]. Patients in the experimental arm experienced better clinical outcomes with a median OS of 25 months versus 19 months (HR 0.73; p = 0.002) and a response rate of 25% versus 5%. Grade 3–4 toxicities occurred in 19% and 37% of patients, respectively. A later data analysis showed that patients were likely to have clinical benefits from nivolumab, even beyond radiological progression, raising the question of pseudoprogression under immunotherapy [64]. In November 2015 and February 2016, nivolumab was approved by the FDA and the EMA, respectively, for the treatment of RCC after progression to TKI therapy (Table 1). The clinical development of nivolumab in RCC is currently very intense; after a phase I clinical trial demonstrating the safety of the combination of nivolumab with the anti-CTLA4 ipilimumab [65], multiple studies are testing the value of this strategy in several ways. The TITAN RCC study [NCT02917772] evaluates the role of boosting the response administering ipilimumab in combination with nivolumab in patients who do not response after 8 cycles to nivolumab in monotherapy. The same combo has been tested in first line mRCC vs sunitinib in the CheckMate -214 and -800 studies [NCT02231749; NCT03029780]; and results are highly awaited [66]. Other combinations being tested are summarized in Table 2. Nivolumab is also being evaluated in the neoadjuvant setting of localized clear cell RCC [NCT02575222]. Avelumab. Avelumab is a human immunoglobulin G1 monoclonal antibody against PD-L1. Avelumab binds to PD-L1 preventing the interaction of this molecule with its receptor (PD-1) and therefore inhibiting its activation and restoring anticancer immune function. Moreover, avelumab can induce an antibody-dependent cellular cytotoxic response against PD-L1-expressing tumor cells. Single agent. A phase I study revealed activity of this compound in multiple solid tumours including RCC and prompted the further clinical development of this drug [67].

Fig. 3. MET pathway and targeted therapies in RCC.

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Table 2 Therapeutic combinations including nivolumab, being currently tested. Study number

Study name

Study phase

Clinical setting

Drugs combined

NCT01472081

Sunitinib, pazopanib or ipilimumab

x

NCT03015740

x

NCT02771626

x

mRCC patients currently treated by nivolumab and likely to benefit from nivolumab mRCC patients before surgery or biopsy, previous treatment is allowed except by anti-PD1, anti-CTLA4 and bevacizumab mRCC patients refractory to 1 or 2 lines of VEGF-targeted therapy mRCC patients

X4P-001, a chemokine receptor type 4 (CXCR-4) antagonist

NCT02210117

Phase I Phase Ib/IIa ‘‘pilot”

Previously untreated mRCC patients (except IFN or IL-2)

NCT02923531

CheckMate 016 x

Phase I/II phase I/II

Sequential. A randomized phase II study named SUAVE is going to compare avelumab followed by sunitinib at progression versus the opposite sequence. This study includes a detailed biomarker analysis to try to define potential predictive factors of response.

Combinations. Avelumab has been evaluated in combination with other compounds with demonstrated activity in metastatic RCC. Thus, the tolerability of axitinib in combination with avelumab was confirmed in a recently communicated phase Ib study with promising activity [68] leading to the launch of a phase III trial in first line comparing sunitinib versus the combination of axitinib +Avelumab which is currently recruiting (JAVELIN Renal 101; NCT02684006) [69]. Other combos involving avelumab are also being tested in phase I trials such as the combination of this compound with cabozantinib (NCT03200587).

Unsuccessful drug development of targeted therapies in RCC Tivozanib (AV-951) Tivozanib is an oral second-generation multitarget VEGFR-TKI. A phase II clinical trial enrolled 272 patients with mRCC and randomized them to receive tivozanib 1.5 mg daily for three weeks in 4-week cycles or placebo. In the experimental arm, the ORR and the median PFS reached 25.4% and 11.8 months, respectively [70]. These results led to the launch of the phase III TIVO-1 trial that compared tivozanib to sorafenib in 517 mRCC patients, a third of them being previously treated with cytokines. Crossover was permitted in the sorafenib arm. The median PFS reached 11.9 months versus 9.1 months, respectively (HR = 0.79; p = 0.042) in the overall population; and 12.7 versus 9.1 months, respectively (HR 0.76; p = 0.037) in the subgroup of previously untreated patients. The most common side effects related to tivozanib were hypertension and dysphonia [71]. However, patients in the experimental arm experienced no benefit in terms of OS – with a doubt on a potential impairment of this endpoint after a 2-year follow-up. The FDA declined approval of this drug in this indication. There is currently another phase III study comparing tivozanib vs sorafenib in patients with mRCC who have failed 2 or 3 prior systemic regimens, one of which includes a VEGFR TKI other than sorafenib or tivozanib (NCT02627963).

Tivantinib Tivantinib (ARQ 197) is an oral selective MET inhibitor. Its antitumor activity was demonstrated in preclinical studies and in one phase I clinical trial including patients with RCC [72]. A phase II trial in patients with mRCC compared tivantinib plus erlotinib versus tivantinib alone and was closed previously because of an absence of tumor response in both arms [73].

Bevacizumab or ipilimumab Sitravatinib (MGCD516), a receptor tyrosine kinase inhibitor targeting MET, AXL, MER, VEGFR, PDGFR, DDR2, TRK and Eph CB-839, a glutaminase inhibitor

Cediranib Cediranib is an oral VEGFR inhibitor that acts on receptors 1–3. Two phase II trials showed the activity of cediranib 45 mg daily in mRCC patients previously untreated with standard VEGFR inhibitors. In both of them, 34–38% of the patients achieved a partial response (PR). In the placebo-controlled trial, cediranib was associated with a better median PFS (12.1 versus 2.8 months, p = 0.017). In the single-arm trial, the median PFS and OS reached 8.9 and 28.6 months, respectively [74]. The main AEs related to the administration of cediranib in both studies were, as other VEGFR inhibitors, hypertension, hand-foot syndrome, diarrhea and fatigue. A phase II clinical trial compared the association of cediranib and saracatinib, a SRC inhibitor, with cediranib alone, but with no clinical success [75]. No phase III trial has ever been designed. Regorafenib Regorafenib is an oral multikinase inhibitor that targets VEGFR 1-3, PDGFR-beta, KIT, Tie-2 and FGFR. Phase clinical I trials determined the suitable dose of 160 mg daily for 3 weeks in 4-week cycles [76]. In the phase II trial evaluating regorafenib as firstline treatment in mRCC, around 40% of patients had a PR, but serious AEs occurred in up to 35% of the patients treated, such as diarrhea, skin reactions, hypertension, fatigue and renal failure [77]. This toxicity profile has been a limitation in the further development of this compound in this indication. Perifosine Perifosine is an AKT inhibitor tested in two phase II clinical trials which were conducted in patients with mRCC refractory to VEGF-targeted therapy and/or mTOR inhibitor. In both studies, the ORR was quite modest (range 4–10%) with a median PFS reaching around 14 weeks. Nausea, diarrhea and fatigue were the main AEs [78]. Dactolisib (NVPBEZ235) NVPBEZ235 is a dual phosphatidylinositol-4,5-bisphosphate 3kinase (PI3 K)-mTOR inhibitor administered orally. A phase Ib/II study of this molecule was previously stopped because of frequent dose-limiting toxicities (DLTs) and absence of any objective response [79]. Further clinical development of this drug was abandoned. BEZ235 was tested in combination with everolimus but the results have not been published yet [NCT01482156]. MK2206 MK2206 is an Akt inhibitor which has been unsuccessfully evaluated in the second line setting of patients with renal cell carcinoma refractory to antiangiogenics. The phase II study randomized 43 patients to MK2206 or to everolimus. The trial was closed for futility because the median PFS reached 3.68 and 5.98 months in the experimental and in the control arm,

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respectively. Moreover, the toxicity profile of MK2206 was less manageable with more rash and pruritis [80]. Combinations of antiangiogenics and mTOR inhibitors The BeST trial randomized 361 untreated metastatic clear cell renal carcinoma into 4 arms: bevacizumab alone, bevacizumab plus sorafenib, bevacizumab plus temsirolimus, sorafenib plus temsirolimus. Compared to the monotherapy arm, the other combinations were not associated with different median PFS [81]. Sonepcizumab Sonepcizumab is an inhibitor of sphingosine 1-phosphate with antiangiogenic activity. In a phase IIa study performed in refractory renal cell carcinoma patients, the median PFS did not reach two months. The toxicity profile was acceptable. The study findings are still to be published [NCT01762033] [80,81]. Upcoming therapies in RCC Last generation antiangiogenics Dovitinib (TKI-258). Dovitinib is an oral TKI of both VEGFR and FGFR-2 tested in a phase II trial in patients with mRCC. The median PFS and OS reached 6.1 and 10.2 months, respectively. In the randomized phase III trial GOLD comparing dovitinib to sorafenib in patients with refractory mRCC, dovitinib was not associated with any improvement both in terms of PFS or OS [82]. A phase Ib clinical trial evaluated the combination of dovitinib with everolimus with little success [83]. The DILIGENCE-1 study is assessing the clinical activity of dovitinib in the first-line setting [NCT01791387]. Trebananib (AMG-386). AMG-386 is a fusion protein that binds angiopoietin 1 and 2, blocking their union with the Tie2 receptor tyrosine kinase. This is an alternative mechanism of angiogenesis different to VEGF/VEGFR pathway. In pre-clinical and clinical phase I studies, treatment with AMG-386 inhibited tumor growth, with a good safety profile [84]. A phase II trial showed that AMG-386 plus sorafenib was associated with a RR of 38% in RCC patients previously treated [85]. In the first line of treatment and combined to sunitinib, trebananib was associated with a median PFS ranging from 13.9 to 16.3 months, according to the dosage of administration. Hypertension and digestive side effects were the most frequent AEs [86]. The results of the combination with sorafenib are still unpublished [NCT00467025]. Aflibercept (VEGF-Trap). Aflibercept is an intravenously administered fusion protein composed of Fc protein of IgG1 and two VEGFR domains. It aims at binding the circulating VEGF in order to prevent its union with the VEGFR [87]. Aflibercept also acts on other pro-angiogenic factors as placental growth factor (PlGF). The optimal dose established in the phase I clinical trial was 4 mg/kg intravenous weekly and antitumor activity was seen in many tumor types including RCC [88]. A phase II evaluated aflibercept at two different dosages in patients with mRCC pre-treated with TKI, and showed some activity at a dose of 4 mg/kg [89]. HIF-2 alpha-inhibitors. The transcription factor HIF-2 Alpha (HIF2A) is critical for the dimerization with HIF-1A and therefore the activation of abnormal angiogenesis in the context of an abnormal VHL function [almost a universal finding in ccRCC]. Until recently HIF-2A had been considered undruggable, yet, a recent report has demonstrated relevant in vitro and in vivo activity of a selective HIF-2 antagonist (PT2399). This compound was more active than sunitinib and showed activity in sunitinib-progressing tumours [90]. Moreover, a patient with extensive heavily pretreated ccRCC whose derived xenograft had shown sensitivity to PT2399 received treatment with a similar compound (PT2385) in a phase 1 trial

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(NCT02293980) showing disease control for >11 months. Studies are ongoing currently in early stages with similar compounds such as PT2977 (NCT02974738). Targeting the PI3K-AKT-mTOR pathway PAN-mTOR kinase inhibitors: sapanisertib. Drugs described in previous sections such as temsirolimus or everolimus are considered first-generation inhibitors of mTORC1 within the full mTOR complex. These compounds allosterically inhibit mTORC1 kinase activity by binding to FKBP12 but do not block the activity of mTORC2 or the AKT feedback. Yet, new compounds are being developed and tested in advanced RCC targetting the PI3K-AKT-mTOR pathway in a more potent manner. MLN0128 (sapanisertib or TAK-228) is a pan-mTOR kinase inhibitor that provides direct, ATP-competitive kinase inhibition of both mTORC1 and mTORC2 and has potent in vitro and in vivo antitumor. MLN0128 has shown anticancer activity in solid tumors in phase I studies and is currently being tested in phase II trials in several tumor types including RCC. PI3K inhibitors: serabelisib. Serabelisib (also known as MLN1117, INK1117, and TAK-117) is an inhibitor of the class I PI3K alpha isoform. MLN1117 is an oral drug that selectively inhibits PI3K alpha kinase, including mutations of PIK3CA, in the PI3K/Akt/mTOR pathway. This mechanism of action is intended to be more efficacious and less toxic than pan PI3K inhibitors. Combinations. The double inhibition of the PI3K-Akt-mTOR pathway is a therapeutic strategy, which is currently assessed in different studies. One phase II open-label study is evaluating the efficacy and safety of single-agent MLN0128 and the combination of MLN0128+MLN1117 compared with everolimus in patients with advanced or metastatic clear-cell RCC that has progressed on vascular endothelial growth factor-targeted therapy (NCT02724020). The I-NET phase I study evaluates the combination of temsirolimus with nelfinavir, an oral Akt inhibitor given twice daily [NCT01079286]. A phase Ib evaluates the association of alpelisib, another PI3K inhibitor, with everolimus. A dose-expansion cohort will include patients with renal cell cancer [NCT02077933]. The combination of a PI3K or Akt inhibitor with other anticancer agents is a promising therapeutic strategy. Buparlisib, named as BKM-120, is a highly selective pan-class I PI3K inhibitor which is being tested in a phase I study, in combination with bevacizumab in refractory metastatic renal cell carcinoma [NCT01283048]. MK2206, which failed to show better anticancer activity in a phase II study compared to everolimus, is currently being assessed in association with hydroxychloroquine in solid tumors, including kidney cancer [NCT01480154] Hydroxychloroquine is also tested with everolimus in a phase I/II clinical trial recruiting patients with metastatic clear cell renal carcinoma [NCT01510119]. Temsirolimus is combined to bryostatin 1, a protein kinase C modulator, in a phase I study of solid tumors, like renal cell cancer [NCT00112476]. The association of erlotinib and sirolimus is being tested in kidney cancer patients [NCT00353301]. MET inhibitors Up-regulation of MET has been described in patients treated with VEGFR inhibitors as a mechanism of resistance of this treatment. MET is, therefore, an emerging targeted therapy potentially effective. Moreover, MET seems to be critical in the tumorigenesis of papillary type I RCC. Foretinib. Foretinib is a MET receptor inhibitor that also acts blocking other receptors involved in angiogenesis, such as VEGFR-2, PDGFR-beta, Tie-2, RON, KIT and FLT-3. In xenograft models, foretinib prevented tumor growth [91]. In the phase I clinical trial of

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foretinib in human advanced solid tumors, papillary RCC were included. The dose-limiting toxicities were aspartate aminotransferase and lipase serum elevations, and the optimal dose was set at 240 mg daily on the first five days of a 14-day cycle [92]. A phase II clinical demonstrated antitumor activity in hereditary or sporadic papillary RCC with an ORR of 13.5% and a median PFS of 9.3 months [11]. AMG 102. AMG102 is an antibody IgG2 targeting the ligand of MET receptor, the hepatocyte growth factor (HGF). In preclinical studies, AMG-102 evidenced antitumor activity in xenograft models [93]. In the phase I clinical trial, were included patients with mRCC, showing remarkable activity and favorable safety profile [94]. A phase II trial included 61 patients with mRCC, and showed a disease control rate of 44% [95]. Savolitinib (AZD6094, HPML504). Savolitinib is an inhibitor of cMET, which is a promising target in papillary renal cell carcinoma. A phase II clinical trial conducted in 109 patients with papillary RCC assessed the clinical efficacy of 600 mg of savolitinib daily, according to the presence of MET molecular abnormality. All of the 8 patients experiencing a PR had a MET-driven abnormality, with a RR reaching 18%. Median PFS was 6.2 (95%CI 4.1–7.0) versus 1.4 (95% CI: 1.4–2.7) months in the MET-driven and the METnegative groups, respectively (p = 0.002). The toxicity profile was manageable and included: nausea (39%), fatigue (27%), edema (18%), abnormal liver function tests (17%), and one death from hepatic encephalopathy [96]. The CALYPSO study is evaluating the combination of savolitinib with durvalumab (MEDI4736), an anti-PD-L1 antibody, in previously treated and untreated patients with papillary RCC [NCT02819596] (see Fig. 3).

Immunotherapy Active immunotherapy. Pembrolizumab (MK-3475). Pembrolizumab is a humanized IgG4 anti-PD1 antibody that showed antitumoral activity in a phase I clinical trial including RCC patients [97]. The main AEs were diarrhea, rash and fatigue. Pembrolizumab alone is being assessed in the neoadjuvant setting for localized RCC and in untreated mRCC patients (Keynote-427 study) [NCT02212730 & NCT02853344]. Table 3 summarizes the therapeutic combinations including pembrolizumab and which are currently assessed. Atezolizumab (MPDL-3280A). Results from a phase I clinical trial with MPDL-3280A, an anti-PDL-1 antibody, yielded promising data in multiple tumor types, including RCC [98]. A further phase Ia trial enrolled 70 mRCC patients, including 63 patients with CCRCC showing remarkable activity. The median PFS and OS reached 5.6 (95%CI 3.9–8.2) and 28.9 (95%CI 20.0- not reached) months. The ORR was 15% (95%CI 7–26) and the toxicity profile was manageable [99]. The IMmotion150, a phase II trial, randomized previously untreated mRCC patients into three arms: Atezolizumab plus Bevacizumab, atezolizumab alone, and sunitinib. A crossover to the combination arm was permitted. Preliminary data have been communicated recently at the 2017 ASCO GU meeting. Compared to sunitinib, both immunotherapy arms did not differ statistically in terms of PFS. Patients treated with atezolizumab alone and with bevacizumab experienced a median PFS of 6.1 (HR 1.19; 95%CI 0.82–1.71) and 11.7 (HR 1.0; 95%CI 0.69–1.45) months, respectively. The trend in the PD-L1+ subgroup pointed to a greater benefit but again not statistically significant. As expected, atezolizumab was better tolerated than sunitinib both in monotherapy and in combination. The incidence of grade 3/4 toxicity reached 57% in the sunitinib arm, 40% and 17% in the

Table 3 Therapeutic combinations including pembrolizumab, being currently assessed. Study number

Study name

Study phase

Clinical setting

Drugs combined

NCT02853331

Keynote-426 x

NCT02811861

x

Phase III

NCT02089685

Keynote-29

Phase I/II

NCT02014636 NCT02348008

Keynote-018 study x

Phase I/II(after a promising phase I/II study) Phase Ib/II

NCT02964078

x

Phase II

NCT02619253

x

Phase I/IIb

NCT02298959 NCT02475213 NCT02432963

x x x

Phase I Phase I Phase I

Previously untreated mRCC patients Previously untreated mRCC patients Previously untreated mRCC patients 2nd line of treatment for mRCC patients Previously untreated mRCC patients Previously treated and untreated mRCC patients Previously untreated mRCC patients Previously untreated mRCC patients Previously treated mRCC patients Previously treated mRCC patients Previously treated mRCC patients

Axitinib vs sunitinib

NCT02133742

Phase III(after a promising phase Ib study) Phase Ib

NCT02646748

x

Phase I

Previously treated mRCC patients

Axitinib Lenvatinib (control arm: sunitinib; 2nd interventional arm: lenvatinib plus everolimus) IFN or ipilimumab Pazopanib Bevacizumab IL-2 Vorinostat, a histone deacetylase (HDAC) inhibitor Ziv-aflibercept Enoblituzumab (MGA271) Vaccine therapy(modified vaccinia virus Ankara vaccine expressing p53) Itacitinib (INCB039110)

Table 4 Therapeutic combinations including atezolizumab, being currently tested. Study number

Study name

Study phase

Clinical setting

Drugs combined

NCT03024437

x

Phase I/II

Entinostat, a benzamide HDAC inhibitor, or bevacizumab

NCT03063762 NCT02543645

x x

Phase I Phase I/II

Previously treated and untreated mRCC patients Previously untreated mRCC patients Previously treated mRCC patients

NCT02655822

x

Phase I

Previously treated mRCC patients

RO6874281, an anti-FAP/IL-2 fusion protein Varlimumab, a human antibody targeting CD27 involved in the activation of lymphocytes CPI-444, which targets the adenosine-A2A receptor on immune system cells

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atezolizumab group in monotherapy and combination, respectively. The IMmotion 151 phase III clinical trial is ongoing to compare this combination to sunitinib the metastatic setting [NCT02420821]. Atezolizumab is also being assessed in combination with other drugs (Table 4). A placebo-controlled phase III clinical trial is evaluating the clinical relevance of atezolizumab in the adjuvant setting of localized RCC [NCT03024996]. Ipilimumab. Ipilimumab is an antibody against CTLA-4 and was the first immunotherapy registered for the treatment of metastatic melanoma patients. A phase II trial studied ipilimumab in patients with mRCC, observing a 10% partial RR, although with a 33% incidence of grade 3–4 immune-mediated toxicity which can be life-threatening in some cases and requires early detection and aggressive management [100]. Ipilimumab is also being investigated in association with other drugs for the treatment of advanced RCC, as discussed previously, like nivolumab within the CheckMate 214 study or pembrolizumab within the Keynote-29 study [NCT02089685] [66]. A ‘‘personalized neoantigen cancer vaccine” called NeoVax is evaluated in a combination with ipilimumab for the treatment of advanced RCC patients [NCT02950766].

Passive immunotherapy. Girentuximab. Monoclonal antibodies are supposed to identify tumor cells by their specific tumor associated antigen expression and either kill them through a direct cytotoxic activity or deliver tumor-killing substances. In this setting, a chimeric monoclonal antibody that binds specifically to the protein carboxy anhydrase IX (CAIX) was designed, resulting in antibody-dependent cell cytotoxicity. This drug, girentuximab, was tested in combination with IFN alfa in 31 patients with mRCC as a part of a phase I/II clinical trial. The patients were enrolled to receive weekly i.v. infusions of 20 mg of girentuximab combined with 3 MIU subcutaneous 3 times a week of IFN alfa-2a. After 16 weeks, disease control was achieved in 65% (17/26) of the evaluable patients, with one complete remission lasting 17 months. The median OS was 30 months [101]. Further development consisted in attaching drugs to this antibody. Thus, phase I and II studies showed encouraging results for Lutentium-177 labeled girentuximab as a treatment option for progressing mRCC patients [102]. In the phase II clinical trial, stable disease was experienced by 57% of the patients with manageable toxicity, especially low blood cell counts [103]. A randomized, double-blind, placebocontrolled phase III clinical trial evaluated girentuximab as an adjuvant therapy in 864 patients with high risk of postoperative recurrence RCC [104]. No difference in terms of DFS and OS were seen between both groups of patients. There might a biological rationale to combine girentuximab with sunitinib in advanced RCC [105]. Modified vaccinia ankara (MVA-5T4; TroVax). TroVax is an attenuated virus modified vaccinia ankara (MVA) used to induce immune responses against 5T4, a target antigen expressed at very low levels in digestive tissues in adult, but highly expressed in >80% of carcinomas of kidney, breast, prostate, ovaries and gastrointestinal tract [106]. In a phase II clinical trial, assessing TroVax with IL-2 in RCC patients, 3 of 25 cases experienced objective tumor responses and 6 patients had a stable disease lasting 6 months [107]. A phase III, placebo-controlled, clinical trial determined whether TroVax could prolong the survival of patients receiving first-line treatment by sunitinib, IL-2 or IFN. No significant difference in OS was shown in the two arms of treatment, so the primary end point of the trial was not fulfilled [108]. No study involving TroVax is currently ongoing.

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Conclusions Parallel to remarkable advances in the knowledge of the molecular biology and cytogenetics of RCC in the last decade, multiple targeted agents have been developed and many others are currently entering clinical development. Angiogenesis-related elements and their regulatory mechanisms are probably the most extensively studied targets and still represent an area of intensive research in RCC therapeutics. Nonetheless, emergent strategies such as the combined MET-AXL-VEGFR-inhibition and different immunomodulatory approaches have been recently incorporated in the treatment armamentarium of RCC and will most likely change treatment paradigms. Despite these major advances there are still critical questions that remain unanswered such as best patient selection, the mechanisms of primary and secondary resistance and the best way of sequencing the available compounds. Research efforts should be directed to these needs in order to obtain the maximum patient benefit and also guarantee a sustainable system. Conflicts of interest Ignacio Duran has participated in compensated advisory boards for Ipsen, Novartis, Roche-Genentech, MSD, Brystol-Myers and GSK. Aránzazu González del Alba has participated as consulting or advisory role for Pfizer, GSK, Novartis, BMS and IPSEN. The rest of the authors declare that they have no conflicts of interest to declare. References [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67:7–30. [2] Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO classification of tumours of the urinary system and male genital organs-Part A: renal, penile, and testicular tumours. Eur Urol 2016;70(1):93–105. [3] Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T. Immunotherapy for advanced renal cell cancer. Cochrane Database systematic review 20159:(12); CD001425. [4] Pavlovich CP, Schmidt LS. Searching for the hereditary causes of renal-cell carcinoma. Nat Rev Cancer 2004 May;4(5):381–93. [5] Nickerson ML, Jaeger E, Shi Y, Durocher JA, Mahurkar S, Zaridze D, et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res 2008;14(15):4726–34. [6] Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999;399(6733):271–5. [7] Cancer Genomic Atlas Research N. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013;499(7456):43–9. [8] Brugarolas J. Molecular genetics of clear-cell renal cell carcinoma. J Clin Oncol 2014;32(18):1968–76. [9] Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, Davis C, et al. Comprehensive molecular characterization of papillary renal-cell carcinoma the cancer genome atlas research network. N Engl J Med 2016;374 (2):135–45. [10] Kovacs G, Fuzesi L, Emanual A, Kung HF. Cytogenetics of papillary renal cell tumors. Genes Chromosomes Cancer 1991;3(4):249–55. [11] Choueiri TK, Vaishampayan U, Rosenberg JE, Logan TF, Harzstark AL, Bukowski RM, et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol 2013;31(2):181–6. [12] Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci USA 2001;98(6):3387–92. [13] Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B, Linehan WM, et al. Renal tumors in the Birt-Hogg-Dube syndrome. Am J Surg Pathol 2002;26 (12):1542–52. [14] Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome. Am J Hum Genet 2005;76 (6):1023–33. [15] Davis CF, Ricketts CJ, Wang M, Yang L, Cherniack AD, Shen H, et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell 2014;26(3):319–30. [16] Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1,

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