Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: New strategies for overcoming resistance to VEGFR and mTORC1 inhibitors

Authors


Correspondence to: Robert A. Figlin, Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, 8700 Beverly Boulevard, Saperstein Critical Care Tower, 1S28 Los Angeles, CA 90048, USA, Tel.: 310-423-1331, Fax: 310-659-3928, E-mail: robert.figlin@cshs.org

Abstract

With the advent of molecularly targeted agents, treatment of metastatic renal cell carcinoma (mRCC) has improved significantly. Agents targeting the vascular endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin complex 1 (mTORC1) are more effective and less toxic than previous standards of care involving cytotoxic and cytokine therapies. Unfortunately, many patients relapse following treatment with VEGFR and mTORC1 inhibitors as a result of acquired resistance mechanisms, which are thought to lead to the reestablishment of tumor vasculature. Specifically, the loss of negative feedback loops caused by inhibition of mTORC1 leads to upregulation of downstream effectors of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway and subsequent activation of hypoxia-inducible factor, an activator of angiogenesis. De novo resistance involving activated PI3K signaling has also been observed. These observations have led to the development of novel agents targeting PI3K, mTORC1/2 and PI3K/mTORC1/2, which have demonstrated antitumor activity in preclinical models of RCC. Several agents—BKM120, BEZ235 and GDC-0980—are being investigated in clinical trials in patients with metastatic/advanced RCC, and similar agents are being tested in patients with solid tumors. The future success of mRCC treatment will likely involve a combination of agents targeting the multiple pathways involved in angiogenesis, including VEGFR, PI3K and mTORC1/2.

Abbreviations
4EBP1

4E-binding protein 1

Ang 1/2

angiopoietin 1 and 2

DLT

dose-limiting toxicity

FDA

United States Food and Drug Administration

GFR

growth factor receptor

HIF

hypoxia-inducible factor

HIFα

hypoxia-inducible factor alpha

IFN-α

interferon-alpha

IL-2

interleukin 2

IRS1

insulin receptor substrate 1

mRCC

metastatic renal cell carcinoma

mTORC1/2

mammalian target of rapamycin complex 1/2

ORR

objective response rate

OS

overall survival

PDGF

platelet-derived growth factor

PDGFR

platelet-derived growth factor receptor

PFS

progression-free survival

PI3K

phosphoinositide 3-kinase

RCC

renal cell carcinoma

SK6

S6 kinase

TKIs

tyrosine kinase inhibitors

VEGF

vascular endothelial growth factor

VEGFR

vascular endothelial growth factor receptor

VHL

von Hippel-Lindau

Renal cell carcinoma (RCC) accounts for more than 2% of all human cancers, and its incidence is steadily rising by approximately 2% per year.[1, 2] In the United States, it is estimated that 65,000 new cases of RCC will be diagnosed and approximately 14,000 related deaths will occur in 2012.3 RCC is usually asymptomatic in its early stages. Therefore, approximately 20% and 25% of patients will present with locally advanced disease and metastatic renal cell carcinoma (mRCC), respectively, at diagnosis.[4] An additional 20–50% of patients will develop metastatic disease after surgery.[4] Treatment of mRCC is difficult because it shows no or limited responsiveness to conventional anticancer therapies, such as radiation and chemotherapy, and cytokine therapy. Over the past few years, a better understanding of the molecular events underlying the pathogenesis of mRCC has resulted in the development of new therapies that target key signaling pathways involved in the disease. These agents specifically inhibit vascular endothelial growth factor (VEGF), its receptor (VEGFR), or the mammalian target of rapamycin complex 1 (mTORC1) and have been shown to be more effective and less toxic than the previous standards of care for mRCC. However, a common limitation of mTORC1- and VEGFR-targeted therapies is the development of drug resistance, which often results in disease relapse. This article reviews the current knowledge of the mechanisms of resistance to VEGFR and mTORC1 inhibitors in mRCC and summarizes recent data on novel agents, particularly inhibitors of phosphoinositide 3-kinase (PI3K), mTOR complex 1 and 2 (mTORC1/2) and mTORC1/2/PI3K, which may have the potential to overcome resistance to mTORC1- and VEGFR-targeted therapies.

Current Regimens for the Treatment of mRCC

First-line treatment for RCC is often surgery; however, roughly 20–50% of patients will relapse, usually within 1–3 years.[1, 4, 5] Surgery may also be indicated in patients with advanced RCC, but most of these patients will experience disease recurrence at the primary or metastatic site.[1] mRCC is generally resistant to most chemotherapies and radiation and shows only limited sensitivity to immune-modulating cytokine therapy. An improvement in survival over chemotherapy has been observed with interleukin 2 (IL-2) and interferon-alpha (IFN-α);[6] however, the clinical benefit of IL-2 and IFN-α is modest in most patients with mRCC (mean response rates, 10–15%[7]) and is achieved at the expense of significant toxicity. Over the last few years, a number of novel targeted therapies have been approved for the treatment of mRCC and have been included in the guidelines of the National Comprehensive Cancer Network and the European Association of Urology as recommended therapies for mRCC.[8-10]

Molecular Mechanisms of VEGFR-Targeted mRCC Therapies

Targeted therapies for mRCC, which are characterized by increased angiogenesis, control tumor growth by inhibiting proangiogenic factors, particularly VEGF. This therapeutic approach exploits the fact that the vast majority of RCC cases, particularly clear cell RCC, are associated with inactivation of the von Hippel-Lindau (VHL) gene—a tumor suppressor that controls the stability of hypoxia-inducible factor (HIF). HIF is a transcription factor whose downstream targets include VEGF and platelet-derived growth factor (PDGF) and is activated in response to tissue hypoxia. In wild-type cells, VHL prevents uncontrolled angiogenesis in the presence of sufficient oxygen by promoting the degradation of HIF, resulting in downregulation of VEGF and PDGF expression. If VHL is mutated, HIF is constitutively stabilized, which leads to deregulation of HIF-dependent transcription and consequently to upregulation of VEGF and PDGF. Thus, aberrant angiogenesis in RCC can be targeted with agents directed against VEGF or PDGF, such as inhibitors of VEGFR and the PDGF receptor (PDGFR), and VEGF neutralizing antibodies.[11-14]

VEGFR- and VEGF-Targeted Therapies

A number of tyrosine kinase inhibitors (TKIs) that target VEGFR or PDGFR have shown significantly greater antitumor activity than cytokine-based regimens or placebo in Phase III trials and have been approved for use in advanced RCC by the United States Food and Drug Administration (FDA) (Table 1). Sorafenib (Nexavar), the first VEGFR/PDGFR-targeted TKI to be approved in 2005, demonstrated improved progression-free survival (PFS) and overall survival (OS) versus placebo [PFS (5.5 vs. 2.8 mo), OS (17.8 vs. 14.3 mo)] in patients with advanced clear cell RCC resistant to standard therapy.[15-17] Sunitinib (Sutent), approved the following year, demonstrated improved PFS, OS and objective response rate (ORR) when compared with IFN-α [PFS (11 vs. 5 mo), OS (26.4 vs. 21.8 mo), ORR (47 vs. 12%)] in patients with treatment-naïve metastatic clear cell RCC.[18, 19] In 2009, pazopanib (Votrient) was approved following a Phase III study in which pazopanib treatment resulted in longer PFS, OS and improved response in comparison with placebo [PFS (9.2 vs. 4.2 mo), OS (22.9 vs. 20.5 mo), ORR (30 vs. 3%)] in patients with locally advanced or metastatic RCC who had received no prior therapy or at least one cytokine-based therapy.[20, 21] Most recently, axitinib (Inlyta) was approved in 2012 for patients with advanced RCC who had failed/progressed on one prior systemic therapy following a pivotal trial in which it demonstrated improved PFS compared with sorafenib (6.7 vs. 4.7 mo) in a similar patient population.[22, 23] Axitinib also showed activity as a first-line therapy in a Phase II trial in mRCC patients without prior systemic therapy, where it resulted in a 40.2% ORR and a median PFS of 13.7 months.[24] The VEGFR inhibitor tivozanib has not yet been approved, but has demonstrated promising results in a Phase III trial in comparison with sorafenib. In patients with RCC who were treatment-naïve or who had received no more than one prior systemic therapy (excluding VEGFR- or mTOR-targeted therapies), tivozanib showed significant improvement in PFS and ORR compared with sorafenib [PFS (11.9 vs. 9.1 mo), ORR (33 vs. 23%)], suggesting that tivozanib may become another option for first-line therapy for mRCC.[25] In addition, the anti-VEGF monoclonal antibody bevacizumab (Avastin), in combination with IFN-α, was approved for use in patients with mRCC after demonstrating improved PFS and response in comparison with IFN-α plus placebo [PFS (10.2 vs. 5.4 mo), ORR (30 vs. 12%)].[26, 27]

Table 1. Targeted agents approved for the treatment of RCC
Drug (class)TargetPivotal trialPatient populationComparatorEfficacyYear of approvalReference
  1. a

    Post-crossover placebo survival data.

  2. b

    Treatment-naïve patients.

  3. c

    Patients with prior cytokine therapy.

  4. Abbreviations: IFN-α: interferon-alpha; mAb: monoclonal antibody; mo: months; mRCC: metastatic renal cell carcinoma; mTORC1: mammalian target of rapamycin complex 1; ORR: objective response rate; OS: overall survival; PDGFR: platelet-derived growth factor receptor; PFS: progression-free survival; RCC: renal cell carcinoma; TKI: tyrosine kinase inhibitor; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor.

Sorafenib (TKI)VEGFR, PDGFRPhase III, TARGETAdvanced clear cell RCC, resistant to standard therapyPlaceboPFS (5.5, vs. 2.8 mo)OS (17.8 vs. 14.3 mo)a200515–17
Sunitinib (TKI)VEGFR, PDGFRPhase IIITreatment-naïve clear cell mRCCIFN-αPFS (11 vs. 5 mo)OS (26.4 vs. 21.8 mo)ORR (47 vs. 12%)200618, 19
Pazopanib (TKI)VEGFR, PDGFR,c-KITPhase IIITreatment-naïve and cytokine-pretreated advanced RCCPlaceboPFS (9.2 vs. 4.2 mo)PFS (11.1 vs. 2.8 mo)bPFS (7.4 vs. 4.2 mo)cOS (22.9 vs. 20.5 mo)ORR (30 vs. 3%)200920, 21
Axitinib (TKI)VEGFR, PDGFR, c-KITPhase III, AXISPhase IImRCC progression following one prior systemic therapyTreatment-naïve clear cell mRCCSorafenibPFS (6.7 vs. 4.7 mo)ORR (40.2%) PFS (13.7 mo)201222, 2324
Bevacizumab (anti-VEGF mAb)VEGFPhase III, AVORENTreatment-naïve mRCCIFN-αPFS (10.2 vs. 5.4 mo)OS (23.3 vs. 21.3 mo)ORR (30 vs. 12%)200926, 27
Temsirolimus (small molecule inhibitor)mTORC1Phase IIITreatment-naïve mRCCIFN-αPFS (5.5 vs. 3.1 mo)OS (10.9 vs. 7.3 mo)200730, 31
     ORR (8.6 vs. 4.8%)  
Everolimus (small molecule inhibitor)mTORC1Phase IIIAdvanced mRCC following failure of prior treatment with sunitinib or sorafenibPlaceboPFS (4.9 vs. 1.9 mo)200932, 33

Molecular Mechanisms of mTORC1-Targeted mRCC Therapies

Another mechanism to prevent HIF/VEGF-mediated angiogenesis is to inhibit mTORC1, one of the two mTOR complexes that couples environmental growth signals to the cellular growth machinery. In response to nutrients, oxygen, growth factors or insulin, mTORC1 activates the translation of key proteins involved in cell proliferation and stress response, including HIF and cyclin D, through phosphorylation of ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1).[28, 29] Loss of VHL function in RCC also leads to deregulation of cyclin D1; thus, mRCC therapies targeted at mTORC1 likely act by downregulating HIF levels and VEGF-mediated angiogenesis as well as by inhibiting cyclin D–dependent tumor cell proliferation.[28]

mTORC1-Targeted Therapies

Temsirolimus (Torisel), a derivative of rapamycin, was the first mTORC1 inhibitor to receive FDA approval in 2007 for the treatment of advanced RCC after demonstrating improved PFS, OS and response in comparison with IFN-α [PFS (5.5 vs. 3.1 mo), OS (10.9 vs. 7.3 mo) and ORR (8.6 vs. 4.8%)] in a Phase III trial.[30, 31] Everolimus (Afinitor), another rapamycin-related mTORC1 inhibitor, was approved in 2009 for the treatment of patients with advanced RCC after failure of treatment with sunitinib or sorafenib based on data from a Phase III trial in which everolimus demonstrated improved PFS over placebo (4.9 vs. 1.9 mo) in patients with mRCC who had progressed following treatment with sunitinib, sorafenib or both.[32, 33]

Limitations of VEGFR- and mTORC1-Targeted Therapies

In comparison with cytokine-based therapies, currently approved VEGFR- and mTORC1-targeted therapies offer significantly improved response rates, PFS and OS in first- and second-line settings; however, they rarely, if ever, induce complete responses, and none have been able to induce sustained disease remission.[14] In some cases, de novo resistance occurs because of the presence of redundant angiogenic pathways, rendering targeted therapies ineffective.[34] However, many patients initially respond to VEGFR and mTORC1 inhibitors but eventually relapse, often because of acquired resistance that develops during treatment.[14, 28, 34]

Resistance to VEGFR- and mTORC1-targeted therapies is characterized by reestablishment of tumor vasculature[35] and is thought to be facilitated through activation of alternative or compensatory pathways of VEGFR and mTORC1 signaling, which leads to upregulation of HIF (Fig. 1).[36] Possible mechanisms of acquired resistance to mTORC1 inhibitors may involve loss of negative feedback loops that are normally induced when mTORC1/S6K is active.[14, 29] One of these feedback loops prevents activation of mTOR complex 2 (mTORC2) and its target AKT; if mTORC1/S6K is inhibited, the negative feedback is lost, leading to mTORC2-dependent activation of AKT and upregulation of HIF.[14, 29, 37-39] Resistance to mTORC1-targeted therapy may also involve loss of a negative feedback loop that normally prevents upstream overstimulation of insulin receptor substrate 1 (IRS1)/PI3K/AKT signaling when mTORC1 is active; inhibition of mTORC1/S6K leads to upregulation of IRS1 protein and therefore the coupling of insulin-like growth factor to the PI3K/AKT/mTOR pathway and, ultimately, activation of HIF.[29, 40-43] In addition to mTOR-dependent acquired resistance, de novo mTOR-independent resistance requiring activated PI3K signaling has been observed.[28, 44] Acquired resistance caused by reestablishment of the tumor vasculature may also be mediated by induction of VEGF-independent angiogenic pathways such as the HIF targets angiopoietin 1 and 2 (Ang1, Ang2), which bind to the kinase Tie2 and activate angiogenesis.[11, 14, 45]

Figure 1.

Mechanisms of resistance to VEGFR and mTORC1 inhibitors. VEGFR and mTORC1 inhibitors prevent signaling pathways that activate angiogenesis directly or through inhibition of downstream target genes, respectively (a). Several mechanisms of resistance to these inhibitors have been suggested (b). Inhibition of S6K leads to the loss of two negative feedback loops targeting IRS1 and mTORC2, which leads to increased PI3K signaling. In addition, increased mTORC2 leads to increased activation and expression of HIFα, which in turn leads to increased activation of target genes (VEGF, PDGF and Ang1/2) involved in angiogenesis. Ang1/2: angiopoietin 1 and 2; GFR: growth factor receptor; HIFα: hypoxia-inducible factor alpha; IGF: insulin-like growth factor; IRS1: insulin receptor substrate 1; mTORC1/2: mammalian target of rapamycin complex 1/2; PDGF: platelet-derived growth factor; PDGFR: platelet-derived growth factor receptor; PI3K: phosphoinositide 3-kinase; SK6: S6 kinase; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor.

Another limitation of VEGFR- and mTORC1-targeted therapies is their safety profiles, which are likely a cause of both on- and off-target effects.[14] Although common adverse events (AEs) with these targeted agents are different and less severe than those observed with cytokines (which include significant fatigue, anorexia and neuropsychiatric, hepatic and hematologic symptoms[7]), they can lead to reduced tolerability, dose modifications or treatment discontinuations.[46] The VEGF TKIs sorafenib, sunitinib and pazopanib have been reported to cause mild to moderate dermatologic and gastrointestinal AEs.[17, 19, 21, 46] The combination of bevacizumab with IFN-α causes common AEs such as gastrointestinal disorders, fatigue and headache and, less frequently, severe AEs, including gastrointestinal perforation, hemorrhage and cardiovascular events.[27, 46] mTORC1 inhibitors are commonly associated with metabolism and nutrition disorders and treatment-related infections.[33, 46] Thus, the AEs associated with current targeted therapies, together with the high risk of developing resistance, represent an unmet need for patients with mRCC.

Novel Therapies Targeting PI3K and mTORC2: Preclinical Data in RCC

Because of their suspected role in both de novo and acquired resistance to VEGFR- and mTORC1-targeted therapies, PI3K and mTORC2 have become the focus for the development of new therapies in mRCC. Consistent with their proposed roles in the development of resistance and pathogenesis of mRCC, a microarray analysis of human RCC tissue specimens showed that high PI3K and mTOR expression levels correlated with late-stage and high-grade tumors and were independent prognostic factors for poor survival.[47] A number of novel PI3K and mTORC2 inhibitors have been developed and have demonstrated promising results in RCC cell lines and xenograft models (Table 2).

Table 2. Small molecule inhibitors targeting the PI3K and mTOR pathways in development
AgentTargetPhase of developmentPreclinical/clinical activity in RCCReference
  1. Abbreviations: mTORC1/2: mammalian target of rapamycin complex 1 and 2; PI3K: phosphoinositide 3-kinase; PR: partial response; RCC: renal cell carcinoma; SD: stable disease.

BKM120PI3KPhase I (RCC, solid tumors) 56,57
XL147PI3KPhase I (solid tumors) 82,83
INK128mTORC1/2Phase I (solid tumors)Activity in RCC xenografts; enhanced by combination with sorafenib or AvastinAntitumor activity observed in patients with RCC48,86
OSI-027mTORC1/2Phase I (solid tumors) 88
AZD8055mTORC1/2Phase I (solid tumors)Activity in clear cell RCC cell lines50,92
AZD2014mTORC1/2Phase I (solid tumors) 93
WYE-132mTORC1/2PreclinicalActivity in RCC xenografts; enhanced by combination with bevacizumab49
BEZ235PI3K/mTORC1/2Phase I/II (RCC)Activity in RCC xenografts; enhanced by combination with sorafenib51,52,73
SF1126PI3K/mTORC1/2Phase I (solid tumors)Activity in RCC xenografts; enhanced by combination with sirolimus53,54,95
   Patient with RCC achieved SD >1 year in Phase I study 
GDC-0980PI3K/mTORC1/2Phase II (RCC) 75,76
XL765PI3K/mTORC1/2Phase I (solid tumors)Patient with RCC achieved SD >3 months98
GSK2126458PI3K/mTORC1/2Phase I (solid tumors)Patient with RCC achieved PR101

INK128, a novel mTORC1/2 inhibitor, has been investigated in RCC cell lines, where it inhibited downstream substrates of mTORC1, phosphorylation of AKT and tumor cell proliferation and induced G1 cell-cycle arrest.[48] In mouse tumor models, INK128 displayed antitumor activity, which could be further enhanced in combination with sorafenib or bevacizumab. The combination resulted in sustained tumor regression through inhibition of tumor cell proliferation (INK128) and tumor angiogenesis (sorafenib/bevacizumab).[48]

WYE-132, another novel mTORC1/2 inhibitor, has also demonstrated promising results in RCC cell lines and mouse models. In a range of tumor cell lines, including the RCC lines A498 and 786-O, WYE-132 inhibited cell proliferation and cell-cycle progression and induced cell apoptosis. In mice with A498 or 786-O tumors, WYE-132 completely inhibited tumor growth (whereas temsirolimus only partially inhibited tumor growth at the same concentration) and induced tumor regression at higher doses. Combination of WYE-132 with bevacizumab enhanced the tumor regression caused by WYE-132 alone.[49]

A third mTORC1/2 inhibitor, AZD8055, showed strong antitumor activity against the clear cell RCC cell lines UOK139 and UOK140.50 In addition to inhibition of mTORC2 signaling and AKT phosphorylation, AZD8055 downregulated 4EBP1. In contrast, rapamycin was not able to downregulate 4EBP1.

BEZ235, an mTORC1/2 inhibitor that can also inhibit PI3K, has demonstrated activity in preclinical studies.[51, 52] In the RCC cell lines A498 and 786-O, BEZ235 showed a greater inhibition of tumor cell proliferation and suppression of cyclin D and HIF2α levels than sirolimus.[51] Similarly, BEZ235 inhibited tumor growth in A498 and 786-O RCC tumor xenografts more effectively than sirolimus, with its inhibitory effect due to its antiproliferative and proapoptotic effects on tumor cells rather than to a change in angiogenesis.[51] In another study in 786-O and Caki-1 RCC cells, the combination of BEZ235 and sorafenib reduced tumor cell growth and increased tumor cell apoptosis more effectively than either agent alone.[52]

The PI3K/mTORC1/2 inhibitor SF1126 was also tested in in vitro and in vivo models of RCC. In the 786-O RCC cell line, SF1126 significantly suppressed signaling pathways downstream of PI3K (AKT, ERK) and abolished hypoxia-induced stabilization of HIF2α.[53] In RCC xenograft models, SF1126 inhibited tumor growth by more than 90%.[53] Furthermore, combination of SF1126 with sirolimus in RCC xenograft models enhanced the antitumor activity of sirolimus monotherapy (54% tumor regression vs. 0% tumor growth).[54]

Novel Therapies Targeting PI3K and mTORC2: Progress in the Clinic

Agents being investigated in RCC

Three agents targeting PI3K and/or mTORC2—BKM120, BEZ235 and GDC-0980—are currently being tested in ongoing clinical trials of RCC; however, data have not yet been reported from these studies (Table 2). A Phase I trial testing the class I PI3K inhibitor BKM120, combined with bevacizumab, is currently recruiting patients with mRCC.[55] In a Phase I trial in patients with advanced solid tumors (n=77), BKM120 was well tolerated with a median treatment duration of 7.5 weeks and showed antitumor activity in 28 of 66 patients [two patients with partial response, 26 patients with stable disease (18 patients had stable disease for ≥16 weeks)].[56, 57] The most frequent AEs were decreased appetite (33%); rash, diarrhea and nausea (27% each); fatigue and hyperglycemia (24% each); anxiety (20%); depression (18%) and mucositis (17%); seven dose-limiting toxicities (DLTs) were observed. BKM120 is now being tested in a number of Phase I and II trials in patients with advanced solid tumors as a monotherapy[58-60] or in combination with chemotherapy[61-63] or other targeted agents.[64-66]

BEZ235, the mTORC1/2 inhibitor that can also inhibit PI3K, is being investigated in a Phase I/II trial in patients with advanced RCC.[67] BEZ235 is also being tested in combination with everolimus in a Phase I trial in patients with advanced solid tumors, particularly mRCC and metastatic breast cancer.[68] In addition, BEZ235 is being tested in several Phase I or I/II trials as a single agent[69, 70] or in combination with chemotherapy[63] or other targeted agents.[71, 72] In a Phase I trial in patients with advanced solid tumors (n=59), BEZ235 was well tolerated and demonstrated preliminary efficacy; two patients achieved a partial response, 16 patients achieved a metabolic response, and 14 patients achieved stable disease lasting ≥4 months after treatment initiation.[73] Frequently reported AEs included nausea, vomiting, diarrhea, fatigue/asthenia, anemia and anorexia, which were generally mild or moderate.

A Phase II trial with a third agent, the PI3K/mTORC1/2 inhibitor GDC-0980, in comparison with everolimus in patients with mRCC who have progressed during or following treatment with a VEGF-targeted therapy is planned.[74] In preclinical studies, GDC-0980 has shown activity against several tumor cell lines and xenograft models.[75, 76] In a Phase I study in 33 patients with solid tumors, GDC-0980 treatment showed tumor shrinkage in patients with mesothelioma (n=3), a patient with a gastrointestinal stromal tumor, and a patient with adrenal cell carcinoma who remained on study for >1 year.[77] Most common AEs observed in ≥10% of patients included fatigue, diarrhea, decreased appetite, nausea, rash, mucositis, hyperglycemia, vomiting and constipation.

Agents being investigated in patients with solid tumors

A number of PI3K and/or mTORC2 inhibitors have been or are currently being tested in Phase I trials in patients with solid tumors (Table 2). The class I PI3K inhibitor XL147 is being tested in several Phase I trials in patients with solid tumors as a single agent[78] or in combination with chemotherapy,[79] the MEK inhibitor MSC1936369B[80] or the EGFR inhibitor erlotinib.[81] As a single agent, XL147 was generally well tolerated in 68 patients, with one patient achieving a partial response and 13 patients continuing on treatment for ≥16 weeks—9 of whom continued for ≥24 weeks.[82] In combination with paclitaxel and carboplatin, XL147 was generally well tolerated in 19 patients, with the most frequently reported drug-related AEs including neutropenia and fatigue (65% each), thrombocytopenia (53%) and anemia (47%).[83] The combination demonstrated antitumor activity in heavily pretreated patients, with five patients achieving partial responses (four confirmed) and 12 patients continuing on treatment for ≥12 weeks (24 weeks in four patients).

The mTORC1/2 inhibitor INK128, which demonstrated efficacy in RCC cell lines and tumor models, is currently being tested in two Phase I studies in patients with advanced solid malignancies as a single agent[84] or in combination with chemotherapy and trastuzumab.[85] As a monotherapy, INK128 was well tolerated in the 52 patients who have been treated thus far, and preliminary antitumor activity was observed in patients with RCC and lung cancer.[86] The most common AEs considered possibly related to INK128 included nausea (51%), hyperglycemia (37%), mucosal inflammation (29%), rash (23%), asthenia (23%), vomiting (26%) and diarrhea (20%).

A second dual mTORC1/2 inhibitor, OSI-027, is being tested in a Phase I trial in patients with advanced solid tumors or lymphoma.[87] OSI-027 was well tolerated in the 34 patients at the doses tested to date, and eight patients (26% of the treated patients) have achieved stable disease lasting ≥12 weeks.[88] The maximum tolerated dose has not yet been reached, and dose escalation of OSI-027 is ongoing. AEs included nausea, vomiting, pneumonia, fatigue, diarrhea, anorexia, elevated creatinine and a reversible increase in QTc.

Other dual mTORC1/2 inhibitors, such as AZD8055, which demonstrated antitumor activity in RCC cell lines, and AZD2014 are being tested in Phase I studies in patients with advanced solid tumors.[89-91] Preliminary data from a Phase I study in 49 patients with advanced solid tumors suggest that AZD8055 was well tolerated.[92] Rash and mucositis, toxicities often associated with mTOR inhibitors, were not dose-limiting. Interim data from 50 patients treated with AZD2014 demonstrated preliminary antitumor activity, with one patient achieving a partial response.[93] The most common AEs included fatigue, stomatitis, decreased appetite, nausea and diarrhea.

The PI3K/mTORC1/2 inhibitor SF1126, which has demonstrated antitumor activity in preclinical studies, is being tested in a Phase I trial in patients with advanced or metastatic solid tumors.[94] SF1126 was well tolerated in 39 patients (toxicities were generally grade 1/2 with one DLT), and 19 of 33 (58%) patients experienced stable disease.[95] Prolonged stable disease >1 year was achieved in two patients, one of whom was a patient with RCC who had previously been treated with temsirolimus.

The PI3K/mTORC1/2 inhibitor XL765 is currently being investigated in two Phase I trials in patients with solid tumors, either as monotherapy[96] or in combination with erlotinib.[97] As a single agent, XL765 was generally well tolerated in 34 patients; five patients achieved stable disease lasting >3 months, including one patient with RCC.[98] The most common related AEs were elevated liver enzymes, nausea and diarrhea.

Another PI3K/mTORC1/2 inhibitor, GSK2126458, is being tested in Phase I trials as a single agent in relapsed or refractory advanced solid tumors[99] as well as in combination with a MEK inhibitor[100] in advanced solid tumors. In the single-agent study, two of 78 patients have achieved a partial response to date, including one patient with RCC.[101] The most commonly reported drug-related AEs were fatigue (15%), nausea (15%) and diarrhea (12%).

Management of Common Toxicities Associated With Inhibition of the PI3K/mTOR Pathway

Toxicities commonly associated with mTORC1 inhibitors, including metabolic and nutritional disorders, mucosal inflammation and treatment-related infections,[33, 46, 102, 103] may also be observed with novel PI3K, mTORC1/2 and PI3K/mTORC1/2 inhibitors in development. Several of these inhibitors have indeed reported incidences of hyperglycemia and mucositis/stomatitis, most of which are low grade.[56, 57, 77, 86, 93, 104] Other nutritional toxicities commonly reported for mTORC1 inhibitors, including hypertriglyceridemia and hypercholesterolemia, have not yet been reported for the PI3K and PI3K/mTORC1/2 inhibitors.[104] Reviews covering the management of PI3K- and mTOR-treatment related toxicities have recently been published.[46, 102, 104] In general, the key to combating these toxicities is frequent monitoring in order to detect and treat the toxicity before it becomes severe.

Conclusions

Over the past decade, treatment of mRCC has been revolutionized by the transition from cytokine-based therapies to agents that target the VEGF and mTOR1 pathways. However, although these targeted agents have improved the PFS and OS of patients, they cannot induce long-term remission, and many patients relapse because of resistance mechanisms.[14] Resistance mechanisms are thought to involve activation of the proangiogenic transcription factor HIF through compensatory mTORC2 and PI3K signaling, which provides a strong rationale for the development of targeted agents designed to inhibit mTORC2 and/or PI3K.[11, 14, 29, 35-44] Numerous inhibitors targeting mTOR and PI3K signaling have shown promising antitumor activity in RCC cell lines and xenograft models.[48-54] Many of these agents are being tested in Phase I trials in advanced solid tumors, and three agents—BKM120, BEZ235 and GDC-0980—are being tested in Phase I or II trials in patients with advanced or mRCC.[55, 67, 68, 74] The clinical benefit of PI3K, mTORC1/2 and PI3K/mTORC1/2 inhibitors may be optimized by combination regimens designed to target multiple nodes, either simultaneously or sequentially, of the various crosstalk and feedback loops affecting angiogenic signaling pathways. Thus, the future of mRCC treatment may involve combination therapies with agents targeting VEGFR, PI3K and mTORC1/2.

Acknowledgements

Dr. Figlin has acted as a consultant for Aveo, Bristol-Myers Squibb, Exelixis, Galena Biopharma and Pfizer, and has received research funding from Novartis, GlaxoSmithKline, Bristol-Myers Squibb and Immatics. Drs. Kaufmann and Brechbiel are employees of Articulate Science, which received funding from Novartis Pharmaceuticals Corporation to provide medical editorial assistance.

Ancillary