Cancer Treatment Reviews 40 (2014) 980–989

Contents lists available at ScienceDirect

Cancer Treatment Reviews

journal homepage: www.elsevierheal th.com/ journals /c t rv

New Drugs

Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammaliantarget of rapamycin (mTOR) pathway: An emerging treatment strategyfor squamous cell lung carcinoma

http://dx.doi.org/10.1016/j.ctrv.2014.06.0060305-7372/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author. Tel.: +1 (479) 936 9900; fax: +1 (479) 936 9944.E-mail addresses: tbeck@hogonc.com (J.T. Beck), aismail@uams.edu (A. Ismail),

ctolomeo@uams.edu (C. Tolomeo).1 Tel.: +1 (479) 531 7274.2 Tel.: +1 (479) 619 6517.

Joseph Thaddeus Beck a,⇑, Amen Ismail b,1, Christina Tolomeo b,2

a Highlands Oncology Group, 3232 North Hills Boulevard, Fayetteville, AR 72703, USAb University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA

a r t i c l e i n f o

Article history:Received 16 December 2013Received in revised form 29 May 2014Accepted 8 June 2014

Keywords:Squamous cell lung carcinomaPI3K/AKT/mTOR pathwayPI3K inhibitormTOR inhibitorBiomarkers

a b s t r a c t

Squamous cell lung carcinoma accounts for approximately 30% of all non-small cell lung cancers(NSCLCs). Despite progress in the understanding of the biology of cancer, cytotoxic chemotherapyremains the standard of care for patients with squamous cell lung carcinoma, but the prognosis is gen-erally poor. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) path-way is one of the most commonly activated signaling pathways in cancer, leading to cell proliferation,survival, and differentiation. It has therefore become a major focus of clinical research. Various altera-tions in the PI3K/AKT/mTOR pathway have been identified in squamous cell lung carcinoma and a num-ber of agents targeting these alterations are in clinical development for use as single agents and incombination with other targeted and conventional treatments. These include pan-PI3K inhibitors, iso-form-specific PI3K inhibitors, AKT inhibitors, mTOR inhibitors, and dual PI3K/mTOR inhibitors. Theseagents have demonstrated antitumor activity in preclinical models of NSCLC and preliminary clinical evi-dence is also available for some agents. This review will discuss the role of the PI3K/AKT/mTOR pathwayin cancer and how the discovery of genetic alterations in this pathway in patients with squamous celllung carcinoma can inform the development of targeted therapies for this disease. An overview of ongo-ing clinical trials investigating PI3K/AKT/mTOR pathway inhibitors in squamous cell lung carcinoma willalso be included.

� 2014 Elsevier Ltd. All rights reserved.

Introduction

Around 1.6 million people worldwide are diagnosed with lungcancer each year, [1] and in the United States (US) alone, therewere 226,160 new cases in 2012 [2]. Lung cancer is the leadingcause of cancer-related death in men, and is second only to breastcancer in women [1]. Tobacco smoking is the leading cause of lungcancer, with 85–90% being caused by active cigarette smoking orpassive exposure to environmental smoke [3]. Despite currenttreatment options, the prognosis for patients with lung cancerremains poor, with average 5-year survival rates after diagnosis(all stages) around 16% [3]. Non-small cell lung cancer (NSCLC)accounts for approximately 85% of all lung cancers, [4] and

squamous cell carcinoma (�30%) and adenocarcinoma (�50%) arethe most frequent NSCLC histologic subtypes [5,6].

Cytotoxic chemotherapy (CT) remains the standard of care forpatients with squamous cell lung carcinoma [7] and, although itcan extend survival, it is rarely curative, with most patients even-tually developing chemo-resistance. Progress in the understandingof cancer biology has led to the personalization of therapy anddevelopment of drugs targeted at blocking the defective metabolicpathways of cancer cells. These drugs aim to act selectively,thereby reducing the wide spread adverse effects often associatedwith systemic CT. Currently, 4 targeted agents are approved by theUS Food and Drug Administration and the European MedicinesAgency for the treatment of advanced NSCLC (www.cancer.gov;www.ema.europa.eu), including bevacizumab (an anti-angiogenicagent), erlotinib, gefitinib and afatinib (tyrosine kinase inhibitorsagainst the epidermal growth factor receptor [EGFR]), and crizoti-nib (an anaplastic lymphoma kinase [ALK]/mesenchymal-epithelial transition [MET] inhibitor) (Table 1). Cetuximab, ananti-EGFR monoclonal antibody, is recommend for the treatment

Table 1Targeted agents approved by the Food and Drug Administration and/or European Medicines Authority for the treatment of advanced non-small cell lung cancer.a

Agent MoA Indication

Bevacizumab Anti-angiogenic

Approved for use in combination with carboplatin and paclitaxel in the US, or in combination with platinum-based CT in Europe, forpatients with non-squamous histology only

Erlotinib Anti-EGFR TKI Approved in the US and Europe as a second- and third-line treatment of advanced NSCLC, and as first-line maintenance therapyGefitinib Anti-EGFR TKI Approved by the FDA for patients with NSCLC who are currently benefiting, or have previously benefited, from gefitinib treatmentAfatinib Anti-EGFR TKI Approved in Europe for the treatment of patients with metastatic NSCLC whose tumors have EGFR mutations. Approved in the US for

the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 substitutionmutations as detected by an FDA-approved test

Crizotinib ALK/METinhibitor

FDA- and EMA-approved for the treatment of advanced/metastatic ALK-positive NSCLC

ALK, alanine lymphoma kinase; CT, chemotherapy; EGFR, epidermal growth factor receptor; MET, mesenchymal epithelial transition factor; TKI, tyrosine kinase inhibitor.a Information available at www.cancer.gov; www.ema.europa.eu.

J.T. Beck et al. / Cancer Treatment Reviews 40 (2014) 980–989 981

of NSCLC in combination with vinorelbine and cisplatin in theNational Comprehensive Cancer Network 2012 treatment guide-lines; however it is not currently approved for the treatment ofNSCLC in the US or Europe [3]. Typically, these targeted agentshave demonstrated poor activity in patients with squamous celllung carcinoma [8,9]. In particular, ALK and EGFR inhibitors maybe less effective in patients with squamous cell lung carcinomathan in patients with non-squamous cell lung carcinoma due tofewer alterations in the ALK and EGFR genes in squamous cell lungcarcinoma. In addition, there are safety concerns over the use ofbevacizumab in patients with squamous cell lung carcinoma, fol-lowing reports that it can lead to major hemoptysis in this patientpopulation [10]. Despite the emergence of effective therapies fornon-squamous cell lung carcinoma, there has been limited or noimpact of such treatments on squamous cell lung carcinomabeyond cytotoxic CT. Thus, there is an urgent unmet need for effec-tive treatments for patients with squamous cell lung carcinoma.

This review explains the role of the phosphatidylinositol3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) path-way in lung cancer and highlights recent genomic findings, whichhave identified mutations and alterations in gene expression in thispathway in patients with squamous cell lung carcinoma. It alsopresents evidence of preclinical activity, and preliminary clinicalactivity, of PI3K/AKT/mTOR pathway inhibitors in patients withadvanced solid tumors, including squamous cell lung carcinoma.

The PI3K/AKT/mTOR pathway in lung cancer

The PI3K/AKT/mTOR pathway plays a diverse role in normalphysiologic and oncogenic processes, including cell proliferation,survival, and differentiation [11]. As one of the most frequentlyactivated signaling pathways in cancer, the PI3K/AKT/mTOR path-way is an attractive target for therapeutic intervention [11]. ThePI3Ks are lipid kinases, which can be divided into 3 classes (I–III)according to their structure and substrate specificity. Of interesthere are the Class IA PI3Ks, which play a major role in a varietyof human cancers and therefore represent potential therapeutictargets. Class IA PI3Ks are heterodimers comprising regulatoryand catalytic subunits. Three genes, PIK3R1, PIK3R2, and PIK3R3encode p85a, p85b, and p85c regulatory subunits, respectively,whereas the catalytic isoforms p110a, p110b, and p110d areencoded by genes PIK3CA, PIK3CB, and PIK3CD, respectively. ClassIA PI3K isoforms are generally activated via receptor tyrosinekinases (RTKs; e.g. EGFR, ErbB3, MET, PDGFR, VEGFR, IGF-1R,HER2/neu) (Fig. 1). After activation, PI3K phosphorylates phospha-tidylinositol 4,5-bisphosphate (PIP2), generating phosphatidylino-sitol 3,4,5-trisphosphate (PIP3), which activates variousdownstream signaling pathways. PIP3 mediates the activation ofAKT by its translocation to the plasma membrane, leading to a con-formational change in, and phosphorylation of, AKT. In turn, AKTactivates many cellular proteins involved in protein synthesis, cell

growth, and survival, including mTOR complex 2 (mTORC2), whichcontributes to the complete activation of AKT via phosphorylationat serine 473. Phosphorylated mTORC1, a substrate of AKT, acti-vates p70 S6 kinase, which enhances mRNA translation and drivescell growth by activating the ribosomal protein S6 and elongationfactor 2. Phosphate and tensin homolog (PTEN) is an importanttumor suppressor that antagonizes PI3K function by dephosphoryl-ating PIP3 back to PIP2. Loss of PTEN results in unrestrained signal-ing by the PI3K pathway [11,12].

Genetic alterations in the PI3K/AKT/mTOR pathway in squamous celllung carcinoma

Numerous genetic alterations have been identified in lung car-cinomas and several studies have identified different genetic pro-files between lung tumors with squamous and non-squamoushistology (including in the pattern of PI3K pathway alterations)(Table 2).

Profiling of 178 lung squamous cell carcinomas from previouslyuntreated patients by The Cancer Genome Atlas (TCGA) ResearchGroup, revealed alterations in the PI3K/AKT pathway (PI3KCA,PTEN, or AKT3) in 47% of squamous tumors, with PIK3CA alteredin 16% and PTEN altered in 15% of the samples [13]. Furthermore,alterations in AKT3 were observed in 16%, AKT2 in 4%, and AKT1in < 1% of samples, [13] which supports previous studies suggest-ing AKT1 alterations are rarer in squamous cell lung carcinoma[14–16]. The TCGA study results also highlight that squamous celllung carcinoma shares many mutations with head and neck squa-mous cell carcinomas (SCCHN), including PIK3CA, PTEN, TP53,CDKN2A, NOTCH1, and HRAS, suggesting that the underlying biol-ogy of these cancers may be similar [13]. This supports the emerg-ing body of evidence that genetics may be useful to classifycancers, in addition to the primary organ affected.

Lockwood et al. 2012 demonstrated that different geneticpathways are involved in the pathogenesis of squamous versusnon-squamous cell lung carcinoma; key genetic and epigeneticalterations distinguishing squamous and non-squamous cell lungcarcinoma included NOTCH3 and FOXM1 (which were overexpres-sed in squamous cell lung carcinoma), and KEAP1 (which wasdeleted and under expressed in adenocarcinomas) [5]. Other stud-ies have suggested FOXM1 and NOTCH are involved in cross-talkwith the PI3K pathway, further implicating them in squamous celllung carcinoma [18,19]. Moreover, as previously mentioned,compared with non-squamous cell lung carcinoma, patients withsquamous cell lung carcinoma typically have lower frequenciesof EGFR, KRAS, and ALK alterations [5,14,20,21].

Driver mutations, which confer a growth advantage and arerelated to the development of the cancer, are an important consid-eration for the development of targeted drug treatments. Whilst itis recognized that squamous cell lung carcinomas have a highsomatic mutation rate; it is possible that many of the mutations

Fig. 1. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. 4EBP1, factor 4E-binding protein 1; IGF, insulin-like growth factor;IGFR1, insulin-like growth factor receptor 1; IRS1, insulin receptor substrate 1; mTORC, mammalian target of rapamycin complex; PDGF, platelet-derived growth factor; PI3K,phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PTEN, phosphatase and tensin homolog; S6K, S6kinase; TGF-a, transforming growth factor alpha; VEGF, vascular endothelial growth factor.

Table 2Phosphatidylinositol 3-kinase (PI3K) pathway alterations in non-small cell lungcancer.

Histotype PIK3CA PTEN

Mutation(%) [36]

Amplification(%) [36]

Mutation(%) [79]

Loss/reduced(by IHC) (%)[80]

Squamous cell 9 37 10 70Adenocarcinoma 0 5 2 77

IHC, immunohistochemistry; PTEN, phosphatase and tensin homolog.

982 J.T. Beck et al. / Cancer Treatment Reviews 40 (2014) 980–989

observed are passenger mutations. The development of successfuldrug therapies will therefore, likely depend on identifying and tar-geting key driver mutations [9].

Squamous cell lung carcinomas appear to be characterized byvarious driver mutations in candidate genes but also by gene copynumber alterations, resulting in tumor proliferation and survival.Yamamoto and colleagues (2008) found that PIK3CA copy numbergains were detected in 33% of squamous cell lung carcinomastested [17]. This study revealed that, unlike adenocarcinomas,most squamous cell carcinomas with PIK3CA gains, had no otheralterations in the genes studied (including KRAS, EGFR, HER2,and BRAF), which indicates that PIK3CA may play a key role inthe pathogenesis of this type of carcinoma. In addition, PIK3CAmutations and copy number gains were shown to occur indepen-dently of one another, indicating that either event may be suffi-cient to drive the cell toward tumorigenesis.

Whilst it is recognized that aberrations in PI3K pathway signal-ing are frequent in squamous cell lung carcinoma, their functionalimpact and therefore predictive value for sensitivity to PI3K inhibi-tion is still under investigation. Improved understanding of themolecular alterations implicated in squamous and non-squamouscell lung carcinoma, and elucidation of the functional effects ofthese alterations (i.e. driver versus passenger mutations) will sup-port the continued development of agents targeted at the specifichistotype.

Targeting the PI3K/AKT/mTOR pathway in squamous cell lungcarcinoma

Given the role of the PI3K pathway in oncogenic processes andthe activating alterations that have been detected in this pathwayin squamous cell lung carcinoma, therapeutic targeting of thispathway may benefit such patients. Agents that target the PI3K sig-naling pathway have the potential to shut down survival pathwaysand restore sensitivity to upstream signaling targeted agents [22].As lung cancer is a heterogeneous disease with multiple mutations,it is unlikely that any single signaling pathway drives the onco-genic behavior of all tumors. In fact, alterations further upstream(e.g. RTKs), or in other pathways that converge with the PI3K path-way (such as those involving NOTCH and FOXM1 as mentioned

above) have also been observed in patients with squamous celllung carcinoma [6,23–25]. Because blocking only one of thesepathways allows others to act as salvage or escape mechanismsfor cancer cells, [26] the success of PI3K pathway inhibitors is likelyto depend on their combination with other therapies [27].

PI3K pathway inhibitors in development for squamous cell lungcarcinoma

There are multiple agents in clinical development that targetthe PI3K/AKT/mTOR pathway, several of which are being testedin NSCLC as single agents and in combination with other treat-ments, such as platinum-based CT or taxanes. These include pan-PI3K inhibitors (buparlisib [BKM120], pictilisib [GDC-0941],SAR245408 [XL147], PX-866), isoform-specific PI3K inhibitors(BYL719), AKT inhibitors (MK-2206), mTOR inhibitors (everolimus,sirolimus/temsirolimus), and dual PI3K/mTOR inhibitors(SAR245409 [XL765], BEZ235) (Table 3). In some of these trials,patients have been stratified according to NSCLC histology (squa-mous or non-squamous) and PI3K pathway activation status.Although few studies have solely included patients with squamouscell lung carcinoma, results of preclinical and clinical studies ofinhibitors of this pathway in other malignancies with squamouscell histology suggest PI3K pathway inhibitors may be effectivein squamous cell lung carcinoma. See Table 4 for further informa-tion on these PI3K inhibitors, including maximum tolerated dose(MTD) and dose-limiting toxicities (DLTs).

Table 3Agents targeting the PI3K/AKT/mTOR pathway in phase II studies for non-small cell lung cancer.

Drug Target(s)/MoA Ongoing trials involving patients with NSCLC

Pan-PI3K inhibitorsBuparlisib (BKM120) Novartis Pharmaceuticals,

East Hanover, NJOral pan-PI3K inhibitor thattargets all 4 isoforms of Class IPI3K (a, b, c, d)

NCT01487265� Phase I/II trial of erlotinib and buparlisib in patients with advanced NSCLC

previously sensitive to erlotinibNCT01297491� A phase II, open-label, 2-stage study of orally administered buparlisib in

patients with metastatic NSCLC with activated PI3K pathwayPictilisib (GDC-0941) Genentech, San Francisco,

CANCT01493843� A phase II, double-blind, placebo-controlled, randomized study evaluating

the safety and efficacy of carboplatin/paclitaxel and carboplatin/paclitaxel/bevacizumab with and without GDC-0941 in patients with previouslyuntreated advanced or recurrent NSCLC

PX-866 Oncothyreon Inc., Seattle, WA An orally available nanomolarpan-isoform wortmannin analogPI3K inhibitor [81]

NCT01204099� Phase I/II study of PX-866 and docetaxel in patients with solid tumors

(phase II portion to determine the antitumor activity and safety of PX-866in combination with docetaxel versus docetaxel alone in patients withNSCLC or head and neck squamous cell carcinomas [SCCHN])

Isoform-specific PI3K inhibitorsBYL719 Novartis Pharmaceuticals, East Hanover,

NJAn a isoform-selective inhibitorthat inhibits wild-type, and themost common somatic mutants,of p110a [82]

NCT01708161� A phase Ib/II study of the combination of BYL719 plus AMG 479 (ganitumab)

in adult patients with selected solid tumors

AKT inhibitorsMK-2206 Merck, Whitehouse Station, NJ An allosteric pan-AKT inhibitor NCT01294306

� Phase II trial of the AKT inhibitor MK-2206 plus erlotinib (OSI-774) inpatients with advanced NSCLC who have progressed after previous response(including stable disease) with erlotinib therapy

mTOR inhibitorsEverolimus Novartis Pharmaceuticals, East

Hanover, NJA rapamycin derivativethat targets mTOR

NCT01427946� A phase I/II study of retaspimycin HCl (IPI-504) in combination with everol-

imus in patients with KRAS-mutant NSCLCSirolimus Pfizer, Philadelphia, PA An allosteric inhibitor of the

mTORC1 complexNCT01737502� A phase II trial of combined protein kinase C iota (PKCiota) and mTOR inhi-

bition as maintenance therapy for patients with stage IV squamous histologyNSCLC without progression following at least 4 cycles of first-line platinumcontaining CT

Temsirolimus Pfizer, Philadelphia, PA A rapamycin analog targetingmTOR

NCT01827267� A phase II study of neratinib and neratinib plus temsirolimus in patients

with NSCLC carrying known HER2-activating mutations

CT, chemotherapy; MoA, mechanism of action.

J.T. Beck et al. / Cancer Treatment Reviews 40 (2014) 980–989 983

Pan-Class l PI3K inhibitors

The first relevant PI3K inhibitors to be described were wort-mannin and its derivative LY294002, with both agents being

Table 4Selected outcomes from the phase I clinical trials of selected PI3K inhibitors.

Agent Administration MTD

Buparlisib [83] Oral, once daily 100 mg

Pictilisib(GDC-0941) [83]

Oral, once or twice daily 245 mg once daily; 180 mgtwice daily

SAR245408(XL147) [83]

Oral, once daily for 21-day cycleor CDD

600 mg (both schedules)

PX-866 [83] Oral, once daily: intermittentor CDD

12 mg (intermittent) 8 mg(CDD)

BYL719 [49] Oral, once daily 400 mg

MK-2206 [52,55] Oral, every other day 60 mg

Everolimus [22,62] Oral, once daily or onceweekly

Recommended: 10 mg/dayor 50 mg/week

Temsirolimus [69] Once-daily IV infusion 15 mg/m2/day (extensivelypretreated) 24 mg/m2/day(minimally pretreated)

AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; CDD, contindose-limiting toxicity; FN, febrile neutropenia; IV, intravenous; MTD, maximum tolerate

shown to increase sensitivity to CT and radiotherapy in variouscancer cell lines. However, due to their associated toxicitythese agents are now predominantly used in preclinical research[11,28].

DLTs in phase I trials Most common AEs in phase I trials

Mood alteration, epigastralgia, rash,hyperglycemia

Rash, hyperglycemia, diarrhea,anorexia, nausea

Headache, pleural effusion, decreasedDLCO

Nausea, fatigue, diarrhea, dysguesia

Rash (21-day cycle) Hypersensitivity(CDD)

Nausea, fatigue, diarrhea, rash, cough

Diarrhea, increased AST(intermittent) Diarrhea (CDD)

Diarrhea, nausea, vomiting, increasedAST/ALT, fatigue

Hyperglycemia, nausea, vomiting,diarrhea

Hyperglycemia, nausea , diarrhea,decreased appetite, vomiting, fatigue

Rash, stomatitis, diarrhea Rash, fatigue, gastrointestinaltoxicities (nausea, vomiting,diarrhea), hyperglycemia

Stomatitis, neutropenia,hyperglycemia

Rash and erythema, stomatitis/oralmucositis, headache (daily dosing)Stomatitis/oral mucositis, headache,fatigue (weekly dosing)

Hypocalcemia, hyperglycemia,stomatitis, increased ALT and AST,vomiting, diarrhea, asthenia

Asthenia, mucositis, nausea,cutaneous toxicity

uous daily dosing; DLCO, diffusing capacity of the lungs for carbon monoxide; DLT,d dose; Pts, patients; Tx, treatment. NB. Sirolimus: data not available.

984 J.T. Beck et al. / Cancer Treatment Reviews 40 (2014) 980–989

Buparlisib (BKM120)

Buparlisib is a pan-Class I PI3K inhibitor that selectively targetsall 4 isoforms of Class I PI3K in biochemical assays and has at least50-fold selectivity against several other protein kinases [29]. Inpreclinical cancer models, buparlisib has provided evidence ofantiproliferative, pro-apoptotic, and anti-angiogenic activity [29].In a panel of 353 cell lines, buparlisib exhibited preferential inhibi-tion of tumor cells bearing PIK3CA mutations, in contrast to othermutations such as KRAS or PTEN. It also demonstrated synergisticactivity with cytotoxic agents (such as docetaxel) and targetedagents including HER2 and MEK inhibitors, [29,30] and improvedsensitivity to cytotoxic drugs in resistant cancer models [31].

An interim analysis of a phase I, dose-escalation study of bupar-lisib (12.5–150 mg/day) in Western patients (N = 35) withadvanced solid tumors reported a partial response (PR) in 1 patient(with triple-negative breast cancer and a KRAS mutation). In addi-tion, 16 patients (of 31; 52%) had stable disease (SD) for more than6 weeks (5 with colorectal cancer, 5 with breast cancer) [32] Over-all, treatment was well tolerated and the most frequent (>30%) sus-pected treatment-related adverse events (AEs) included rash,hyperglycemia, diarrhea, anorexia, and mood alteration (37% each),and nausea (31%) [32]. A similar phase l dose-escalation study ofbuparlisib (25–100 mg/day) in Japanese patients (N = 15) withadvanced solid tumors revealed SD (defined by the Response Eval-uation Criteria in Solid Tumors [RECIST]) in 5 patients (8–24 weeks’duration). Five patients experienced serious AEs (all-cause): abnor-mal hepatic function (n = 3), pneumonitis, dyspnea, hyperglycemia,pneumonia, and delirium (n = 1 each) [33]. These data add to evi-dence suggesting that buparlisib may be effective in patients withsquamous cell carcinoma. Buparlisib is currently being investigatedin patients with NSCLC in a number of phase I and II clinical trials,including some in patients with squamous cell lung carcinoma.

Buparlisib is also under investigation in combination withmTOR inhibitors. In preclinical models, buparlisib in combinationwith rapamycin led to synergistic growth inhibition in NSCLC can-cer lines, and in combination with everolimus also led to inhibitionof the growth of lung cancer cells in vitro and in murine lung cancerxenograft models [34]. A phase I study of buparlisib in combinationwith everolimus for the treatment of patients with advanced solidtumors who no longer benefit from, or are unable to tolerate, stan-dard therapy is ongoing (NCT01470209). This aims to assess thesafety of combining these agents and to determine the appropriatedoses of the 2 drugs in combination. It will also assess biomarkersin the blood and tumor tissue, with the aim of investigatingwhether levels of specific biomarkers are predictive of treatmentresponse or development of AEs.

BASALT-1 (NCT01297491) is an ongoing, phase ll study inpatients with pre-treated metastatic NSCLC and activated PI3Kpathway, stratified according to squamous or non-squamous his-tology. In the first stage, patients receive buparlisib (100 mg/day). In the second stage, patients are randomized to receive eitherbuparlisib (100 mg/day) or docetaxel (75 mg/m2 every 3 weeks) ifthey have squamous histology, or buparlisib (100 mg/day), doce-taxel (75 mg/m2 every 3 weeks), or pemetrexed (500 mg/m2 every3 weeks) if they have non-squamous histology. This study aims toassess the efficacy of buparlisib, as measured by progression-free survival (PFS). A further phase ll study, BASALT-2(NCT01820325), has been initiated in patients with squamous celllung carcinoma to evaluate buparlisib (starting dose 80 mg/day)with or without paclitaxel (200 mg/m2) plus carboplatin (areaunder the curve [AUC] 6) every 3 weeks as first-line treatment.Other trials of buparlisib in NSCLC are underway; however manyof these trials are enrolling patients with non-squamous histology.Additional studies assessing buparlisib are also underway in otherindications.

Pictilisib (GDC-0941)

Pictilisib is a potent pan-Class I PI3K inhibitor that has demon-strated high oral bioavailability [35]. Squamous cell lung carci-noma cell lines harboring PI3K pathway alterations, includingPIK3CA mutations or amplifications, and loss of PTEN proteinexpression, have been shown to be highly sensitive to pictilisib[36]. In addition, the combination of pictilisib with paclitaxel, erl-otinib, or a mitogen-activated protein-extracellular signal-regu-lated kinase inhibitor was shown to have greater effects on cellviability than PI3K inhibition alone [36].

A phase Ib trial (N = 18) of pictilisib (60–250 mg) plus 3-weeklypaclitaxel (200 mg/m2)/carboplatin (AUC 6 mg/mL min) in combi-nation with bevacizumab (15 mg/kg) in patients with non-squa-mous cell lung carcinoma or without bevacizumab in patientswith squamous cell lung carcinoma, in advanced NSCLC was car-ried out [37]. Confirmed PRs were seen in 8/18 (44%) patients,including a patient with squamous cell lung carcinoma [37]. Com-mon (P20% of patients) AEs were alopecia, asthenia, nausea, sto-matitis, and neutropenia [37]. A phase I trial (NCT00975182;N = 57) of pictilisib in combination with erlotinib in patients withadvanced solid tumors and patients with metastatic NSCLC is alsoongoing, and other phase I and ll studies evaluating pictilisib aloneor in combination with other therapies, are currently underway.

SAR245408 (XL147)

SAR245408 is a potent and orally bioavailable pan-Class I PI3Kinhibitor [38]. In various preclinical models, SAR245408 has beenshown to inhibit PI3K signaling. In xenograft tumor models,SAR245408 demonstrated strong tumor growth inhibition as asingle agent, and in combination with various targeted (i.e. rapa-mycin) and chemotherapeutic agents (i.e. paclitaxel and carbo-platin), it demonstrated enhanced antitumor efficacy [38].

In a phase I trial (N = 68) of SAR245408 in patients with solidtumors, 1 patient with NSCLC receiving 225 mg/day achieved aconfirmed PR, with a 33% reduction in the target lesion [39].SAR245408 was generally well tolerated up to 600 mg/day. Aphase I/ll trial of SAR245408 (up to 600 mg/day) in combinationwith erlotinib (150 mg/day) was conducted in advanced solidtumors, with an expansion phase in patients with advanced ormetastatic NSCLC no longer responding to therapy [40]. Among23 patients (NSCLC, n = 8), 1 EGFR inhibitor-naïve NSCLC patienthad a confirmed PR, with a 59% reduction in the sum of longestdiameter of target lesions. Moreover, 1 patient with SCCHNshowed a reduction in 2-[fluorine-18]fluoro-2-deoxy-D-glucose(FDG) uptake by positron emission tomography (PET) (indicatingaltered tumor metabolism) and shrinkage of tumor bulk. The com-bination of SAR245408 and erlotinib was generally well toleratedat daily doses up to 400 mg/day SAR245408 and 150 mg/day erloti-nib with no major pharmacokinetic (PK) interaction. In tissue biop-sies, evidence of clinical activity and robust simultaneousinhibition of PI3K and EGFR signaling were demonstrated [40].

A further phase I trial in patients with advanced solid tumorsfound that SAR245408 at doses up to 200 mg/day in combinationwith paclitaxel (150–175 mg/m2)/carboplatin (AUC 5–AUC 6)every 3 weeks was generally well tolerated and there was no majorPK interaction between SAR245408, paclitaxel, and carboplatin[41]. One patient achieved a confirmed complete response, and 4patients achieved confirmed PRs (2 of which were patients withsquamous cell carcinoma).

PX-866

PX-866 is a pan-Class I PI3K inhibitor that has the ability to bindirreversibly to PI3K. In human tumor xenograft models, PX-866

J.T. Beck et al. / Cancer Treatment Reviews 40 (2014) 980–989 985

caused prolonged inhibition of PI3K signaling with acceptablepharmacokinetics [42]. PX-866 has also exhibited single-agentin vivo antitumor activity and increased the antitumor effects ofcisplatin and radiation treatment [42]. Furthermore, PX-866 hasdemonstrated in vivo antitumor efficacy in SCCHN models withPIK3CA mutations and NOTCH1 inactivating mutations [43].

Phase I and II clinical studies of PX-866 have included patientswith squamous cell lung carcinoma. In a phase I trial (N = 84) inadvanced solid tumors, [44] the best response was SD in 22% ofevaluable patients with intermittent dosing and 53% with continu-ous dosing. The most frequent study drug-related AEs were gastro-intestinal disorders (69.0%) [44]. A further phase I/II trial of PX-866(4–8 mg/day) in combination with docetaxel (75 mg/m2 every21 days) in advanced solid tumors (N = 43; NSCLC n = 5), led to adisease control rate of 85% (28/33) after 2 cycles of therapy and58% (19/33) after 4 cycles of therapy [45]. The best responses inevaluable patients were PR (6%), SD (79%), and progressive disease(15%). Combination treatment had no impact on the PK profile ofeither drug and the treatment was well tolerated. Biomarker anal-ysis (including PIK3CA mutations, KRAS mutations, and PTEN sta-tus) in this study did not identify specific patient populationswith significantly extend PFS. An ongoing phase I/II study(NCT01204099; N = 206) of PX-866 (8 mg/day) in combinationwith docetaxel (75 mg/m2 every 21 days) in patients withadvanced NSCLC (including those with squamous histology) orSCCHN will further evaluate this.

Isoform-specific PI3K inhibitors

Isoform-specific inhibition may allow drug administration attherapeutic doses without being limited by off-target toxicity.

BYl719

BYL719 is an oral inhibitor that selectively targets the a isoformof Class I PI3K [46]. In preclinical models, BYL719 has demon-strated activity in PIK3CA-mutated cell lines, with these cells dis-playing a higher sensitivity to BYL719 across a range of differenttumor types [47,48]. In vivo, BYL719 shows statistically significantdose-dependent antitumor efficacy in PIK3CA mutant xenograftmodels in rodents [46]. Furthermore, in vitro BYL719 sensitivityis positively associated with PIK3CA mutation, ERBB2 amplification,and PIK3CA amplification/copy number gain [47].

In an ongoing first-in-human study (NCT01219699) in patientswith PIK3CA-mutated solid tumors, BYL719 was well tolerated, andpreliminary signs of clinical activity were observed [49]. Initialresults from an interim analysis revealed PRs in 7 patients (2 inestrogen-receptor positive breast cancer patients and 1 each in cer-vical, trichemmal, endometrial, ovarian, and SCCHN patients).Ongoing studies include a phase I/II study (NCT01602315) ofBYL719 and cetuximab in patients with recurrent or metastaticSCCHN who are platinum-resistant, and a phase l/ll study(NCT01822613) of BYL719 in combination with LJM716 versus tax-anes or irinotecan in patients with previously treated esophagealsquamous cell carcinoma. A phase Ib open-label study(NCT01449058) is also underway to assess BYL719 in combinationwith MEK162 in patients with a range of advanced solid tumors(including NSCLC).

AKT inhibitors

AKT inhibitors have the ability to block the serine/threoninekinase AKT, which is a crucial component of the PI3K pathway. Inpreclinical studies, however, AKT inhibitors have been implicatedas a cause of hyperglycemia and concerns have been raised about

the potential limitations of these agents due to their associatedmetabolic toxicities [50,51].

MK-2206

MK-2206 is a highly potent, allosteric pan-AKT kinase inhibitor[52]. In vitro, MK-2206 synergistically inhibited cell proliferation ofhuman cancer cell lines in combination with molecular targetedagents, including erlotinib and lapatinib [53]. It also demonstratedsynergistic responses in combination with CT agents such as 5-flu-orouracil, docetaxel, and carboplatin in non-squamous lung NCI-H460 tumor cells, [53] and with paclitaxel in SCCHN cell lines [54].

In a phase l study of MK-2206 (45–90 mg every other day or90–200 mg every 3 weeks) in combination with carboplatin (AUC6)/paclitaxel (200 mg/m2) every 3 weeks in patients with advancedsolid tumors, there was a PR in 1 patient with SCCHN and 6patients demonstrated SD lasting for >6 months [55]. MK-2206 iscurrently being tested in combination with erlotinib as part of aphase ll study in patients with advanced NSCLC (squamous ornon-squamous histology) who have progressed after previousresponse to erlotinib (NCT01294306).

mTOR inhibitors

mTOR is a serine–threonine kinase that regulates cell growth,proliferation, and survival via mTORC1 and mTORC2. Despite theirsuccess in various types of cancer, such as renal cell carcinoma,mTOR inhibitors have been associated with pneumonitis, whichis an important consideration in patients with NSCLC as the lungis the organ affected by primary disease [56].

Everolimus (RAD001)

Everolimus is an orally available rapamycin derivative that hasshown significant antitumor activity as a single agent and in com-bination with other anticancer agents (including erlotinib), in bothin vitro and in vivo tumor models [57–61].

A phase I trial of everolimus (20–70 mg/week or 5–10 mg/day)in 55 patients with advanced solid tumors led to clinical benefit in4 patients, including 1 patient with colorectal cancer (treated with20 mg/week) achieving a PR [62]. A phase II non-randomized study(n = 85) compared the efficacy of everolimus (10 mg/day) inpatients with advanced NSCLC previously treated with CT alone(n = 42) or with CT and EGFR inhibitors (n = 43). Overall responserate was 4.7% and overall disease control rate was 47.1% [56]. Com-mon AEs (PGrade 3) were fatigue, dyspnea, stomatitis, anemia,thrombocytopenia, and pneumonitis [56]. A further phase II studyof everolimus (5 mg/day) in combination with gefitinib (250 mg/day) in 62 patients with advanced NSCLC has been carried out;however, the PR rate did not meet the predefined response to jus-tify further investigation [63].

Everolimus is currently under investigation in a phase I/II studyin combination with retaspimycin HCl (IPI-504) in patients withKRAS-mutant NSCLC (NCT01427946): a phase I study in combina-tion with CT in patients with stage IV lung cancer(NCT01700400); and a phase I study in combination with radio-therapy in patients with NSCLC (NCT01167530). It is not clearwhether these studies will stratify patients according to squamousor non-squamous histology.

Sirolimus

Sirolimus is an allosteric inhibitor of the mTORC1 complex thathas demonstrated antifungal, immunosuppressive, and antiprolif-erative activity [64]. Preclinical data suggest that sirolimus maypossess the ability to block the growth of human NSCLC cells

986 J.T. Beck et al. / Cancer Treatment Reviews 40 (2014) 980–989

[65–67]. A phase I study of continuous once-daily treatment ofafatinib plus sirolimus in patients with NSCLC harbouring an EGFRmutation and/or disease progression following prior erlotinib orgefitinib is underway (NCT00993499). A phase II study of auranofinand sirolimus as maintenance therapy in patients with stage IVsquamous cell lung carcinoma without progression following atleast 4 cycles of first-line platinum-containing CT is also ongoing(NCT01737502).

Temsirolimus (CCI-779)

Temsirolimus is a rapamycin analog. In preclinical studies,temsirolimus inhibited tumor cell proliferation in NSCLC cell linesin a dose-dependent manner [68]. A phase I dose-escalation studyof temsirolimus (0.75–24 mg/m2 daily) in patients with advancedcancer (N = 63) led to a confirmed PR, which was maintained for12.7 months in a patient with NSCLC [69]. Three patients (2 withrenal cancer and 1 with soft-tissue sarcoma) had unconfirmedPRs and 2 patients (1 with nasopharyngeal cancer and 1 with gas-tric cancer) had SD for 24 weeks. Asthenia, mucositis, nausea andcutaneous toxicity were the most frequent drug-related AEs [69].Temsirolimus is currently under investigation in a phase I trial(NCT01155258) in combination with vinorelbine ditartrate inpatients with unresectable or metastatic solid tumors (includingNSCLC). In addition, a phase II study of neratinib and neratinib plustemsirolimus in patients with NSCLC carrying known HER2-acti-vating mutations is ongoing (NCT01827267).

Dual PI3K/mTOR inhibitors

One effect of selectively inhibiting only part of a signaling path-way, such as mTOR, is the consequent activation of PI3K, which canultimately enhance tumor growth [70]. Therefore, more effectiveinhibition might be expected by targeting both PI3K and mTORconcurrently [71,72].

SAR245409 (XL765)

SAR245409 is a selective inhibitor of Class I PI3Ks, TORC1, andTORC2 [73]. In tumor xenograft models, SAR245409 has demon-strated efficacy including in models where the PI3K pathway isactivated [74]. In these models, co-administration of SAR245409also enhanced the apoptotic potential of paclitaxel and carboplatin[74].

Phase I and II clinical studies of SAR245409 have includedpatients with NSCLC, including squamous cell carcinoma. An ongo-ing phase I/ll trial (NCT00777699; N = 21) of SAR245409 (30–70 mg/day or 20 mg twice a day) in combination with erlotinib(100 mg/day) in patients with advanced solid tumors (NSCLCn = 14 [13 of whom had been previously treated with erlotinib][73] revealed reductions in pAKT (57%), p4EBP1 (60%), pERK(61%), and pEGFR (38%) in tumor biopsies from a patient with anadenocarcinoma, suggesting satisfactory dual PI3K and EGFR sig-naling inhibition. No major PK interaction between SAR245409and erlotinib was observed and the combination was generallywell tolerated.

BEZ235

BEZ235 is an orally available PI3K/mTOR inhibitor. In humantumor cell lines, BEZ235 has been shown to effectively block thedysfunctional activation of the PI3K pathway and induce cell cyclearrest [75]. When administered in vivo in models of human cancer,similar effects were observed. In these models, BEZ235 alsoenhanced the efficacy of the anticancer agent temozolomide whenused in combination [75].

A phase Ib study (NCT01337765) is ongoing to assess the com-bination of BEZ235 with the MEK inhibitor MEK162 in patientswith selected advanced solid tumors, including patients withNSCLC.

Clinical use of PI3K pathway inhibitors in squamous cell lungcarcinoma

For patients with squamous cell lung carcinoma, the standard ofcare is cytotoxic CT, consisting of a platinum-based doublet otherthan pemetrexed (which has not demonstrated efficacy in patientswith squamous cell lung carcinoma) [76]. Docetaxel is approved asa single agent in the second-line treatment of NSCLC. However,most patients eventually develop chemo-resistance, and therehas been little improvement in overall survival rates in patientswith squamous cell lung carcinoma. Targeted therapies are there-fore under investigation for these patients. Based on preclinical andclinical data published to date, it would seem that an effective sin-gle-agent approach is unlikely for patients with advanced squa-mous cell lung carcinoma, owing to feedback and cross-talk withother pathways and the development of treatment resistance. Aspreviously discussed, buparlisib has demonstrated synergisticactivity with cytotoxic and targeted agents, [29,30] and there isevidence of improved sensitivity to these drugs in resistant cancermodels [31]. In addition, pictilisib in combination with paclitaxel,erlotinib, or a mitogen-activated protein-extracellular signal-regu-lated kinase inhibitor had greater effects on cell viability than PI3Kinhibition alone [36]. Agents that target pathways other than thePI3K pathway are also under clinical investigation.

Predictive biomarkers in NSCLC

Identification and validation of genomic and proteomic bio-markers to help predict which patients are most likely to respondto targeted therapies is an essential unmet medical need in NSCLC.With this in mind, many trials in patients with NSCLC are nowadopting a biomarker-based approach to study design. The BAT-TLE-2 (NCT01248247) trial, for example, is a follow-up study tothe BATTLE trial, [77] which was the first completed prospective,biopsy-mandated, biomarker-based, adaptively randomized studyin non-squamous cell lung carcinoma patients. The study is under-way to test the pan-AKT inhibitor MK-2206 in combination withother targeted agents in patients with NSCLC. Another ongoingphase I/II study (NCT01204099; estimated enrolment N = 206) ofPX-866 in combination with docetaxel in patients with advancedNSCLC or SCCHN is also evaluating biomarkers of response [45].Preliminary phase I data for 20 patients revealed that PIK3CA-mutated patients showed a trend towards a longer time on study(n = 5; median = 183 days [range 64–342]) than patients without,or with other mutations, including: PIK3CA/KRAS wild-type(n = 13, median = 91 days [range 28–286]); KRAS mutation (n = 3;median = 141 days [range 125–361]); and PIK3CA/KRAS mutations(n = 2; median = 96 days [range 86–105]) [45].

The recent TCGA publication reported a significant proportionof PIK3CA and PTEN alterations in squamous lung carcinomas[13]. In theory, this suggests that patients with squamous cell lungcarcinoma may experience a greater benefit from a pan-PI3K inhib-itor than an a-selective PI3K inhibitor. As discussed, the BASALT-1study (NCT01297491) is evaluating single-agent buparlisib versusdocetaxel or pemetrexed in patients with squamous or non-squa-mous metastatic NSCLC with PI3K pathway alterations (PIK3CAmutation and/or PTEN alteration). Future research is necessary toinvestigate whether these patients respond better to buparlisibthan to an a-selective PI3K inhibitor, such as BYL719. As men-tioned earlier, Huang et al. 2012 found that BYL719 sensitivity ispositively associated with PIK3CA mutation, ERBB2 amplification,

J.T. Beck et al. / Cancer Treatment Reviews 40 (2014) 980–989 987

and PIK3CA amplification/copy number gain. PTEN and BRAF muta-tions on the other hand, are associated with BYL719 insensitivities[47].

Future clinical perspectives

The predictive nature of PI3K pathway alterations in relation toclinical response to PI3K pathway inhibitors has not been unequiv-ocally determined. One analysis in patients with advanced tumorsof various types showed that patients with PIK3CA mutations had ahigher rate of PRs, whereas coexisting PIK3CA and KRAS mutationswere associated with lack of response [78]. However, early evi-dence from the pan-PI3K inhibitor buparlisib has not shown a cor-relation between clinical response and PI3K/AKT/mTOR pathwayactivation status [32]. The difficulty in predicting response to ther-apy based on pathway alteration is complex, due to the heteroge-neous range of cancers treated in many trials, use of archivalspecimens for biomarker assessment, and a low number ofresponses to single-agent PI3K inhibitors. Trials that assess PI3Kinhibitors as combination therapy in more homogenous patientpopulations may be more likely to establish a relationship betweentypical PI3K alterations and clinical response.

Advances in non-invasive technologies, such as circulating DNAand/or tumor cell analysis, may eventually address these difficul-ties. Deeper analysis into pathway alterations and signaling, usinghigh throughput next-generation sequencing or phosphoproteo-mic analyses may further benefit patients with squamous cell lungcarcinoma.

Conclusions

At one time, overall survival rates for squamous and non-squa-mous cell lung carcinoma were similar; however, new treatmentoptions have improved outcomes for adenocarcinoma, but not forsquamous cell lung carcinoma [7]. The existence of PI3K/AKT/mTOR pathway alterations in squamous cell lung carcinoma hasled to the investigation of agents that inhibit this pathway in thisindication. Several PI3K/AKT/mTOR pathway inhibitors have dem-onstrated antitumor activity in preclinical models of NSCLC andthere is preliminary evidence of clinical activity with some inhibi-tors. Cross-talk and feedback inhibition along parallel pathwayssuggests that the success of these inhibitors will depend on theircombination with other therapies. Clinical trials investigatingPI3K/AKT/mTOR pathway inhibitors as single agents and in combi-nation with other targeted and conventional treatments are ongo-ing in squamous cell lung carcinoma. Carefully designed studiesbased on large-scale genomic analyses are needed to improve theoutcomes of patients with squamous cell lung carcinoma. In themeantime, it is essential that more patients with squamous cellcarcinoma are enrolled in prospective trials targeted at the molec-ular deficits frequently observed in those tumors.

Acknowledgments

Financial support for medical editorial assistance was providedby Novartis Pharmaceuticals. We thank Nicole Meinel PhD andAlex Coulthard BSc (Hons) for their medical editorial assistancewith this manuscript.

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