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Commentary

Daniel MorgenszternDivision of Medical Oncology, Washington UniversitySchool of Medicine, St. Louis, MOAlvin J. Siteman Cancer Center, St. Louis, MORamaswamy GovindanDivision of Medical Oncology, Washington UniversitySchool of Medicine, St. Louis, MOAlvin J. Siteman Cancer Center, St. Louis, MO

Clinical Lung Cancer January 2014

Clinical Lung Cancer, Vol. 15, No. 1, 16-20

Summary Report From the 13th Annual TargetedTherapies of the Treatment of Lung Cancer Meeting

IntroductionThe 13th Annual Targeted Therapies of the Treatment of Lung

Cancer Meeting, which was held February 20 to 23, 2013, in SantaMonica, CA, under the auspices of the International Associationfor the Study of Lung Cancer (IASLC), featured several presentationson novel therapies for thoracic malignancies. The summary reportedhere highlights selected presentations from the Santa Monica meeting.

Epidermal Growth Factor Receptor,Human Epidermal Growth FactorReceptor 2, and Human EpidermalGrowth Factor Receptor 3

Dr Fred Hirsch presented data on antieepidermal growth factorreceptor (EGFR) monoclonal antibodies for the treatment ofadvanced nonesmall-cell lung cancer (NSCLC). The ongoingSWOG 0819 phase III trial is comparing chemotherapy with car-boplatin plus paclitaxel (and bevacizumab in eligible patients) eitheralone or in combination with cetuximab in the frontline setting.The fully humanized EGFR antibody necitumumab has beenstudied in 2 phase III randomized clinical trials for patients withpreviously untreated NSCLC. The INSPIRE study comparingtreatment with cisplatin plus pemetrexed with and without neci-tumumab in patients with stage IV nonsquamous NSCLC wasterminated by the Independent Data Monitoring Committee afterenrollment of 634 patients, because of the increased risk forthromboembolism in the experimental arm. The SQUIRE study,comparing cisplatin plus gemcitabine with and without necitumu-mab in patients with squamous cell carcinoma completed accrual onFebruary 22, 2012, with 1097 patients enrolled. Dr Lecia Sequistpresented data on MM-121, a fully humanized antiehumanepidermal growth factor receptor (HER)3 antibody. Preclinical datafrom mouse xenografts with A549 cells showed synergy betweenMM-121 and erlotinib. The dose-finding phase I study enrolled 3different cohorts of patients with advanced NSCLC: wild-typeEGFR without previous treatment with EGFR tyrosine kinase in-hibitor (TKI) (group A), mutant EGFR without prior EGFR TKI

treatment (group B), and mutant EGFR resistant to EGFR TKI(group C). In a phase II study, erlotinib-naive patients will berandomized to erlotinib therapy alone or in combination withMM0121, whereas patients previously treated with erlotinib willreceive the combination regimen. Dr. Geoffrey Oxnard presentedupdates on studies involving U3-1287, a fully human anti-HER3monoclonal antibody. In a phase I study involving patients withsolid tumors, there were no responses among the 17 patients withNSCLC. In a phase Ib/II trial (HERALD), U3-1287 was combinedwith erlotinib to treat patients with advanced NSCLC who hadbeen previously treated with 1 or 2 lines of chemotherapy. In thephase Ib portion of this study, although no response was seen in 7patients, 4 patients achieved stable disease (SD) lasting more than60 days. A phase II study with 3 arms, including 2 different regi-mens of U3-1287 in combination with erlotinib or erlotinib alone,completed accrual on May 29, 2012.

Despite impressive response to the reversible EGFR TKIs erlo-tinib and gefitinib, virtually all patients eventually develop acquiredresistance. Several new EGFR TKIs have been developed, includingsecond-generation inhibitors such as afatinib and dacomitiniband third-generation inhibitors such as CO-1685 and WZ4002.Afatinib has been recently approved for use in the United Statesas a frontline therapy for patients with EGFR-mutant NSCLCbased on the results from the LUX-3 trial.1 Dr Thomas Lynchdiscussed the rationale for a randomized phase II/III trial comparingafatinib plus cetuximab therapy with single-agent afatinib therapy intreatment-naive patients with sensitizing EGFR mutation. Dr RossCamidge presented data for dacomitinib, a pan-HER inhibitor withanti-T790M activity in vitro. The phase IIa study A7471017enrolled patients with advanced NSCLC who were nonsmokers orformer light-smokers and had tumors with EGFR mutation, HER2mutation, or HER2 amplification. All 45 patients with exon 19 or21 mutations had tumor reduction, with 37 (82%) achieving partialresponse (PR). Median progression-free survival (PFS) for patientswith EGFR exon 19 or 21 mutation were 16.4 and 18.3 months,respectively. Among the initial 18 patients with HER2 mutation,

1525-7304/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.cllc.2013.11.010

3 patients (16.6%) achieved PR, 13 (72.2%) had SD, and 2(11.2%) had progressive disease (PD). A randomized phase III trial(ARCHER 1009) comparing dacomitinib with erlotinib as treat-ment for molecularly unselected advanced NSCLC with 1 to 2 priorlines of therapy is ongoing. Two additional studies are beingplanned: a phase III study comparing dacomitinib therapy withgefitinib therapy in patients with sensitizing EGFR mutations and aphase IIa study using pulse dosing of dacomitinib to treat patientswith EGFR T790M mutations. Dr Jonathan Goldman revieweddata on CO-1686, a third-generation EGFR TKI that inhibits thekey activating and T790M resistance mutations. The planned phaseI trial will enroll patients with acquired resistance to EGFR TKI,and the recommended dose will be used in the expansion phaselimited to patients with T790M mutations.

The management of patients with EGFR-mutant NSCLC whodevelop PD after therapy with an EGFR TKI remains quite chal-lenging. Dr Paul Paik argued that it is not safe to stop TKI therapyat progression, because of the risk of disease flare. Dr Joel Nealsuggested second-line chemotherapy followed by reintroduction of aTKI as third-line therapy as a possible option for these patients.

Anaplastic Lymphoma KinaseDr Alice Shaw presented the update on the PROFILE 1007, a

phase III study comparing crizotinib with chemotherapy usingeither pemetrexed or docetaxel previously treated in patients withadvanced anaplastic lymphoma kinaseepositive (ALKþ) NSCLC.Median PFS, the primary endpoint, was significantly higher forpatients in the crizotinib arm than for those in the chemotherapyarm (7.7 vs. 3 mo; hazard ratio [HR] 0.49; P < .0001). Inter-estingly, when the analysis was subdivided by type of chemo-therapy, patients receiving pemetrexed had improved PFScompared with those receiving docetaxel (4.2 vs. 2.6 mo; HR0.30; P < .0001), whereas PFS for patient who received crizotinibremained significantly higher than that for patients in eitherchemotherapy arm. Crizotinib was also associated with a signifi-cant improvement in the quality of life. Nevertheless, 111 of 174patients (63%) in the chemotherapy arm received crizotiniboutside of the trial, and there was no differences in overall survival(OS), which reached 20.3 months for patients in the crizotinibarm and 22.8 months for patients in the chemotherapy arm. DrShaw also presented data on the second-generation ALK inhibitorLDK378. A phase I study enrolled patients with advanced ALKþ

tumors, regardless of previous use of ALK inhibitors. The medianPFS was 8.6 months, there was activity in central nervous systemlesions, and the treatment was well tolerated, with nausea, diar-rhea, vomiting, and fatigue reported as the most common toxic-ities. Dr Paul Bunn reviewed the design of SWOG 1300, inwhich patients with advanced ALKþ and pemetrexed-naiveNSCLC progressing on crizotinib therapy are being randomizedto treatment with pemetrexed plus crizotinib or treatment withsingle-agent pemetrexed followed by reintroduction of crizotinibat progression, with PFS as the primary endpoint.

Mesenchymal Epithelial TransitionFactor

Dr David Spigel presented data on onartuzumab, an antibodyagainst the MET receptor. In the phase II study, 137 patients

with advanced NSCLC were randomized to treatment witherlotinib alone or in combination with onartuzumab. Amongpatients with MET positive tumors, defined as � 50% cells withmoderate or strong staining intensity by immunohistochemistry,the combination therapy was associated with a significant increasein PFS (2.9 vs. 1.5 mo; HR 0.53; P ¼ .04) and OS (12.6 vs. 3.8mo; HR 0.37; P ¼ .37). Ongoing first-line trials with onartu-zumab include the GO27821 trial comparing chemotherapy(platinum plus pemetrexed or carboplatin plus paclitaxel andbevacizumab) with or without onartuzumab in patients withnonsquamous histology, the GO27820 trial comparing treatmentwith carboplatin and paclitaxel with or without onartuzumab inpatients with squamous cell carcinoma, and a phase III studycomparing treatment with erlotinib alone or in combination withonartuzumab in patients with MET positive tumors and EGFRmutation. Dr Mark Socinski reviewed data on rilotumumab(AMG 102), a fully human monoclonal IgG2 antibody againsthepatocyte growth factor, the only known ligand of the METreceptor. The maximum tolerated dose (MTD) was not reachedin the phase I trial. An ongoing phase I/II trial is evaluating thecombination of rilotumumab with erlotinib as treatment forpreviously treated stage IV NSCLC patients. In the initial eval-uation, there was no dose-limiting toxicity (DLT) among the 8patients treated in the phase I portion of the study nor unexpectedtoxicity among the first 13 patients treated at the recommendeddose of erlotinib 150 mg daily plus rilotumumab 15 mg/kg every3 weeks.

Dr Alan Sandler presented data on tivantinib (ARQ 197), anoneadenosine triphosphate competitive inhibitor of MET.Preclinical data have shown greater inhibition with the combi-nation of tivantinib and EGFR inhibitors than with either agentalone, and the combination therapy was considered safe in aphase I trial. The phase II trial randomized 167 previouslytreated patients with advanced NSCLC to treatment with erlo-tinib alone or in combination with tivantinib.2 Although thedifference in median PFS favored the combination arm, it wasnot significantly different (3.8 vs. 2.3 mo; HR 0.81; P ¼ .24).Nevertheless, the exploratory analysis suggested a significantbenefit from the addition of tivantinib in the KRAS-mutantpopulation. The MARQUEE phase III trial comparing erlotinibalone or in combination with tivantinib using a similar eligibilityto the phase II study was closed following a planned interimanalysis showing that the primary endpoint of OS improvementwas not expected to be met. Dr Geoffrey Oxnard presented thedesign of an ongoing phase II study comparing treatment witherlotinib plus tivantinib to chemotherapy in patients with pre-viously treated advanced NSCLC with documented KRAS mu-tation. Dr Heather Wakelee presented data on cabozantinib(XL184), an oral inhibitor of MET, vascular endothelial growthfactor receptor (VEGFR)2, and rearranged during transfection(RET) protein. In the phase I trial combining cabozantinib witherlotinib for patients with previously treated NSCLC, 4 (8%) outof 53 evaluable patients achieved PR. The ongoing ECOG 1512is comparing erlotinib to cabozantinib or the combinationregimen in patients with predominantly nonsquamous stage IVNSCLC without EGFR mutation or prior treatment witherlotinib.

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Targeted Therapy for Lung Cancer

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Poly (AdenosineDiphosphateeRibose) Polymerase

Poly (adenosine diphosphateeribose) polymerase (PARP) plays asignificant role in repairing single strand breaks (SSBs), whereashomologous repair (HR) is the preferred repair mechanism fordouble strand breaks (DSBs). PARP inhibition impairs the repairof SSBs, which are converted to DSBs during replication, increasingthe burden for HR. In the presence of HR abnormalities such asbreast cancer susceptibility (BRCA) protein or ataxia telangiectasiamutated (ATM) protein deficiency, the DSBs are repaired bynonhomologous end-joining (NHEJ) protein, which, unlike HR,is error prone, leading to genomic instability and cell death.Dr Geoffrey Shapiro reviewed the current strategies to sensitizeHR-proficient cells to PARP inhibition, including combinationswith HSP90 inhibitors, proteasome inhibition, checkpoint kinaseinhibition, and histone deacetylase (HDAC) inhibition. Dr PhillipBonomi presented results from a phase II study of iniparib, a PARPinhibitor. In this study, 119 patients with advanced squamouscell carcinoma of the lung were randomized to treatment withcarboplatin and gemcitabine with or without iniparib. Modestimprovements in median PFS (5.7 vs. 4.3 mo) and median OS(11.2 vs. 8.5 mo) were noted with the addition of iniparib. A phaseIII study with the same design has enrolled 780 patients with theprimary endpoint of improving OS. Results from this study are stillpending. Dr Giuseppe Giaccone reported that treatment with thecombination of olaparib with cisplatin and gemcitabine was asso-ciated with significant myelosuppression. Ongoing trials with PARPinhibitor in advanced NSCLC include the phase II PIN (PARPInhibition in Advanced NSCLC) study, the randomized trial ofolaparib maintenance compared with placebo in patients withoutprogressive disease after induction chemotherapy, and the phase IIIPIPSeN (PARP Inhibitor Maintenance in Platinum-SensitiveAdvanced NSCLC) study.

Heat Shock Protein 90Heat-shock proteins (HSPs) are molecular chaperones that help

nascent polypeptides fold correctly.3 HSP90 participates in thestabilization and activation of multiple proteins, usually called“client proteins,” including receptor tyrosine kinases and tran-scription factors. Cancer cells may use the HSP90 chaperonecomplex, which includes HSP70 and co-chaperones, to protectmutated and overexpressed proteins from misfolding and degrada-tion. Dr Suresh Ramalingan reviewed data on ganetespib, whichaccumulates preferentially in the tumors and does not have thecommon ocular toxicity observed with earlier generation HSP in-hibitors. Preclinical data with ganetespib have shown synergywith docetaxel, cisplatin, bevacizumab, and the BRAF inhibitorvemurafenib. The initial monotherapy trial accrued 99 previouslytreated patients with advanced NSCLC with mutant EGFR, mutantKRAS, or wild types for both genes.4 Among the 8 patients positivefor ALK translocation and crizotinib naive, 4 patients achievedPR, 3 had SD ranging from 121 to 218 days, and 1 had PD. The2 patients with ALK translocation and previous use of crizotinib hadPD. No other patient from any other cohort achieved PR. The mostcommon toxicities were diarrhea, fatigue, nausea, and anorexia. In aphase I study evaluating the combination of ganetespib with

Clinical Lung Cancer January 2014

docetaxel, the DLTs were myelosuppression and diarrhea, with therecommended phase II doses of docetaxel 75 mg/m2 on day 1 andganetespib 150 mg/m2 on days 1 and 15. The GALAXY-1 studywas a randomized phase II trial comparing docetaxel alone or incombination with ganetespib as therapy for patients with advancedNSCCL and 1 prior line of therapy. The combination therapywas associated with a significant increase in the risk of diarrhea(42% vs. 12%) and febrile neutropenia (10% vs. 2%). The efficacyresults with the first 172 patients showed improved response rate(16% vs. 8%, P ¼ .078) and PFS (4.2 vs. 2.8 mo; P ¼ .076) for thecombination arm. Dr Frederic Levy presented data on Debio 0932,an orally available HSP90 inhibitor. In a phase I trial evaluating theadministration of Debio 0932 daily or every 2 days, the recom-mended dose was 1000 mg daily, whereas the every-2-day regimenis ongoing. There were 2 PRs among the 20 patients treated every2 days (10%) and no responder in the daily-dosing arm. DrGeoffrey Shapiro presented data on the HSP90 inhibitor AT13387.In a phase I study involving 57 patients, there were no respondersamong the 9 patients with NSCLC. An ongoing phase II study isevaluating AT13387 alone or in combination with crizotinib inALK positive tumors.

Fibroblast Growth Factor ReceptorFibroblast growth factor receptor (FGFR) signaling plays a

significant role in several physiologic processes including embryo-genesis, adult tissue homeostasis, and wound healing.5 The 2 maindownstream pathways activated by FGFRs are the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase(PI3K). Two of the ligands, FGF1 and FGF2, stimulate angio-genesis, both through direct effects on the endothelial cells andthrough synergy with VEGF and platelet-derived growth factor(PDGF) pathways. FGFR1 amplifications have been reported inapproximately 20% of patients with squamous cell lung cancer,making FGFR an attractive target for treatment.6 Dr Lecia Sequistpresented data on BGJ398, a pan-FGFR kinase inhibitor. In a phaseI trial involving 31 patients with FGFR mutation or amplification,the drug has been well tolerated and there were early signs of clinicalactivity. There is an ongoing expansion cohort for patients withsquamous cell lung cancer and FGFR1 amplification. Dr Joel Nealpresented the preliminary data on dovitinib, a potent tyrosine kinaseinhibitor of FGFRs, VEGFRs, c-Kit and FLT3. In a phase I trial,the MTD was 500 mg 5 days per week, with the most commongrade 3-4 toxicities being nausea (75%), diarrhea (64%) andvomiting (61%). Dr Ross Camidge presented data on ponatinib.Ongoing trials are evaluating the use of ponatinib in NSCLCharboring either FGFR amplification or RET mutation.

Phosphatidylinositol-3KinaseeMammalian Target ofRapamycin

The phosphatidylinositol-3 kinase (PI3K) pathway is importantin cell proliferation and survival.7,8 Activation of PI3K by receptortyrosine kinase or G-coupled receptors results in the phosphory-lation of phosphatidylinositol-4,5 biphosphate (PIP2) to producephosphatidylinositol-3,4,5 triphosphate (PIP3), which providesdocking sites at the membrane for signaling proteins with

Daniel Morgensztern, Ramaswamy Govindan

pleckstrin homology domains, including phosphoinositide-dependent kinase-1 (PDK1) and AKT. PDK1 activates AKT,which in turn promotes cell survival by decreasing apoptosis. AKTalso phosphorylates tuberous sclerosis (TSC)1, inhibiting theGTPase activity of the TSC1-TSC2 dimer, leading to the activa-tion of mammalian target of rapamycin (mTOR), which increasesprotein synthesis through phosphorylation of eukaryotic initiationfactor 4E and ribosomal S6 protein. Phosphate and tensin homolog(PTEN) antagonizes the PI3K pathway by dephosphorylatingPIP3. The PI3K pathway is commonly altered in NSCLC. ATCGA (The Cancer Genome Atlas) study of squamous cell lungcancer showed several abnormalities in the PI3K pathway involvingPTEN (15%), PIK3CA (16%), AKT (20%), and TSC (5%).9

Several drugs targeting the PI3K pathway are being actively stud-ied. Dr Karen Reckamp reviewed the study design for the combi-nation of BKM120, an oral inhibitor of PI3K, with carboplatin andpemetrexed in patients with advanced nonsquamous lung cancer.Patients will receive standard doses of chemotherapy with escalatingdoses of BKM120 from 60 to 100 mg daily. Dr Juliane Jurgen-smeier presented data on AZD8186, a PI3Kbeta/delta inhibitorwith increased activity against PTEN null cell lines with additiveeffects when combined with docetaxel. Dr Faye Johnson revieweddata on BEZ235, an oral inhibitor of PI3K, mTOR1, andmTOR2, which is synergistic with erlotinib, may circumventerlotinib resistance in EGFR mutant NSCLC, and may have a rolein combination with MEK inhibitors in KRAS-mutant tumors. In aphase I study, the DLTs were thrombocytopenia, fatigue, diarrhea,mucositis, and hyperglycemia.

ImmunotherapyThe melanoma-associated antigen-A3 (MAGE-A3) is a tumor-

specific antigen encoded by the MAGE-A3 gene, which isexpressed during embryogenesis but not in normal adult tissues,with the exception of testis and placenta tissue. Because neithertestis nor placenta bear surface human leukocyte antigen molecules,MAGE-A3 represents a tumor-specific antigen. In a phase II studywith adjuvant MAGE-A3, although the primary endpoint ofimproved disease-free interval (DFI) compared with that of theplacebo arm was not met, the treatment was well tolerated, the DFIwas numerically superior, and all patients showed a humoral im-mune response to the MAGE-A3 antigen.10 Dr RamaswamyGovindan provided an update on the MAGRIT phase III trial, inwhich patients with completely resected MAGE-A3 positiveNSCLC stage IB to IIIA were randomized to vaccine or placeboarms. Accrual of participants from 500 sites in 34 countries wascompleted in August 2012 with a total of 2315 patients. MAGE-A3 expression was observed in 33% of the screened patients,including 47% of those with squamous tumors and 26% of thosewith nonsquamous tumors. Results from this large study are eagerlyanticipated.

Transforming growth factor beta 2 (TGFb2) has an immuno-suppressive role, inhibiting cytotoxic T-cell activation and causingthe conversion of naive T cells into regulatory T cells by the in-duction of Foxp3, helping tumors to evade immunosurveillance.11

Belagenpumatucel-L is an allogeneic tumor cell vaccine made with4 irradiated NSCLC cell lines modified with TGF-b2 antisenseplasmid. In a phase II study, 75 patients with NSCLC stages II to

IV received belagenpumatucel-L either monthly or every othermonth in 3 cohorts: 1.25, 2.5 and 5 � 107 cells per injection.12

Treatment was well tolerated, and outcomes were dose depen-dent, with improved survival for patients in cohorts 2 and 3compared with that of patients in cohort 1. Dr Luda Bazhenovadescribed the design of the phase III STOP trial, which randomized532 patients with NSCLC stage IIIA (T3N2), IIIB, or IV who didnot progress after first-line therapy with a platinum doublet, tobelagenpumatucel-L 2.5 � 107 cells per injection monthly for 18months followed by 2 quarterly boosters or placebo. The primaryendpoint is OS. Accrual of participants occurred between October2008 and June 2012, with 532 patients enrolled.

L-BPL25 (emepepimut-S) is a liposome vaccine targeting mucin1. In a phase IIB trial, patients with stage IIIB or IV disease whohad PR or SD after first-line chemotherapy were randomized toL-BPL25 or supportive care.13 Treatment was well tolerated, butthe improvement in median OS (13 mo to 17.4 mo) with the use ofL-BPL25 did not reach statistical significance (HR 0.73; 95% CI0.50-1.07; P ¼ .11). The greatest difference in survival wasobserved in patients with stage IIIB disease in which the medianOS was not reached compared with a median OS of 13.3 months inpatients in the best supportive care arm (HR 0.52; 95% CI 0.26-1.052; P ¼ .06). Therefore, the investigators decided to pursue alarger study evaluating maintenance vaccine therapy in patientswith stage III disease. Dr Charles Butts presented the results of theSTART phase III trial, in which patients with unresectable stage IIINSCLC were randomized to L-BLP25 weekly � 8 followedmaintenance once every 6 weeks until progression or placebo. Thestudy did not meet the primary endpoint of statistically significantimprovement in OS.

Lorvotuzumab mertansine (LM) (IMGN901) is an antibody-drug conjugate composed of a CD56-targeting antibody com-bined to the maytansinoid DM1 attached via a disulfide linker.CD56 is expressed in virtually all patients with small-cell lungcancer (SCLC) and Merkel cell carcinoma (MCC) by immuno-histochemistry. On binding to CD56, LM is rapidly internalizedand cleaved, with the release of DM1, which disrupts tubulinpolymerization and microtubule assembly. In a phase I trialenrolling patients with CD56þ patients, the MTD was 75 mg/m2

daily for 3 consecutive days every 21 days.14 Among the 26 patientswith SCLC, there was 1 PR and 3 SD for more than 90 days. In aphase I/II study evaluating the combination of IMGN901 withcarboplatin and etoposide, the recommended phase II dose wascarboplatin area under the curve (AUC) 5, etoposide 100 mg/m2 ondays 1 to 3, and IMGN905 112 mg/m2 on days 1 and 8.15 Themost common grade 3 or 4 toxicities were thrombocytopenia,leukopenia, and anemia. Although approximately half of thepatients developed neuropathy, the vast majority was of grade 1 or2. Among the 13 patients with SCLC, 6 achieved partial response(46%), including 4 out of 10 patients previously treated withplatinum-based chemotherapy and 2 out of 3 chemotherapy naïvepatients. Dr Daniel Morgensztern reviewed the phase II trial 0007,in which patients with chemotherapy-naive extensive SCLC arebeing randomized 2:1 to carboplatin plus etoposide and IMG907 orchemotherapy alone. The planned accrual is 120 patients withfurther development if more than 42 of the 80 patients in theexperimental arm remain without PD at 6 months.

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The Seneca Valley virus 001 (SVV-001) is a naturally occurringreplication-competent picornavirus with potent and selectivetropism for neuroendocrine cancer cell types.16 In a phase I trial, 30patients were treated, with no severe toxicity. Although there wereno responders, 1 of the 6 patients with SCLC achieved diseasestabilization for 10 months after rapid progression on first-linecarboplatin plus etoposide therapy and second-line irinotecantherapy, remaining alive for more than 3 years after the SVV-001treatment. Dr Charles Rudin presented the design for the phaseII alliance N0923 trial in which patients with extensive-stage SCLCwithout progression after 4 cycles of platinum-based chemotherapywere randomized to SVV-001 or placebo. The trial, however, wasclosed to accrual based on interim futility analysis.

The recognition of antigens presented by the major histocom-patibility complex (MHC) to the T-cell receptor (TCR) is notenough to induce a T-cell response, which is instead regulated bymultiple costimulatory and coinhibitory interactions.17 Undernormal physiological conditions, coinhibitory molecules, which arebroadly categorized as immune checkpoints, are crucial for themaintenance of self-tolerance and protection of tissues fromdamage during immune response to pathogenic infections. Thereare currently 2 key inhibitory pathways under clinical developmentfor the treatment of lung cancer, the cytotoxic T-lymphocyteeassociated antigen 4 and the programmed cell death protein(PD1)e1. Results with the initial antibodies targeting PD1 and itsligand (PDL1) have been recently reported.18,19 Dr Roy Herbstdescribed a phase Ia trial involving the anti-PDL1 agentMPDL3280A, in which the dose was escalated from 0.01 mg/kgto 20 mg/kg every 3 weeks, followed by the expansion phaseinvolving patients with NSCLC, renal cell carcinoma, melanoma,or other tumor types. MPDL3280A is an engineered immuno-globulin G1 antibody without antibody-dependent cellular cyto-toxicity that may have the advantage of leaving the PD1-PDL2interaction in the lungs intact, possibly decreasing the risk forautoimmune pneumonitis.

ConclusionThere has been a significant increase in the number of novel drugs

being tested in clinical trials for patients with lung cancer over thepast few years. Several promising targets were reviewed at the 2013Annual Targeted Therapies of the Treatment of Lung CancerMeeting, including the second-generation EGFR and ALK in-hibitors and the checkpoint inhibitors. TCGA identified potentialtargetable genes in 114 out of 178 (64%) patients with squamouscell carcinoma. The preliminary data on genomic analysis of ade-nocarcinomas from TCGA are expected soon. With the rapidtechnologic advances and decreasing costs, the use of whole exome ora large panel of selected cancer genes may eventually replace single-gene mutation tests. Recent studies have also highlighted the value ofserial biopsies in patients progressing through targeted therapy for

Clinical Lung Cancer January 2014

identification of genomic alterations that confer acquired resistance.There are several ongoing studies evaluating anti-PD1 and anti-PDL1 that target immune checkpoints in patients with NSCLC.Unfortunately, despite the large number of new drugs currentlybeing tested for lung cancer, long-term disease control and cureremain elusive. Only through better understanding of tumor biologyand innovative approaches will we be able to dramatically improvethe outcomes of patients with metastatic NSCLC.

DisclosureThe authors have stated that they have no conflicts of interest.

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