molecularly targeted therapies in locally advanced non–small-cell lung cancer
TRANSCRIPT
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Review
Molecularly Targeted Therapies in LocallyAdvanced Non–Small-Cell Lung Cancer
Siddhartha Devarakonda,1 Daniel Morgensztern,2 Ramaswamy Govindan3
AbstractApproximately a third of the patients with non-small cell lung cancer (NSCLC) present with locally advanced diseasenot amenable to curative resection. Concurrent chemoradiation is currently the treatment of choice for these patients.Outcomes in patients with locally advanced NSCLC treated with concurrent chemoradiation are modest at best. Nosignificant progress has been made over the past decade in this subset of patients with NSCLC. Several trials haveexamined the role of molecular targeted therapies in this setting. We review the results of these trials and present theoutline of a proposed prospective clinical trial to evaluate targeted drugs in molecularly selected group of patientswith locally advanced NSCLC.
Clinical Lung Cancer, Vol. 14, No. 5, 467-72 © 2013 Elsevier Inc. All rights reserved.
Keywords: Concurrent chemoradiation, Locally advanced NSCLC, NSCLC, Targeted therapymoie
IntroductionLung cancer is the leading cause of cancer-related mortality, with
an estimated 160,340 deaths in the United States for the year 2012.1
Approximately 85% of patients with lung cancer have the non–small-cell lung cancer (NSCLC) subtype.2 Among patients withNSCLC, approximately 25%-30% present with locally advancednon–small-cell cancer, for which concurrent chemotherapy and ra-diation offer the best potential for cure.3,4 Even though concurrenthemoradiation significantly improves outcomes in this patient cohortompared with radiation alone or sequential chemoradiation, most ofhe patients eventually relapse at a distant site. We appear to haveeached a plateau in terms of efficacy with currently available cytotoxichemotherapy regimens that are used in conjunction with thoracic radi-tion. There is an urgent need to develop novel therapies to improve theutcomes of patients with locally advanced lung cancer.
Over the past decade, several targeted agents have received ap-roval for the management of a wide variety of cancers. Agents thatarget the epidermal growth factor receptor (EGFR), angiogenesisvascular endothelial growth factor [VEGF] pathway), and the echi-oderm microtubule–associated-like 4-anaplastic lymphoma kinaseEML4-ALK) fusion gene are currently approved for the manage-
1Department of Internal Medicine, St. Luke’s Hospital, Chesterfield, MO2Department of Medicine, Yale University, New Haven, CT3Department of Medicine, Washington University School of Medicine, St Louis, MO
Submitted: Jan 5, 2013; Accepted: Mar 19, 2013; Epub: May 14, 2013
Address for correspondence: Ramaswamy Govindan, MD, Division of MedicalOncology, Washington University School of Medicine, 660 S. Euclid, Box 8056, St.Louis, MO 63110
dE-mail contact: [email protected]
1525-7304/$ - see frontmatter © 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.cllc.2013.03.005
ent of metastatic lung cancer. The efficacy these agents have dem-nstrated in advanced stage disease led to the design of several trialsnvestigating their role in the management of locally advanced dis-ase.5–7 We will review the results of clinical trials involving molec-
ularly targeted agents in the treatment of locally advanced NSCLC.
Epidermal Growth FactorReceptor Inhibitors
It is estimated that nearly 16% of advanced stage nonsquamouslung carcinomas carry EGFR gene mutations.8 Mutations in EGFRoften result in the constitutive activation of several downstream sig-naling pathways leading to cellular proliferation. Specific mutationsin the EGFR tyrosine kinase (TK) domain have been associated withresponses to EGFR TK inhibitors such as gefitinib or erlotinib.9
Preclinical studies have shown that the EGFR pathway is activated intumors after radiation.10–12 Addition of EGFR inhibitors could po-tentiate responses to radiation therapy.13,14
Monoclonal AntibodiesCetuximab
It is hypothesized that monoclonal antibodies such as cetuximab,nimotuzumab, and panitumumab bind with the extracellular por-tion of the EGFR and inhibit pathway activation by blocking recep-tor dimerization.15 The efficacy of combining these molecules withradiation therapy for the management of locally advanced NSCLC isbeing actively investigated. In the NEAR (NSCLC Erbitux and Ra-diotherapy) trial, 30 patients deemed “unfit” or unwilling to receiveconcurrent chemoradiation were treated with cetuximab (loadingdose of 400 mg/m2 intravenously on day 1, followed by 7 weekly
oses of 250 mg/m2) during concurrent radiation with 66 Gy, fol-
Clinical Lung Cancer September 2013 467
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Molecularly Targeted Therapies in Locally Advanced NSCLC
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lowed by 13 weekly cycles of cetuximab.16 An overall response rate of63% was reported by the investigators. The median overall survivalin this study was 19.6 months with a median progression-free survival of8.5 months. Although differences in the stage (IIIa vs. IIIb) or histologydid not seem to significantly influence patient survival in this trial, theinvestigators reported a trend favoring adenocarcinoma. In a similar USmulticentric phase II trial (N 0422) that set out to examine the role oftherapy with cetuximab alone, 57 patients (aged � 65 years or withECOG [Eastern Cooperative Oncology Group] performance status of2) received cetuximab during concurrent radiation with 60 Gy.17 The
edian survival and time to cancer progression in this study populationere 15.1 and 7.2 months, respectively.Regimens combining cetuximab with conventional chemoradia-
ion were investigated in 4 clinical trials. The combination of cetux-mab and thoracic radiation (64 Gy) after induction with 4 cycles oflatinum-based chemotherapy was evaluated in a small phase I studySCRATCH).18 In this trial, 8 of the 12 patients (75%) enrolled
were alive at the end of first year. The Swedish Lung Cancer StudyGroup trial was a multicentric phase II trial in which patients re-ceived 2 cycles of induction chemotherapy with cisplatin and do-cetaxel.19 Cetuximab treatment was started one week prior to the8-Gy course of radiation therapy, at an initial dose of 400 mg/m2
followed by a weekly maintenance dose of 250 mg/m2. The mediansurvival was 17 months among 71 patients with inoperable locallyadvanced NSCLC who participated in this trial. Kotsakis and col-leagues conducted a phase II study to investigate the effect of cetux-imab in locally advanced NSCLC.20 Thirty-eight patients who were
eemed eligible to participate in this trial received cetuximab alongith thoracic radiation, followed by consolidation chemotherapy.he median overall survival and progression-free survival were 17.1
Table 1 Cetuximab Based Clinical Trials in the Setting of Loca
Trial Size Use of Agent(Regimen/Phase)
NEAR16 30
Concurrent radiation
Cetuximab continued afteradiation
N 042217 57 Concurrent radiation
Swedish Lung Cancer Study Group19 71Concurrent radiation(following induction
chemotherapy)
SCRATCH18 12 Concurrent radiation
Kotsakis et al20 38
Concurrent radiation
With consolidationchemotherapy
RTOG 032421 87
Concurrent chemoradiation
With consolidationchemotherapy
CALGB 3040723 101Concurrent chemoradiation(followed by consolidation
with pemetrexed)
Abbreviations: CALGB � Cancer and Leukemia Group B; NEAR � NSCLC Erbitux and Radiothea Progression failure rate of 55.2% at 24 months.
nd 9.3 months, respectively, with a favorable progression-free sur- r
Clinical Lung Cancer September 2013
ival trend (P � .07) in patients whose tumors were positive forGFR according to fluorescent in situ hybridization (FISH) analysis.The Radiation Therapy Oncology Group (RTOG) 0324 conducted
phase II study in which 87 patients received cetuximab combined witheekly carboplatin-paclitaxel and 63 Gy of radiation.21 After concurrent
chemoradiation, patients also received consolidation chemotherapy.The median survival was 22.7 months and the response rate was 62%. At24 months, the progression failure rate and survival rate were 55.2% and49.3%, respectively. These promising results with cetuximab are beinginvestigated further in the phase III setting in the RTOG 0617 trial. Thestudy was initially designed to investigate the role of cetuximab withconventional dose radiation (60 Gy) chemoradiation and high dose ra-diation (74 Gy) chemoradiation. The high-dose radiation arms of thetrial were closed to accrual after the demonstration of futility in an in-terim analysis.22 However, the role of cetuximab is still being evaluatedas planned, and results are awaited. The Cancer and Leukemia Group B(CALGB) conducted a randomized phase II trial (CALGB 30407) tostudy 2 novel chemotherapy regimens in patients with locally advancedlung cancer.23 CALGB 30407 randomized 101 eligible patients to re-eive 70 Gy of radiation therapy with concurrent carboplatin and pem-trexed with or without cetuximab. Patients in both arms received con-olidation therapy with 4 cycles of pemetrexed. The median overallurvival among the 53 patients in the cetuximab arm was 25.2 monthsith a median failure-free survival of 12.3 months. The median overall
urvival and failure-free survival in patients who did not receive cetux-mab were 21.2 and 12.6 months, respectively. Although the random-zed study was not designed to assess the superiority of either regimen, aigher overall survival rate at the end of 18 months was reported in theon-cetuximab arm (58% vs. 54%). Survival outcomes in these cetux-
mab-based trials (Table 116–21,23) compare favorably with outcomes
vanced Non–Small-Cell Lung Cancer
adiation Dose Overall Survivalin Months
Progression-Free Survivalin Months
66 Gy 19.6 8.5
60 Gy 15.1 7.2
68 Gy 17 NR
64 Gy NR NR
73.5 Gy 17.1 9.3
63 Gy 22.7 NRa
70 Gy 25.2 12.3
TOG � Radiation Therapy Oncology Group.
lly Ad
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eported in trials investigating other traditional chemoradiation regi-
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Siddhartha Devarakonda et al
mens.24 However, only a randomized phase III trial can clearly definethe role of cetuximab in the treatment of patients with locally advancedNSCLC. Unfortunately, no molecular marker has yet been shown toreliably identify patients who are likely to respond to cetuximab.
Nimotuzumab and PanitumumabPreclinical studies with nimotuzumab and panitumumab in NSCLC
cell lines and xenografts suggest a favorable interaction between theseantibodies and radiation therapy.25,26 Although the safety and tolerabil-ty of concurrent administration of nimotuzumab with radiation ther-py was established in 2 clinical trials, there are no data regarding thefficacy of these agents in the setting of locally advanced NSCLC.27,28
Tyrosine Kinase InhibitorsGefitinib
Initial phase I studies showed gefitinib to be well tolerated whencoadministered with radiation and/or chemotherapy. In a phase Itrial with 9 patients carried out by Okamoto and colleagues, pulmo-nary toxicity resulting in discontinuation of therapy was reported in2 patients when gefitinib was administered concurrently with 60 Gyof radiation.29 Although the median overall survival for the study wasess than a year, 2 patients whose tumor cells harbored EGFR exon
Table 2 Gefitinib- and Erlotinib-Based Clinical Trials in the Set
Agent Trial Population Use of Agent (Regimen
G SWOG 002335 243Maintenance (following conchemoradiation and consol
chemotherapy)
G CALGB 3010634 63 Poor risk groupa: induction, cradiation, maintenanc
Good risk groupb: induction, cchemoradiation, mainten
G Okamoto et al29 9 Induction, concurrent radimaintenance
G Center et al30 16 Concurrent chemoradiation, co(along with chemotherapy), ma
G Rothschild et al31 14 Concurrent chemoradiation, m
G Stinchcombe et al33 23 Concurrent chemoradiation (induction chemotherap
G JCOG 040232 37 Concurrent radiation and mai(following induction chemot
E Choong et al37 34 Arm 1: concurrent chemora(followed by consolidation chem
Arm 2: concurrent chemora(following induction chemot
E Martinez et al36 23 Concurrent radiation, maint
E Komaki et al38 48 Concurrent chemoradiation (foconsolidation chemother
E Socinski et al39 45Concurrent chemoradiationconsolidation (following ind
chemotherapy in cohorts 2
Abbreviations: CALGB � Cancer and Leukemia Group B; E � erlotinib; G � gefitinib; JCOG �a Poor risk was � 5% weight loss and/or performance status 2.b Good risk was � 5% weight loss and performance status 0-1.c Coadministered with bevacizumab.
9 deletions had an overall survival of more than 5 years. In another a
hase I study conducted by Center and colleagues, 16 patients werereated with docetaxel and thoracic radiation.30 All patients received
gefitinib along with chemoradiation. In addition, gefitinib was con-tinued in the maintenance phase until disease progression. The treat-ment regimen was well tolerated and associated with a mediansurvival of 21 months. The combination of gefitinib with a plati-num-based chemoradiation regimen was also shown to be feasibleand well tolerated in a small phase I study.31 However, survivaloutcomes were not reported in this study. An induction regimenwith gefitinib, cisplatin, and vinorelbine was not considered feasiblebecause of toxicity in a Japanese Clinical Oncology Group trial—JCOG 0402.32 Toxicities observed in this trial included grade 3– 4liver enzyme elevations (aspartate aminotransferase in 20% and ala-nine aminotransferase in 37.1% patients) and 1 case of grade 3 pneu-monitis. Stinchcombe and colleagues reported a study involving in-duction chemotherapy with carboplatin, irinotecan, and paclitaxelfollowed by concurrent radiotherapy with carboplatin, paclitaxel,and gefitinib in patients with locally advanced NSCLC.33 Althoughhe treatment was well tolerated, the results were disappointing.
The CALGB 30106 trial stratified patients with locally advancedSCLC into good and poor risk groups based on performance status
of Locally Advanced Non–Small-Cell Lung Cancer
e) RadiationDose
Median OverallSurvival in Months
Median Progression FreeSurvival in Months
t61 Gy 23 8.3
ent 66 Gy 19 13.4
ent 13 9.2
60 Gy NR NR
tionnce 70 Gy 21 NR
nce 63 Gy NR NR
ng 74 Gy 16 9
ce) 60 Gy 28.5 11.2
apy) 66 Gy 10.2 NR
) 13.7 NR
e 66 Gy NR NR
by 63 Gy 25.8 13.6
c74 Gy 18.4 10.2
se Clinical Oncology Group; SWOG � Southwest Oncology Group.
ting
/Phas
currenidation
oncurre
oncurrance
ation,
nsolidaintena
aintena
followiy)
ntenanherapy
diationother
diationherapy
enanc
llowedapy)c anductionand 3)
Japane
nd weight loss (poor risk group: performance status 2, � 5% body
Clinical Lung Cancer September 2013 469
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Molecularly Targeted Therapies in Locally Advanced NSCLC
470
weight loss).34 Patients from the poor risk group only received gefitinibalong with 66 Gy of radiation, while those from the good risk groupreceived additional chemotherapy with carboplatin-paclitaxel. Patientsfrom both groups received induction therapy with gefitinib and carbo-platin-paclitaxel and gefitinib maintenance therapy. Surprisingly, themedian overall survival among patients in the poor risk group was 19months compared with 13 months in the good risk group (progression-free survival 13.4 months in the poor risk group vs. 9.2 in the good riskgroup). Furthermore, a molecular analysis revealed that EGFR muta-tional status did not influence survival. Unfortunately, this study wasunderpowered to correlate EGFR TK mutation with efficacy of EGFRTK inhibitors in patients with locally advanced NSCLC.
The role of maintenance therapy with gefitinib was studied in thephase III SWOG (Southwest Oncology Group) 0023 trial, in which243 patients with locally advanced NSCLC and good performancestatus were randomized to gefitinib or placebo after concurrentchemoradiation therapy with 2 cycles of cisplatin, etoposide, and61-Gy radiation followed by consolidation therapy with 3 cycles ofdocetaxel.35 Disappointingly, the median overall survival in patients
ho received gefitinib was 23 months compared with 35 monthsP � .013) in patients who received placebo. Similarly, progression-ree survival was also lower in the gefitinib arm (8.3 vs. 11.7 months,� .17). Toxicities associated with gefitinib therapy were diarrhea,
neumonitis, and rash. The reasons for these rather unexpected re-ults are not entirely clear.
ErlotinibTrials with erlotinib in the locally advanced NSCLC setting have
demonstrated feasibility without additional toxic effects when coad-ministered with chemoradiation.36,37 In a phase I trial carried out by
hoong and colleagues,37 34 patients were randomized to arm Aith cisplatin-etoposide and thoracic radiation followed by docetaxel
Table 3 Summary of Currently Recruiting Clinical Trials UsingAdvanced Non–Small-Cell Lung Cancer Listed On the
Phase Trial Identification Sponsor EEn
1 NCT01118676 Institut Claudius Regaud
1 NCT01146756 Christie Hospital NHS Foundation Trust
1 NCT00738452 City of Hope Medical Center
2 NCT01102231 Intergroupe Francophone deCancerologie Thoracique
2 NCT01391260 ZhuGuangYing, Beijing Cancer Hospital
2 NCT00620269 National Cancer Center, Korea
2 NCT01091376 Zhejiang Cancer Hospital
2 NCT00979212 Radiation Therapy Oncology Group
2 NCT00983307 Thomas Jefferson University
Abbreviations: MEK � Mitogen-activated protein kinase (MAPK).a Yttrium 90 anti-CEA monoclonal antibody cT84.66.
onsolidation, or to arm B with induction and concurrent chemora- d
Clinical Lung Cancer September 2013
iation with carboplatin-paclitaxel. Patients in both arms receivedrlotinib at escalating doses from 50 to 150 mg daily during concur-ent chemoradiation. The median overall survival was 10.2 and 13.7onths in patients from arm A and arm B, respectively. TumorGFR FISH and immunohistochemistry analysis status did not
eem to influence survival in this trial. In a phase II trial, 48 patientsere treated with erlotinib, carboplatin, paclitaxel, and thoracic ra-iation.38 All patients received consolidation therapy with 2 cycles of
carboplatin and paclitaxel. The median overall survival in this study was25.8 months with a 1-year overall survival rate of 84%. Table 2 summa-izes the results of these studies.
Vascular Endothelial GrowthFactor Pathway InhibitorsBevacizumab
Bevacizumab is a monoclonal antibody that blocks circulatingVEGF. Patients with both squamous (n � 12) and nonsquamous cell(n � 33) NSCLC were treated with induction therapy with paclitaxel,carboplatin, and bevacizumab in a phase I/II study by Socinski andcolleagues.39 Concurrent chemotherapy with thoracic radiation was ad-ministered along with bevacizumab or bevacizumab and erlotinib. Inaddition, patients received consolidation therapy with bevacizumab anderlotinib. The squamous cell cohort of the trial was closed after a highrate of pulmonary hemorrhage. The median overall survival was 18.7months in the nonsquamous cohort and 17.1 months in the squamouscohort. Different studies to date that have investigated the role of bev-acizumab with concurrent radiation have reported the development oftracheoesophageal fistulas as a serious complication.40 Toxicities result-ng from bevacizumab-based regimens led to early termination of mul-iple clinical trials involving concurrent administration of thoracic radi-tion. The use of bevacizumab for locally advanced disease is strongly
tion Therapy and Targeted/Immune Agents in Locallyaltrials.gov Registry (Accessed on September 4, 2012)47
tedent
Expected Timeof Completion Details: Regimen
August 2013 Cilengitide (integrin antagonist) withchemoradiation
February 2015 AZD6244 (MEK inhibitor) with radiation
August 2013 Radiation immunotherapy (Y-90-Mx-DTPA-cT84.66)a with chemoradiation
December 2012 Cetuximab with chemoradiation
July 2017 Gefitinib with radiation in EGFR mutated tumors
March 2015Induction, chemoradiation and consolidationwith erlotinib in patients with known EGFR
mutation status
March 2013 Erlotinib with radiation
April 2015 Chemoradiation with panitumumab (cetuximabarm closed)
October 2013 Erlotinib with radiation
RadiaClinic
stimarollm
24
33
30
100
30
212
75
97
25
iscouraged outside of the setting of a carefully designed clinical trial.
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Siddhartha Devarakonda et al
Results from 2 completed clinical trials examining the role of bevaci-zumab in this setting are awaited (NCT00773188, NCT00578149).
Other Novel AgentsSeveral other agents have been evaluated in the setting of locally ad-
vanced NSCLC. Reasonable tolerability and a median overall survival of25 months were observed in a phase 1 trial (N 0321 trial) in whichbortezomib, a proteasome inhibitor, was administered along with plati-num doublet and thoracic radiation to 27 patients.41 However, in thehase II setting, despite demonstrating evidence of activity (12-monthurvival rate of 71% and a median overall survival of 19 months) theegimen was associated with a high level of hematological toxicity.42 TheCOG trial (ECOG 3598) investigated the role of thalidomide in lo-ally advanced NSCLC with chemoradiation.43 In this large phase IIIrial with 546 patients, the median overall survival was 15.3 months inhe thalidomide group compared with 16 months in the control groupP � .99) and the progression-free survival 7.4 months in the thalido-ide group versus 7.8 months in the control group (P � .96). A higher
ncidence of grade 3 or higher toxicities were reported in the thalidomideroup compared with the control group.
Other agents that have been tested with chemoradiation in the settingf locally advanced NSCLC include radiation-sensitizing agents like PR-50 (doranidazole), and the shark cartilage product AE-941.44,45 In a
phase I/II clinical trial (WJTOG-0002), 37 patients were treated with60-Gy radiation therapy and concurrent PR-350 after induction che-motherapy with either carboplatin-paclitaxel or cisplatin-paclitaxel.44 A
edian survival time of 15.9 months was reported in this trial. Sixteenercent of the patients (6/37) experienced grade 3 or worse radiationneumonitis, including 2 treatment-related deaths. In a large random-
Figure 1 Schema of the Proposed RTOG 1306-A 31101 Study
Screen patiadvanced Nmutations
f
EGFR mutant NSCLC
Arm 1:Erlotinib for 12
weeks followed bychemoradiation
Arm 2:Chemoradiation
Concurrent chemor64 Gy thoracic radiatcisplatin-etoposide o
Abbreviations: EGFR � epidermal growth factor receptor; EML4-ALK � echinoderm microtubu
zed phase III clinical trial with AE-941, participants received concurrent k
latinum-based chemoradiation with either AE-941 (n � 188) or pla-ebo (n � 191) after induction chemotherapy.45 Survival outcomes
reported were disappointing with a median overall survival of 14.4months in the AE-941 group and 15.6 months in the placebo group(P � .73).
A summary of ongoing actively recruiting clinical trials (from theclinicaltrials.gov database) testing regimens incorporating novel mo-lecular therapies with concurrent radiation for the management oflocally advanced NSCLC is presented in Table 3.46
ConclusionsThe outcomes for patients with locally advanced NSCLC remain
suboptimal with a high recurrence rate.47 The fact that many relapsesccur in distant sites suggest that further progress can only be made inhis subset of patients by controlling systemic disease more effectively.he results we have seen so far with the use of molecularly targeted
herapies in this setting have been rather disappointing. Unfortunately,hese studies have been conducted in a molecularly unselected group ofatients. To the best of our knowledge, no studies have been conductedpecifically in patients with locally advanced NSCLC whose tumor cellsarbor EGFR TK mutation or EML4-ALK fusion. Considering the
mpressive benefits observed with erlotinib in patients with EGFR TKutation and crizotinib in those with EML4-ALK fusion gene, we be-
ieve it is rational to study these 2 agents in the molecularly selectedatients with locally advanced NSCLC. The US National Cancer Insti-ute has recently approved a prospective clinical trial to address this issue.nlike the strategies employed previously, targeted therapy (erlotinib or
rizotinib) will be used only in the induction phase in a carefully selectedroup of patients with locally advanced NSCLC whose tumors have
ith locally for EGFRML4-ALK
EML4-ALK fusionpositive NSCLC
Arm 4:Chemoradiation
Arm 3:Crizotinib for 12
weeks followed bychemoradiation
onth eitheroplatin-paclitaxel
ciated-like 4-anaplastic lymphoma kinase; NSCLC � non–small-cell lung cancer.
ents wSCLC
and Eusion
adiatiion wir carb
nown ‘sensitive’ mutations in the EGFR TK domain (for erlotinib) or
Clinical Lung Cancer September 2013 471
2
2
2
2
2
2
2
3
3
3
3
3
3
4
4
4
4
44
Molecularly Targeted Therapies in Locally Advanced NSCLC
472
EML4-ALK fusion rearrangement (for crizotinib). The induction ther-apy will be followed by concurrent chemoradiation. This study will bejointly led by the RTOG and the newly formed Alliance CooperativeGroup (RTOG 1306-A 31101). The schema is outlined in Figure 1.The ongoing efforts by TCGA (The Cancer Genome Atlas) project andother large-scale genomic studies will, no doubt, identify some noveltargets of therapy in NSCLC. If the proposed RTOG 1306-A 31101study is successful, it will be imperative to study novel agents in molec-ularly selected groups of patients with localized disease to significantlyimprove the cure rates of patients with NSCLC.
DisclosureThe authors have stated that they have no conflicts of interest.
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