30 october 2013 | sydney, australia wclc 2013 - etop-eu.org

WCLC 2013

Developed in association with theEuropean Thoracic Oncology Platform

27 October – 30 October 2013 | Sydney, Australia

Sponsored with support from Eli Lilly and Company.

Eli Lilly and Company has not influenced the content of this publication

Letter from Prof Rolf StahelDear Colleagues

It is my pleasure to present this ETOP slide set which has been designed to highlight andsummarise key findings in thoracic cancers from the major congresses in 2013: ASCO,ECCO-ESMO and WCLC. This slide set specifically focuses on WCLC and is available intwo languages – English and Italian.

The area of clinical research in oncology is a challenging and ever changing environment.Within this environment we all value access to scientific data and research which helps toeducate and inspire further advancements in our roles as scientists, clinicians andeducators. I hope you find this review of the latest developments in thoracic cancers ofbenefit to you in your practice. If you would like to share your thoughts with us we wouldbenefit to you in your practice. If you would like to share your thoughts with us we wouldwelcome your comments. Please send any correspondence to [email protected].

I would like to thank our ETOP members Drs Solange Peters, Enriqueta Felip and MartinReck for their roles as Editors – for prioritising abstracts and reviewing slide content – alsoDr Serena Ricciardi for overseeing translation to Italian. The slide set you see before youwould not be possible without their commitment and hard work.

And finally, we are also very grateful to Lilly Oncology for their financial, administerial andlogistical support in the realisation of this complex yet rewarding activity.

Yours sincerely,Rolf StahelPresident, ETOP Foundation Council

ETOP Medical Oncology Slide Deck Editors 2013

Focus: biomarkers (all stages)Dr Enriqueta Felip

Focus: stage III & IVDr Solange PetersMultidisciplinary Oncology Center, Lausanne Cancer Center, Lausanne, Switzerland

Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain

Focus: early stage I, II, other malignancies including SCLC, MPMand rare tumoursDr Martin ReckDepartment of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, Germany

Table of contents

• Biomarkers / screening (click here)

• Early stage / locally advanced NSCLC (click here)

• Metastatic NSCLC (click here)

• SCLC / MPM / rare tumours (click here)

Note: Right click on the (click here) and Openhyperlink from the menu to take you to that section

Table of contents – Biomarkers / screening

Author(right click on name and Open hyperlink frommenu to jump to slides)

Content

Li Li miR-200c expression and EGFR-TKIMok Dynamic change in EGFR mutationHoreweg Lung cancer probability and CT-detected nodulesKris Targeted therapy based on oncogenic driversFernandez-Cuesta CD74-NRG1 fusion geneJen Oncogene mutations in never smokersJen Oncogene mutations in never smokersInfante Seven-year results from the DANTE trialMascaux EGFR TKI resistance in xenograft modelsPark Genomic analysis of East-Asian lung cancersMartin Genotyping of Latin American NSCLCShao-Weng Tan Inter-tumour heterogeneity in nsNSCLCKerr ALK expression in the ETOP LungScape cohortVeronesi Six-year results of PET in lung cancer screeningKerr Gene expression and response to pemetrexedCarbone ARAF in lung adenocarcinomaOxnard Characterising germline EGFR mutationsCosta EGFR exon 20 insertion mutationsBrambilla LACE-Bio study: new classification systemScagliotti Next-generation sequencing of MPMKarachaliou EML4-ALK status and clinical outcome

Table of contents – Early stage /locally advanced NSCLC


Content

Komaki Erlotinib + chemoradiation in NSCLCSoria Safety of CO-1686 in NSCLCKimura Adjuvant treatment with activated killer T-cellsSenthi High-risk features in NSCLC and responseWerner-Wasik SBRT in central and peripheral tumoursGaron Safety and efficacy of MK-3475 in NSCLCGaron Safety and efficacy of MK-3475 in NSCLCAtagi Radiotherapy ± carboplatin in NSCLCLiang Thoracic radiotherapy + chemotherapy in NSCLC

Table of contents – Metastatic NSCLC


Content

Xu NSCLC surgical treatment strategies: A reviewPaz-Ares Necitumumab + first-line chemotherapy in NSCLCMasters Efficacy of cetuximab added to chemoradiotherapyZhou Bevacizumab in Chinese patients with NSCLCNoonan Evaluating the watch-and-wait approach in NSCLCCorre Management of elderly patients with NSCLCCorre Management of elderly patients with NSCLCOu Efficacy of alectinib in ALK+ NSCLCHorn MPDL3280A in NSCLCWakelee Tissue & plasma levels of EGFR T790M in NSCLC

Table of contents – SCLC / MPM / Rare tumours

Author(right click on name and Openhyperlink from menu to jump to slides)

Content

Rintoul MESOVats: Pleurectomy vs. pleurodesis in MPMLuchtenborg Survival in SCLC following lung resectionCao Extrapleural pneumonectomy vs. radical pleurectomy in MPMKim Irinotecan vs. etoposide in Korean SCLCHavel Alisertib in SCLC: A phase II trialMacbeth FRAGMin® + standard therapy in SCLC/NSCLCMacbeth FRAGMin® + standard therapy in SCLC/NSCLC

BIOMARKERS

O01.05 EGFR wild-type NSCLC patients with high miR-200cexpression can benefit from EGFR-TKI – Li J et al

• Study objective

– To characterise miR-200c expression (a regulator of epithelial-to-mesenchymal transition)in NSCLC and its role in TKI sensitivity in EGFR wild-type NSCLC

• Study type/design

– Real-time quantitative reverse transcription-PCR (qRT-PCR) was used to identifymiR-200c levels from 7 NSCLC cell lines; the miR-200c precursor was up-regulated inH1975 and A549 cells using a lentivirus construct and down-regulated in PC9 cells usingan miRNA inhibitoran miRNA inhibitor

– Samples from 141 advanced NSCLC patients were analysed; miR-200c expression andEGFR mutations were examined using qRT-PCR and amplification refractory mutationsystems, respectively

• Key results

– An association between miR-200c expression, epithelial phenotype and sensitivity to TKIswas observed; in A549 and H1975 cells, increased expression of miR-200c up-regulatedE-cadherin and down-regulated ZEB1, vimentin, pERK and pAKT expression.Up-regulated miR-200c increased sensitivity of primary resistant cells A549 to gefitinib

Li et al. J Thorac Oncol 8, 2013; (Suppl 2; O01.05)

High miR-200c expression and EGFR-TKIs: results

• Key results (continued)

– Of the NSCLC samples, patients with EGFR mutation who were treated with second- orthird-line targeted therapy had PFS of 12 months compared with 1.8 months for patientswith EGFR wild-type (p<0.0001; table)

– High expression of miR-200c was positively associated with longer PFS in NSCLC withEGFR wild-type (HR 0.375; 95% CI 0.198, 0.712; p=0.003)

– ORR was higher in patients with higher expression of miR-200c

Cox regression of PFS

• Key conclusions

– miR-200c appears to target ZEB1 and thereby regulate EMT in NSCLC cell lines

– Experimentally up-regulating miR-200c etopic expression partially restored sensitivityto gefitinib

– Expression of miR-200c could be a predictive biomarker in patients with NSCLC EGFRwild-type receiving EGFR TKIs and further studies are warranted

Li et al. J Thorac Oncol 8, 2013; (Suppl 2; O01.05)

HR 95% CI P-value

EGFR status 0.303 0.190–0.483 <0.0001

miR-200c expression 0.635 0.414–0.974 0.038

Cox regression of PFS

O01.06 Dynamic change in plasma EGFR mutation DNA inresponse to first line therapy for advanced stage non-smallcell lung cancer (NSCLC) – Mok T et al

• Study objectives

– To examine the dynamic quantitative change in EGFR mutation DNA (pEGFRmut) duringfirst-line therapy for NSCLC, as well as the diagnostic utility of pEGFRmut in patients withdistant organ metastasis (assumed to have higher level of plasma DNA)


– Using FFPET and plasma samples from 451 patients in the FASTACT 2 study,retrospective EGFR mutation testing was performed at baseline, and in plasma aftercycle 3 (C3) and at tumour progression (according to RECIST criteria)cycle 3 (C3) and at tumour progression (according to RECIST criteria)

– Patients received chemotherapy (gemcitabine plus carboplatin or cisplatin) plus erlotinibor chemotherapy alone

• Key results

– Complete results from plasma samples were available for 305 patients; matched tumourand plasma samples were available for 238 patients

– Sensitivity, specificity and overall concordance between tumour and plasma samples were75%, 96% and 88%, respectively

– There was a greater rebound of pEGFRmut copies at tumour progression for patientstreated with chemotherapy only, compared with chemotherapy + erlotinib

– Positive pEGFR at baseline followed by negative pEGFR at C3 was associated withimproved outcomes, while patients positive at baseline and still positive at C3 experiencedworse outcomes

Mok et al. J Thorac Oncol 8, 2013; (Suppl 2; O01.06)

Plasma EGFR mutation DNA in NSCLC: results


– Outcomes according to C3 pEGFRmut status and treatment arms (all patients were pEGFR positive atbaseline [n=122])

ORR PFS OS

C3 pEGFR mut+GC+P (n=33)GC+E (n=9)

24.2%66.7%

OR = 6.25(95% CI 1.26, 30.90)

Median, months6.87.8

HR = 0.38(95% CI: 0.17, 0.90)


HR = 0.98(95% CI: 0.40, 2.42)

• Key conclusions

– Total plasma DNA and EGFR mutation-specific DNA decrease at C3 but increase again at time ofprogression

– In patients receiving chemotherapy + erlotinib as first-line therapy, who were pEGFR positive atbaseline and at C3 was predictive of worse OS and PFS

– C3 pEGFR mutation status may be a predictive biomarker for EGFR mut+ patients receiving first-lineEGFR TKI and warrants further study

Mok et al. J Thorac Oncol 8, 2013; (Suppl 2; O01.06)

(95% CI 1.26, 30.90) (95% CI: 0.17, 0.90) (95% CI: 0.40, 2.42)

C3 pEGFR mut–GC+P (n=23)GC+E (n=57)

26.1%82.5%

OR = 13.32(95% CI 4.20, 42.23)


HR = 0.23(95% CI: 0.13, 0.41)


HR = 0.61(95% CI: 0.31, 1.21)

PL03.01 Lung cancer probability in subjects withCT-detected pulmonary nodules – Horeweg N et al

• Study objective

– To evaluate the current recommended algorithm (based on Fleischner criteria) and a new proposedalgorithm (based on probability of lung cancer) for the management of pulmonary nodules/lung cancer


– Lung cancer probability was determined based on diameter, volume and volume-doubling time (VDT)of non-calcified nodules with data from the NELSON (European lung cancer screening) trial; follow-upwas 2 years

– Nodule results were linked with lung cancer diagnoses from the national cancer registry

• Key results• Key results

– CT screening detected 9,681 non-calcified nodules among 7,155 Dutch individuals

Horeweg et al. J Thorac Oncol 8, 2013; (Suppl 2; PL03.01)

Lung cancer probability

NEGATIVE*Nodule volume <100 mm³

(≤0.7%) or maximumtransverse diameter <5 mm

(≤0.6%)

INDETERMEDIATENodules volume ≥100–300 mm³

(1.5–5.8%) or a diameter≥5–10 mm (0.4–2.9%);

Further stratified by VDT:0.0–1.0% for VDTs >600 days,4.1% for VDTs 400–600 days,

6.7–25.0% for VDTs <400 days

POSITIVENodule volume ≥300 mm³(8.9–25.7%) or diameters≥10 mm (11.1–31.6%),even with long VDTs

*Probability not significantly different from individuals withoutnodules (0.4%)

Lung cancer probability in subjects withCT-detected pulmonary nodules: results

• Key results

– Increasing the diameter of recommended thresholds would lower the number ofrequired CT examinations but provide comparable or slightly higher sensitivity(93.9% vs. 92.4%) and specificity (91.8% vs. 89.2%)

• Raising the thresholds for nodule size from 4 mm to 5 mm for an indeterminate resultand from 8 mm to 10 mm for a positive result would reduce the number of follow-up CTexaminations (from 29.8% to 22.2%) and result in fewer additional diagnosticprocedures (from 11.6% to 9.1%)procedures (from 11.6% to 9.1%)

• Key conclusions

– Small nodules (diameter <5 mm or volume <100 mm³) are not predictive forlung cancer

– VDT assessment with follow-up CT is advocated only for patients withintermediate size nodules (diameter <5 mm to 10 mm; volume 100–300 mm3)

– Immediate diagnostic evaluation is necessary for patients with large nodules(diameter ≥10 mm or volume ≥300 mm³)

Horeweg et al. J Thorac Oncol 8, 2013; (Suppl 2; PL03.01)

• Study objective

– To screen metastatic lung adenocarcinoma tumours and identify gene alterations; to usethe results to provide matched-treatments and examine patient outcomes


– Patients with metastatic lung adenocarcinomas were enrolled at 14 Lung Cancer MutationConsortium (LCMC) sites

– Multiplexed assays were performed on tumour samples to detect activating mutations in10 established oncogenic driver genes

PL03.07 Treatment with therapies matched to oncogenic driversimproves survival in patients with lung cancers: results from the LungCancer Mutation Consortium (LCMC) – Kris MG et al

10 established oncogenic driver genes

• Key results

– In total, 1,007 patient samples weretested for at least one geneand 733 for all 10 genes

– An oncogenic driver waspresent in 622 (63%) of the samples

Kris et al. J Thorac Oncol 8, 2013; (Suppl 2; PL03.07)n=244

LCMC: Frequency of oncogenic drivers733 specimens with all 10 drivers assayed

Lung Cancer Mutation Consortium: results


1

2

3

4

5 Median survival by driver and targeted therapy

Me

dia

nsu

rviv

al(%

)

• Key conclusions

– Actionable oncogenic drivers were identified in 63% of tumours and can define patient groups withdistinct clinical course

– Using targeted therapy towards specific oncogenic drivers was shown in this study to improve survivalin patients with metastatic lung adenocarcinomas – taking into consideration the risk of significantimbalance between two groups (such as co-morbidities and PS? Targeted treatment availability? Age?Successive lines of treatment?)

• Multiplexed assays assisted physicians in the choice of treatment and 28% of patients receivedtargeted therapy Kris et al. J Thorac Oncol 8, 2013; (Suppl 2; PL03.07)

0

1

Driver +genotype-directed

therapy(n=264)

Oncogenic driverwith no genotype-directed therapy

(n=313)

Nodriver

(n=361)

Me

dia

nsu

rviv

al(%

)

O04.01 Identification of CD74-NRG1, a new recurrent fusiongene in invasive mucinous lung adenocarcinomas of neversmokers – Fernandez-Cuesta L et al

• Study objective

– To identify additional genome kinase alterations in never-smoker patients with lungadenocarcinoma to provide therapeutic targets


– Transcriptome sequencing was performed on 25 specimens that were collected fromnever smokers who lacked KRAS or EGFR mutations

• Key results

– In five cases of stage I invasive mucinous lung adenocarcinomas, a new chimerictranscript fusing CD74 to the EGF-like domain of NRG1 III-β3 isoform was identified thatled to the expression of EGF-like domain in tumour tissue otherwise NRG1-negative

– CD74-NRG1 fusion protein signals through the ERBB2-ERBB3 receptor complex leadingto the activation of the PI3K-AKT pathway

• Key conclusion

– CD74-NRG1 is a new recurrent oncogenic fusion gene, associated with stage I invasivemucinous lung adenocarcinomas of never smokers and may provide a potentialtherapeutic opportunity

Fernandez-Cuesta et al. J Thorac Oncol 8, 2013; (Suppl 2; O04.01)

O04.03 Oncogene mutations and novel transcript fusions inlung adenocarcinoma from never smokers – Jen J et al

• Study objective

– To examine tumour-specific genetic changes (common oncogene mutations and transcript fusions) inlung adenocarcinoma from never smokers from the Mayo Clinic Epidemiology and Genetics of LungCancer Research Program


– Samples from 89 patients with lung adenocarcinomas who were never smokers were examined with amultiplex assay designed to detect 187 mutations in 10 actionable oncogenes

– Transcript fusions were identified with NextGen sequencing

– Reverse transcriptase PCR, FISH and IHC were used to verify the novel fusions

• Key results

– In total, 64 tumours had at least one of the tested oncogenes involving EGFR; 12 had mutationinvolving two of ten tested genes and 9 had transcript fusion involving an oncogene; of the 89 originalsamples 70 had at least one mutation known to respond to targeted therapy

– RNAseq identified five transcript fusions among 20 tested tumours, two known transcript fusions(EZR-ROS1 and KIF5B-RET) as well as three novel fusions involving SND1-BRAF, EML4-BIRC6and GMEB2-TERT genes

• Screening of all 89 samples identified in 3 additional tumours with identical SND1-BRAF fusiontranscript, two of which also had mutation in the EGFR gene (S768I) and one had a mutation inthe ERBB2 gene (M774_A775ins)

Jen et al. J Thorac Oncol 8, 2013; (Suppl 2; O04.03)

Novel transcript fusions in lung adenocarcinoma fromnever smokers: results


– Genetic structure of fusion between SND1-BRAF (figure)

Chromosome 7 7q

32

7q

34

SND1 BRAF

1 9 10 24 18 3 2 1

– The fusion BRAF protein up-regulated its downstream targets MEK and ERK proteins

• Key conclusions

– Almost 80% of lung adenocarcinomas from never smokers carry ≥1 genetic mutation in atargetable gene

– A transcript fusion of SND1-BRAF was identified in lung adenocarcinoma, a fusion thatwas present in tumours also having EGFR or ERBB2 mutations

Jen et al. J Thorac Oncol 8, 2013; (Suppl 2; O04.03)

1 9 10 24 18 3 2 1

SND1-BRAF

1–9 2–18

2148bp716AA

1255bp343AA

O05.01 The DANTE trial, a randomized study of lung cancerscreening with spiral CT: 7-year results – Infante MV et al

PDKey patient inclusion criteria

• Male patients

Screening withlow-dose spiral CT,repeated every year

(n=1,403)

Prospective, randomised study

Objective: To compare screening with spiral CT vs. no screening on lung cancer mortality in ahigh-risk population

Primary endpoint

• Lung cancer mortality

Secondary endpoints

• Incidence, stage and resectability of cancer

R

PD

• Male patients

• Aged 60–75 years

• Smokers of >20 pack-years

(n=2,811)Control (no screening,

yearly clinical review only)(n=1,408)

(n=1,403)

Infante et al. J Thorac Oncol 8, 2013; (Suppl 2; O05.01)

The DANTE trial: results

• Key results

– As of November 2012

• 13,541 person-years follow-up had been completed: median follow-up 75.5 months for spiral CT(1,255 evaluable patients) and 73.1 months for control (n=1,195)

• 301 patients had died, 163 (12.8%) in the spiral CT group and 138 (11.5%) in control

5152

34

80

100 Lung Cancer Stage Distribution

NA

I

• Key conclusions– Smoking exposure and mean age differ between screening trials. Age in particular is higher in DANTE

than in other trials– A high number of events have been observed, of which 28% cannot be attributed to a specific cause

23 26

9 5

23

39

26 16

13

4

29

31

51

1647

13

0

20

40

60

LDCT CTRL LDCT CTRL LDCT CXR

I

II-III

IV

DANTE Danish Trial NLST /10

3

Infante et al. J Thorac Oncol 8, 2013; (Suppl 2; O05.01)

O08.07 Patient-derived primary non-small cell lung carcinoma (NSCLC)xenograft models for mechanistic studies of resistance to EGFRtyrosine kinase inhibitor therapy – Mascaux C et al

• Study objective

– To examine the clinical relevance (correlate patient genotpye and response, identifymarkers or mechanisms of resistance) of using patient-derived primary lung tumourxenograft models with EGFR mutations


– Non-obese diabetic SCID mice were implanted with surgically resected early stageNSCLC. When tumours were of ~6 mm in diameter, therapy was initiated with EGFR TKI(daily PO gavage for erlotinib 50 mg/kg and dacomitinib 3 mg/kg plus weekly IP cetuximab(daily PO gavage for erlotinib 50 mg/kg and dacomitinib 3 mg/kg plus weekly IP cetuximab50 mg/kg)

• Key results

– Three xenograft models were successfully propagated

– Model 148 (L858R mutation) demonstrated intrinsic resistance to all treatments

• The tumour came from a patient who received pre-operative erlotinib and did not respond; relapseoccurred after surgery and no additional TKI therapy was given

– Model 137 (exon19 E746-A750 deletion mutation) had complete response to erlotinib anddacomitinib but despite this, viable tumour cells remained at the implant site

• The matched patient subsequently developed disease recurrence and responded to third-linegefitinib

Mascaux et al. J Thorac Oncol 8, 2013; (Suppl 2; O08.07)

Using xenograft models for mechanistic studies ofresistance to EGFR tyrosine kinase inhibitortherapy: results


– Model 164 (double exon19 L747-T751 deletion/T790M mutations) did not respond toerlotinib but responded to cetuximab alone; tumour growth transiently stabilised withdacomitinib, but progressive growth developed after 2 weeks of treatment. Resistancewas reversible each time the dacomitinib-resistant tumour was propagated, without drug innew mice

• The matched patient developed recurrence after surgery and did not respond to second-line erlotinibtreatmenttreatment

• Key conclusions

– Patient-derived primary lung cancer xenograft models may reflect clinical tumourbehaviour more closely than other models

– These models may be used to study mechanisms of resistance to targeted therapies andtest novel treatment strategies that may improve treatment efficacy

Mascaux et al. J Thorac Oncol 8, 2013; (Suppl 2; O08.07)

MO10.01 Integrative and comparative genomic analysis ofEast-Asian lung squamous cell carcinomas – Park K et al

• Study objective

– To identify somatic genome alterations of lung squamous cell carcinoma (SqCC) from Koreanpatients


– Using DNA from 104 lung SqCC samples and matched normal DNA, whole-exome sequencingwas conducted; in a subset of samples copy number analyses and transcriptome analyseswere performed

• Key results

– This cohort of Korean patients exhibited a very high mutational burden, with an average of261 somatic exonic mutations per tumour and a mutational spectrum indicating exposure tocigarette smoke

– Seven genes were identified that illustrated statistical enrichment for mutation: TP53, RB1,PTEN, NFE2L2, KEAP1, MLL2 and PIK3CA; a similar spectrum of alterations was observedbetween this population and that from a North American sample

– Repeated occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SqCC wasdiscovered

• Key conclusion

– Whole-genome sequencing of lung SqCC from Korean patients identified at least sevenmolecular alterations – as well as the discovery of a new fusion FGFR3-TACC3 – that mayrepresent potential actionable targets for targeted strategies

Park et al. J Thorac Oncol 8, 2013; (Suppl 2; MO10.01)

MO10.02 Update genotyping non-small cell lung cancer(NSCLC) in Latin America: Latin-American Consortium forthe Investigation of Lung Cancer (CLICaP) – Martin C et al

• Study objective

– To determine the frequency of EGFR mutations in patients with NSCLC in Latin America


– Genomic DNA was extracted from lung biopsies from patients with NSCLC in Argentina,Colombia, Mexico and Peru; direct sequencing of EGFR (exons 18 and 21) geneswas performed

• Key results

– A total of 4,605 patients were enrolled– A total of 4,605 patients were enrolled

– The EGFR mutation was found in 1,176 patients (25.5%, 95% CI 24.2, 26.7)

Martin et al. J Thorac Oncol 8, 2013; (Suppl 2; MO10.02)

Pro

po

rtio

n(%

)

14.4

24.7

33.6

51.1

0

20

40

60

Argentina Colombia Mexico Peru

The frequency of EGFR mutations in NSCLC bycountry

NSCLC genotyping in Latin America: results

• Key results

EGFR mutation EGFR wild type P-value

Age (years)≤60≥60

20.120.9

78.979.1

0.895

GenderFemaleMale

29.816.7

70.283.3

<0.001

HistologyAdenocarcinomaLCCNOS/non-differentiated

23.821.420.5

76.278.679.5

<0.001

• Key conclusion

– The frequency of EGFR mutations in Latin American patients with NSCLC is between the frequencyobserved in Caucasian and Asian populations; this may be related to common ethnic origin or geneticsusceptibility to carcinogens

Martin et al. J Thorac Oncol 8, 2013; (Suppl 2; MO10.02)

NOS/non-differentiatedSCC

20.57.5

79.592.5

Factor of expositionSmokerNever smoker

15.625.8

84.472.4

<0.001

EthnicityCaucasianHispanicBlackNA

1335.4

029.9

8764.610077.1

<0.001

KRASPositiveNegative

3.316.9

96.783.1

<0.001

MO10.06 Intertumour heterogeneity revealed by integrative analysis of targetedsomatic mutation profiling and whole genome copy-number alterations innon-squamous non-small cell lung carcinomas – Shao-Weng Tan D et al

• Study objective

– To explore the potential clinical impact of genomic heterogeneity (co-existing mutations and copy-number alterations) within molecular subtypes of NSCLC from patients in Singapore and Paris


– MassARRAY LungCarta™ panel was used to examine Stage I, adenocarcinoma or large cell;214 mutations from 26 oncogenes and tumour suppressor genes were analysed

• Key results

– Of 230 tumours that were examined there were 185 mutations detected; 138 (60%) had ≥1 mutation, 97(42.2%) were single mutations in single genes, 36 (15.7%) had two mutations, 4 (2.2%) had threemutations and 1 (0.4%) had four mutationsmutations and 1 (0.4%) had four mutations

– The most frequent mutations are shown in the charts below

Shao-Weng Tan et al. J Thorac Oncol 8, 2013; (Suppl 2; MO10.06)

KRAS, 10,11%

EGFR, 35,39%

TP53, 8,9%

MET, 13,14%

STK11, 9,10%

PIK3CA, 2,2%

ERBB2, 2,2%

Unknown,12,

13%

Singapore (n=91)

KRAS, 44,32%

EGFR, 14,10%

TP53, 21,15%

MET, 3,2%

STK11, 4,3%

PIK3CA, 6,4%

BRAF, 2,1%

AKT, 1,1%

Unknown, 4432%

Paris (n=139)

Intertumour heterogeneity in non-squamous NSCLC:results


– Poorer prognosis was observed for patients with ≥1 mutation, some specific somatic mutations (e.g.PIK3CA, left figure) and those patients with both KRAS mutation and high copy-number alteration(3q22.3 copy loss) but not for KRAS mutation alone (right figure)

Mutational status for PIK3CA

10

.80

.6

Ove

rall

su

rviv

al(%

)

10

.80

.6

Mutational status for KRAS

• Key conclusions

– Within molecular subtypes significant inter-tumour heterogeneity exists, by integrating these datasetssubgroups of patients with distinct clinical outcomes can be identified

– Single gene assays are not adequate for precise patient stratification and this has implications for futurecombined therapeutic strategies

Shao-Weng Tan et al. J Thorac Oncol 8, 2013; (Suppl 2; MO10.06)

0.6

0.4

0.2

12 24 36 48 60 72 84 96

Time after surgery (months)

Ove

rall

su

rviv

al(%

)

Without PIK3CA mutation

With PIK3CA mutation

p=0.024

0.6

0.4

0.2

12 24 36 48 60 72 84 96

Time after surgery (months)

Without KRAS mutation

With KRAS mutation

p=0.155

MO10.07 ALK immunohistochemistry and fluorescencein-situ hybridization in lung adenocarcinomas from theETOP Lungscape tumour cohort – Kerr KM et al

• Study objective

– To characterise ALK status in patients with primary resected lung adenocarcinomas


– Cases of adenocarcinoma from the European Thoracic Oncology Platform (ETOP)LungScape database with >2 years clinical follow-up were selected (n=1,281)

– ALK status was determined with immunohistochemistry (IHC) and fluorescence in-situhybridisation (FISH)

– Test positive cases were matched (1:2) by stage, gender, smoking status, study centre,year of surgery and age with test negative cases

• Key results

– In total, 34.1% of IHC positive cases (n=82) were FISH positive; while none of IHCnegative cases were FISH positive

– Sensitivity of FISH was 87% for IHC 3+. Of 54 IHC positive/FISH negative cases, mostwere IHC 1+ (75.9%), followed by IHC 2+ (18.5%) and IHC 3+ (5.5%)

– For IHC positive cases with H-score of >120 96% were FISH positive, while those withH-score of <120 only 5.4% were FISH positive

Kerr et al. J Thorac Oncol 8, 2013; (Suppl 2; MO10.07)

In ALK IHC positive casesHazard of event decreases by:

32% for RFS (p=0.03)36% for OS (p=0.02)39% for TTR (p=0.02)

Multivariate analysis:Current/Former Smokers

have a higher hazard of death

Association of IHC and FISH with clinical outcomes: results

ALK IHC a significant predictorof RFS, OS and TTR inmultivariate models

than Never Smokers


Association of IHC and FISH with clinical outcomes: results


– There were significantly more never smokers in the ALK IHC positive group (29.3%) thanthe IHC negative group (18.3%, p=0.011)

– In IHC positive cases the hazard of an event decreased by 32% in relapse-free survival(p=0.03) and by 38% in both time-to-relapse (p=0.02) and OS (p=0.016)

– IHC-ALK was a significant predictor of relapse-free survival, time-to-relapse or OS

– Significantly higher OS was retained in IHC positive (HR 0.59; p=0.04) and FISH positive(HR 0.34; p=0.03) cases in the matched cohorts, but there was no significant association(HR 0.34; p=0.03) cases in the matched cohorts, but there was no significant associationwith 3-year survival status

• Key conclusions

– Among patients with surgically resected primary lung adenocarcinoma, 6.4% were ALKIHC positive

• IHC 3+ staining (prevalence 1.8%) showed 87% probability of ALK FISH positivity

– ALK IHC positivity was higher in never smokers and was associated with better clinicaloutcomes


MO11.01 Positron emission tomography in lung cancerscreening: Six-year results – Veronesi G et al

• Study objective

– To evaluate the utility of CT/PET screening in characterising indeterminate nodules in lung cancer


– Annual low-dose CT was performed on asymptomatic high-risk individuals (≥20 pack-years, aged ≥50years) in the 10-year COSMOS screening study

– Nodules of ≤5.0 mm were screened with low-dose CT a year later; nodules between 5.1 and 8 mmwere screened with low-dose CT 3 months later and nodules of >8.0 mm were screened with CT/PET(unless considered benign)

– Outcomes were based on pathological surgical results or findings at follow-up

• Key results

– A total of 5,203 individuals were enrolled in the study; 383 nodules were identified in 351 patients

– When distinguishing between benign and malignant nodules, the accuracy, specificity and overallsensitivity of CT/PET was 76%, 89% and 64%

• For nodules ≥15 mm in diameter sensitivity was 87% and specificity was 73%; sensitivity was lowfor nodules investigated at annual repeat CT compared with baseline CT (p<0.0001, sensitivity30–71%) and non-solid vs. solid nodules (p<0.0001; sensitivity 22% vs. 79%)

• Key conclusion

– For solid nodules and those >15 mm, CT/PET is a highly sensitive diagnostic for screening-detectednodules; for sub-solid nodules, CT/PET sensitivity is low and other diagnostic tests (e.g. volume-doubling time and CT characteristics) should be used

Veronesi et al. J Thorac Oncol 8, 2013; (Suppl 2; MO11.01)

MO12.02 Association between gene expression profiles and clinical outcome ofpemetrexed-based treatment in patients with advanced non-squamous non-small cell lung cancer: exploratory results from a phase II study – Kerr KM et al

• Study objective

– To examine the relationship between gene expression and clinical outcomes in patients withnon-squamous NSCLC treated with pemetrexed


– In a Phase II study, treatment-naïve patients with non-squamous NSCLC (stage IIIB/IV)received 4 cycles of first-line pemetrexed/cisplatin; those that did not progress receivedpemetrexed maintenance treatment

– Gene array-expression profiling was performed and thymidylate-synthase (TS) expression was– Gene array-expression profiling was performed and thymidylate-synthase (TS) expression wasdetermined; the relationship between genes and PFS/OS was examined with Cox-proportionalhazard models

• Key results

– Of 70 biopsies, 51 samples were available and 9 genes (out of 1,030) were significantlyassociated with both PFS and OS (unadjusted p<0.01)

– Five of these genes (C16orf89, NAPSA, SFTPB, AQP4 and NKX2-1 (TTF-1)) were significantlynegatively correlated with nuclear TS expression (unadjusted p<0.01)

• Key conclusion

– Exploratory gene array-expression profiling identified 9 genes significantly associated with PFSand OS, although these should not be considered prognostic or predictive nor providesevidence for changing the current histology-based treatment approach with pemetrexed


MO15.05 Oncogenic ARAF mutation in lungadenocarcinoma – Carbone DP et al

• Study objective

– To examine ‘outlier responses’ in a patient with advanced stage lung adenocarcinomasuccessfully treated with sorafenib


– Whole genome sequencing and RNA sequencing was performed on primary tumour andnormal samples from a patient that experienced a complete remission and radiographicremission for 5 years following sorafenib treatment


– The patient had no mutations in driver oncogenes (KRAS, EGFR, ERBB2, BRAF,PIK3CA), known tumour suppressors (TP53, CDKN2A, RB1, NF1 or ATM) or ‘canonical’sorafenib targets (Raf-1, BRAF, MEK, ERK, PDGFRB, FLT3, VEGFR1-3, RET, KIT,FGFR1)

– A somatic mutation, ARAF S214C, was identified and was expressed at high levels

– ARAF mutants were shown to transform immortalised human airway epithelial cells andwere associated with in-vitro sorafenib sensitivity

• Key conclusions

– Mutant ARAF may be a novel oncogenic driver and an indicator of response to sorafenibin late stage lung adenocarcinoma

– ARAF represents a potential actionable (rare) somatic alteration

Carbone et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract MO15.05)

MO15.06 A prospective internet-based study of patients with lungcancer harboring baseline EGFR T790M to identify germline carriersand characterize familial risk – Oxnard GR et al

• Study objective

– To identify patients and families carrying germline EGFR mutations in order to characterise phenotypeand cancer risk


– A prospective study to enrol individuals in three cohorts: 1) those with EGFR T790M-positive cancer(excluding acquired T790M); 2) those with first- or second-degree relatives who are known to begermline carriers; or 3) those who are already known to carry a germline EGFR mutation

– Individuals carrying germline EGFR mutations received chest CT scans; nodule prevalence andcharacteristics were examined. Pathology review and advanced genetic analyses were performed oncharacteristics were examined. Pathology review and advanced genetic analyses were performed ontumour specimens

• Key results

– At present, 70 individuals have been remotely screened using the website; 16 are eligible and 13 wereenrolled from 9 families

– Among four probands with lung cancer and germline T790M, only two have first-degree relatives withlung cancer

• Key conclusions

– Preliminary data suggest that some individuals are at high-risk

– A cohort of individuals has been recruited and it is intended that 100 patients will be studied over3 years to understand the natural history and risks associated with this familial cancer syndrome

Oxnard et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract MO15.06)

MO16.06 Clinical, structural and biochemical characterizationof EGFR exon 20 insertion mutations in lung cancer– Costa DB et al

• Study objective

– To understand the patterns of resistance or response to EGFR TKIs in tumours with EGFR mutations


– In-vitro systems, structural models and clinical data relating to EGFR exon 20 insertion mutations wereanalysed for patterns of resistance or response

• Key results

– Three mutations within the C-helix and 4 mutations following the C-helix were selected and almost allEGFR exon 20 insertions were resistant to gefitinib or erlotinib

• Post-helix mutations favoured the active conformation, did not alter the binding pocket of EGFR and• Post-helix mutations favoured the active conformation, did not alter the binding pocket of EGFR andwere less sensitive than EGFR TKI-sensitive mutations

• Response rates to gefitinib or erlotinib in patients with EGFR exon 20 mutated NSCLCs weresignificantly higher for A763_Y764insFQEA (2/3; 66.6%) when compared with all other mutationswithin or following the C-helix (0/17, 0%; p=0.0158)

• Key conclusions

– EGFR exon 20 insertion mutations affecting amino acids within or following the C-helix (Y764 to V774)should be classified as non-sensitising to reversible EGFR TKIs (gefitinib and erlotinib)

– Only EGFR exon 20 insertion mutation EGFR A763_Y764insFQEA can be inhibited by clinicallyachievable doses of gefitinib and erlotinib

– An EGFR TKI-insensitive mutation (D770_N771insNPG) showed an active kinase with an unalteredATP-binding pocket that led to lack of response to EGFR TKIs

– Lack of structural alterations near the ATP binding cleft in typical EGFR exon 20 insertions may indicatethere will be difficultly in developing EGFR TKIs that are selective vs. wild-type EGFR receptor in thesemutants

Costa et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract MO16.06)

O17.01 Prognostic and predictive value of a new IASLC/ATS/ERS lungadenocarcinoma classification in a pooled analysis of four adjuvantchemotherapy trials: a LACE-Bio study – Brambilla EM et al

• Study objective

– To examine prognostic utility of a new IASLC/ATS/ERS classification system inpatients with invasive lung adenocarcinoma


– Pooled review of data from 4 clinical trials in the LACE-Bio study

– Histological diagnosis was reviewed and tumours were subgrouped to one offive categories by predominant growth pattern and then as three groups (LEP,five categories by predominant growth pattern and then as three groups (LEP,ACN+PAP and MPP+SOL)

– Primary outcome was OS; secondary outcomes included DFS and specific DFS(DFS without cancer-related deaths)

• Key results

– Data from 1,766 patients were analysed

– Univariate analyses found significant differences in DFS and specific DFS(p=0.02) but not for OS (p=0.19) across the five subtypes

Brambilla et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract O17.01)ACN, acinar; LEP, lepidic; MPP, micropapillary;PAP, papillary; SOL, solid

Use of new lung adenocarcinoma classification system:results


– The prognostic and predictive value of growth patterns was assessed in thethree subgroups: LEP, ACN+PAP and MPP+SOL

• No significant differences in OS were observed across the three groups(p=0.21)

• The MPP+SOL growth pattern predicted both DFS (HR 0.59, 95% CI 0.43,0.81; p=0.001) and specific DFS (HR 0.58, 95% CI 0.42, 0.81; p=0.001)0.81; p=0.001) and specific DFS (HR 0.58, 95% CI 0.42, 0.81; p=0.001)

• Key conclusions

– Patients with MPP and SOL predominant patterns of growth showed a trendtowards poorer DFS and specific DFS, but a significantly greater benefit fromadjuvant chemotherapy, than other subtypes

– IASLC/ATS/ERS classification of adenocarcinoma subtypes may have utility asa stratification factor for future trials examining adjuvant chemotherapy

Brambilla et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract O17.01)

O22.01 Next generation sequencing in malignant pleuralmesothelioma: preliminary data from a retrospective cohortof 123 patients – Scagliotti GV et al

• Study objective

– To examine the use of next generation sequencing (NGS) to improve understanding of tumour-specificgenomic alterations in malignant pleural mesothelioma (MPM) and correlation with clinical-pathologicalfindings


– NGS profiling was conducted on DNA extracted from FFPE tissue samples from patients with advancedstage MPM

• Key results

– Samples were available from 123 patients with advanced stage MPM who were treated withpemetrexed-based chemotherapy; interim results are presented

– Of 107 patients screened, 996 non-synonymous, 8 del-ins, 62 nonsense, 637 intronic, 204 regulatoryand 1,140 synonymous somatic sequence variations were observed (allele frequency cut-off ≥10%)

– The most frequently altered genes in MPM patients were: CSF1R, TP53, KDR, SMARCB, KIT, APC,PIK3CA, EGFR, ATM, CDKN2A and SMAD4

• Key conclusions

– Preliminary results from NGS profiling suggest that mutations can be detected from FFPE MPMsamples and indicate a complex genetic pattern with some patients having accumulated mutationswhile others just have one or two altered genes

– Those novel mutations may help to understand the molecular landscape of MPM and could be newputative prognostic and therapeutic markers

Scagliotti et al. J Thorac Oncol 8, 2013; (Suppl 2; O22.01)

MO26.08 The concomitant presence of echinoderm microtubule associated protein like 4- anaplastic lymphoma kinase (EML4-ALK) EML4-ALK fusion gene in EGFR-mutant non-small-cell lung cancer (NSCLC) patients treated with erlotinib or chemotherapy in theEURTAC trial – Karachaliou N et al

• Study objective

– To determine the frequency and impact of the concomitant presence of EML4-ALK in patients withNSCLC harbouring EGFR mutations


– In the EURTAC trial, 173 patients with NSCLC and EGFR mutations received erlotinib or standardchemotherapy with cisplatin or carboplatin plus docetaxel or gemcitabine; tumour specimens wereavailable for 95 patients for EML4-ALK analysis by PCR and sequencing

• Key results

– There were 15 patient samples (15.8%)

1.0

– There were 15 patient samples (15.8%)positive for EML4-ALK: nine had variant 1 andsix had variant 3

– PFS for patients with the EML4-ALK (ALK+)fusion gene was 10.4 (95% CI 1.3, 18.4) vs.7.1 (5.8, 8.8) months for patientswithout EML4-ALK (ALK-)

• Key conclusions

– The EML4-ALK fusion gene is present in a considerable number of patients with EGFR-mutant NSCLCand may positively effect clinical outcome

– This study suggests the further research on other genetic factors is relevant to find therapeuticinterventions for patients with EGFR mutations

Karachaliou et al. J Thorac Oncol 8, 2013; (Suppl 2; MO26.08)

0

0.2

0.4

0.6

0.8

ALK+

ALK-

Su

rviv

al

pro

ba

bil

ity

6 12 18 24 30 36 42 48 54Time (months)

22.9

NA

EARLY STAGE / LOCALLYADVANCED NSCLC

O02.03 Value of adding erlotinib to thoracic radiationtherapy with chemotherapy for stage III non-small cell lungcancer: A prospective phase II study – Komaki R et al

Single-institution Phase II study

Objective: To determine whether the addition of erlotinib to concurrent chemoradiation therapyimproves survival and response rates in NSCLC without increasing toxicity

Key patient inclusion criteria

• Previously untreated, locally

Radiotherapy(63 Gy/35 fractions)

+

Primary endpoint

• Time to progression

Secondary endpoints

• Toxicity, response, OS

• Disease control rates

Paclitaxel 45 mg/m² +carboplatin AUC2 +erlotinib 150 mg/day

for 7 weeks, followed bytwo paclitaxel-

carboplatin cycles

PD

• Previously untreated, locallyadvanced, inoperable,stage III NSCLC

• Karnofsky’s performancestatus >70

(n=48)

Komaki et al. J Thorac Oncol 8, 2013; (Suppl 2; O02.03)

+

Erlotinib for NSCLC: results

• Key results

– Among 46 patients who were evaluable for a response

• Median time to progression was 14.5 months and was not affected by EGFR status; median OS andPFS were 34.1 and 13.7 months

n (%) CR PR SD or PD Not available*

All cases (n=46) 14 (30) 23 (50) 8 (18) 1 (2)

EGFR mutation (EGFR-M) (n=4) 3 (75) 0 (0) 0 (0) 1 (25)

EGFR wild-type (n=36) 11 (30) 19 (53) 6 (17) 0 (0)

*One patient was not evaluable for tumour response due to no follow-up image

– No grade 4 or 5 adverse events were reported; 6 grade 3 adverse events (acne, esophagitis andpneumonitis) were observed

• Key conclusions

– It appears that erlotinib when given in combination with chemoradiation might confer a radiosensitisationeffect

– The role of maintenance erlotinib after radiochemotherapy in the EGFR mutated patients require furtherevaluation and remains undefined

– A randomised prospective trial is needed to validate these findings

Komaki et al. J Thorac Oncol 8, 2013; (Suppl 2; O02.03)

EGFR wild-type (n=36) 11 (30) 19 (53) 6 (17) 0 (0)

No EGFR data (n=5) 0 (0) 4 (80) 1 (20) 0 (0)

O03.06 First-in-human evaluation of CO-1686, anirreversible, highly, selective tyrosine kinase inhibitor ofmutations of EGFR (activating and T790M) – Soria JC et al

CO-1686 administeredcontinuously in PD


• EGFR-mutant NSCLC

Dose-finding study

Objective: To examine safety, pharmacokinetics and efficacy of CO-1686 (a novel TKIspecifically targeting mutated EGFR) in patients with NSCLC

Primary endpoint

• Safety

Secondary endpoints

• Pharmacokinetics and efficacy

continuously in21-day cycles

PD• Prior EGFR TKI therapy

(n=45)

Soria et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract O03.06)

CO-1686 in NSCLC: results

• Key results

– In total, 56 patients were enrolled (mean age 60 years; 80% female; 45% hadreceived ≥2 prior EGFR TKI including erlotinib, gefitinib, afatinib, dacomitinib)

– AEs occurring in >10% of patients included nausea, diarrhoea, fatigue, vomitingand decresed appetite

• No acneiform rash was observed consistently with absence of EGFR wild-type inhibitiontype inhibition

– There was a 67% RECIST response rate in evaluable T790M+ patients treatedwith 900 mg BID

– A hydrobromide formation of CO-1686 showed improved exposure and reducedPK variability

• Key conclusions

– CO-1686 had a good tolerability and efficacy profile in patients with T790M+EGFR mutant NSCLC

– Recommended Phase II dose remains to be established

– A Phase I trial in Japanese patients is to be initiated in early 2014Soria et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract O03.06)

MO08.07 Randomized controlled phase III trial of adjuvant chemo-immunotherapy with activated killer T cells and dendritic cells inpatients with resected primary lung cancer – Kimura H et al

• Study objective

– To evaluate the efficacy of post-surgical adjuvant chemo-immunotherapy using activated killer T-cellsand dendritic cells (AKT-DC) obtained from patients with lung cancer


– Phase III study, patients with post-surgical NSCLC were randomised to chemo-immunotherapy(group A) or chemotherapy (group B); immunotherapy was adoptive transfer of autologous AKT-DC

– Primary endpoint: OS; secondary endpoints: recurrence-free survival, toxicity and AEs

• Key results

– There were 50 patients in group A (tumour stage IB/II/IIIA/IIIB/IV in 7/8/22/8/5) and 51 in group B– There were 50 patients in group A (tumour stage IB/II/IIIA/IIIB/IV in 7/8/22/8/5) and 51 in group B(6/7/24/11/3, respectively)

– OS rates at 2- and 5-years were 93.4% and 81.4% in group A, compared with 66.0% and 48.3% ingroup B (log-rank p=0.005, generalised Wilcoxon test p=0.0005); hazard ratio was 0.229 (95% CI0.093, 0.564, p=0.0013)

– Two-year recurrence-free survival rates were 68.5% and 41.4% for groups A and B, respectively(log-rank p=0.002); hazard ratio was 0.423 (95% CI 0.241, 0.743, p=0.0027)

– From 762 courses, 6.8% were associated with chill and shiver, 6.2% fever; no AEs were reported for28 out of 50 cases treated with immunotherapy

• Key conclusion

– Immunotherapy with AKT-DC in patients with lung cancer might inhibit the growth of disseminatedmicrometastases, control recurrence and subsequently increase OS. These results deserve largerscale prospective validation including risk/prognostic factors stratification

Kimura et al. J Thorac Oncol 8, 2013; (Suppl 2; MO08.07)

O10.05 Blinded assessment of radiological changes afterstereotactic ablative radiotherapy for early-stage lungcancer: local recurrences versus fibrosis – Senthi S et al

Serial follow-up CTKey patient inclusion criteria

• Early-stage NSCLC

Clinical matched-cohort study

Objective: To validate the predictive value of seven high-risk features* of local recurrence (LR)following stereotactic ablative radiotherapy (SABR) in patients with early-stage NSCLC

Endpoint

• Predictive value of high-risk featuresof LR

images for high-riskfeatures were

assessed

PD

• Early-stage NSCLC

• Treated with SABR whohad local recurrence

(n=12)

Senthi et al. J Thorac Oncol 8, 2013; (Suppl 2; O10.05)

Matched 1:2 with patientswithout LR based on

• tumour location, SABRfractionation, PTV size andfollow-up duration

*Enlarging opacity at primary site, growth in cranio-caudal direction,sequential enlarging opacity, enlarging opacity after 12 months,bulging margin, loss of linear margin and loss of air bronchograms

Predicting local recurrence following SABR usinghigh-risk features: results

• Key results

– All high-risk features were significantly associated with LR (p<0.01)

• Opacity enlargement after 12 months was the best individual predictor of LR(100% sensitivity, 83% specificity, p<0.001)

– In 42% of patients, cranio-caudal growth and enlarging opacity were both detected≥3 months prior to actual diagnosis of LR

– For each additional high-risk feature identified in an individual patient, the odds ofrecurrence increased 4-foldrecurrence increased 4-fold

• The presense of ≥3 high-risk features in an individual patient was highly sensitive andspecific for recurrence (both >90%)

• Key conclusions

– The presence of high-risk features on post-treatment CT scans can accurately predict LRfollowing SABR

– This approach my reduce unnecessary diagnostic procedures and ensure salvagetherapies are used earlier

Senthi et al. J Thorac Oncol 8, 2013; (Suppl 2; O10.05)

MO17.05 Recurrence, survival, and toxicity after stereotactic lung radiotherapy(SBRT) for central versus peripheral stage I non-small cell lung cancer (NSCLC):results from an international collaborative research group – Werner-Wasik M et al

• Study objective

– To compare outcomes and safety following cone-beam CT (CBCT) image-guidedstereotactic lung radiotherapy (SBRT) for central vs. peripheral NSCLC


– A retrospective examination of 959 lung tumours treated with SBRT across 5international centres in the Elekta Collaborative Lung Research group between1998–2012

• Key results

– Of 959 tumours, 90% were stage I and 92% were PET-staged

Werner-Wasik et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract MO17.05)

Patient characteristic Central(n=100)

Peripheral(n=859)

p-value

Maximum tumour dimension, cm 3.1 2.4 <0.001

Baseline maximum SUV 10.5 6.9 <0.001

Biopsy, % 84 59 <0.001

Dose per fraction, Gy 10.2 15.1 <0.001

Radiotherapy dose BED10 104.0 ± 18.6 129.2 ± 26.2 <0.001

SBRT for central versus peripheral NSCLC


– Grade ≥2 pneumonitis was more frequent in central (8%) than peripheral (1%) tumours, as was chestwall pain (12% vs. 5%, respectively)

– Mean follow-up in all cases was 1.8 (0.1–7.7) years

– Comparing central and peripheral tumours:

3-year rates (%) Central Peripheral p value

Overall survival 50 51 0.70

• Key conclusions

– SBRT in central and peripheral tumours was safe and associated with similar overall survival; grade 2pneumonitis was higher for central tumours

– Compared with peripheral tumours, central tumours were larger, had higher baseline SUVmax,received lower doses of radiotherapy and were associated with higher local failures

Werner-Wasik et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract MO17.05)

Cause-specific survival 75 88 <0.001

Cause-specific death 25 12 <0.001

Local recurrence 16 6 <0.001

Regional recurrence 12 12 0.69

Distant metastasis 19 20 0.75

MO18.02 Preliminary clinical safety and activity of MK-3475monotherapy for the treatment of previously treated patients withnon-small cell lung cancer (NSCLC) – Garon EB et al


• Patients with NSCLC

• Prior treatment with two

Phase 1 study

Objective: To assess the safety and efficacy of MK-3475 (a humanised IgG4 antibody with highaffinity for PD-1) in previously-treated patients with NSCLC

Primary endpoint

• Safety

Secondary endpoints

• ORR

MK-3475 10 mg/kgq3w

PD

• Prior treatment with twosystemic therapies

• ≥1 measurable tumour lesion

• ECOG PS 0–1

(n=38)

Garon et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract MO18.02)

MK-3475 monotherapy in NSCLC: results

• Key results

– There were no drug-related deaths

– At least one drug-related AEs was reported in 53% of patients, the most common(occurring in ≥5%) were rash, pruritus, fatigue, diarrhoea, arthralgia, back pain, cough anddecreased appetite

• One case each occurred for the following drug-related AEs of interest: hyperthyroidism(grade 2), hypothyroidism (grade 2), pneumonitis (grade 2) and pulmonary oedema(grade 3)(grade 3)

– The ORR was 24% (95% CI 11, 40; determined by investigator immune-related responsecriteria) and 21% (95% CI 9, 39; determined by RECIST v1.1)

• Of those patients with evaluable tumour PD-L1 expression, all confirmed responsesoccurred in patients with tumours positive for PD-L1

• Key conclusions

– MK-3475 was well tolerated and associated with durable objective responses in previouslytreated patients with NSCLC

– Preliminary data suggest that PD-L1 expression levels may be associated with responsesto MK-3475

– Studies of MK-3475 in NSCLC and other cancers are ongoingGaron et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract MO18.02)

MO25.02 Thoracic radiotherapy with or without concurrent daily low-dosecarboplatin in elderly patients with locally advanced non-small cell lung cancer:updated results of the JCOG0301 and pooled analysis with the JCOG9812 trial– Atagi S et al

• Study objective

– Preplanned pooled analysis of results from two Phase III trials that compared low-dose carboplatin plusradiotherapy with radiotherapy alone in elderly patients with stage III NSCLC


– Patients aged ≥71 years with unresectable stage IIIA/IIIB NSCLC were randomised to receive radiotherapyalone (RT arm: 60 Gy) or chemoradiotherapy (CRT arm: radiotherapy, 60 Gy plus concurrent carboplatin,30 mg/m2 per fraction up to the first 20 fractions). Pooled endpoints were OS, PFS, RR and toxicities

• Key results

– A total of 246 patients were included in the pooled analysis– A total of 246 patients were included in the pooled analysis

– Median OS for the RT (n=121) and CRT (n=122) arms was 16.3 (95% CI 13.4, 18.6) and 20.7 (16.3, 26.9)months, respectively, HR 0.672 (95% CI 0.502, 0.898; p=0.0034, using stratified log-rank one-sided test).Median PFS was 6.5 vs. 8.8 months for RT and CRT, HR 0.671 (95% CI 0.514, 0.875, p=0.0015). RR for theRT and CRT arms were 46.3% and 53.3%, respectively

– Grade 3/4 toxicities occurring in ≥5% (either group) for CRT vs. RT arms were: leucopenia (62.2% vs. 1.7%),neutropenia (54.6% vs. 0), thrombocytopenia (30.3% vs. 3.3%), anaemia (6.7% vs. 0%) and dyspnoea (5.0%vs. 4.2%); use of radiotherapy quality control in one of the trials reduced the incidence of grade 3/4pneumonitis (from 4.4% to 2.1%) and treatment-related deaths (from 8.9% to 3.6%)

– Subgroup analyses identified age ≤75 years, stage IIIA, male, ECOG PS 0 and smoking history as factorsassociated with significant improvement in OS in the CRT arm

• Key conclusion

– Combination chemoradiotherapy for elderly patients with locally advanced NSCLC provides clinically significantbenefits; employing radiotherapy quality control measures improved treatment outcomes

Atagi et al. J Thorac Oncol 8, 2013; (Suppl 2; MO25.02)

MO25.04 Phase II study comparing cisplatin/etoposide and weeklypaclitaxel/carboplatin regimens with concurrent thoracic radiotherapy inpatients with locally advanced non-small cell lung cancer – Liang J et al

• Study objective

– To compare the efficacy and safety of concurrent thoracic radiotherapy (TRT) with cisplatin/etoposide(PE) with weekly paclitaxel/carboplatin (PC) in patients with stage III NSCLC


– Patients were randomised to PE+TRT (cisplatin 50 mg/m2 d1, 8, 29 and 36, etoposide 50 mg/m2 d1–5and 29–33 + 60 Gy) or PC+TRT (carboplatin AUC=2 and paclitaxel 45 mg/m2 + 60 Gy)

• Key results

– Of 156 enrolled patients,PE+TRT PC+TRT p-value

Median survival time, months 22 20– Of 156 enrolled patients,149 were randomised(PE n=73, PC n=76);median follow-up was 38 months

• Key conclusion

– Compared with PC+TRT, PE+TRT was associated with a non-significant improvement in PFS and OSin patients with stage III NSCLC; the incidence of grade ≥2 radiation pneumonitis was lower withconcurrent PE but esophagitis was higher

Liang et al. J Thorac Oncol 8, 2013; (Suppl 2; MO25.04)

Median survival time, months 22 20

Median progress-free time, months 13 11

2-year OS, % 44.9 36.5

3-year OS, % 39.5 27.6 0.323

2-year PFS, % 27.7 22.1

3-year PFS, % 24.5 20.5 0.449

Grade 3 bone marrow depression, % 34.2 23.7 0.29

Grade 3 esophagitis 15.1 5.3 0.047

Grade ≥2 pneumonitis , % 19.2 26.3 0.059

METASTATIC NSCLC

O02.07 Is there a survival benefit in patients with stage IIIA(N2) non-small celllung cancer under neoadjuvant chemotherapy and/or radiotherapy followed bysurgery administration: a systematic review and meta-analysis – Xu Y et al

• Study objectives

– A systematic review and meta-analysis was undertaken to determine if:

• There is a survival benefit for patients with stage IIIA (N2) NSCLC undergoingsurgery alone, chemotherapy and/or radiotherapy alone, or resection

• Neoadjuvant treatment with chemoradiotherapy is superior to neoadjuvantchemotherapy alone

• Study type/design• Study type/design

– A systematic literature review was conducted using the PubMed, Embase,Medline databases to identify randomised controlled trials that compared thespecific treatments in patients with pathologically confirmed stage IIIA (N2)NSCLC and reported survival outcomes (OS, PFS or DFS)

– Results were reviewed as per PRISMA standards

Xu et al. J Thorac Oncol 8, 2013; (Suppl 2; O02.07)PRISMA, Preferred Reporting Items for Systematic Reviews andMeta-Analyses

The effect of surgery on survival in patients with stage IIIA(N2) NSCLC

• Key results– Of 984 records identified, seven studies were included in the analyses– There was no evidence that surgery after induction therapy improved survival in patients

with stage IIIA (N2) NSCLC– Although a trend towards better DFS and OS was observed in patients treated with

neoadjuvant chemoradiotherapy compared with neoadjuvant chemotherapy, there was nosignificant difference between the two groups• Neoadjuvant chemoradiotherapy was shown to significantly increase mediastinal

pathological CR (p=0.04)pathological CR (p=0.04)

• Key conclusions– There are potential limitations and methodological issues with this study including

heterogeneity among selected studies, the type of resection and method of lymph nodesampling, but this meta-analysis showed that surgery did not improve survival

– Neoadjuvant chemoradiotherapy does not lead to improved survival compared withneoadjuvant chemotherapy alone, but can lead to better mediastinal downstaging and wascorrelated with better PFS/DFS and OS

– Although this meta-analysis indicated that surgery did not improve survival in unselectedpatients, no definitive statement can be made regarding the preferred multimodalitytherapy. In stage III, surgery remains recommended according to stringent clinicalcharacteristics, restricted to experienced centres and if possible within clinical trials

Xu et al. J Thorac Oncol 8, 2013; (Suppl 2; O02.07)

O03.02 Randomized Phase-3 trial (INSPIRE) of necitumumab plus cisplatin-pemetrexed versus cisplatin-pemetrexed alone as first-line therapy in stage IVnon-squamous NSCLC – Paz-Ares L et al

PD


Standard chemotherapy +necitumumab 800 mg IV

d1 and 8 q3w

Randomised, international Phase III study

Objective: To examine the effect of necitumumab in combination with first-line chemotherapy inpatients with advanced non-squamous NSCLC

Primary endpoint

• OS

Secondary endpoints

• PFS, ORR, safety, EGFR expression

R

PD


• Stage IV non-squamous NSCLC

• ECOG PS 0–2

(n=633)Standard

chemotherapy q3w

Paz-Ares et al. J Thorac Oncol 8, 2013; (Suppl 2; O03.02)Standard chemotherapy: cisplatin 75 mg/m2 IV +pemetrexed 500 mg/m2 IV day 1 for up to 6 cycles

Stratification

• Smoking status, ECOG PS, diseasehistology and geographic region

INSPIRE: results

• Key results

– Enrollment was stopped at 633 patients due to an observed imbalance in fatalthromboembolic events and fatal events potentially related to thromboembolism betweennecitumumab + chemotherapy and chemotherapy alone predominantly during first 2 cycles

Necitumumab +chemotherapy

Chemotherapyalone

HR (95% CI); p-value

Median OS, months 11.3 (9.5, 13.4) 11.5 (10.1, 13.1) 1.01 (0.84, 1.21); 0.956

Median PFS, months 5.6 (5.1, 6.0) 5.6 (4.8, 5.7) 0.96 (0.80, 1.16); 0.664

– Treatment-related grade ≥3 AEs occurred in 58.6% of patients receiving necitumumab +chemotherapy compared with 42.9% of patients receiving chemotherapy alone

– The most common grade ≥3 AEs of interest occurring in ≥5% of patients in either treatmentgroup were neutropenia (18.1% vs. 18.3%), fatigue (11.2% vs. 6.1%), hypomagnesaemia(7.6% vs. 2.2%), rash (14.8% vs. 0.3%) and venous thromboembolic events (7.6% vs.3.5%) for necitumumbab + chemotherapy vs. chemotherapy alone

Paz-Ares et al. J Thorac Oncol 8, 2013; (Suppl 2; O03.02)

Median PFS, months 5.6 (5.1, 6.0) 5.6 (4.8, 5.7) 0.96 (0.80, 1.16); 0.664

ORR (CR+PR), % 31.1 32.1

Median OS by EGFR1 expression (H-score)High (≥200–300)Low (0–<200)

15.0 (10.9, 16.6)9.0 (7.6, 11.2)

13.3 (10.8, 16.8)9.7 (8.7, 12.5)

1.03 (0.75, 1.43)1.07 (0.83, 1.38)

Conclusions

• In patients with advanced non-squamous NSCLC, the addition of necitumumab tocisplatin and pemetrexed did not improve OS and was associated with anincreased rate of grade ≥3 adverse events for rash, hypomagnesaemia andthromboembolism

• EGFR1 H-score was not statistically significantly predictive of efficacy outcomes ofnecitumumab combined with cisplatin and pemetrexed. It may, however, have aprognostic value

• Necitumumab is still in development for squamous NSCLC with a Phase III trial(SQUIRE) ongoing (primary endpoint met according to press release, data awaited)

Paz-Ares et al. J Thorac Oncol 8, 2013; (Suppl 2; O03.02)

PL03.05 An intergroup randomized phase III comparison of standard-dose (60 Gy) versushigh-dose (74 Gy) chemoradiotherapy (CRT) +/- cetuximab (cetux) for stage III non-smallcell lung cancer (NSCLC): Results on cetux from RTOG 0617 – Masters GA et al

PD

Stratification


• Newly diagnosed,unresectable stage IIIA/B

Chemotherapy + cetuximaband RT (60 or 74 Gy) then

consolidation chemotherapy(n=237)

2x2 factorial randomised trial

Objective: To compare the effect of adding cetuximab to concurrent chemoradiotherapy withchemoradiotherapy alone in patients with NSCLC

Primary endpoint

• OS

Secondary endpoints

• PFS and safety

R

PD

Stratification

• RT technique, Zubrod PS,PET staging, histology

unresectable stage IIIA/BNSCLC

• Zubrod 0–1

• Aged ≥18 years

(n=465)

Chemotherapy andRT (60 or 74 Gy) then

consolidation chemotherapy(n=228)

Chemotherapy, carboplatin AUC2 and paclitaxel 45 mg/m2 for6–7 weeks; cetuximab, 400 mg/m2 load + 250 mg/m2/weekConsolidation chemotherapy, carboplatin AUC6 and paclitaxel200 mg/m2 q21d for 2 cycles; cetuximab, 250 mg/m2/week Masters et al. J Thorac Oncol 8, 2013; (Suppl 2; PL03.05)

RTOG 0617: results

• Key results

– There was no significant difference in OS (HR 0.99, 95% CI 0.78, 1.27, p=0.4838) or PFS (HR 0.96,95% CI 0.77, 1.19, 0.3471) between treatment groups

80

100

6 months

12 months

Ove

rall

su

rviv

al(%

)

Masters et al. J Thorac Oncol 8, 2013; (Suppl 2; PL03.05)

0

20

40

60

60 Gy 74 Gy 60 Gy + Cetux 74 Gy + Cetux

12 months

18 months

Ove

rall

su

rviv

al(%

)

RTOG 0617: results

EGFR and Cetux interaction for OS

HR: High vs. low expression (RL)

p = 0.02

Cetux subsetp = 0.38

No Cetux subset

HR: No Cetux vs. Cetux (RL)

− Incidence of grade 3–5 toxicities was significantly greater with cetuximab + chemotherapy compared withchemotherapy alone (non-haematologic 70.5% vs. 50.7% and overall 85.2% vs. 69.2%; both p<0.0001)

HR: No Cetux vs. Cetux (RL)p = 0.09

Low expression subsetp = 0.11

High expression subset

0.5 1.0 1.5 2.0 2.5

Hazard ratio


Conclusions

– Cetuximab added to chemoradiotherapy does not improve OS or PFS inpatients with unresectable stage III NSCLC but was associated with asignificant increase in grade 3–5 toxicities

– Greater benefit with cetuximab may occur in patients with high EGFRexpression, although further study including prospective validationis required

– High-dose radiotherapy is not superior to standard-dose radiotherapy in– High-dose radiotherapy is not superior to standard-dose radiotherapy inpatients with unresectable stage III NSCLC

– Compared with standard-dose radiotherapy, risk of death was greaterwhile local failure and esophagitis were more common with high-doseradiotherapy


MO06.13 BEYOND: a randomized, double-blind, placebo-controlled, multicentre,phase III study of first-line carboplatin/paclitaxel (CP) plus bevacizumab (Bv) orplacebo (Pl) in Chinese patients with advanced or recurrent non-squamousnon-small cell lung cancer – Zhou C et al


• Locally advanced, stage IIIB/IVmetastatic or recurrentadvanced non-squamous

Bv 15 mg/kg IV on day 1of each cycle + CP

(n=138)

Randomised, double-blind, placebo-controlled, multicentre, Phase III study

Objective: To determine the efficacy of first-line carboplatin/paclitaxel (CP) plus bevacizumab (Bv)in Chinese patients with advanced or recurrent non-squamous NSCLC

Primary endpoint

• PFS

Secondary endpoints

• ORR, OS, exploratory biomarkers andsafety

R1:1

PD

advanced non-squamousNSCLC

• ECOG PS 0–1

• No prior treatment


(n=276)

Placebo + CP(n=138)

Zhou et al. J Thorac Oncol 8, 2013; (Suppl 2; MO06.13)CP, paclitaxel 175 mg/m2 IV & carboplatin AUC6 IVon day 1 q3w, up to 6 cycles

Stratification

• Gender, smoking status and age

BEYOND: results

• Key resultsM

onth

s

9.2

8.0

6.5

5.3 54.4

94.488.7

Bv + CPPlacebo +…

Rate

(%)

HR 0.40 (95% CI 0.29–0.54)p<0.0001

p<0.0001

• Key conclusions

– Adding bevacizumab to first-line, platinum-based chemotherapy improves PFS in Chinese patients withnon-squamous NSCLC and no new safety signals were observed

– VEGF-A and VEGFR-2 biomarkers are not correlated with bevacizumab efficacy

– OS is currently immature with results expected in 2014

Zhou et al. J Thorac Oncol 8, 2013; (Suppl 2; MO06.13)

Month

s

5.3

Median PFS Median durationof response

26.3

ORR Disease controlrate

Rate

(%)

O15.01 Evaluation of a "watch and wait" approach for patientswith newly diagnosed advanced non-small cell lung cancer ina diverse community population – Noonan K et al

• Study objective

– To determine the effect of a ‘watch-and-wait’ (WW) approach on survivaloutcomes in patients with metastatic NSCLC


– A retrospective review was performed on all patients with stage IIIb/IV NSCLCaged ≥18 years visiting a medical oncologist in British Columbia

– Patient characteristics, treatments and outcomes were examined among– Patient characteristics, treatments and outcomes were examined amongpatients who received chemotherapy >8 months after consult (WW-treated) andthose on a WW strategy but did not receive chemotherapy (WW-missed)

• Key results

– Of 694 patients seen by a medical oncologist, 319 received upfrontchemotherapy, 166 WW and 209 were considered not to be eligible forchemotherapy (poor ECOG/comorbidities) and received best supportive care

Noonan et al. J Thorac Oncol 8, 2013; (Suppl 2; O15.01)

“Watch-and-wait" in NSCLC: results


– Among the 166 patients on WW, an opportunityfor chemotherapy was missed in 43% (figure)

– OS was 11.8 (CI 9.6, 14.0) months inWW-treated, compared with 14.2 (12.2, 16.2)months for upfront chemotherapy and4.4 (8.7, 11.1) months for WW-missed (p<0.0001)

Reason for missedchemotherapy among WW

Poor ECOG

Death

Asymptomatic

Illness

1%1%

50%48%

4.4 (8.7, 11.1) months for WW-missed (p<0.0001)

– Factors predictive of poorer OS (by multivariate analyses) were ECOG >2 andsquamous histology

– After controlling for age, sex and ECOG, OS for upfront chemotherapy andWW-treated were similar (HR 1.02, CI 0.74, 1.40; p=0.93) but those inWW-missed had significantly lower OS (HR 2.23, CI 1.69, 2.94; p<0.0001)

• Key conclusion

– A WW strategy may be detrimental to patient outcomes due to patients neverreceiving chemotherapy; follow-ups should be frequent on a WW strategy toensure chemotherapy is timed appropriately

Noonan et al. J Thorac Oncol 8, 2013; (Suppl 2; O15.01)

O15.03 Phase III, randomized, multicenter study comparing in elderly patients(≥70 years) with stage IV non small-cell lung cancer (NSCLC) a standardstrategy of treatment allocation (carboplatin based bi-therapy or monotherapywith docetaxel) based on performance – Corre R et al

PD


• Stage IV NSCLC

CGA strategyCarboplatin-based doublet for fit

patients; docetaxel 38 mg/m2 (d1-8)for vulnerable patients and

BSC for frail patients

Prospective, randomised, multicentre Phase III trial

Objective: To determine if the use of comprehensive geriatric assessment (CGA) can improvethe first-line management of elderly patients with NSCLC vs. standard treatment strategy

Primary endpoint

• TFFS

Secondary endpoints

• ORR, safety, OS, QoL

R

PD

• Stage IV NSCLC

• Aged >70 years

• ECOG PS 0–2

• No prior chemotherapy

(n=494) Standard strategy (PS & age)Carboplatin-based doublet in PS 0–1

& age ≤75 years; monotherapy inPS =2 and/or age >75 years

Corre et al. J Thorac Oncol 8, 2013; (Suppl 2; O15.03)

Stratification

• Carboplatin (AUC5, d1) was given with pemetrexed(500 mg/m2,d1) in non-squamous tumors and togemcitabine (1000 mg/m2, d1–8) for squamoustumours

BSC, best supportive care; TFFS, treatment failure-free survival

CGA vs. standard strategy: results

• Key results

– There were no complete responses

Standard strategy CGA strategy

Alln=241

C-pemn=62

C-gemn=21

Docn=158

Alln=232

C-pemn=84

C-gemn=25

Docn=73

BSCn=50

Median TFFS(months)

3.25 4.4 4.53 3.05 3.21 4.9 4.8 2.7 1.3

All AEs 224 200

– Multivariate analyses of TFFS identified BMI, former/current smoker, ADL score <5,Charlson index ≥2 and GDS 5 score 4–5 were associated with significantly higher HR(p<0.05 for all)

• Key conclusions

– In terms of TTFS, CGA was not superior to standard treatment strategy in elderly patientswith stage IV NSCLC

– There were significantly fewer toxicity-related treatment failures with CGA strategy

Corre et al. J Thorac Oncol 8, 2013; (Suppl 2; O15.03)

All AEs 224(93.0%)

200(86.2%)*

AE ≥grade 3 172(71.3%)

158(68.1%)

*p=0.0162

C-pem, carboplatin-pemetrexed; C-Gem, carboplatin-gemcitabine;Doc, docetaxel

O16.07 Consistent therapeutic efficacy of CH5424802/RO5424802 in brainmetastases among crizotinib-refractory ALK-positive non-small cell lung cancer(NSCLC) patients in an ongoing phase I/II study (AF-002JG/NP28761,NCT01588028) – Ou SHI et al


• ALK+ NSCLC

Phase I/II study

Objective: To examine the efficacy and pharmacokinetics of CH5424802 (alectinib) in patientswith ALK-rearranged NSCLC and CNS lesions

Primary endpoint

• ORR

Secondary endpoints

• PFS, cerebrospinal and plasma levels

Alectinib300–900 mg PO BID

PD• Asymptomatic brain

metastases

• Prior unsuccessful crizotinibtherapy

(n=47)

Ou et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract O16.07)

Alectinib in brain metastases: results

• Key results

– Of the enrolled patients, 21 had baseline CNS lesions

• Prior brain radiotherapy had been performed for >4 weeks for 14 (67%) and ≤4 weeksfor 3 (14%)

CR PR SD PD

Number of responses (%) 6 (29) 5 (24) 8 (38) 2 (10)

• Nine had measurable CNS lesions and received no prior radiation within 4 weeks fromfirst dose of alectinib; five of whom achieved CNS PR, two had CNS SD and 2 hadCNS progression

– Of the 47 enrolled patients, alectinib

• Had activity (2 CR, 1 PR and 1 SD) in 4 patients with asymptomatic CNS metastasisand no prior brain radiotherapy

• Delayed progression in 17 patients with irradiated CNS metastatic lesions

• Key conclusion

– In patients with ALK+ NSCLC who progressed on crizotinib, alectinib provided rapidclinical activity and reduced the size of brain metastases

Ou et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract O16.07)

MO18.01 An analysis of the relationship of clinical activity to baseline EGFRstatus, PD-L1 expression and prior treatment history in patients with non-smallcell lung cancer (NSCLC) following PD-L1 blockade with MPDL3280A(anti-PDL1) – Horn L et al

• Study objective

– To assess the safety and efficacy of MPDL3280A, a human monoclonal antibody targeting PD-L1, inpatients with metastatic NSCLC


– Phase I dose-escalation study; patients received MPDL3280A IV q3w for up to 12 months. Primaryendpoint: safety and tolerability; ORR, EGFR and KRAS status, PD-L1 expression were also examined

• Key results

– As of April 2013 there were 85 evaluable patients who received doses <20 mg/kg

– Treatment-related AEs occurred in 56 (66%) of patients and were mostly grade 1/2 that did not require– Treatment-related AEs occurred in 56 (66%) of patients and were mostly grade 1/2 that did not requireintervention; grade 3/4 AEs occurred in 9 (11%). Fatigue and nausea were the most commonly reported(20% and 14%) with grade 3/4 of these AEs (2% and 1%)

– No maximum tolerated dose was observed nor were there any dose-limiting toxicities or grade 3/5pneumonitis. One treatment-related death (cardio-respiratory arrest) was reported

– Of 53 patients with known PD-L1 status evaluable for efficacy, the ORR was 23% (n=12); ORR was greaterin former/current smokers (26%) and KRAS wild-type (30%), but comparable for EGFR wild-type (23%) andlower in never smokers (10%), KRAS mutant (10%) and EGFR mutant (17%)

• Key conclusions

– MPDL3280A up to 20 mg/kg was generally well tolerated and associated with rapid and durable responsesin some heavily pretreated patients with NSCLC

– Responses were improved in PD-L1 positive tumours; smoking status and KRAS status may influenceresponse to MPDL3280A

– Further studies are ongoing or plannedHorn et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract MO18.01)

MO21.10 Serial monitoring of plasma EGFR T790M levels andevaluation of EGFR mutational status in matched tissue and plasmafrom NSCLC patients treated with CO-1686 – Wakelee HA et al

• Study objective

– To examine EGFR mutations in circulating free DNA from plasma and the concordance of EGFR mutations inmatched plasma and tumour tissue in newly diagnosed or relapsed advanced NSCLC


– Samples were acquired from 97 patients with stage IIIB/IV NSCLC (including 41 that had received CO-1686)from an ongoing Phase I/II trial and an observational study; two allele-specific PCR assays, the cobas® EGFRFFPET and cobas® EGFR blood tests were used to assess matched tissue and plasma samples; BEAMingwas used in patients treated with CO-1686


– Agreement between tissue and plasma was 73% (57/78) for activating mutations and 62% (21/34) for T790M

– Mutations were more readily detected in plasma of patients with distant metastatic disease (M1b) comparedwith local disease (M1a/M0) with activating mutations detected in 43 (88%) vs. 12 (50%) and T790M detectedin 19 (90%) vs. 2 (13%) (both p<0.001), respectively

– Agreement between BEAMing and cobas® EGFR blood test was 87% (26/30) for T790M in plasma

– Among patients who received CO-1686, changes in circulating tumour DNA mirrored clinical response

• Key conclusions

– A high proportion of EGFR mutations identified in tissue were also detected in plasma using cobas®

– Mutations were more detectable in patients with M1b than M1a disease

– Agreement between cobas® and BEAMing was high; these techniques have utility in the non-invasiveassessment and monitoring of EGFR mutations in NSCLC patients

Wakelee et al. J Thorac Oncol 8, 2013; (Suppl 2; MO21.10)

SCLC / MPM / RARE TUMOURS

PL03.03 MesoVATS: A multi-centre randomised controlled trial of videoassisted thoracoscopic pleurectomy versus talc pleurodesis inmalignant pleural mesothelioma – Rintoul RC et al


• Any sub-type of confirmed orsuspected MPM*

VAT partialpleurectomy (n=87)

Randomised, open-label, parallel-group, controlled, multicentre study

Objective: To compare video-assisted thoracoscopic (VAT) pleurectomy with talc pleurodesis inpatients with malignant pleural mesothelioma (MPM)

Primary endpoint

• 1-year survival

Secondary endpoints

• QoL, control of pleural effusion,complications, length of hospital stay,lung function

R

PD

suspected MPM*

• Pleural effusion

• Aged >18 years

• No previous pleurodesis orprimary treatment

(n=196)Talc pleurodesis (n=88)

Rintoul et al. J Thorac Oncol 8, 2013; (Suppl 2; PL03.03)*21 suspected cases were confirmed not to be MPMand were excluded from the main analysis

MesoVATS: results

• Key results

– Survival at 12 months was not significantly different between talc pleurodesis (57%) and VAT (52%,log-rank test p=0.83)

Time period

Difference VATs-Talc,adjusted for baseline

(95% CI)p-

value

1 month (n=137) –0.06 (–0.13, 0.004) 0.06

3 months (n=129) 0.04 (–0.03, 0.12) 0.267

EQ

5D

me

an

an

d9

5%

CI

6

7

8

9 Talc pleurodesis

VATs pleurectomy

– Pleural effusion was significantly controlled with VAT compared with talc pleurodesis at 1 month (59%vs. 37%; p=0.008) and 6 months (76% vs. 57%; p=0.04), but control was similar at 9 and 12 months

– Compared with talc pleurodesis, hospital stays were significantly longer (6 vs. 8 days, p<0.001) andcomplications (e.g. air leak) were more common with VAT; the incidence of serious AEs did not differbetween groups

• Key conclusions

– Overall survival did not differ between VAT partial pleurectomy and talc pleurodesis, but control ofpleural effusion and QoL were improved by VAT partial pleurectomy

Rintoul et al. J Thorac Oncol 8, 2013; (Suppl 2; PL03.03)

6 months (n=109) 0.08 (0.003, 0.16) 0.042

12 months (n=68) 0.19 (0.05, 0.32) 0.006

5EQ

5D

me

an

an

d9

5%

CI

6

Baseline 1 3 6 12

Time (months)

MO13.07 Survival of small cell lung cancer patientsundergoing lung resection in England 1998-2009– Luchtenborg M et al

• Study objective

– To examine survival rates for patients with a first primary lung cancer in England and the effect ofsurgical resection


– Retrospective review of patients diagnosed with a first primary lung cancer between 1998 and 2009 inEngland from the National Cancer Data Repository; patients were grouped by histology (SCLC orNSCLC) and surgical resection status

– Kaplan-Meier and Cox regression analyses (adjusted for age, sex, comorbidity and socio-economicstatus) were used to examine survivalstatus) were used to examine survival

• Key results

– The repository contained data for 45,848 patients with SCLC (465 with resection) and 314,025 patientswith NSCLC (29,670 with resection)

– Five-year survival of resected SCLC patients was 31% compared with 45% for resected NSCLC; bothwere higher than SCLC and NSCLC patients that were not resected (3%)

– The difference in survival rates for SCLC vs. NSCLC decreased with time after surgery

– Survival was greater among patients with SCLC that had elective resection than those patients whohad incidental resection (where diagnosis was probably made after resection)

• Key conclusions

– Survival rates for patients with early stage SCLC approach those of NSCLC, suggesting that surgicalresection may be of benefit in selected patients with SCLC

– If surgery is being performed, it should be combined with chemo- and radiotherapy based on additionalretrospective data

Luchtenborg et al. J Thorac Oncol 8, 2013; (Suppl 2; MO13.07)

MO14.03 Meta-analysis of extrapleural pneumonectomyversus radical pleurectomy for patients with resectablemalignant pleural mesothelioma – Cao C et al

• Study objective

– To compare the clinical outcomes of patients with malignant pleural mesothelioma (MPM)who receive extrapleural pneumonectomy (EPP) or extended pleurectomy/decortication (P/D)


– Following a search of five electronic databases, published data comparing extended P/D andEPP were systemically reviewed

– Perioperative mortality, morbidity and OS were examined


– A total of 7 studies were identified that included 632 patients receiving EPP and513 extended P/D

– Compared with EPP, perioperative mortality and morbidity were significantly lower withextended P/D (6.8% vs. 2.9%, p=0.02 and 62.0% vs. 27.9%, p<0.0001, respectively)

– Median OS ranged from 12–22 months for EPP vs. 13–29 months for extended P/D

• Key conclusions

– Among patients with MPM, extended P/D has been associated with lower perioperativemorbidity and mortality and comparable OS to patients selected for EPP

– EPP and extended P/D are not interchangeable procedures and should be selected on anindividual basis following the recommendations of an experienced MDT

Cao et al. J Thorac Oncol 8, 2013; (Suppl 2; MO14.03)

O21.02 Phase III trial comparing irinotecan plus cisplatin (IP) withetoposide plus cisplatin (EP) in Korean patients with extensive disease(ED) small cell lung cancer (SCLC) – Kim D-W et al

PD

Stratification


• Korean patients withextensive disease SCLC

IP (irinotecan 65 mg/m2 IV ond1 & 8 + cisplatin 70 mg/m2 IV

on d1, q3w)n=181

Prospective, randomised, multicentre Phase III trial

Objective: To compare irinotecan plus cisplatin (IP) with etoposide plus cisplatin (EP) in patientswith SCLC

Primary endpoint

• OS

R

PD

Stratification

• ECOG status

• Centre

extensive disease SCLC

• No prior chemotherapy

• ECOG PS 0–2

• Measurable disease

(n=362)

EP (etoposide 100 mg/m2 IV ond1–3 plus cisplatin 70 mg/m2 IV

on d1, q3w)n=181

Kim et al. J Thorac Oncol 8, 2013; (Suppl 2; O21.02)

Secondary endpoints

• ORR, PFS and safety

Irinotecan plus cisplatin (IP) with etoposide pluscisplatin (EP) in SCLC

• Key results– Mean (± SD) number of cycles administered were 4.59 (1.98) for IP and 4.37 (1.96) for EP, while

duration of follow-up was 12.5 (95% CI 11.2, 13.8) and 11.4 (95% CI 10.4, 12.4) months, respectively– OS did not significantly differ between IP and EP (median 10.9 vs. 10.3 months; HR 0.879, 90% CI 0.73,

1.05; p=0.1207), nor did PFS (median 6.5 vs. 5.8 months; HR 0.846, 90% CI 0.71, 1.01; p=0.1158)

OS according to pre-defined subgroups

Subgroup n HR (90% CI)

Male

Age <65 years

328

164

0.812 (0.671–0.984)

0.717 (0.543–0.947)

– ORR (CR + PR) was significantly higher for IP (62.4%) vs. EP (48.2%, p=0.0064)– Grade ≥3 anaemia, nausea and diarrhoea were significantly more common with IP than EP (27.0% vs.

17.7%, 4.2% vs. 0.5% and 10.2% vs. 2.7%, respectively, all p<0.05)

• Key conclusions– Among Korean patients with extensive disease SCLC, IP was not superior to EP for OS– OS was prolonged by IP compared with EP in male patients, those with younger age (<65 years) and

those with good ECOG performance status– Although ORR was higher with IP than EP, IP was associated with more grade 3 toxicities

Kim et al. J Thorac Oncol 8, 2013; (Suppl 2; O21.02)

0 1 2

Age <65 years

ECOG 0/1

164

308

0.717 (0.543–0.947)

0.812 (0.667–0.989)

Favours IP Favours EPHR

O21.06 MLN8237 (alisertib), a selective aurora a kinase(AAK) inhibitor, in patients with relapsed/refractory smallcell lung cancer (SCLC): phase 2 results – Havel L et al

Alisertib 50 mg BID


• Relapsed/refractory SCLC

• ECOG PS 0–1

Phase II 5-arm study

Objective: To evaluate the efficacy and safety of the recommended Phase II dose of MLN8237(alisertib) in the cohort of patients with SCLC

Primary endpoint

• ORR

Secondary endpoints

• Safety, TTP, DOR and PFS

Alisertib 50 mg BIDfor 7 days

(21-day cycles)PD

• ECOG PS 0–1

• ≤2 prior cytotoxic regimens


(n=48)

Havel et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract O21.06)DOR, duration of response; TPP, time to progression

Alisertib in SCLC: results

• Key results

All SCLC arm patients[response-evaluable] (n=48)

Chemo-sensitive(n=36)

Chemo-refractory(n=12)

Median cycles, n (range) 2.5 (1–21) 4.5 (1–21) 2 (2–6)

Best response, n (%)ORR (PR)SDPD

10 (21)16 (33)22 (46)

7 (19)13 (36)16 (44)

3 (25)3 (25)6 (50)

– Grade ≥3 AE occurred in 72% with the most common (≥5%): fatigue, neutropenia, anaemia, diarrhoea,stomatitis, thrombocytopenia, decreased WBC, confusional state and febrile neutropenia

• Key conclusions– The safety profile of alisertib was generally manageable, but safety has to be monitored closely– Alisertib had antitumor activity in SCLC patients with sensitive or resistant/refractory relapse– A follow-up randomised Phase II of alisertib in combination with paclitaxel will start soon

Havel et al. J Thorac Oncol 8, 2013; (Suppl 2; Abstract O21.06)Sensitive, recurrence >90 days of frontline therapyResistant/refractory, recurrence ≤90 days of frontline therapy

Median PFS, months 2.11 2.58 1.74

Median TTP, months 2.6 2.8 1.4

Median DOR, months 4.1 4.4 3.1

O27.02 Preliminary results from the FRAGMATIC trial: A randomised Phase IIIclinical trial investigating the effect of FRAGMin® Added to standard Therapy Inpatients with lung Cancer – Macbeth F et al

• Study objective

– To establish if adding low-molecular weight heparin (dalteparin, Fragmin®) to standard treatmentimproves outcomes in patients with primary bronchial carcinoma


– This open-label, multicentre, randomised, controlled Phase III trial enrolled patients who had beendiagnosed with NSCLC or SCLC in the previous 7 weeks and had an ECOG PS of 0–3

– Dalteparin 5000 IU was administered SC daily for 24 weeks in addition to chemotherapy; the controlgroup received only chemotherapy

– Primary outcome was OS; secondary outcomes included: toxicity, venous thromboembolism (VTE)-free– Primary outcome was OS; secondary outcomes included: toxicity, venous thromboembolism (VTE)-freesurvival, metastasis-free survival, QoL and cost utility

• Key results

– In total 2,202 patients were enrolled, 82.2% had NSCLC in both treatment groups

– There was no significant difference in OS (HR 0.98; 95% CI 0.89, 1.07) between the two treatmentgroups; median survival was 10.6 vs. 11.1 months and 1-year survival rate was 44.4% vs. 46.3% fordalteparin and control groups, respectively

– Bleeding events were more common with dalteparin (19.6%) than for control (13.9%). Fewer VTEswere observed with dalteparin (n=33, 3.0%) compared with control (n=66, 6.0%)

• Key conclusions

– The addition of dalteparin to chemotherapy did not improve OS or metastasis-free survival but didsignificantly reduce the risk of VTEs

– Routine prophylactic dalteparin is not recommended in this patient group

Macbeth et al. J Thorac Oncol 8, 2013; (Suppl 2; O27.02)

30 october 2013 | sydney, australia wclc 2013 - etop-eu.org

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