developed in association with the european thoracic

ASCO 2011

Supported by Eli Lilly & Company

Developed in association with the European Thoracic Oncology Platform

3-7 June 2011 | Chicago, USA

Special thanks to the ETOP reviewers

•  Éric Dansin, Lille, France •  Radj Gervais, Caen, France •  Enriqueta Felip, Barcelona, Spain •  Solange Peters, Lausanne, Switzerland •  Sanjay Popat, London , UK

Table of contents

• Biomarkers • Early-stage/locally-advanced NSCLC • Metastatic NSCLC

– 1st line – Maintenance – Later lines – Elderly

• SCLC and MPM

BIOMARKERS

#7566: ALK rearrangement in a selected population of advanced non small cell lung cancer patients. FISH and immunohistochemistry diagnostic methods, prevalence and clinical outcomes - Pablo Martinez et al

•  Study objective –  To explore FISH and IHC as diagnostic methods, prevalence and clinical outcomes of

ALK rearrangement in a selected population of NSCLC •  Study type/design

–  Patients with NSCLC who had previously been screened for EGFR mutation (June 2006 - January 2010) were selected

–  ALK rearrangement was identified using FISH and IHC (D5F3 monoclonal antibody-mAb) –  For IHC ALK protein expression, positivity was defined as tumour-specific staining of any

intensity in ≥10% of tumour cells •  Patients

–  Data available for 71 patients: median age: 61 years (range 36-83), 51% female, 80% adenocarcinomas (ADK), 7% squamous, 13% NOS carcinomas, 32% never smokers and 30% former smokers

Martinez et al. J Clin Oncol 29: 2011 (suppl; abstr 7566)

Key results

ALK R: ALK rearrangement; EGFR M: EGFR mutant; ALK WT: ALK wild type; EGFR WT: EGFR wild type Martinez et al. J Clin Oncol 29: 2011 (suppl; abstr 7566)

•  Patient characteristics according to presence of ALK rearrangement and EGFR mutation

•  ALK positive and EGFR mutants have a better survival than WT/WT patients (p=0.003 and

p=0.03, respectively)

ALK R / EGFR WT (n=6, 8.5%)

EGFR M / ALK WT (n=9, 12.7%)

ALK WT & EGFR WT (n=56, 78.8%)

Median age 53 (38-68) 59 (36-76) 62 (42-83)

Sex Male Female

3 3

2 7

30 26

Smoking Never Former Current

4 0 2

5 3 1

12 18 26

Histology ADK SCC NOS

5 0 1

9 0 0

43 5 8

Conclusions •  The prevalence of ALK rearrangement is 8.5% in a caucasian-selected

population of NSCLC •  ALK-positive patients have different clinical features and a better prognosis

than EGFR WT and ALK-negative patients •  IHC with D5F3 mAb against ALK is a promising method for detecting ALK

rearrangements in NSCLC patients

Martinez et al. J Clin Oncol 29: 2011 (suppl; abstr 7566)

#7575: DIRECT (DNA-mutation Inventory to Refine and Enhance Cancer Treatment): A catalogue of clinically relevant somatic mutations in lung cancer - Leora Horn •  Study type/design

–  Systematic review of the literature and identification of papers reporting on patients with EGFR mutations

–  Demographic data collection: age, ethnicity, smoking status, EGFR mutation, therapy administered (chemo, TKI), response and survival

–  General linear modeling used to assess association between mutation, therapy and response

•  Patients –  >1000 papers reviewed and 115 papers identified –  Data on 1152 individual patients with EGFR mutations (91% patients with

adenocarcinoma) –  62% never smokers, 92% stage IV NSCLC

Horn et al. J Clin Oncol 29: 2011 (suppl; abstr 7575)

Key results •  Mutations

–  154 different mutations identified: 48% exon 19 deletion, 27% L858R, 3% G719X, 1% L861Q and 21% other

•  EGFR TKI –  74% patients had first line EGFR TKI –  There was no significant difference in response to EGFR TKI for

patients with L858R or L861Q mutation compared with patients with exon 19 deletion

–  Patients with G719X and other mutations had a significantly worse outcome when treated with EGFR TKIs


Conclusions •  The DIRECT database is the start of a larger catalogue of clinically-

relevant somatic mutations in lung cancer –  Catalogue being created to aid physicians within the clinic in their

selection of therapies for patients with various mutations and lung cancer

•  The DIRECT database has started with patients with known EGFR mutations, but the programme will be expanded to incorporate all known mutations with potential clinical significance –  Reporting of mutation data (as they emerge) is encouraged

•  It is planned to make the DIRECT database amenable to query to further enable a genetically-informed approach in the treatment of lung cancer


#7590: Initial detection of the double epidermal growth factor receptor (EGFR) mutation (L858R or deletion in exon 19 [del 19] plus T790M) in non-small-cell lung cancer (NSCLC) patients (p) with brain metastases (mets) and the influence of first-line chemotherapy on outcome to erlotinib – Teresa Moran et al

•  Study objective –  To investigate if site of metastases and/or prior chemotherapy influences

outcome in NSCLC patients with double EGFR mutations •  Study type/design

–  T790M mutation was assessed in 129 advanced NSCLC patients by TaqMan assay in the presence of a peptide-nucleic acid designed to inhibit the amplification of the wild-type allele

•  Patients –  129 patients harbouring EGFR mutations (del 19, mut 21), evaluable for RR,

PFS and OS, and tumour tissue availability to allow baseline assessment of T790M

Moran et al. J Clin Oncol 29: 2011 (suppl; abstr 7590)

Key results •  T790M mutations

–  De novo T790M mutations were identified in 35% (45 of 129) of EGFR-mutant patients before receiving erlotinib

–  T790M mutation was detected more frequently in patients with bone metastases (35.6% vs 16.7%; P=0.03)

•  Survival and PFS –  PFS was 12 months for patients with double mutations and 18 months for patients with

only L858R or del 19 (P=0.02) –  No effect on PFS or median survival was observed in patients with T790M mutation

according to bone, lung, liver or pleura metastases –  When patients with T790M were divided according to the presence of brain metastases

•  PFS: 1 month for 4 patients with brain metastases vs 13 months for 41 patients without brain metastases (p=0.002)

•  Median survival: 6 months for patients with brain metastases vs 36 months for those without (p=0.009)

–  Overall, in the multivariate analysis, the presence of double mutation did not affect the risk of shorter median survival (HR, 1.3; P=0.49), but patients who had received prior chemotherapy had significantly longer median survival (HR 0.48; P=0.02)


Conclusions •  In pre-treatment EGFR mutant lung cancers, T790M has a negative impact

on PFS, which is associated with the EGFR-sensitizing exon 19 deletion •  The presence of T790M was associated with very poor outcome only in

patients only with original brain metastasis, with a PFS of 1 month and median survival of 6 months

•  However, patients with brain metastasis without pre-treatment T790M demonstrated an outcome which did not differ from other EGFR mutant lung cancers with other metastases

•  In the multivariate analysis, patients receiving erlotinib as second-line therapy had better PFS and survival compared with those receiving erlotinib in the first-line setting


#7056: BRCA1 mRNA expression patterns in a large lung cancer cohort Karen Kelly et al University of California, Davis, Sacramento, California, USA

Objective & methods •  Objective:

–  To examine the distribution of BRCA1 expression in NSCLC and to determine the relationship between BRCA1 expression and ERCC1, tumour histology and patient demographics, using specimens from the extensive response Genetics Inc (RGI) tumour collection

•  Methods: –  BRCA1 mRNA levels were quantified from micro-dissected, formalin-fixed,

paraffin-embedded lung cancer specimens from the RGI data by RT-PCR –  Data were correlated with patient demographics and ERCC1 mRNA

expression levels

Kelly et al. J Clin Oncol 29: 2011 (suppl; abstr 7056)

Patient specimens

Patient specimens •  Median age:

66 years (range: 34-90) •  Sex: 53% female •  Stage of disease:

early: 4%, late 96% •  Histology: adenocarcinoma: 60%,

squamous cell: 15%, NOS/other: 25%

All patients Squamous cell Adenocarcinoma P value N 425 72 256 Mean 1.24 2.99 0.80 <0.0001 Median 0.81 2.39 0.57 <0.0001 Range 0.0-12.05 0.03-12.05 0.0-3.8

Relationship between BRCA and ERCC1

R2 = 0.190 p<0.0001

16 8 4 2 1

0.5 0.25

0.125 0.0625

0.03125

0.12

5

0.25

0.5 1 2 4 8 16

BR

CA

ERCC1


Relationship between BRCA and gender / histology

14

12

10

BR

CA

1 Le

vels

4

3

2

1

0

Gender and Histology

p=0.49 p=0.5 14

12

10

RT-

PCR

Uni

ts 4

3

2

1

0 Squamous Adeno

p<0.0001

BRCA1 Levels


Conclusions & future directions •  Conclusions:

–  BRCA1 expression levels are significantly higher in squamous cell carcinoma vs adenocarcinoma

–  BRCA1 expression levels correlate modestly with ERCC1 expression levels, but not sufficiently to predict the expression of the other

•  Future directions: –  A PARP inhibitor in combination with DNA damaging agent(s) may lead

to increased cytotoxicity in tumours with deficient or reduced BRCA1 levels

–  Adenocarcinomas may benefit from this approach due to their lower BRCA1 expression levels

–  A randomized Phase II study of chemotherapy +/- a PARP inhibitor in patients with lung adenocarcinoma is planned


#7506: Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI’s Lung Cancer Mutation Consortium (LCMC) Mark G. Kris et al Memorial Sloan-Kettering Cancer Center, New York, NY

Study design •  Study objectives

–  To test 1000 tumour specimens from patients with lung adenocarcinoma for KRAS, EGFR, BRAF, HER2, PIK3CA, AKT1, NRAS, MEK1 and EML4-ALK, and MET amplification

–  To use the information in real time to either select erlotinib with EGFR mutations or recommend a ‘LCMC-linked’ clinical trial of an agent targeting the specific mutation identified

•  Patient enrollment

–  1234 patients consented

–  170 patients (14%) ineligible/inadequate tissue

–  1064 patients in study group

Kris et al. J Clin Oncol 29: 2011 (suppl; abstr 7506)

Use Data to Select Therapy

(Erlotinib with EGFR mutation)

Recommend Clinical Trial of Agent

Specific for Target

Patients and study plan


1000 patients Stage IV

ECOG PS 0-2 Lung Adenocarcinoma

Sufficient Tissue (Paraffin) Informned Consent

Central Confirmation of

Adenocarcinoma Diagnosis (1 slide)

Report to LCMC Cirtual

Database

Report to Physician

Mutational Analysis CLIA-Certtified lab at LCMC site: KRAS, EGFR, EML4-ALK, BRAF,

HER2, PIK3CA, NRAS, MEK1, AKT1, MET amplification

Key findings: incidence of single driver mutations


Doublemutants 3%

No mutation detected

KRAS22%

EGFR17%EML4-ALK

7%

BRAF

MEK1

NRASAKT1

PIK3CA

HER2MET AMP

Mutation found in 54% (280/516) of tumours completely tested (CI 50-59%)

Key findings: 97% of mutations mutually exclusive


# Single mutations ALK AKT BRAF EGFR HER2 KRAS MEK1 MET NRAS PIK3CA

ALK (38) X 1 2 1 1

AKT1 (0) X

BRAF (9) X 1

EGFR (89) X 1 3

HER2 (3) X

KRAS (114) X 1

MEK1 (2) X 1 1

MET AMP (3) X

NRAS (2) X

PIK3CA (6) X

Number of patients with variants in indicated combination of genes, 3% (14/516)

Using LCMC data to guide care – MSKCC patients


121 Enrolled

102 Multiplex mutation testing

and/or FISH completed

60 (59%) Driver mutations found

31 (30%) Received therapy targeted

to specific mutation

19 – erlotinib as initial therapy

16 – clinical trial of agent for identified mutation target

Conclusions •  An actionable driver mutation was detected in 54% of individuals with lung

adenocarcinoma

•  Information is used in real time to select erlotinib as initial therapy and direct patients to linked trials

•  New driver mutations can quickly be added to the multiplexed process in place at 11 sites

•  Plans have been made to maintain and expand the scope of the LCMC when ARRA funding ends – LCMC 2.0

•  The process is a model for lung and other cancers


#7007: Use of a three-microRNA signature to discriminate prognostic groups in early-stage NSCLC patients in the IFCT-0002 trial – Celine Mascaux et al

•  Study objective –  To test hypothesis that microRNA (miRNA) expression profile could

discriminate prognostic groups in early-stage NSCLC patients •  Study type/design

–  17 miRNAs selected based on their association with lung cancer –  277 formalin-fixed, paraffin-embedded, surgically-resected tumour

specimens macrodissected •  Total RNA was extracted from these samples

–  Expression of 17 miRNAs was successfully analyzed by Taqman qRT-PCR in 276 (99%) samples

–  Multivariate analysis with Cox model for overall survival (OS) was validated with a two-step bootstrap resampling analysis

Mascaux et al. J Clin Oncol 29: 2011; (suppl; abstr 7007)

Key results •  Low miR210, miR21, and miR15a expression significantly predicted better survival when

adjusted for stage and number of administered cycles •  A model including the three miRNAs discriminates three prognostic groups:

–  Group 1: patients with the three miRNAs under the defined cut-off (n=129) –  Group 2: among the remaining patients, patients with miR21 under Q1, independently of

status of the two other miRNAs (n=82) –  Group 3: all remaining patients (n=65)

•  Univariate analysis –  Group 1: showed the best OS (> 83 months) –  Group 2: showed intermediate OS (66 months) –  Group 3: showed shortest OS (36 months, p=0.001, log-rank test) –  Adjusted HRs for OS with Group 3 as reference were 0.445, 95%CI [0.290-0.682],

p=0.0002 and 0.632, 95%CI [0.406-0.986], p=0.043 for Group 1 and 2, respectively –  Harrell’s concordance index of 0.83, 95%CI [0.67-0.95] showed a good predictive

accuracy –  A first bootstrap with 300 random resampling demonstrated stability of the miR model

which significantly predicted OS in 257 samples (85.7%) •  Reproducibility of model was confirmed by a second similar bootstrap procedure


Conclusions •  A miRNA model associating mIR15a, mIR21 and mIR210 accurately

discriminates three prognostic groups in early-stage NSCLC patients treated by perioperative chemotherapy

•  Predicted or validated targets of those three miRs include Rho and Ras regulators, angiogenesis and invasion genes, hippo pathway and DNA repair genes


#7008: Association between DNA-repair gene and glutathione S-transferase gene polymorphisms and clinical outcome in patients (pt) with localized non-small cell lung cancer (NSCLC) treated with sequential radiochemotherapy – Jan Stoelmacher-Williams et al

•  Study objective –  To evaluate the impact of DNA-repair and glutathione S-transferase gene polymorphisms on clinical

outcome measured by PFS and OS in patients with localized NSCLC •  Study type/design

–  DNA for genotyping was extracted from archived paraffin embedded formalin-fixed tumor tissues –  Genotyping and analysis of genomic polymorphisms of ERCC1, XRCC1, XRCC2, XPA, GSTP1,

GSTT1 and GSTM1 •  Patient population

–  116 patients with NSCLC Ib-IIIb 85% received cisplatin-based chemotherapy prior to radiation •  Key results

–  Patients: median age 63 years; ECOG 0/1 and 2: 90%, 10%; 87% male –  Responses: 72 patients (62%) achieved CR or PR, 32 patients (27%) SD and 14 patients (11%) PD –  Median OS (all patients) was 23.4 months and median PFS was 9.8 months –  GSTP1-105Val/Val genotype was associated with superior PFS and OS –  XPD-312N/N genotype group was was associated with superior median OS –  Performance status (p<0.001), XPD-312N/N (p=0.007), GSTT1 presence (p=0.002) and surgical

resection (p<0.001) were independent predictors of OS •  Key conclusion

–  DNA-repair and GST polymorphisms may be associated with clinical outcome in NSCLC patients with localized disease and multimodal chemoradiation

Stoelmacher-Williams et al. J Clin Oncol 29: 2011; (suppl; abstr 7008)

#7009: Genetic variations in multiple drug action pathways and survival in advanced-stage non-small cell lung cancer treated with chemotherapy – Ping Yang et al •  Study objective

–  To systematically investigate genetic variants in glutathione metabolism (GSH), DNA repair, cell cycle and EGFR pathways and their association with survival in advanced-stage NSCLC treated with commonly used chemotherapy drugs

•  Study type/design –  A total of 894 tagging single nucleotide polymorphisms (SNPs) in 70 genes from the four pathways were

genotyped in a 1076-patient cohort •  Key results

–  Poorer survival was observed in patients with genetic variations in MAP3K1 from the EGFR pathway (HR=1.25, 95% CI=1.05-1.50) and GSS from the GSH pathway (HR=1.45, 95% CI=1.20-1.77)

–  Subgroup treated with platinum-taxane doublet: •  Predictive yet opposite effect on survival was observed in MAP3K1 (HR=1.38, 95% CI=1.11-1.72) vs in

RAF1 (HR=0.64, 95% CI=0.5-0.82) variations of the EGFR pathway (subgroup treated with platinum-taxane doublet)

–  Subgroup treated with platinum-gemcitabine doublet: •  RAF1 and GPX5 (GSH pathway) variations showed protective effects on survival (HR=0.54, 95%

CI=0.38-0.77; HR=0.67, 95% CI=0.52-0.85, respectively) •  NRAS (EGFR pathway) and GPX7 (GSH pathway) variations showed hazardous effects on survival

(HR=1.91, 95% CI=1.30-2.8; HR=1.83, 95% CI=1.27-2.63, respectively) •  Key conclusions

–  Genetic variations in genes involved in the EGFR and glutathione pathways may be associated with OS among patients with advanced-stage NSCLC treated with platinum-, taxane, and/or gemicitabine combinations

Yang et al. J Clin Oncol 29: 2011; (suppl; abstr 7009)

#7024: Predictive value of thymidylate synthase and folylpoly-glutamate synthetase for clinical benefit from pemetrexed in malignant pleural mesothelioma – Daniel C. Christoph et al

•  Study objective –  To evaluate if folylpoly-γ-glutamate synthetase (FPGS) and thymidylate

synthase (TS) protein expression may predict response and outcome following pemetrexed (PMX) treatment in patients (pts) with malignant pleural mesothelioma (MPM)

•  Study type/design –  Retrospective analysis of pre-treatment tumour samples from 69 pts –  All pts received first-line PMX-based CT :

•  Cisplatin 50 mg/m2 (d1/8) + 500 mg/m2 PMX (d1) Q3W •  Carboplatin AUC 5 + 500 mg/m2 PMX, both on d1 Q3W or •  500 mg/m2 PMX alone on d1 Q3W

–  TS and FPGS protein expression levels were evaluated by IHC using the H-Scoring system (ranging from 0 to 300), which relies on the product of intensity of specific tumour cell immunoreactivity (range 0 to 3) and the percentage of positive tumour cells

–  Radiologic evaluation of response was performed according to RECIST

Christoph et al. J Clin Oncol 29: 2011; (suppl; abstr 7024)

Key efficacy and safety data •  FPGS but no TS expression levels were associated with PFS •  FPGS also correlated with ORR but not OS •  TS expression was associated with a trend towards better OS


100

75

50

25

0

Surv

ival

(%)

0 200 400 600 800 1000

FPGS H-score < median FPGS H-score ≥ median

PFS (days)

100

75

50

25

0

Surv

ival

(%)

0 200 400 600 800 1000

TS H-score < median TS H-score ≥ median

PFS (days)

PFS (days) p-value (Log-rank test) p-value (Wilcoxon test) HR 95% CI

FPGS H-score < median H-score ≥ median

185.0 252.2

0.0441 0.0046 1.997 1.018−3.917

TS H-score < median H-score ≥ median

252.0 203.0

0.8012 0.4295 0.9271 0.5144−1.671

Conclusions •  FPGS is a novel predictive biomarker for PMX therapy •  High FPGS protein expression in MPM correlates with

response to PMX therapy and improved PFS, but not with prolonged OS

•  Further predictive validation of the prognostic and predictive value of FPGS expression in MPM is warranted


#7517: The introduction of systematic genomic testing for patients with non-small cell lung cancer (NSCLC) at Dana-Farber Cancer Institute (DFCI) – Taylor M. Ortiz et al •  Study objective

–  To use systematic genomic testing to identify potential predictive biomarkers to select targeted therapy for NSCLC

•  Study type/design –  Prospective study in patients with advanced non-squamous NSCLC –  Pathology specimens were dissected and analyzed for mutations in selected exons of EGFR, KRAS, BRAF,

PIK3CA and HER2 –  ALK rearrangements were detected with FISH

•  Key results –  226 consecutive patients were tested (median age 62 years; 134 [59%] female; 195 [86%] adenocarcinoma) –  5 patients had two different specimens tested –  Of 231 specimens, 25 (11%) either failed analysis or were inconclusive (most frequent reason for inconclusive

results was less than 50% tumour in the specimen [15/25]) –  Of the remaining 206 specimens (204 patients), all underwent mutation testing for BRAF, HER2 and PIK3CA;

197/204 for EGFR, 187/204 for KRAS and 116/204 for ALK rearrangements –  Mutations were identified in 110/204 (54%) patients (EGFR 30; KRAS 52; BRAF 9; HER2 9; ALK 8; PIK3CA 5)

of whom three had concurrent mutations, all involving PIK3CA –  31 of 61 (51%) patients with EGFR, HER2, BRAF or EML4-ALK alterations were treated with molecularly

targeted therapy based on their genetic alteration (9.6% patients with KRAS mutations received erlotinib compared with 67% of patients with EGFR mutations)

•  Key conclusion –  Large scale testing for alterations in EGFR, KRAS, BRAF, PIK3CA, HER2 and EML4-ALK is feasible and has

an impact on treatment Ortiz et al. J Clin Oncol 29: 2011; (suppl; abstr 7517)

#7518: SNaPshot genotyping of non-small cell lung cancers (NSCLC) in clinical practice – Lecia V. Sequist et al

•  A retrospective chart review of all NSCLC patients treated at Mass General genotyped via SNaPshot from March 2009 to May 2010

•  SNaPshot was performed only in adenocarcinomas during the first 6 months; HER2 and IDH were added to the panel after 1 year

Sequist et al. J Clin Oncol 29: 2011; (suppl; abstr 7518)

NSCLC Patients at Mass General 3/09–5/10

N=1,016

Specimens on which SNaPshot was ordered

N=589

Insufficient Tissue N=37

Successful Genotyping

N=552

ALK FISH only N=21

SNaPshot Version 2 N=100

SNaPshot Version 1 N=431

Genotypes included in SNaPshot Testing ALK FISH, mutations in: AKT, APC, beta-catenin, BRAF, EGFR, HER2, IDH1, KIT, KRAS, NOTCH1, NRAS, PIK3CA, PTEN, TP53 (this assay captures only a subset of TP 53 mutations expected to exist in NSCLC)

Genotypes detected Frequency of each mutation and overlap


Association of mutations with smoking status

TP53 5% PIK3CA 4%

CTTNBI 2% BRAF 1% NRAS 1%

HER2 IDH1

No mutation 49%

KRAS 25%

EGFR 13%

ALK 5% KRAS 129 isolated (135 total)

EGFR 63 isolated (73 total)

PIK3CA (22 total)

12

ALK 27 8

6

BRAF

NRAS (1) HER2

TP53 (25 total)

5 1 2

B-cat (11 total)

(1) IDH1

15

4

1 1 2 6

4 1

Overall Group KRAS* NRAS* PI3K

EGFR* ALK* B-cat* BRAF

Never Former Current

*significantly different smoking distribution compare with wild-type

Conclusions •  In this study, 51% of cancers were positive for a mutation/

translocation –  Many genotypes segregate significantly by smoking status

•  Clinical characteristics should not be used to select patients for genotyping as trends for different driver mutations diverge

•  32% of patients with advanced disease and a targetable mutation were able to receive genotype-directed therapy

•  SNaPshot genotyping can be integrated into SoC


#7529: Exploratory biomarker analyses from OAM4558g: A placebo-controlled Phase II study of erlotinib ± MetMAb in patients with advanced non-small cell lung cancer (NSCLC) – Wei Yu et al •  Study objective

–  To explore tumour biomarkers related to c-Met and/or EGFR signalling in patients treated with erlotinib ± MetMAb in the OAM4558g study

•  Study type/design –  Exploratory biomarker levels were measured by FISH, qRT-PCR or various mutation detection

techniques, using archival tumour tissue specimens –  Plasma HGF levels were measured by ELISA –  Analyses with outcome were carried out independent of Met Dx status

•  Patients and samples –  Baseline characteristics of patients with available tumour or plasma specimens were

comparable –  MET gene copy number was evaluated in 96 specimens

•  Results –  There was a non-significant trend towards improved OS when MET-positivity was ≥5 copies/cell

(HR 0.47, p=0.019) but not at lower thresholds (i.e. ≥4 copies/cell) –  EGFR mutations were detected in 6/7 responders –  KRAS mutation status did not affect OS for patients on MetMAb –  High expression levels of MET, HGF, EGFR, AREG, or EREG mRNA did not independently

predict OS –  There was a trend towards improved OS in patients with low baseline plasma HGF on MetMAb

(HR 0.46, p=0.11) •  Conclusions

–  These data support c-MET IHC as a sensitive independent predictor of OS benefit from MetMAb –  Continued investigation of biomarkers is warranted in future clinical studies

Yu et al. J Clin Oncol 29: 2011 (suppl; abstr 7529)

#7530: Use of negative thyroid transcription factor (TTF-1) status to predict for negative epidermal growth factor receptor (EGFR) mutations (Mts) status with a high negative predictive value (NPV) in patients (pts) with adenocarcinomas (AC) of the lung – Neeta Somaiah et al.

•  Background/rationale for study –  TTF-1 is expressed in approximately 72% of ACs –  EGFR mutations are present in 13-15% of an unselected patient population,

but results of this test take approximately 4 weeks in most commercial laboratories •  May delay selection of the most appropriate treatment

•  Study objective –  To determine whether ACs negative for TTF-1 would also be negative for

EGFR mutations •  Study design

–  Micro-dissected formalin-fixed, paraffin-embedded tissue from 693 patients with NSCLC were analyzed for EGFR mutations by allele-specific PCR •  Of these, 301 were ACs •  TTF-1 status was known for all AC specimens

–  The NPV for a range of true prevalence of EGFR mutation was estimated using a Bayesian model

Somaiah et al. J Clin Oncol 29: 2011; (suppl; abstr 7530)

Key results •  EGFR mutations were present in 224 of 301 ACs

•  The sensitivity, specificity and NPV describing the association between TTF-1 and EGFR mutation status is shown in the table below –  ACs of the lung that areTTF-1 negative have a 99% probability of being EGFR WT


EGFR Mutation Total

Positive Negative

TTF-1 Positive 222 49 271 Negative 2 28 30

Total 224 77 301

Parameter % 95% CI Sensitivity 99.1 96.8–99.9 Specificity 36.4 25.7–48.1 NPV 99.5 98.6–99.9

Conclusions •  Patients with ACs of the lung that are that are TTF-1 negative

have a high (99%) probability of being EGFR WT •  As such, these patients could be initiated on chemotherapy

while awaiting their results of EGFR mutation testing –  Would enable earlier initiation of chemotherapy treatment in

approximately 30% of patients


#7534: Comparison of high sensitive IHC, FISH, and RT-PCR direct sequencing for detection of ALK translocation in lung cancer - Tetsuya Mitsudomi et al •  Study objective

–  To evaluate the reliability of currently available methodologies to assess ALK translocation in lung cancer

•  Study type/design –  RNA was extracted from frozen tumour samples or touch imprint cytologic preparations –  RT-PCR direct sequencing for EML4-ALK fusion, or KRAS or EGFR gene mutations was performed –  IHC was performed using a mouse monoclonal antibody for ALK –  An ALK break-apart probe was used for FISH

•  Patients and samples –  345 resected lung cancer specimens and 44 biopsy specimens were used

•  Conclusions –  IHC using commercially available antibody and high sensitivity visualization kit was feasible for archival

samples and small biopsy specimens –  This method was simple and reliable, and so was considered the most suitable method for screening

ALK-positive tumours

Mitsudomi et al. J Clin Oncol 29: 2011 (suppl; abstr 7534)

IHC FISH +/-

RT-PCR direct sequence

Tissue microarray (n=345)

+12 -333

12/0 Not determined

8/0/0/4 0/132/33/168

Biopsy specimens (n=44)

+6 -38

6/0 0/38

6/0/0/0 0/15/1/22

#7003: Proteomic analysis for detection of NSCLC: Results of ACOSOG Z4031 – David Harpole Jr et al. •  Study objective

–  To prospectively determine whether the serum proteomic profile can predict the presence of primary NSCLC in patients with CT suspicious lung lesions

–  Secondary objectives: correlation of serum proteomic with pathological nodal status, histopathologic features of NSCLC and survival

•  Study type/design –  Patients with a clinically suspicious stage I (cT1-2 N0 M0) lung lesion were enrolled in

Z4031 between 02/2004 and 05/2006 (n=1074) •  913 eligible patients (723 patients with NSCLC and 190 patients with benign nodules)

–  Resection for NSCLC: lobectomy with MLNS –  Fresh-frozen and FFPE tumour with pre- and post-operatively (60-90 days post resection)

blood were collected prospectively after informed consent –  Ciba Chrome Blue was used to capture low molecular weight proteins in pre-operative

serum (un-digested) followed by mass analysis on a prOTOF 2000 MALDI-TOF mass spectrometer (MS) in duplicate

–  The spectra were normalized and the maximum and sum amplitudes within a m/z bin were used as abundance values

–  Features were identified by m/z values

Harpole et al. J Clin Oncol 29; 2011 (suppl; abstr 7003)

Key efficacy and safety data •  Patients with NSCLC were older (median 67.2 yrs vs 59.7 yrs, p < 0.0001) and had

larger nodules (57.9% vs. 29.3% ≥ 2.0 cm, p < 0.0001) •  Of patients with NSCLC, 28% were squamous, 61.3% were adenocarcinoma and

10% were other NSCLC •  690 eligible patients had at least one analyzable spectra •  The MS proteomic profiles failed to discriminate between the groups

–  Lack of high signal proteins in the spectra: only a few per patients (20-25 usable spectra)

–  m/z Bins with significant values were often in the noise region of the spectra and did not contain identifiable proteins

•  MS proteomic profiles failed to accurately discriminate between the following groups (p<0.05) –  benign vs NSCLC –  squamous vs benign –  adenocarcinoma vs benign –  squamous vs adenocarcinoma


Conclusions •  Z4031 is the largest prospective multi-institutional lung cancer trial that

collected biological material (blood before and after resection, frozen tumour and frozen non-cancerous lung, FFPE tumour and non-cancerous lung) –  Usable serum MALDI proteomic profiles were successfully created from

more than 90% of samples •  The predictive accuracy of the proteomic model lacked sufficient power for

clinical utility •  The limit of detection for the newest MS platforms are not sufficient for

discovering discriminate protein profiles due to the dynamic range of the human proteome


EARLY-STAGE LOCALLY-ADVANCED NSCLC

#7029: Maintained sensitivity of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung cancers that recur after adjuvant TKI – Geoffrey Oxnard et al •  Hypothesis: Lung cancers that recur after stopping TKI therapy would not

harbour the T790M mutation and so would be sensitive to re-treatment with an EGFR TKI

•  Methods: –  Patients with recurrent EGFR-mutant lung cancer who received

adjuvant or neoadjuvant TKI therapy were identified from an institutional database

–  Eligible patients: Stage I-III NSCLC with an EGFR sensitizing mutation identified either at diagnosis or in the recurrent tumour specimen •  Recurrent tumour specimens were also evaluated for the T790M

resistance mutation –  Patients receiving retreatment with TKI therapy were followed for

response, PFS and OS

Oxnard et al. J Clin Oncol 29: 2011; (suppl; abstr 7029)

Results •  22 patients were identified

–  Median age: 61 (range: 37-88) –  All had adenocarcinoma histology –  64% had exon 19 EGFR mutation; 36% had

exon 21 mutation –  32% experienced recurrence during TKI; 68%

had recurrence after stopping TKI therapy •  Patients received adjuvant TKI for a median of 17

months (range 1-37)

•  14 patients with recurrence after stopping TKI were retreated –  Radiographic response was seen in 8 of 11

(73%) –  Median TTP: 10 months –  Median OS: 23 months

Oxnard et al. J Clin Oncol 29: 2011; (suppl; abstr 7029)

Median survival Median TTP

% p

rogr

essi

on fr

ee/a

live

100

80

60

40

20

0 0 6 12 18 24 30 36

Months from start of TKI re-treatment

T790M neg, 9

T790M pos, 0

0% T790M

Recurred after stopping TKI

Recurred on TKI

T790M neg, 9

T790M pos, 0

66% T790M

Group N Median months on TKI

Median months to recurrence

Recurred on adjuvant TKI

7 16 16

Stopped TKI due to intolerance

8 5 15

Completed planned course of TKI

7 25 39

Conclusions •  EGFR-mutant lung cancers that recur after stopping adjuvant TKI therapy

do not harbour T790M and can have durable responses to TKI retreatment •  Recurrence after adjuvant TKI therapy should not preclude TKI retreatment

–  A Phase II trial evaluating erlotinib in this setting is ongoing –  Future studies of adjuvant TKI therapy must prospectively consider the

important role of retreatment with TKI therapy for many of these patients •  An active drug given as adjuvant therapy may fail to show a survival

benefit for many reasons: –  Primarily cytostatic anti-tumour effects, but inadequately cytotoxic to

micrometastases –  Magnitude of toxicity outweighs anti-tumour effects –  Negative impact on tumour biology (accelerating metastases or

resistance) –  Negative impact on subsequent therapy due to a reluctance towards

retreatment at recurrence Oxnard et al. J Clin Oncol 29: 2011; (suppl; abstr 7029)

#7051: Outcomes of stereotactic body radiotherapy in patients with clinical stage I non-small cell lung cancer who are fit to undergo surgery – Suresh Senan et al •  Study objective

–  Patient outcomes after SBRT in potentially operable stage I NSCLC •  Study type/design

–  Analysis of data from a single institutional prospective database –  25% of lung SBRT cases (n=177 patients) were found to be potentially operable –  Patients consisted of 101 males and 76 females; median age 76 years; 60% staged as T1 and 40% T2 –  An SBRT dose of 60 Gy was delivered using a risk-adapted scheme in 3, 5 or 8 once-daily fractions,

depending on tumour size and location; follow-up chest CT scans were obtained at 3, 6 and 12 months, and yearly thereafter

•  Key results –  Median follow-up was 32 months –  Median OS was 61.5 months with 1-, 3- and 5-year survival of 94.7%, 84.7% and 51.3%, respectively –  OS at 3 years in pts with (n=59) and without (n=118) histological diagnosis did not differ significantly

(96% versus 81%, respectively, p=0.39) –  Post-SBRT 30-day mortality was 0% –  Toxicity was mild with grade ≥3 radiation pneumonitis and rib fractures in 2% and 3%, respectively.

•  Key conclusions –  Potentially operable patients who undergo primary SBRT have a median OS exceeding 5 years –  These findings support the ongoing randomized clinical trials that are comparing surgery and SBRT in

operable stage I NSCLC

Senan et al. J Clin Oncol 29: 2011 (suppl; abstr 7051)

#7015: Adjuvant chemotherapy (AC) in stage IB non-small cell lung cancer (NSCLC): Long-term follow-up of Cancer and Leukemia Group B (CALGB) 9633 – Gary M Strauss et al •  Study objective

–  To provide updated OS data for CALGB 9633 and correlate results with subgroups incorporated in the new 2010 AJCC staging system

•  Study type/design –  Resected stage IB patients were randomized to paclitaxel 200 mg/m2 and carboplatin AUC 6 q3wks x4

cycles or observation –  OS was the primary endpoint.

•  Patient population (including patient numbers) –  344 patients were randomized (1996-2003)

•  Key results –  Median follow-up is 9 years –  Study remains negative but there is a powerful trend toward improved OS for all patients (HR=0.82;

90% CI 0.65-1.04; p=0.084) –  6% advantage in 8-year OS favouring AC (51% vs. 45%; p=0.386) –  Median OS is 8.2/6.6 years in chemo/control groups –  Subgroup analysis using a 4 cm cut-off continues to show a strong OS signal favouring AC for those

with large tumours •  Key conclusions

–  While not statistically significant, long term follow-up of this underpowered study shows a strong OS signal for all pts and for pts with tumours ≥4 cm

–  Long-term data justifies AC in resected node negative NSCLC ≥4 cm in diameter Strauss et al. J Clin Oncol 29: 2011; (suppl; abstr 7015)

#7016: Phase I/II trial of bevacizumab (B) and erlotinib (E) with induction (IND) and concurrent (CON) carboplatin (Cb)/paclitaxel (P) and 74 Gy of thoracic conformal radiotherapy (TCRT) in stage III non-small cell lung cancer (NSCLC) – Tom Stinchcombe et al •  Study objectives and endpoints

–  Phase I: evaluate safety and toxicity, and determine erlotinib dose –  Phase II: PFS at 1-year (primary); ORR, OS and evaluate the feasibility of consolidation BE

•  Study type/design –  Patients (pts) received:

•  IND: Cb (AUC=6), P (225 mg/m2) and B (15 mg/kg) Q3W for 2 cycles •  CON (from d43): Cb (AUC=2) and P (45 mg/m2) weekly x 7 + TCRT 74 Gy

–  cohort 1 (n=5): B 10 mg/kg Q2W, cohort 2 (n=5) and cohort 3 (n=5): B 10 mg/kg Q2W and E at 100 mg/day (cohort 2) and 150 mg/day (cohort 3)Tuesday-Friday of each week

•  Consolidation: B 15 mg/kg Q3W + E 150 mg/day for 6 cycles •  Key results

–  45 patients (any histology) were accrued; median age 61 yrs (range 34 to 74), 33 non-SQ and 12 SQ; 29 stage IIIA and 16 stage IIIB; 33 pts PS 0 and 12 PS of 1

–  The recommended dose for Phase II was E 100 mg/day + B 10 mg/kg Q2W concurrent with TCRT 74 GY –  1-year PFS rate was 44% (95% CI, 30-58%) and median PFS was 10 months (95% CI, 8.4-20.3) –  Median OS was 18.7 months (95% CI, 13.4 to 33.2) (median OS in the non-SQ and SQ cohorts was 18.7 and 17.1

months, respectively) –  Primary Grade ≥ 3 toxicity observed with IND therapy was neutropenia (42%) –  Main Grade ≥ 3 toxicities observed with CON were oesophagitis (29%), pneumonitis (2%), neutropenia (16%), anaemia

(7%), thrombocytopenia (7%) •  Key conclusions

–  IND with CbPB is well tolerated and active –  CON with BE is associated with significant toxicity –  Consolidation therapy with BE after IND is not feasible in this setting –  PFS and OS with the addition of BE to CbP with TCRT 74 Gy appears similar to previous experience with CbP alone

with TCRT 74 Gy

Strauss et al. J Clin Oncol 29: 2011; (suppl; abstr 7016)

#7017: Phase II study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III non-small cell lung cancer – Joe Y. Chang •  Study objective

–  To improve toxicity and survival in patients with unresectable stage III NSCLC by using proton-beam therapy to escalate the radiation dose to the tumour

•  Study type/design –  44 patients with stage III NSCLC treated with 74 Gy (RBE) proton therapy with weekly carboplatin (AUC 2) and

paclitaxel (50 mg/m2) –  Disease was staged with PET/CT and treatments were simulated with 4-dimensional CT to account for tumour

motion •  Key results

–  Median follow-up was 19.7 months (range 6.1-44.4 months) and median OS was 29.4 months –  No patient experienced grade 4 or 5 proton-related AEs –  Most common non-haematological grade 3 toxicities were dermatitis (n=5), oesophagitis (n=5), and

pneumonitis (n=1) –  9 patients (20.5%) experienced local disease recurrence but only 4 (9.1%) had isolated local failure –  4 patients (9.1%) had regional lymph node recurrence (1 patient, 2.3%) had isolated regional recurrence –  19 patients (43.2%) developed distant metastasis –  OS and PFS rates were 86% and 63% at 1 year.

•  Key conclusions –  High-dose proton therapy with concurrent chemotherapy is well tolerated –  The 29.4-month median survival time and 20.5% total local failure rate are encouraging for inoperable stage III

NSCLC –  These findings have led to an ongoing Phase II study comparing proton therapy vs intensity-modulated RT to

74 Gy with concurrent CT in Stage III NSCLC Chang et al. J Clin Oncol 29: 2011; (suppl; abstr 7017)

METASTATIC NSCLC 1st line

#7502: Randomized phase III placebo-controlled trial of carboplatin/paclitaxel (CP) with or without the vascular-disrupting agent vadimezan (ASA404) in advanced non-small cell lung cancer (NSCLC) Primo Lara University of California, Davis, Sacramento, California, USA

Study design •  Randomized, double-blind, placebo-controlled Phase III study to evaluate

the efficacy and safety of carboplatin/paclitaxel +/- ASA404 (vadimazen) as first-line therapy in patients with Stage III or IV NSCLC

•  Primary endpoint: OS; secondary endpoints: PFS, tolerability

Paclitaxel + carboplatin 6 cycles ASA404 until progression

Paclitaxel + carboplatin 6 cycles placebo until progression

N=1200

Ran

dom

izat

ion

1:

1

•  HR for OS of 0.80 (9 vs 11.25 months), type 1 error of α=0.025 (one-sided) and 90% power

•  Interim analysis of OS after 238 deaths (25% of events); trial to be stopped for futility if HR>0.9985

•  Stage IIIB/IV NSCLC •  First-line chemo-

naïve •  Asian 25% •  SCC 20% •  PS 0: 40% •  Ex/never smokers

53% •  Stratification:

•  Sex •  Squamous vs

non-squamous

Lara et al. J Clin Oncol 29: 2011 (suppl; abstr 7502)

Efficacy

HR 1.008 95% CI: 0.850-1.195 p=0.535

HR 1.042 95% CI: 0.911-1.193 p=0.727

Ove

rall

surv

ival

Prog

ress

ion-

free

sur

viva

l

0

100

0

100

Time after date of randomization (months) Time after date of randomization (months) 0 9 18 0 9 18

ASA404 + PC Placebo + PC 13.4 months (11.4, 16.6)

ASA404 + PC Placebo + PC 12.7 months (11.3, 14.4)

Med survival (95% CI)

5.5 months (5.2, 5.6)

5.5 months (5.4, 5.6)

ASA404 + PC

Placebo + PC

ASA404 + PC

Placebo + PC


Selected AEs

AE, % All

grades Grade 3 Grade 4 All

grades Grade 3 Grade 4

Neutropenia 56.8 25.1 26.6 50.7 23.7 19.0

Fatigue 35.6 3.5 0.2 35.0 3.4 0.0

Anaemia 24.6 4.6 0.8 25.0 4.5 0.3

Diarrhoea 24.5 2.4 0.2 20.5 1.0 0.2

Arthralgia 24.3 1.1 0.0 23.4 2.1 0.3

ASA404 + PC (n=629) Placebo + PC (n=625)


Conclusions •  This was a negative Phase III study

–  Misleading efficacy signal from the Phase II study –  ASA404 suboptimal dose


Possible reasons for ASA404 Phase III study failure •  Suboptimal dose of ASA404 as no formal Phase IB combination study with

carboplatin/paclitaxel was performed •  The “efficacy signal” seen in the randomized Phase II study was not real

due to poor survival in the control arm •  Various other antiangiogenic and targeted agents have also failed to

improve OS in Phase III studies in combination with chemotherapy –  Have we already seen the best of antiangiogenic therapy in NSCLC with

bevacizumab?


#7551: Survival results of a randomized, phase 3 trial of nab-paclitaxel and carboplatin compared with cremophor-based paclitaxel and carboplatin as first-line therapy in advanced non-small cell lung cancer - Mark Socinski et al

•  Study objective –  To investigate survival with albumin-bound (nab) paclitaxel and carboplatin compared with

cremophor-based paclitaxel and carboplatin as first-line therapy in advanced NSCLC •  Study type/design

–  First-line stage IIIB or IV NSCLC patients (ECOG 0/1) were randomized to receive carboplatin AUC6 q3w and either nab-paclitaxel 100 mg/m2 qw w/o pre-medication (n=521) or paclitaxel 200 mg/m2 q3w with pre-medication (n=531)

–  Primary endpoint was ORR (secondary endpoints included PFS, OS and safety) •  Key results

–  Baseline and histologic characteristics were well balanced between arms –  nab-paclitaxel and carboplatin produced higher ORR compared with cremophor-based paclitaxel

and carboplatin (33 vs 25%, P=0.005), particularly in patients with squamous histology (41% vs 24%; P<0.001)

–  No significant difference in PFS or OS between treatment arms, with HRs trending in favour of nab-paclitaxel and carboplatin

–  Increased rate of grade 3/4 anaemia, reduced rates of grade 3/4 neurotoxicity and myalgia with nab-paclitaxel and carboplatin

•  Key conclusion(s) –  nab-paclitaxel and carboplatin is efficacious and safe as first-line therapy for advanced NSCLC

Socinski et al. J Clin Oncol 29: 2011 (suppl; abstr 7551)

#7552: Phase III study comparing the effects of carboplatin plus S-1 and carboplatin plus paclitaxel in chemotherapy-naïve patients with advanced non-small cell lung cancer: An updated report of the LETS study (WJTOG3605) – Tomonori Hirashima et al

•  Study objective –  To compare the effects of carboplatin + S-1 with carboplatin + paclitaxel in previously

untreated patients with NSCLC (updated data from LETS study) •  Study type/design

–  Phase III, randomized, controlled study –  Patients received carboplatin AUC (5 mg/mL/min) on day 1 plus oral S-1 (80 mg/m2/day;

40 mg/m2 BID) on days 1–14 (n=282) or carboplatin AUC (6 mg/ mL/min) plus paclitaxel (200 mg/m2) on day 1 every 21 days (n=282)

–  Primary endpoint: OS •  Patient population (ITT, n=564)

–  Chemotherapy-naïve patients with advanced stage (IIIB/IV) NSCLC, ECOG PS 0-1 •  Key results

–  Median OS (446 deaths; 79%) was 15.2 months (95% CI, 12.3–17.8) in the carboplatin/S-1 arm and 13.1 months (95% CI, 11.7–14.9) in the carboplatin/paclitaxel arm (adjusted 95% CI of the HR for OS of 0.956 was 0.793–1.151 in the ITT population)

–  The safety profile was consistent with previously reported findings from the LETS study •  Key conclusion

–  Updated data suggests carboplatin + S-1 is a therapeutic option for the first-line treatment of advanced NSCLC Hirashima et al. J Clin Oncol 29: 2011 (suppl; abstr 7552)

#7561: Bevacizumab (B) and erlotinib (E) as first-line therapy in metastatic non-squamous non-small cell lung cancer (NSCLC) followed by platinum-based chemotherapy (CT) at disease progression (PD): A multicenter phase II trial SAKK 19/05 – Francesco Zappa et al

•  Objective: –  To assess the efficacy and safety of

BE as first-line combination therapy followed by CT at PD in metastatic non-squamous NSCLC

•  This was a prospective, multicentre, single-arm Phase II study

•  Eligible patients had Stage IIIB-IV non-squamous NSCLC, WHO PS 0-1 and no brain metastases

•  Primary endpoint: disease stabilization rate (DSR) after 12 weeks of BE

•  Secondary endpoints: best overall response, TTP, DSR at 6 and 18 weeks, AEs, TTTF, QoL

Enrollment Stage IIIB/IV chemo-naïve non-squamous

NSCLC, PS 0-1

Treatment Bevacizumab 15 mg/kg on day 1 of each

21-day cycle Erlotinib 150 mg once daily for 21 days

until progression or toxicity

Chemotherapy Cisplatin 80 mg/m2 or carboplatin AUC 5 on

day 1 in combination with gemcitabine 1250 mg/m2 on day 1 and 8

for 6 cycles or until progression

Follow-up Every 3 months until death

Zappa et al. J Clin Oncol 29: 2011 (suppl; abstr 7561)

Key efficacy and safety data •  Between January 2006 and April 2009, 103 patients were enrolled

–  Median age: 65 years (range: 32-80), 52.5% male, 52.5% ECOG PS 0 •  The observed side effects with BE were as expected

–  Grade 3/4 AEs were rare –  Most frequent Grade 3/4 AEs were neutropenia (14), thrombocytopenia (13), fatigue (5) and

anorexia (3) •  Efficacy:

–  During BE therapy, 72.3% of patients had ≥SD –  RR was higher in patients with exon 19 or 21 mutations vs EGFR wild type

Endpoints Phase Result

DSR at 12 weeks BE 54.5% (44.2−64.4%)

TTP BE 4.1 months (2.9−5.5 months)

TTP CT 3.0 months (2.5−6.0 months)

OS Both 14.1 months (10.7−19.0 months

All pts Without EGFR Exon 19&21 mutation pts Without EGFR Exon 19&21 mutation and NA pts With EGFR Exon 19&21 mutation pts 1.0

0.8

0.6

0.4

0.2

0 0 4 8 12 16 20 24 28 32 36 40 44 48

Ove

rall

surv

ival

Time (months) Zappa et al. J Clin Oncol 29: 2011 (suppl; abstr 7561)

Conclusions •  Bevacizumab + erlotinib followed by chemotherapy at progressive disease

is feasible in advanced non-squamous NSCLC with low toxicity and promising activity

•  The OS reported here is similar to that observed with first-line chemotherapy regimens –  These findings raise the question as to whether BE could be used as

first-line therapy for an unselected patient population with advanced non-squamous NSCLC

•  Patients with EGFR mutations had a higher ORR and longer OS and TTP. However, overall results remain unchanged when these patients are excluded, suggesting that the addition of B increases the efficacy of E in an unselected patient population –  Final analysis of the gene expression arrays in this study may provide

more information regarding which patients derive most benefit from first-line therapy with BE

Zappa et al. J Clin Oncol 29: 2011 (suppl; abstr 7561)

#7503; Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: Interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial Rafael Rosell et al Catalan Institute of Oncology, Barcelona, Spain

Study design

Primary endpoint •  Progression-free survival (PFS)

–  interim analysis planned at 88 events

Secondary endpoints •  Objective response rate •  Overall survival (OS)

•  Location of progression •  Safety •  EGFR mutation analysis in serum •  Quality of life

  Chemonaїve   Stage IIIB/IV NSCLC   EGFR exon 19 deletion or

exon 21 L858R mutation   ECOG PS 0–2

(n=174)

R

Platinum-based doublet chemotherapy

q3wks x 4 cycles*

PD

Erlotinib 150mg/day PD

Stratification •  Mutation type •  ECOG PS (0 vs 1 vs 2)

Rosell et al. J Clin Oncol 29: 2011; (suppl; abstr 7503)

ECOG = Eastern Cooperative Oncology Group; PS = performance status; PD = progressive disease *Cisplatin 75mg/m2 d1 / docetaxel 75mg/m2 d1; cisplatin 75mg/m2 d1 / gemcitabine 1250mg/m2 d1,8; carboplatin AUC6 d1 / docetaxel 75mg/m2 d1; carboplatin AUC5 d1 / gemcitabine 1000mg/m2 d1,8

Baseline characteristics Interim analysis

(Aug 2, 2010) Updated analysis

(Jan 26, 2011) Erlotinib (n=77)

Chemotherapy (n=76)

Erlotinib (n=86)

Chemotherapy (n=87)

Median age, yrs (range) 64 (24–82) 64 (29–82) 65 (24–82) 65 (29–82)

Gender, % Male Female

32 68

21 79

33 67

22 78

ECOG PS, % 0 1 2

30 57 13

34 54 12

31 55 14

34 52 14

Smoking status, % Current smoker Former smoker Never smoker

4

26 70

13 13 74

8

26 66

14 14 72

EGFR mutation type, % Exon 19 deletion L858R mutation

64 36

63 37

66 34

67 33

Rosell et al. J Clin Oncol 29: 2011; (suppl; abstr 7503) N.B. All patients were Caucasian and the majority (~90%) had stage IV disease and adenocarcinoma

Key efficacy data: PFS in ITT population*


PFS

pro

babi

lity

1.0

0.8

0.6

0.4

0.2

0

Erlotinib (n=77) Chemotherapy (n=76)

HR=0.42 (0.27–0.64) Log-rank p<0.0001

Time (months) 0 3 6 9 12 15 18 21 24 27

Patients at risk Erlotinib 77 53 42 26 17 11 7 5 2 0 Chemo 76 40 14 7 5 3 2 1 0 0

9.4 5.2

IRC-assessed PFS confirmed these results

*Data cut-off and interim analysis (2 August 2010)

Key efficacy data: PFS in ITT population (updated analysis)*

PFS

pro

babi

lity

Erlotinib (n=86) Chemotherapy (n=87)

HR=0.37 (0.25–0.54) Log-rank p<0.0001

Time (months) 0 3 6 9 12 15 18 21 24 27 30 33

Patients at risk Erlotinib 86 63 54 32 21 17 9 7 4 2 2 0 Chemo 87 49 20 8 5 4 3 1 0 0 0 0

1.0

0.8

0.6

0.4

0.2

0

9.7 5.2

Rosell et al. J Clin Oncol 29: 2011; (suppl; abstr 7503) *Data cut-off and updated analysis (26 Jan 2011)

Summary of safety data* Erlotinib (n=75) n (%)

Chemotherapy (n=74) n (%)

Any adverse events (AEs), all grades Treatment-related AEs, all grades

72 (96) 69 (92)

73 (99) 70 (95)

Grade 3 / 4 AEs 34 (45) 60 (81) Dose modification / interruption due to AE

Dose modification / interruption due to treatment-related AE

20 (27) 17 (23)�

39 (53) 35 (47)

Discontinuation due to AEs Discontinuation due to treatment-related AE

9 (12) 4 (5)

11 (15) 10 (14)

Any serious AEs Treatment-related serious AEs Treatment-related death

20 (27) 5 (7) 1 (1)

19 (26) 12 (16)

2 (3)

Rosell et al. J Clin Oncol 29: 2011; (suppl; abstr 7503) *Data cut-off and interim analysis (2 August 2010)

Conclusions •  EURTAC is the first prospective study of an EGFR tyrosine-kinase inhibitor

(TKI) versus chemotherapy for first-line treatment of EGFR mutation-positive NSCLC in Caucasian patients

•  The study results confirms significant benefit in PFS of erlotinib over standard chemotherapy –  63% reduction in risk of progression (HR=0.37)

•  OS data are immature, with high level of known crossover •  No new safety findings (as expected)

–  Tolerability of erlotinib consistent with previous studies •  Erlotinib provides significant benefits over first-line chemotherapy in EGFR

mutation-positive disease


#7504: Innovations: Randomized phase II trial of erlotinib (E)/bevacizumab (B) compared with cisplatin (P)/gemcitabine (G) plus B in first-line treatment of advanced nonsquamous (NS) non-small cell lung cancer (NSCLC) – Michael Thomas et al

•  Study objective –  To assess feasibility and efficacy in the first-line setting E + B was compared with P/G+B

in cisplatin-eligible patients •  Study type/design

–  Chemotherapy-naïve patients with stage IIIB/IV non-squamous NSCLC and ECOG 0-1 (amenable to cisplatin treatment)

–  Patients were randomized on E (150 mg/daily) / B (15 mg/kg d1, q d 22) until progressive disease (PD) or P (80 mg/m2 d1, q d22) / G (1250 mg/m2 d1, q d22) up to 6 cycles+ B (15 mg/kg d1, qd 22) until PD

–  Treatment continuation until disease progression –  Response evaluation every 6 weeks

•  Study endpoints –  Primary: PFS in both treatment arms –  Secondary: RR, DCR - 6 weeks, OS, PFS and OS in EGFR wt and EGFR mut patients

•  Patient characteristics –  224 patients were randomized (EB: 111 / PGB: 113) –  Baseline characteristics were well balanced (median age 62.5 [range 39.5-84.6] and 59.9

[range 35.7-83.0]; female 43%/44%; ECOG 0, 1, 2: 43%, 55%, 2% and 47%, 50%, 4%) Thomas et al. J Clin Oncol 29: 2011 (suppl; abstr 7504)

Key efficacy and safety data •  PFS by treatment arm:

•  Toxicity (EB vs PGB) –  Haematological grade 3: 6.5% vs 27.3%; grade 4: 0.9% vs 27.3% –  Non-haematological grade 3: 34.3% vs 34.6%; grade 4: 9.3% vs 24.6% –  Treatment-related mortality 4.6% vs 4.6%

Thomas et al. J Clin Oncol 29: 2011 (suppl; abstr 7504)

PGB also showed significant superiority to EB for RR (p <0.0001) and favored OS (HR=0.73 [95%-CI 0.50-1.06], p=0.1) EB EGFR mut (n=20): median PFS was 4.4 mo (95% CI 2.1-8.3) and median OS was 16.9 months (10.3-24.0) EGFR WT (n=59): median PFS was 3.5 mo (95% CI 2.5-4.4) and median OS was 10.3 months (8.0-n/a) PGB EGFR mut (n=12): median PFS was 5.7 mo (95% CI 2.8-8.4) and median OS was 10.0 months (6.0-19.8) EGFR WT (n=70): median PFS was 8.1 mo (95% CI 6.5-9.7) and median OS was 18.1 months (12.0-n/a)

1.00

0.75

0.50

0.25

0

Prop

ortio

n pr

ogre

ssio

n fr

ee

0 6 12 18 24 30 Time (months)

EB (n=111) PGB (n=113)

Median (95% CI) 1 yr-rate EB 3.5 (2.8–4.2) 15% PGB 7.7 (6.2–9.1) 23% HR 1.77 (1.33–2.36) p<0.0001

Conclusions •  In unselected patients with advanced non-squamous NSCLC, PGB is

significantly superior to EB for RR and PFS •  Treatment-related mortality were similar between treatment arms •  PGB showed a favourable PFS (7.7 months) and OS (16.1 months; 1-year

rate 60%) compared with 3.5 months and 12.6 months; 1-year-rate 54% with EB

•  EGFR mutations identify patients most likely to benefit from EB

Thomas et al. J Clin Oncol 29: 2011 (suppl; abstr 7504)

#LBA7512: An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) – Giorgio Scagliotti et al

•  Study objective –  To determine whether motesanib (a selective oral inhibitor of VEGFR 1, 2 and 3; PDGFR and Kit) in

combination with C/P improved OS compared with placebo plus C/P in patients (pts) with advanced non-squamous NSCLC and in a subset of patients with adenocarcinoma histology

•  Study endpoints

–  Primary: OS (secondary: PFS, adverse events (AEs), ORR, and association between placental growth factor change and OS)

•  Key eligibility criteria –  Histologically confirmed unresectable stage IIIB with pericardial or pleural effusion or stage IV/recurrent

non-squamous NSCLC; measurable or non-measurable disease; ECOG PS 0-1; no prior treatment

Scagliotti et al. J Clin Oncol 29: 2011; (suppl; abstr LBA7512) Study initially enrolled all histologies but was amended to exclude pts with squamous NSCLC owing to a high rate of haemoptysis

Ran

dom

izat

ion Arm

A Motesanib 125 mg QD

C/P

Arm B

Placebo QD C/P

1:1

Treatment until: •  disease progression •  Unacceptable toxicity •  Consent withdrawn

Tumour assessments: •  CT or MRI scans of chest, abdomen and pelvis every 6 weeks •  Per RECIST v1.0by investigator

Key efficacy data

Scagliotti et al. J Clin Oncol 29: 2011; (suppl; abstr LBA7512)

OS – All nonsquamous patients* PFS – All nonsquamous patients*

100

80

60

40

20

0

100

80

60

40

20

0

100

80

60

40

20

0

100

80

60

40

20

0

0 16 32 48 64 80 96 112 128 144 160 176 0 16 32 48 64 80 96 112 128 144 160

0 16 32 48 64 80 96 112 128 144 160 176 0 16 32 48 64 80 96 112 128 144 160

Motesanib + C/P

Placebo + C/P

N Patients with

events, n Median OS,

months (95% CI)

541 359 13.0 (11.2–14.0)

549 394 11.0 (10.1–12.4)

Hazard ratio (95% CI): 0.90 (0.78–1.04)

P 0.14

Motesanib + C/P

Placebo + C/P

N Patients with

events, n Median PFS,

months (95% CI)

541 389 5.6 (5.4–6.2)

549 451 5.4 (4.7–5.5)

Hazard ratio (95% CI): 0.79 (0.68–0.90)

P 0.0006

Motesanib + C/P

Placebo + C/P

N Patients with

events, n Median OS,

months (95% CI)

448 294 13.5 (11.3–14.7)

442 314 11.0 (9.9–12.4)

Hazard ratio (95% CI): 0.88 (0.75–1.03)

P 0.11

OS – Adenocarcinoma subset**

Motesanib + C/P

Placebo + C/P

N Patients with

events, n Median PFS,

months (95% CI)

448 323 5.6 (5.4–6.4)

442 360 5.4 (4.7–5.5)

Hazard ratio (95% CI): 0.78 (0.67–0.91)

P 0.0016

Surv

ival

(%)

Surv

ival

(%)

PFS – Adenocarcinoma subset**

*All randomized patients with nonsquamous histology **All randomized patients with adenocarcinoma histology

Key safety data Arm A: Motesanib + C/P

(N=533) Arm B: Placebo + C/P

(N=539)

Patients with grade ≥3 adverse events, n (%) 388 (73) 319 (59)

Grade 3 201 (38) 192 (36)

Grade 4 113 (21) 77 (14)

Grade 5 74 (14) 50 (9)

Serious adverse events 261 (49) 184 (34)

Patients with serious grade ≥3 adverse events, n (%)* 239 (45) 161 (30)

Neutropenia 28 (5) 12 (2)

Diarrhoea 25 (5) 4 (<1)

Febrile neutropenia 23 (4) 15 (3)

Pneumonia 20 (4) 7 (1)

Dehydration 19 (4) 4 (<1)

Non-small-cell lung cancer 16 (3) 12 (2)

Thrombocytopenia 14 (3) 6 (1)

Pulmonary embolism 12 (2) 17 (3)

Anaemia 12 (2) 11 (2)

Dyspnoea 11 (2) 20 (4)

Vomiting 11 (2) 7 (1)

General physical health deterioration 11 (2) 4 (<1)

Cholecystitis 11 (2) 0 (0)

*Patient incidence ≥2% Scagliotti et al. J Clin Oncol 29: 2011; (suppl; abstr LBA7512)

Conclusions •  Treatment with motesanib plus C/P did not significantly improve OS

compared with placebo plus C/P in either the overall non-squamous patient population or the adenocarcinoma subset

•  Numeric increases in PFS (5.6 months vs 5.4 months for placebo) and ORR (40% vs 26% for placebo) suggest evidence of motesanib activity in NSCLC

•  The incidence of adverse events (including serious grade ≥ adverse events) was greater in the motesanib treatment arm than in the placebo arm

Scagliotti et al. J Clin Oncol 29: 2011; (suppl; abstr LBA7512)

#7519: Final overall survival results of NEJ002, a phase 3 trial comparing gefitinib to carboplatin (CBDCA) plus paclitaxel (TXL) as the first-line treatment for advanced non-small cell lung cancer (NSCLC) with EGFR mutations – Akira Inoue et al

Inoue et al. J Clin Oncol 29: 2011; (suppl; abstr 7519)

•  NSCLC with sensitive EGFR mutations (N=230)*

•  Stage IIIB/IV •  Chemo-naïve •  PS 0-1 •  Age of 20-75

years

Gefitinib (250 mg/day)

n=114

CBDCA (AUC 6) + PTX (200 ng/m2)

n=114**

Primary endpoint •  PFS

Secondary endpoints •  OS •  Response •  Side-effects •  QoL

Randomize balanced: • Institution • Sex • Stage

Study Design of NEJ002

*Although the sample size of NEJ001 was initially calculated to be 320 in total, eventually patient accrual was stopped early due to the positive result of an interim analysis in May 2009

**For the FPS analysis, 4 patients in CBDCA plus PTX arm were excluded •  One patient in each arm was ineligible, thus the number of patients as intent-to-treat population in each arm was 114

Key efficacy data: progression-free survival


100

90

80

70

60

50

40

30

20

10

0

Prog

ress

ion-

free

sur

viva

l (%

)

0 100 200 300 400 500

Gefitinib CBDCA + TXL

Days after randomization

p<0.001***

2009 100

90

80

70

60

50

40

30

20

10

0 0 100 200 300 400 500 600 700 800

Days after randomization

p<0.001***

2011

Key efficacy data: overall survival (final analysis)


Median OS: 30.5 (gefitinib) 23.6 (CBDCA + TXL)

Median OS: 27.7 (gefitinib) 26.6 (CBDCA + TXL)

Influence of EGFR TKI and subsequent therapies on OS

100

80

60

40

20

0 Ove

rall

surv

ival

(%)

0 200 400 600 800 1000 1200 1400 Days after randomization

Gefitinib CBDCA + TXL p=0.307

2009 2011 100

80

60

40

20

0 Ove

rall

surv

ival

(%)

0 200 400 600 800 1000 1200 Days after randomization

100

80

60

40

20

0 Ove

rall

surv

ival

(%)


100

80

60

40

20

0 Ove

rall

surv

ival

(%)


Gefitinib CBDCA + TXL p=0.483

EGFR-TKI + / Platinum + (n=186) EGFR-TKI + / Platinum – (n=40) EGFR-TKI – / Platinum + (n=2)

Median OS A: 27.7 monthsa B: 25.9 months Log-rank test A vs. B p=0.482

EGFR-TKI + / Platinum + with Pemetrexed or Docetaxel (n=81) EGFR-TKI + / Platinum + without Pemetrexed and Docetaxel (n=105)

Median OS A: 35.8 monthsa B: 23.4 months Log-rank test A vs. B p<0.001

Conclusions •  These updated data continue to show a significant superiority for gefitinib

in terms of PFS •  There was no difference in OS between treatments, most likely due to the

high level of patient crossover •  These data suggest that for patients with a good PS, triplet sequential

therapy with EGFR TKI, platinum-based regimen and then pemetrexed or docetaxel may be preferable

•  Findings from this study show that gefitinib is associated with superior benefits over CBDCA +TXL in terms of PFS and QoL. As such, gefitinib should be considered as the first-line treatment for EGFR-mutated advanced NSCLC


#7520: Updated efficacy and quality of life (QoL) analyses in OPTIMAL, a phase III, randomized, open-label study of first-line erlotinib vs gemcitabine/carboplatin in patients with EGFR activating-mutation positive (EGFR Act Mut+) advanced non-small cell lung cancer (NSCLC) – Caicun Zhou et al.

•  Study design

–  Erlotinib given until unacceptable toxicity or progressive disease –  Patients stratified by histology, smoking status and mutation type –  QoL questionnaire administered at randomization and every 6 weeks until PD

•  Study endpoints –  Primary: PFS –  Secondary: ORR, overall survival, QoL (FACT-L, TOI, LCSS) and safety

Zhou et al. J Clin Oncol 29: 2011; (suppl; abstr 7520)

Chemonaive patients with stage IIIB/IV NSCLC (ECOG PS 0–2) and

EGFR Act Mut+ (n=165)

Ran

dom

izat

ion

1:1 Erlotinib

150 mg/day

Gemcitabine (G: 1,000 mg/m2 days 1 and 8), carboplatin (C: AUC=5 day 1) every 3 weeks up to 4 cycles

Key efficacy data

•  In total, 154 patients were included •  First-line treatment with erlotinib

demonstrated a significant improvement in PFS vs G/C. Median PFS (E vs G/C; months): –  Primary analysis: 13.1 vs 4.6 –  Updated analysis (after an additional

6 months of follow-up): 13.7 vs 4.6 •  Patients receiving erlotinib experienced

clinically relevant improvements in QoL vs G/C –  Similar results obtained using exon

type, smoking history and histological subtype as covariates


100 80 60

40 20 0 PF

S pr

obab

ility

0 5 10 15 20 25 30 Days after randomization

n

Events n (%)

Median (months)

95% CI

Erlotinib 82 58 (70.73) 13.7 10.58–15.28 G/C 72 64 (88.89) 4.6 4.21–5.42

Log-rank p<0.0001 HR=0.164 (95% CI:0.105–0.256)

Patients at risk Erlotinib 82 70 51 29 8 2 0 G/C 72 26 4 1 0 0 0

HR (95% CI n Overall 0.16 (0.10–0.26) 154

Stage IV 0.18 (0.11–0.28) 138 Stage IIIB 0.27 (0.06–1.16) 16

Female 0.13 (0.07–0.24) 91 Male 0.26 (0.14–0.50) 63

Age ≥65 years 0.17 (0.07–0.43) 38 Age <65 years 0.19 (0.11–0.31) 116 ECOG PS 0-1 0.16 (0.10–0.26) 144

ECOG PS 2 0.21 (0.04–1.28) 10 Non-smoker 0.14 (0.08–0.25) 109

Current/former smoker 0.21 (0.09–0.49) 45 Adenocarcinioma 0.17 (0.11–0.28) 134

Non-adenocarcinioma 0.22 (0.06–0.73) 20

0 0.5 1.0 1.5

Favours erlotinib Favours G/C HR

Conclusions •  This updated analysis of the OPTIMAL study showed that erlotinib is

associated with a significant PFS benefit vs standard chemotherapy as first-line treatment for patients with advanced NSCLC whose tumours harbour activating mutations

•  The PFS benefit with erlotinib was regardless of age, gender, PS, disease stage, tumour histology and smoking status

•  Patient QoL was also significantly improved with erlotinib compared with G/C

•  Erlotinib appears to be an important agent in the first-line treatment of EGFR Act Mut+ NSCLC


#7521: FCT-0504 trial: Mucinous (M) and non-mucinous (NM) cytological subtypes interaction effect in first-line treatment of advanced bronchioloalveolar carcinoma (BAC), by erlotinib (E) or carboplatin/paclitaxel (C/P) – Jacques Cadranel et al •  Objective: to determine the best therapeutic strategy for advanced BAC •  This was a multicentre randomized Phase II trial to evaluate the efficacy and tolerability of first-line treatment with E

or C/P with a cross-over at progression and pemetrexed as third-line therapy

•  Study endpoints –  Primary: 4-month disease control rate (DCR) –  Secondary: PFS, tolerance, QOL, OS and subgroups analyses

by arms, prediction of efficacy according to clinical and biological biomarkers •  Key patient inclusion criteria

–  Previously untreated, cytopathologically proven advanced BAC, PS ≤2 Cadranel al. J Clin Oncol 29: 2011; (suppl; abstr 7521)

R*

E E E

C/P

C/P C/P

C/P erlotinib

150 mg/day

carboplatin/ paclitaxel

Control Control

Progression >10%

C/P

E

C/P

E

E Progression >10%

Control

Control

Control

Progression

2nd progression

Progression

2nd progression

pemetrexed

pemetrexed

2nd progression >>pemetrexed

2nd progression >>pemetrexed

A

B

Early evaluation 4 weeks

16-week evaluation (and every 12 weeks after)

*Stratified by: -  sex -  smoking status -  PS

Key efficacy and safety data •  133 patients enrolled

–  Median age: 68 (range 20-83) –  PS: 0/1 –  Non-smokers: 27%

•  There was no significant difference in DCR between treatment groups at 4 months

•  Factors associated with DCR: sex (p=0.0083), age (p=0.0057) and respiratory symptom score (p=0.0048)

•  Median PFS: 3.2 (A) vs 6.1 (B) months –  C/P was effective in both cytological

subtypes –  E was as effective as C/P in non-

mucinous BAC •  E was associated with a more

favourable toxicity profile

Cadranel al. J Clin Oncol 29: 2011; (suppl; abstr 7521)

DCR at 4 months (eligible patients, n=130)

Effect of cytological subtype on PFS

Total (n=130) Arm E (n=64) Arm C/P (n=66) P value

CR 2 (1.5%) 2 (3.1%) 0 (0%)

PR 24 (18.5%) 10 (15.6%) 14 (21.2%)

SD 34 (26.2%) 13 (20.3%) 21 (31.8%)

DCR 60 (46.2%) IC 95% [37.6–54.7%]

25 (39.1%) IC 95% [27.1–51.0%]

35 (53.0%) IC 95% [41.0–65.1%]

0.110

PD 49 (37.7%) 27 (42.2%) 22 (33.3%)

NA 19 (14.6%) 10 (15.6%) 9 (13.6%)

NE 2 (1.5%) 2 (3.1%) 0 (0%)

0 6 12 18 24 30 36 42 48

1.0

0.8

0.6

0.4

0.2

0.0

Month 0 6 12 18 24 30

1.0

0.8

0.6

0.4

0.2

0.0

Month

PFS – non-mucinous subgroup (n=60)

HR (E vs C/P)=0.89 [0.52–1.53]; p=0.6707

E (n=31)

C/P (n=29)

PFS – mucinous subgroup (n=55)

HR (E vs C/P)=2.86 [1.50–5.47]; p=0.0015

E (n=24)

C/P (n=31)

Pro

babi

lity

Pro

babi

lity

Conclusions •  E or C/P resulted in a 46% DCR at 4 months without significant difference

between the two treatment arms (primary objective) •  C/P C/P was effective in both cytological subtypes

–  E was as effective as C/P in non-mucinous BAC –  E was associated with a more favourable toxicity profile than C/P

•  Data from this study suggests that a strategy including C/P and E contributes towards an improved OS in advanced BAC –  OS of 13.4 months in the IFCT-0401 study versus 20.1 months in this

study

Cadranel al. J Clin Oncol 29: 2011; (suppl; abstr 7521)

METASTATIC NSCLC Maintenance

#7553: Single agent maintenance therapy for advanced stage non-small cell lung cancer: a meta-analysis - Madhusmita Behera et al •  Study objective

–  To evaluate the effect of single agent maintenance therapy on survival in NSCLC •  Study type/design

–  Meta-analysis of randomized studies that evaluated the effect of single agent maintenance therapy on survival in NSCLC using an electronic literature search of public databases (Medline, EMBASE, Cochrane library) and a manual search of conference proceedings from ASCO and WCLC

–  Primary outcome: OS (secondary outcome: PFS) •  Key results

–  210 published reports reviewed, 10 (3 abstracts, 7 publications) eligible for inclusion with a total of 3451 patients

–  OS (HR 0.87, 95% CI 0.82-0.94, p=0.0003) and PFS (HR 0.84, 95% CI 0.80-0.88, p< 0.0001) were superior with maintenance therapy

–  ‘Switch’ maintenance therapy was associated with significant OS and PFS improvement (HR 0.86 CI 0.80-0.93, p= 0.00046; PFS HR 0.71 CI 0.66-0.77, p<0.0001)

–  ‘Continuation’ maintenance therapy was not associated with survival benefit –  Improvements in OS and PFS were observed with EGFR-targeted agents (HR 0.86, CI 0.78-0.95, p= 0.006;

HR 0.76, CI 0.70-0.83, p<0.0001) and cytotoxic agents (HR 0.88, CI 0.80-0.97, p=0.018; HR 0.87, CI 0.82-0.91, p<0.0001).

•  Key conclusions –  Single agent maintenance therapy improves overall survival, though statistical significance was only noted with

‘switch’ maintenance –  A survival benefit was observed with chemotherapy and EGFR-targeted therapy

•  Results of PARAMOUNT and the gefitinib maintenance study from ASCO 2011 were not included in this analysis

Behera et al. J Clin Oncol 29: 2011 (suppl; abstr 7553)

#7562: AVAPERL1 (MO22089): Maintenance (mtc) bevacizumab (bev) with or without pemetrexed (pem) in patients (pts) with advanced nonsquamous non-small cell lung cancer (nsNSCLC) treated with first-line (1L) bev-cisplatin (cis)-pem: Interim safety data Fabrice Barlesi et al. APHM, Hôpital Sainte Margueritte, Marseille, France

Study design

Barlesi et al. J Clin Oncol 29: 2011 (suppl; abstr 7562)

Open-label, randomized, multicentre, Phase III study (Study ongoing: preliminary analysis presented)

Primary endpoints: PFS Secondary endpoints: OS, safety

Stratification factors include gender, smoking status (never smoker vs past/current smoker) and disease control (CR/PR vs SD)

Inclusion criteria: stage IIIB/IV or recurrent non-squamous NSCLC; measurable disease; ECOG PS 0-2 Exclusion criteria: history of Grade ≥2 haemoptysis, tumour invading major blood vessels, uncontrolled hypertension, clinically significant cardiovascular disease

Previously untreated stage IIIB/

IV non-squamous NSCLC

Bevacizumab/ pemetrexed/cisplatin

every 3 weeks

Criteria: CR/PR/SD (RECIST)

1:1

Bevacizumab every 3 weeks

Bevacizumab/ pemetrexed every

3 weeks PD

4 cycles induction therapy (N=373)

Treatment until disease progression

PD

Patient enrollment and disposition


Screened patients (n=414)

Safety population

(N=373; 90%)

Received maintenance

therapy (n=244; 59%)

No maintenance

therapy (n=129; 31%)

Arm A: bevacizumab (n=119; 29%)

Arm B: bevacizumab +

pemetrexed (n=125; 30%)

244 patients with CR, PR or SD received maintenance therapy

31% of patients are on treatment, 30% are in follow-up and 39% are off study

Patient demographics


Characteristic Safety population (N=373)

Bevacizumab (n=119)

Bevacizumab + pemetrexed (n=125)

Age, median (range) 60.0 (27-83) 60.0 (41-75) 60.0 (34-76)

Male, n (%) 220 (59.0) 68 (57.1) 72 (57.6)

Current stage, n (%) IIIB IV

29 (7.8)

344 (92.2)

13 (10.9)

106 (89.1)

8 (6.4)

117 (93.6)

ECOG PS, n (%) 0 1 2

163 (45.5) 190 (53.1)

5 (1.4)

48 (42.5) 64 (56.6)

1 (0.9)

65 (52.4) 57 (46.0)

2 (1.6)

Histology, n (%) Adenocarcinoma Large cell carcinoma Other

327 (87.7)

33 (8.8) 13 (3.5)

109 (91.6)

8 (6.7) 2 (1.7)

106 (84.8)

12 (9.6) 7 (5.6)

Key safety data: adverse events Safety population

(n=373) Bevacizumab

(n=119) Bevacizumab +

pemetrexed (n=125)

Any grade AEs No of events Patients with event, %

3450

95

1105 96

1500

97

Grade ≥3 AEs No of events Patients with event, %

349 53

76 40

106 47

SAEs No. events Patients with event, %

218 39

35 23

70 36

Any-grade AEs by phase at which they began Induction Patients with event, % Induction + maintenance Patients with event, % Maintenance Patients with event, % Follow up Patients with event, %

88

47

55 5

84

71

79 3

89

74

90 3


Conclusions •  First-line therapy with cisplatin, pemetrexed and bevacizumab was well

tolerated; no new or unexpected toxicities were observed •  Any grade AEs, Grade ≥3 AEs and SAEs occurred more frequently in

patients treated with bevacizumab + pemetrexed than in those treated with bevacizumab alone after induction


#7610: Time course of skin toxicity (tox) secondary to erlotinib (E) therapy in patients (pts) with non-small cell lung cancer (NSCLC) enrolled in the SATURN study – Roman Perez-Soler et al •  Study objective

–  To evaluate the incidence, severity, time course and duration of skin toxicity secondary to E and effects of E dose modifications on this toxicity, in the context of the SATURN study

•  Study type/design –  Retrospective analysis of skin toxicity in patients from the SATURN study

•  Patient population –  438 patients received E and 451 patients received placebo

•  Key results –  A total of 266 E treated patients experienced skin toxicity –  The incidence of skin toxicity was 61% in patients treated with E and 9% in patients treated with

placebo –  Dose modifications secondary to E treatment occurred in 43 patients (16%) –  Most skin toxicity events were reported in the first 2 weeks (70%) –  The incidence and intensity of skin toxicity increased by week 3, peaked on week 5 and progressively

decreased thereafter –  Non-significant trend with E toward improved OS in patients experiencing any grade rash by week 10

•  Key conclusions –  Skin toxicity secondary to E presents within the first 2 weeks in the majority of patients, peaks on week

5, and decreases thereafter –  Rash severity decreased with time even without E dose reductions –  Presence of cutaneous toxicity with E is associated with prolonged survival

Perez-Soler et al. J Clin Oncol 29: 2011; (suppl; abstr 7610)

#CRA7510: PARAMOUNT: Phase III Study of Maintenance Pemetrexed (Pem) Plus Best Supportive Care (BSC) Versus Placebo Plus BSC Immediately Following Induction Treatment with Pem Plus Cisplatin for Advanced Nonsquamous Non-small Cell Lung Cancer LG Paz-Ares et al. University Hospital - Virgen del Rocio, Seville, Spain

PARAMOUNT: study design

•  Randomized, placebo-controlled, double-blind, phase III study •  Folic acid and vitamin B12 administered to both arms •  Objectives: primary : PFS; secondary: OS, RR, PRO, resource utilization,

AEs

Study Treatment Period Progression

Induction therapy (4 cycles)

Maintenance therapy (until PD) 21 to 42 Days

500 mg/m2 pemetrexed + 75 mg/m2 cisplatin, d1, q21d

CR, PR, SD

PD

Placebo + BSC, d1, q21d

500 mg/m2 pemetrexed + BSC, d1, q21d

2:1 Randomization

Patients enrolled if: •  Nonsquamous NSCLC •  No prior systemic treatment for

lung cancer •  ECOG PS 0/1

Stratified for: •  PS (0 vs 1) •  Disease stage (IIIB vs IV) prior to induction •  Response to induction (CR/PR vs SD)

Paz-Ares et al. J Clin Oncol 29: 2011; (suppl; abstr CRA7510)

PARAMOUNT: patient demographics •  1022 patients screened, 939 patients enrolled into induction phase •  539 patients randomized to maintenance phase: 359 to pemetrexed and

180 to placebo

Patient characteristics (randomized patients)

Pemetrexed (n=359)

Placebo (n=180)

Median age, years 61 62 Age <65 years, n (%) 238 (66) 112 (62) No of males, n (%) 201 (56) 112 (62) Caucasian, n (%) 339 (94) 171 (95) Smoking status

Ever smoker Never smoker

275 (77) 82 (23)

144 (80) 34 (19)

ECOG PS 0 1 2/3*

115 (32) 243 (68) 1 (0.3)

55 (31)

123 (68) 2 (1)

Response to induction therapy CR/PR SD PD/unknown*

166 (46) 186 (52)

7 (2)

76 (42) 94 (52) 10 (6)

Paz-Ares et al. J Clin Oncol 29: 2011; (suppl; abstr CRA7510) *Protocol violations

PARAMOUNT: efficacy

PFS Pemetrexed (n=359)

Placebo (n=180)

Investigator-assessed events

184 (51%) 118 (66%)

Progression events 173 (94%) 113 (96%)

Deaths 11 (6%) 5 (4%)

PFS (investigator assessment) •  PFS in all subgroups (stage, induction response,

pre-randomization PS, smoking status, age, sex histology) favoured pemetrexed treatment

•  PFS from induction: 6.90 (pemetrexed) vs 5.59 months (placebo), HR 0.59 (0.47-0.74), p<0.0001

PFS during maintenance therapy (independent assessment):

•  88% patients independently reviewed •  Median PFS: 3.9 (pemetrexed) vs 2.6 months

(placebo), HR 0.64 (0.51-0.81), p=0.0002 Response to maintenance therapy (independent

assessment): •  RR: 2.8% (pemetrexed) vs 0.6% (placebo),

p=0.176 •  DCR: 71.8% (pemetrexed) vs 59.6% (placebo),

p=0.009 PRO: •  No statistical differences in EQ-5D index score

or visual analogue scale observed between treatment groups

PFS during maintenance therapy (investigator assessment)

Pem + BSC

Placebo + BSC

Pemetrexed: median =4.1 mos (3.2-4.6) Placebo: median =2.8 mos (2.6-3.1) Log-rank P=0.00006 Unadjusted HR: 0.62 (0.49-0.79)

Time (months)

Sur

viva

l pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15


PARAMOUNT: safety

•  Significantly higher incidence of Grade 3/4 AEs with pemetrexed vs placebo (Fischer’s exact test p≤0.05):

–  Fatigue: 4.2% vs 0.6% –  Anaemia: 4.5% vs 0.6% –  Neutropenia: 3.6% vs 0%

Drug-related safety events (%) Pemetrexed (n=359) Placebo (n=180) Deaths* 0.6 0.6

SAEs† 8.9 2.8

Discontinuations 5.3 3.3

≥1 Grade 3/4 laboratory AEs† 9.2 0.6

≥1 Grade 3/4/5* non- laboratory AEs 8.9 4.4

* On-study deaths: one on pemetrexed (pneumonia); one on placebo (NOS); one death within 30 days (endocarditis on pemetrexed) † Statistically significant between arms (Fisher’s exact test P≤0.05)


PARAMOUNT: conclusions •  PARAMOUNT met its primary endpoint •  Pemetrexed as maintenance therapy significantly improved PFS versus

placebo (HR 0.62) –  Investigator-assessed PFS was confirmed by the independent

assessment •  Pemetrexed was well tolerated, with a safety profile similar to that reported

previously in a study of pemetrexed as maintenance therapy in NSCLC1 •  These data suggest that pemetrexed is effective as maintenance therapy

in patients with advanced nonsquamous NSCLC who have received pemetrexed + cisplatin induction therapy

1Ciuleanu T, et al. Lancet 2009;374:1432-40 Paz-Ares et al. J Clin Oncol 29: 2011; (suppl; abstr CRA7510)

#LBA7511: Efficacy, tolerability and biomarker analysis from a Phase III, randomized, placebo-controlled, parallel group study of gefitinib as miantenance therapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC; INFORM; C-TONG 0804) Li Zhang et al University Cancer Center, Guangzhou, China

Study design •  This was a randomized Phase III, placebo-controlled study to evaluate the

efficacy and safety of maintenance therapy in patients who have achieved disease control after first-line platinum-based doublet chemotherapy

Patients •  Age ≥18 years

•  Completed 4 cycles of first-line platinum-based chemotherapy without PD or unacceptable toxicity

•  Life expectancy ≥12 weeks

•  WHO PS 0-2

•  Measurable Stage IIB/IV disease

Endpoints Primary •  Progression-free survival (PFS) Secondary •  Objective response rate (ORR) •  Disease control rate (DCR) •  Overall survival (OS) •  Quality of life •  Safety and tolerability

Exploratory •  Biomarkers − EGFR mutation

Gefitinib (250 mg/day)

Placebo (once daily)

1:1 randomization

Li Zhang et al. J Clin Oncol 29: 2011; (suppl; abstr LBA7511)

Patient demographics •  Between September 2008 and August 2009, 298 patients were screened and 296

were randomized Gefitinib (n=148) Placebo (n=148)

Age <65 years, n (%) 129 (87.2) 130 (87.9) Median age (range), years 54 (31−79) 54 (20−75) Gender,† n (%)

Female Male

65 (43.9) 83 (56.1)

56 (37.8) 92 (62.2)

Asian ethnicity, n(%) 148 (100.0) 148 (100.0) WHO PS, n (%)

0, 1, 2

69 (46.6), 76 (51.4), 3 (2.0)

72 (48.6), 72 (48.6), 4 (2.7) Smoking history,† n (%)

Smoker (ex- or current smoker) Never smoker

69 (46.6) 79 (53.4)

67 (45.3) 81 (54.7)

Histology,† n (%) Adenocarcinoma Squamous

105 (70.9) 27 (18.2)

104 (70.3) 30 (20.3)

Disease stage, n (%) IIIB IV

42 (28.4)

106 (71.6)

32 (21.6) 115 (77.7)

First-line taxane-based chemotherapy, n (%) 60 (40.5) 66 (44.6) Response (CR/PR, SD) to first-line therapy, n (%) 58 (39.2), 90 (60.8) 51 (34.5), 97 (65.6)


Progression-free survival (according EGFR status)

The greatest magnitude of effect of PFS was observed in patients with EGFR mutation-positive tumours

EGFR mutation-unknown 100

80

60

40

20

0

PFS

(%)

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Time (weeks)

Gefitinib (n=108) Median PFS†, 6.0 months No. events, 90 (83.3%)

Placebo (n=109) Median PFS†, 2.7 months No. events, 105 (96.3%) HR (95% CI) = 0.40 (0.29, 0.54)

EGFR mutation-negative

100

80

60

40

20

0

PFS

(%)

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Time (weeks)



EGFR mutation-positive

100

80

60

40

20

0

PFS

(%)

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Time (weeks)




Other efficacy endpoints

•  There was no significant difference in OS between treatment groups

•  Overall response data were consistent with findings from the PFS analysis

0.7

23.6

0

10

20

30

40

50

OR

R (%

)

Odds ratio (95% CI) = 54.1 (7.17, 408); p=0.0001

Gefitinib Placebo (n=148) (n=148)

50.7

71.6

01020304050607080

DC

R (%

)

Odds ratio (95% CI) = 2.69 (1.62, 4.46); p=0.0001

Gefitinib Placebo (n=148) (n=148)

100 80 60 40 20 0

OS

(%)

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128

Time (weeks)

Gefitinib (n=148)

Placebo (n=148)

Median OS, months 18.7 16.9 6-month survival rate, % 82.2 84.9 12-month OS rate, % 68.8 66.0 No. events, n (%) 79 (53.4) 93 (62.8)


Safety profile

•  Most common AEs (G vs P, >5% difference between treatment groups): –  Rash: 49.7% vs 9.5% –  Diarrhoea: 25.5% vs 8.8% –  ALT: 22.1% vs 8.1% –  AST: 14.3% vs 4.1% –  Cough: 6.1% vs 13.5%

All AEs Treatment-related AEs†

n (%)

Gefitinib (n=147

Placebo (n=148)

Gefitinib (n=147

Placebo (n=148)

AE 118 (80.3) 79 (53.4) 98 (66.7) 34 (23.0)

SAE 10 (6.8) 5 (3.4) 3 (2.0) 0 (0.0)

AE leading to death 9 (6.1) 2 (1.4) 3 (2.0) 0 (0.0)

AE leading to discontinuation 9 (6.1) 2 (1.4) 3 (2.0) 0 (0.0)

CTC grade 3-5 22 (15.0) 4 (2.7) 10 (6.8) 0 (0.0)

ILD-type AE 2 (1.4) 0 (0.0) 2 (1.4) 0 (0.0)


Conclusions •  The INFORM study was the first randomized maintenance study •  The study met its primary endpoint and demonstrated a statistically

significant increase in PFS with gefitinib vs placebo •  ORR and DCR were consistent with findings from the PFS analysis •  The greatest magnitude of PFS benefit was seen in patients with EGFR

mutation-positive tumours •  There was no statistically significant difference in OS between treatment

groups •  Gefitinib was well tolerated as maintenance treatment after first-line

chemotherapy

METASTATIC NSCLC Later lines

#7500: An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as monotherapy in patients with advanced non-small cell lung cancer (NSCLC) Kwok-Kin Wong et al University of California, Davis, Sacramento, California, USA

Study design

Wong et al. J Clin Oncol 29: 2011 (suppl; abstr 7500)

Ganetespib 200 mg/m2 once weekly for 3 weeks of a 4-week cycle

Previously treated stage IIIB/IV NSCLC ECOG PS 0-1 Documented disease progression at study entry Genotyping*

Stratification

Cohort A: mEGFR (n=16)

Cohort B: mKRAS (n=17)

Cohort C: wild-type EGFR/wild-type KRAS (n=25) Cohort D: Adenocarcinoma only (n=37)

Stage 1 (n=14); (if n≥2 progression free at week 16

Primary endpoint: PFS at 16 weeks Secondary endpoints: ORR, DCR at 8, 16 weeks; PFS, OS, TTF, safety

*1 patient with unknown genotype First patient first visit, December 2009 Last patient first visit, May 2011

Stage 2

CT scans every 8 weeks

Evaluable population

(n=76)

Follow up until

PD

CT scans n=96*

ITT population

Patient demographics Cohort A

(n=16) Cohort B

(n=17) Cohort C and D

(n=62)

Median age (range) 60 (49-79) 64 (28-76) 62 (36-82)

Sex (n, %) Male Female

6 (37.5)

10 (62.5)

4 (23.5)

13 (76.5)

35 (56.5) 27 (43.5)

ECOG status (n, %) 0 1

7 (43.8) 9 (56.3)

4 (23.5)

13 (76.5)

14 (22.6) 46 (74.2)

Stage (n, %) IIIB IV

2 (12.5)

14 (87.5)

0

17 (100.0)

0

62 (100.0)

Histology (n, %) Adenocarcinoma Squamous cell Large cell Other

16 (100.0)

0 0 0

15 (88.2) 2 (11.8)

0 0

54 (87.1)

5 (8.1) 2 (3.2) 1 (1.6)

Number of previous treatments Mean Median Range

3 2

(1-6)

2 2

1-4

3 2

1-10


Key efficacy data: clinical activity (investigator assessment of evaluable patients*)

Total n=76 (%)

PFS at 16 weeks (95% CI)

24.1 (13.6,36.1)

Objective response rate** CR + PR (95% CI)

4 (5.3) (1.5,12.9)

Disease control rate CR+PR+SD ≥8 weeks (95% CI)

41 (54.0) (42.1, 65.5)

Disease control rate (CR+PR+SD ≥16 weeks (95% CI)

16 (21.1) (12.5, 31.9)

Wong et al. J Clin Oncol 29: 2011 (suppl; abstr 7500) *Received at least 1 cycle of ganetespib and had at least 1 follow-up scan **One patient is not yet due for a confirmation scan

For crizotinib-naive patients: 7/8 (88%) patients with ALK-positive tumours had disease control lasting at least 16 weeks. 6/8 (75%) patients with ALK-positive tumours had tumour shrinkage in target lesions. 4/8 (88%) patients with ALK-positive tumours had objective response.

Key safety data: adverse events


0

10

20

30

40

50

60

70

80

90

Diarrhoea

Fatigue

Nausea

Decrease

d appeti

te

Dyspnoea

Constipati

on

Back pain

Vomiting

Cough

Dehydrat

ion

Dizziness

Insomnia

Anxiety

Headach

e

Hyponatr

aemia

Increase

d ALT

Increase

d ALK PHOS

Hyperglyc

aemia

Muscular

weakness UTI

G5G4G3G2G1

Conclusions •  Ganetespib once weekly is well tolerated in advanced pretreated

NSCLC patients –  Most common AE: diarrhoea; generally Grade 1 and 2, manageable

with supportive care •  Ganetespib demonstrated promising clinical activity as single agent in

NSCLC patients with actively progressing disease •  All patients with durable objective responses had tumours harbouring

ALK rearrangement •  Further biomarker analysis is in progress to identify genetic profiles

sensitive to ganetespib single-agent treatment •  The favourable safety profile and clinical activity in this difficult-to-treat

patient population has prompted evaluation of ganetespib in combination; a Phase IIb/III study of ganetespib in combination with docetaxel has been initiated in second-line advanced NSCLC


#7501: Open-label, randomized multicenter phase II clinical trial of a toll-like receptor-2 (TLR2) agonist mycobacterium w (Cadi-05) in combination with paclitaxel plus cisplatin versus paclitaxel plus cisplatin in advanced non-small cell lung cancer (NSCLC) – CP Belani et al

•  A randomized Phase II study to evaluate the efficacy and safety of treatment with paclitaxel + cisplatin +/- Cadi-05 in patients with advanced NSCLC

•  Eligible patients: Age ≥18 years with histologically confirmed Stage IIIB or IV NSLCL, PS 0/1, life expectancy ≥24 weeks

•  Study objectives: primary: OS; secondary: PFS, RR, toxicity

RANDOMIZE

Control arm Chemotherapy alone

Cadi-05 arm Chemoimmunotherapy

Chemotherapy: 4 cycles Paclitaxel 175 mg/m2

Cisplatin 100 mg/m2

Cycle duration: 3 wks

Immunotherapy: Cadi-05 0.2 ml one wk before 1st cycle 0.1 ml on day 8 & 15 of each

cycle and every month thereafter

Chemo Chemo Chemo Cycle 1 Cycle 2

Chemo Chemo Chemo 0.2ml Cadi-05

0.1ml Cadi-05

0.1ml Cadui-05

0.1ml Cadi-05

0.1ml Cadi-05

Results •  221 patients randomized, median age: 56

(Cadi-05) and 59 years (control), >90% male in both groups, ECOG PS 0/1: 44/63% (Cadi-05) and 46/66% (control)

•  Grade 3/4 toxicities:

•  Median OS in squamous cell NSCLC patients: 299 days (Cadi-05) vs 172 days (control), HR 0.54 (0.31-0.94), p=0.0312

•  Median OS in patients who completed 4 cycles of therapy: 299 days (Cadi-05) vs 233 days (control), HR 0.64 (0.41-0.98), p=0.0438

•  Median PFS (ITT): 199 days (Cadi-05) vs 97 days (control), HR 0.69 (0.47-1.00), p=0.0522

•  Response (Cadi-05 vs control): –  CR/PR: 47% vs 37% –  SD: 42% vs 48% –  PD: 11% vs 16%

OS (ITT analysis)

Surv

ival

dis

trib

utio

n fu

nctio

n

0

1.00

0 350 700 Time (days)

MST: Cadi-05 208 days / Control 196 days HR = 0.86 (95% CI: 0.63–1.19) p= = 0.3804

n = 109 n = 112

0 2 4 6 8 10 12

Neutropenia

Leukopenia

Anemia

Fatigue

Nausea &Vomiting

Diarrhoea

Dyspnea

Control armCADI-05 arm

Grade 4 toxicity

No of patients

Belani et al. J Clin Oncol 29: 2011 (suppl; abstr 7501)

Conclusions •  Adding Cadi-05 to paclitaxel/cisplatin did not improve OS in the overall

patient population in this study –  There was a trend towards improved PFS (p=0.0522)

•  The addition of Cadi-05 to paclitaxel/cisplatin significantly improved OS (p=0.0438) and PFS (p=0.0019) in the pre-specified subgroup of patients who completed 4 cycles of therapy

Belani et al. J Clin Oncol 29: 2011 (suppl; abstr 7501)

#7555: Pemetrexed vs pemetrexed plus carboplatin in pretreated patients with advanced non-small cell lung cancer (NSCLC): Pooled analysis of two randomized trials – Andrea Ardizzoni et al •  Study objective

–  To evaluate the benefit of adding carboplatin (C) to pemetrexed (P) chemotherapy (CT) in second-line therapy of advanced NSCLC

•  Study type/design –  Pooled analysis of data from two identical randomized phase II trials (GOIRC 02.2006 and

NVALT-7) to assess impact of adding C to P in terms of OS –  Patients were randomized to P 500 mg/m2 alone or combined with C AUC 5 Q3W

•  Patient population –  A total of 479 patients with advanced NSCLC were randomized

•  Key results –  In the overall population, survival was not improved by the addition of C to P; the HR for

death was 0.88 (95% CI: 0.71-1.07; p=0.202; P for heterogeneity = 0.693) –  Objective response rate was increased in the C-containing arm with an OR of 1.78 (95%

CI: 1.01-3.12; p=0.046; P for heterogeneity = 0.060) –  Trend for increase in PFS favouring combined CT was observed

•  Key conclusion –  Single agent P remains the standard of care second-line CT in pts with relapsed non-

squamous lung tumours Ardizzoni et al. J Clin Oncol 29: 2011 (suppl; abstr 7555)

#7603: Randomized phase III trial of gefitinib or pemetrexed as second-line treatment in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01) – Myung-Ju Ahn et al

•  Objective: –  To compare the efficacy of gefitinib vs pemetrexed as second-line therapy in

never-smokers with pulmonary adenocarcinoma •  This was a prospective, multicentre, open-label Phase III study •  Eligibility criteria: histologically confirmed pulmonary adenocarcinoma (including

BAC), Stage IIIB-IV disease, never smokers, one prior platinum-based CT, ECOG PS 0-2 and measurable disease

•  Primary endpoint: PFS

Previously platinum treated advance NSCLC

and Adenocarcinoma

never-smoker

R A N D O M I Z A T I O N

Gefitinib 250 mg/d (3 weeks/cycle)

Pemetrexed 500 mg/m2 every 3 weeks Ev

ery

6 w

eeks

Until Disease progression

or Intolerable toxicities

R E S P O N S E E V A L U A T I O N Stratified by

1. Gender 2. ECOG PS (0-1 vs. 2) Ahn et al. J Clin Oncol 29: 2011 (suppl; abstr 7603)

Results •  Between January 2008 and June 2010,

141 patients were randomized

•  The study closed early due to licensed indication changes for both pemetrexed (non-squamous) and gefitinib (EGFR mutation positive tumours) in South Korea as of April 2010

•  Median no of treatment cycles: –  Gefitinib: 10 (1-30) –  Pemetrexed: 4 (1-33)

N HR (95% CI) All 135 0.60 (0.40−0.89) Stage

IIIB IV

12

123

0.33 (0.07−1.48) 0.62 (0.41−0.94)

Gender Male Female

20 115

1.36 (0.51−3.63) 0.50 (0.32−0.77)

Age <65 years ≥65 years

82 53

0.54 (0.33−0.91) 0.76 (0.39−1.48)

ECOG PS 0-1 2

123 12

0.60 (0.39−0.91) 0.60 (0.16−2.18)

EGFR mutation positive negative unknown

40 31 64

0.44 (0.19−1.01) 0.33 (0.14−0.77) 0.84 (0.49−1.46)

Subgroup analysis of progression-free survival

0.1 1.0 5.0 Favours gefitinib Favours pemetrexed

G. Pem. P

Median PFS 9.4 Mo. 2.9 Mo. 0.01

Progression-free survival (primary end point) 1.0

0.8

0.6

0.4

0.2

0

PFS

0 5 10 15 20 25 Months

Gefitinib Pemetrexed

Ahn et al. J Clin Oncol 29: 2011 (suppl; abstr 7603)

Key safety data Adverse events (occurring in at least 10% of pts in either arm)

Gefitinib (n=68) Pemetrexed (n=67) p CTC* grades (n, %) All grades grade 3/4 All grades grade 3/4 Rash acneiform 31 (45.6) 1 (1.5) 3 (4.5) 0 <0.0001 Pruritus 21 (30.9) 0 6 (9.0) 0 0.004 Dry skin 11 (16.2) 0 0 0 − Cough 25 (36.8) 0 24 (35.8) 0 0.89 Dyspnoea 13 (19.1) 0 18 (26.9) 0 0.37 Chest pain 12 (17.6) 0 20 (29.9) 1 (1.5) 0.16 Sensory neuropathy (pph) 11 (16.2) 0 7 (10.4) 0 0.35 Infection 11 (16.2) 1 (1.5) 4 (6.0) 2 (3.0) 0.07 Fatigue 15 (22.1) 0 14 (20.9) 0 0.85 Anorexia 22 (32.4) 1 (1.5) 20 (29.9) 0 0.76 Nausea 11 (16.2) 0 11 (16.4) 0 1.0 Diarrhoea 18 (26.5) 0 3 (4.5) 0 0.001 Constipation 5 (7.4) 0 10 (14.9) 0 0.20 Dizziness 5 (7.4) 0 8 (11.9) 0 0.41


Conclusions •  Gefitinib was associated with superior efficacy to pemetrexed as second-

line therapy in clinically selected Korean patients with NSCLC

•  Gefitinib may be preferable to pemetrexed as second-line therapy in enriched NSCLC patients


#7604: Safety data and patterns of progression in met diagnostic subgroups in OAM4558g; A phase II trial evaluating MetMAb in combination with erlotinib in advanced NSCLC – Anshu Vashishtha et al

•  Study objective –  To assess safety and progression with MetMAb + erlotinib (M+E) in Met diagnostic (Dx) subgroups (Dx

+ and Dx-) •  Study type/design

–  Phase II, double-blind, randomized trial of M+E or placebo + erlotinib (P+E) in second- and third-line NSCLC

–  Tumour growth rate, onset of new lesions and MetMAb-related toxicities were evaluated •  Patient population

–  137 patients with stage IIIB/IV NSCLC (second/third-line) were enrolled: 136 were evaluable for safety –  128 patients had evaluable Met status: 66 Met Dx+ and 62 Met Dx-

•  Key results –  Overall, the pattern of AEs were similar in the two treatment arms, with the exception of peripheral

oedema (higher with M+E) regardless of c-Met expression levels –  No new substantial toxicities observed with MetMAb –  The rate of tumour growth was not significantly different between treatment arms or Met subgroups

(power to detect difference limited by small number of subjects in study) •  Key conclusions

–  The combination of M+E did not substantially alter the safety profile of erlotinib and differences in AEs do not clearly explain the PFS and OS outcomes observed in Met Dx subgroups on M+E

–  The addition of M to E in Met Dx- patients did not appear to alter tumour growth rates or patterns of disease progression

Vashishtha et al. J Clin Oncol 29: 2011 (suppl; abstr 7604)

#7505: Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC David R Spigel et al Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN

Study design Phase II: Erlotinib ± MetMAb in 2nd/3rd-line NSCLC

1:1 R A N D O M I Z A T I

O N

Key eligibility: •  Stage IIIB/IV NSCLC •  2nd/3rd-line NSCLC •  Tissue required •  PS 0-2

MetMAb (15mg/kg IV Q3W)

+ erlotinib

(150mg daily)

Placebo (IV Q3W)

+ erlotinib

(150mg daily)

Add MetMAb

Stratification factors: •  Tobacco history •  Performance status •  Histology

n=69

n=68

n=27

Arm A

Arm B

Co-primary objectives: •  PFS in ‘Met Diagnostic

positive’ patients (est. 50%) •  PFS in overall ITT population

Other key objectives: •  OS in ‘Met Diagnostic positive’

patients •  OS in overall ITT population •  Overall response rate •  Safety/tolerability

Must be eligible to be treated with MetMAb

*128 NSCLC patients enrolled from 3/2009 to 3/2010 plus 9 SCC patients enrolled through 8/2010 Data presented includes >5 additional months of follow-up

PD

n=137*

Spigel et al. J Clin Oncol 29: 2011 (suppl; abstr 7505)


ITT Met Dx Negative Met DX Positive

Placebo + erlotinib (n=68)

MetMAb + erlotinib (n=69)





Median (range) 63 (42–83) 64 (30–83) 61 (42–83) 63 (45–82) 64 (44–82) 66 (30–83) Sex: Male 62% 58% 55% 65% 65% 51% Race: White 90% 88% 90% 87% 90% 91% ECOG PS: 0/1 97% 94% 100% 90% 94% 97% Squamous cell 29% 29% 39% 45% 16% 14% Never smoker 12% 15% 3% 7% 19% 20%

Line of therapy: 2nd 3rd

68% 32%

67% 33%

65% 35%

68% 32%

71% 29%

63% 37%

Met Dx positive* 50% 53% 0% 0% 100% 100% KRAS mutant** 23% 23% 25% 24% 23% 23% EGFR mutant** 11% 13% 14% 0% 8% 23%

Baseline characteristics were well balanced for most prognostic factors *Of 128 patients with evaluable tissue samples **Of 112 patients with evaluable tissue samples

Met Dx+: Met Diagnostic Positive Met Dx–: Met Diagnostic Negative


Efficacy Placebo + erlotinib

MetMAb + erlotinib

Median (mo) 1.5 2.9 HR 0.53 (95% CI) (0.28–0.99) Log-rank p-value 0.04 No. events, n (%) 27 20

Placebo + erlotinib

MetMAb + erlotinib


Placebo + erlotinib

MetMAb + erlotinib


100

80

60

40

20

0

Prob

abilit

y of p

rogr

essio

n fre

e

0 3 6 9 12 15 18 Time to progression (months)

PFS (Met Dx+ patients)

PFS (Met Dx- patients) 100

80

60

40

20

0

Prob

abilit

y of p

rogr

essio

n fre

e


PFS (ITT population) 100

80

60

40

20

0

Prob

abilit

y of p

rogr

essio

n fre

e



Efficacy in additional subpopulations Pr

obab

ility

of s

urvi

val

MET FISH+ (≥5 copies) OS: HR=0.60; p=0.35

1.0

0.8

0.6

0.4

0.2

0 0 3 6 9 12 15 18

n=11

n=8

Met Dx+ / FISH– OS: HR=0.37; p=0.01

1.0

0.8

0.6

0.4

0.2

0 0 3 6 9 12 15 18

n=20

n=17

Met Dx+ EGFR non-mutant (nm) OS: HR=0.42; p=0.010

1.0

0.8

0.6

0.4

0.2

0 0 3 6 9 12 15 18

Overall survival (months)

n=28

n=29

Met Dx+ / FISH– / EGFR nm OS: HR=0.45; p=0.07

1.0

0.8

0.6

0.4

0.2

0 0 3 6 9 12 15 18

Overall survival (months)

n=15

n=17

Placebo + erlotinib MetMAb + erlotinib

The benefit from MetMAb is not driven by EGFR mutation or FISH status Spigel et al. J Clin Oncol 29: 2011 (suppl; abstr 7505)

Safety profile (AEs reported in ≥10% of patients) Met Diagnostic Positive (n=66) Met Diagnostic Negative (n=62)





Rash 61.3% 62.9% 58.1% 58.1% Diarrhoea 41.9% 51.4% 54.8% 25.8% Fatigue 38.7% 45.7% 35.5% 19.4% Nausea 29.0% 37.1% 32.3% 29.0% Decreased appetite 32.3% 28.6% 16.1% 12.9% Dyspnoea 25.8% 22.9% 19.4% 12.9% Cough 19.4% 20.0% 22.6% 12.9% Peripheral oedema 6.5% 22.9% 9.7% 22.6% Anaemia 19.4% 17.1% 9.7% 12.9% Dermatitis acneiform 9.7% 14.3% 19.4% 16.1% Dry skin 16.1% 14.3% 16.1% 6.5% Vomiting 16.1% 5.7% 22.6% 6.5% Pyrexia 9.7% 14.3% 6.5% 16.1% Asthenia 6.5% 14.3% 9.7% 12..9% Back pain 16.1% 5.7% 6.5% 16.1% Pain 3.2% 11.4% 19.4% 0% Haemoptysis 9.7% 2.9% 6.5% 16.1% Urinary tract infection 6.5% 5.7% 12.9% 6.5% Chest infection 6.5% 2.9% 16.1% 3.2% Pneumonia 3.2% 2.9% 6.5% 12.9%


Conclusions •  MetMAb is a potent and selective inhibitor of the Met pathway •  MetMAb + erlotinib improves PFS and OS in Met Dx+ patients

–  Not driven by key sub populations or imbalances in prognostic characteristics

•  Differences in outcomes between different subpopulations highlight the importance of diagnostic development

•  A Phase III study evaluating MetMAb + erlotinib in Met Dx+ patients is expected to start accruing patients later this year


#7507: Impact of crizotinib on survival in patients with advanced, ALK-positive NSCLC compared with historical controls Alice T. Shaw et al Massachusetts General Hospital Cancer Center, Boston, MA

Study design •  Study objectives

–  To examine OS of crizotinib-treated ALK-positive NSCLC patients; to compare survival outcomes of crizotinib-treated vs crizotinib-naïve, ALK-positive NSCLC patients; to explore prognostic significance of ALK rearrangement by comparing survival outcomes of crizotinib-naïve ALK-positive and ALK-negative NSCLC patients

•  Study type/design –  82 ALK+ patients who enrolled in the

expansion cohort of the phase I trial of crizotinib (Kwak et al., NEJM, 2010)

–  Comparators were 37 ALK+ patients not treated with crizotinib (ALK+ controls), and 253 ALK-/EGFR- patients (ALK- controls)

–  All ALK+ and ALK- controls had advanced NSCLC

ALK CRIZOTINIB

ALK-positive Crizotinib-treated

N=82

US/Australia N=56

2nd/3rd line N=30

ALK CONTROLS

US/Australia N=36

2nd line N=23

Never/light smoker

AdenoCA N=21

ALK-positive Crizotinib-naïve

WT/WT CONTROLS

US (MGH) N=253

2nd line N=125

Never/light smoker

AdenoCA N=48

ALK-negative EGFR-wildtype

Never/light smoker

AdenoCA N=28

Shaw et al. J Clin Oncol 29: 2011 (suppl; abstr 7507)



ALK Crizotinib N=56

ALK Controls N=36

p-value

Age, yrs Median 51 51 0.90

Range 28–78 32–78

Sex, n M/F 30/26 16/20 0.52

Race, n (%) Caucasian 48 (86) 31 (86) 1.00

Asian 4 (7) 3 (8)

Smoking history, n (%) Never smoker 46 (82) 24 (67) 0.25

≤ 10 pack-years 7 (13) 7 (19)

> 10 pack-years 3 (5) 5 (14)

Histology, n (%) Adenocarcinoma 54 (96) 34 (94) 0.64

Squamous 1 (2) 1 (3)

Other 1 (2) 1 (3)

Brain metastases* No/Yes 27/29 19/17 0.83

* At any time

Key efficacy data Overall survival of ALK-positive

NSCLC patients treated with crizotinib (N=82)

Overall survival (second-line subset)

Median OS: Not reached (NR) 1-yr OS: 74%; 2-yr OS: 54% 61% of patients in follow-up for OS with median follow-up of 18 mos

74%

54%

1 2 3 4 0 0%

20%

40%

60%

80%

100%

From first crizotinib dose

Years

ALK Crizotinib

(n=30)

ALK Control (n=23)

WT/WT Control (n=125)

Median Survival, mo NR 6 11 1-yr Survival, % 70 44 47 2-yr Survival, % 55 12 32

From 2nd/3rd line crizotinib HR = 0.49, p=0.02


1 2 3 4 0 0%

20%

40%

60%

80%

100%

Years

Conclusions •  Overall survival of patients with advanced, ALK-positive NSCLC treated

with second-/third-line crizotinib is significantly longer than that of clinically comparable, crizotinib-naïve controls

•  ALK rearrangement is not a favorable prognostic factor in advanced NSCLC

•  Crizotinib may prolong overall survival and fundamentally alter the natural history of ALK-positive NSCLC


#7513: A randomized phase II study of pemetrexed (PEM) with or without sorafenib (S) as second line therapy in advanced non-small cell lung cancer (NSCLC) of non-squamous histology: NCCTG N0626 study - Julian R Molina et al

•  Study objective –  To evaluate the safety and efficacy of the combination of sorafenib (S) plus pemetrexed

(PEM) vs PEM alone, as second line-treatment in non-squamous NSCLC •  Study type/design

–  A lead-in phase to determine the tolerability of S plus PEM was followed by a 1:1 randomization of either PEM 500 mg/m2 q21 days plus S 400 mg po BID for 21 days (Arm A; n=49) or PEM 500 mg/m2 q21 days (Arm B; n=51)

–  Polymorphisms in VEGFA, VEGFR1-3, FPGS, GGH, SLC19A1 and TYMS were evaluated in germline DNA and correlated with outcomes •  96 DNA samples from eligible patients were genotyped for 68 tagSNPs

•  Patient population –  Patients with advanced non-squamous NSCLC –  Baseline age, gender, and ECOG performance status were balanced between arms

•  Study endpoints –  Primary: PFS –  Secondary: OS, tumour response, adverse events

•  Inclusion criteria: stage IIB or IV non-squamous NSCLC; previously treated; ECOG PS 0-1 (exclusion criteria: any clinically significant infection)

Molina et al. J Clin Oncol 29: 2011; (suppl; abstr 7513)

Key efficacy and safety data •  Efficacy data

–  PFS and OS was similar between treatment arms

•  Safety data –  PEM + S had a significantly increased rate of grade 3 non-haematological adverse events

(76% vs. 39%, p < 0.001).

CT+TT genotypes of VEGFA rs3025039 were associated with worse PFS in A than in B (interaction p=0.03)

0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24

100

80

60

40

20

0

100

80

60

40

20

0

Progression-free survival Overall survival

% p

rogr

essi

on fr

ee a

nd a

live

PEM+S (43/49 events), median=3.4 months (95% CI: 2.6–5.7) PEM (50/51 events), median=4.1 months (95% CI: 1.6–5.7)

Log-rank p=0.26

Time from registration (months)

PEM+S (30/49 events), median=9.4 months (95% CI: 5.9–19.5) PEM (43/51 events), median=10.4 months (95% CI: 7.2–13.5)

Log-rank p=0.24

Time from registration (months)

% a

live


Conclusions •  Although the trial did not meet the protocol specified success criteria, post-

hoc sub group analyses suggests a marginal improvement in PFS for patients on S plus PEM with prior exposure to BEV

•  Polymorphisms in VEGFA appear to predict for a worse outcome in patients receiving S –  The presence of the variant allele in VEGFA rs3025039 was

significantly associated with inferior PFS in patients receiving S, while no association was found in PEM alone

–  Variant alleles in TYMS rs2647153 and FPGS rs10760502 were significantly associated with inferior PFS or OS in these patients

•  These preliminary findings warrant further investigation.


#7514: Initial phase 2 results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005 – L Crinò et al

•  Study objective –  To asses anti-tumour efficacy and safety of crizotinib in patients with advanced ALK-positive

NSCLC who failed at least one line of previous platinum-based therapy •  Study type/design

–  Phase II open-label multicentre study –  Ongoing study included patients from 57 sites in 12 countries with ALK-rearranged NSCLC (by

centralized FISH test) who progressed after ≥1 chemotherapy for recurrent/advanced/metastatic disease (including treated brain metastases)

–  Patients received oral crizotinib 250 mg BID continuously in 3-week cycles until progression –  Disease response was evaluated every 6 weeks and safety/patient-reported outcomes every 3

weeks •  Study endpoints

–  Treatment response, ORR, DCR, adverse events •  Key patient inclusion criteria

–  ALK positivity by break-apart FISH –  ECOG PS 0-3 –  Measurable lesions –  Failure with at least one prior line of platinum-based chemotherapy

Crinò et al. J Clin Oncol 29: 2011; (suppl; abstr 7514)

Key efficacy and safety data

•  Most frequent treatment-related AEs were nausea (46%), vision disorder (45%), vomiting

(39%), and diarrhea (29%), mostly Grade 1/2 •  Treatment-related Grade 3/4 AEs were reported in 15% of pts (mostly increased ALT,

dyspnea and neutropenia) •  Patients had clinically significant (≥10 points) improvements in pain, cough, dyspnea and

fatigue seen as early as cycle 2 •  Overall, QoL was maintained


Characteristic N=133

Response, n (%) CR PR SD Disease progression

1 (>1.0) 67 (50.4) 45 (33.8) 10 (7.5)

ORR, n (%) [95% CI] 68 (51.1) [42.3, 59.9]

DCR, n (%) [95% CI] Week 6 Week 12

113 (85.0) [77.7, 90.6] 98 (73.7) [65.3, 80.9]

Conclusions


•  Preliminary data from this Phase II open-label study suggest crizotinib was well tolerated in patients with pretreated ALK-rearranged NSCLC

•  Evidence of antitumor activity with crizotinib was demonstrated by a 51% ORR (including 1 CR and 67 PRs)

•  Patients reported clinically meaningful reductions in pain, dysnoea, cough and fatigue symptoms –  QoL was maintained with treatment

•  Data support previous efficacy and safety findings from a Phase I expanded cohort of crizotinib in patients with ALK-positive advanced NSCLC

#7515: Comparative analyses of overall survival of anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) patients who did not receive ALK inhibitors – Dong-Wan Kim et al

•  Study objective –  To investigate OS of advanced ALK-positive NSCLC patients who were managed in the

pre-ALK inhibitors era •  Study type/design

–  Retrospective, single-centre case matched study –  A total of 1,100 stage IIIB/IV patients with non-squamous histology were collected in the

NSCLC database of the Seoul National University Hospital (SNUH) between January 2003 and January 2009

–  ALK screening by FISH was performed on 257 cases that were either EGFR WT or non-responders to prior EGFR TKI therapy

–  One patient with ALK-positive tumour was matched with two patients with EGFR mutation-positive tumours and two patients with ALK WT / EGFR WT (WT/WT)

–  Patients were stratified by treatments received (first-line chemotherapy, EGFR TKIs as any line of therapy)

•  Study endpoints –  Primary: OS –  Secondary: PFS with first-line chemotherapy, PFS with EGFR TKI therapy (any line)

Kim et al. J Clin Oncol 29: 2011; (suppl; abstr 7515)

Key efficacy data •  Median OS was significantly longer in the EGFR mutation positive matched cases regardless of therapy, •  Median OS in the WT/WT cases were not significantly different from the ALK-positive cases •  Median PFS for cases who received first-line chemotherapy was similar for all tumour type groups: 3.87

(ALK-positive), 4.87 (EGFRmut) and 3.40 (WT/WT) months •  Median PFS for cases who received EGFR TKIs was significantly longer for EGFR mutation-positive and

WT/WT cases: 10.7 (EGFRmut) and 2.03 months (WT/WT) vs 1.37 months (ALK-positive) (p<0.001 and p=0.035, respectively)


100

75

50

25

0

Surv

ival

(%)

0 20 40 60 80 100 Time (months)

ALK-positive (N=22) EGFR mutation positive (N=44) WT/WT (N=44)

ALK-positive EGFR mutation positive WT/WT

OS Median (95% CI) P-value* vs ALK-positive Hazard ratio

N=22 10.37

(6.51, 14.23)

1

N=44 28.03

(20.40, 35.67) 0.012 0.498

(0.281, 0.883)

N=44 14.53

(8.929, 20.131) 0.384 0.730

(0.417, 1.277)

PFS − first-line chemotherapy Median (95% CI) P-value* vs ALK-positive

N=20 3.87 (0.00, 8.60)

N=32 4.87 (2.93, 6.81)

0.591

N=34 3.40 (2.16, 4.64)

0.174

PFS − EGFR TKI Median (95% CI) P-value* vs ALK-positive

N=10†

1.37 (1.07, 1.67)

N=40 10.70 (6.37, 15.02)

<0.001

N=24 2.03 (0.54, 3.52)

0.035

*Log rank comparison of Kaplan-Meier estimates for patients with ALK-positive tumours compared with patients having other tumour types. †Excludes patients that were enrolled due to previous non-response to EGFR TKIs

Conclusions •  Patients with ALK-positive tumours tended to have a shorter OS compared

with those with EGFR mutation-positive or WT/WT tumours in the pre-ALK inhibitors era

•  Although patient responses to first-line chemotherapy were not different in those with ALK-positive tumours compared with those with EGFRmut or WT/WT tumours, they were more resistant to EGFR TKI treatment, even compared with patients with WT/WT tumours


#7516: Safety and activity of IPI-504 (retaspimycin hydrochloride) and docetaxel in pretreated patients (pts) with metastatic non-small cell lung cancer (NSCLC) – Gregory J. Riely et al

•  Study objective –  To evaluate IPI-504 (heat shock protein 90 [Hsp90] inhibitor ) in combination with docetaxel in pts with

NSCLC and Karnofsky performance status ≥70 •  Study type/design

–  Expansion of a Phase Ib trial to evaluate IPI-504 in combination with docetaxel –  Patients received docetaxel 75 mg/m2 IV once every three weeks (wks) and IPI-504 300 mg/m² IV once

per wk –  All pts were evaluated for safety, pharmacokinetics and tumour response (RECIST)

•  Patient population –  Pts with NSCLC and Karnofsky performance status ≥70 (n=23)

•  Key results –  Median patient age was 61 years (range 31-77); 13 female (57%) –  Median PFS and OS: 2.8 months (95% CI, 2.5-4.1) and 7.9 months (95% CI, 2.8-10.2), respectively –  ORR: 33% in current or former smokers, 43% in squamous cell carcinoma and 36% in KRAS wild type –  Majority of adverse events were Grade 1 or 2: most common treatment-related adverse events were

fatigue (66% total, 9% ≥Grade 3), diarrhoea (39%, 9%) and nausea (39%, 13%) –  Docetaxel pharmacokinetics were unaltered by IPI-504 co-administration

•  Key conclusion –  IPI-504 in combination with docetaxel was well tolerated and resulted in clinical activity in pts with

pretreated metastatic NSCLC

Riely et al. J Clin Oncol 29: 2011; (suppl; abstr 7516)

#7522: A randomized, double-blind phase III study of icotinib versus gefitinib in patients with advanced non-small cell lung cancer (NSCLC) previously treated with chemotherapy (ICOGEN) – Yan Sun et al

•  Study objective –  To investigate icotinib (Ic) versus gefitinib (Ge) in patients with

advanced NSCLC previously treated with chemotherapy •  Study type/design

–  Patients (Pts) with NSCLC who progressed after one or two lines of chemotherapy were randomized to receive Ic (150mg tid; n=199) or Ge (250mg qd; n=196)

–  EGFR gene mutational analysis was performed by using DsX Scorpion ARMS

•  Study endpoints –  Primary: PFS –  Secondary: OS, ORR, TTP, QoL and tolerability

Sun al. J Clin Oncol 29: 2011; (suppl; abstr 7522)


•  Ic demonstrated 35 day (d) median PFS extension compared with Ge (Ic vs Ge: 137 d vs 102, HR 0.84, 95% CI 0.67-1.05) •  With 49.4% maturity, OS was similar between Ic and Ge groups (median OS was 504 d and 531 d, respectively) •  ORR (Ic vs Ge: 27.6% vs 27.2%), DCR (75.4% vs 74.9%), TTP (156 d vs 111 d ) and QoL (101.4 ± 9.6 vs 103.0 ± 19.1) were

comparable between Ic and Ge groups •  Adverse response rate in Ic group was 60.5%, which was significantly lower than that in Ge group (70.4%) (p=0.04) •  39.5% pts in Ic developed rash compared to 49.2% in Ge; 18.5% pts in Ic had diarrhoea compared with 27.6% in Ge

(p=0.03)

Sun et al. J Clin Oncol 29: 2011; (suppl; abstr 7522)

50 150 100 250 350 300 200 400 0

0.2

0.0

0.4

0.8

0.6

1.0

Pro

babi

lity

of P

FS

Icotinib Gefitinib

N 199 196

Events 151 (75.88%) 157 (80.10%)

Censored 48 (24.12%) 39 (19.90%)

Cox analysis with covariates

HR (95% CI)=0.835 (0.667–1.046)

Median time 137 102

Log Rank P-value 0.1300

Gefitinib

Icotinib

Days

Conclusions •  The study met the primary endpoint which demonstrated non-inferiority of

icotinib to gefitinib in terms of PFS •  The non-inferiority of icotinib also extends to the secondary endpoints of

OS, ORR, DCR and improvement of QoL •  Icotinib has a more favourable tolerability profile compared with gefitinib •  Similar to gefitinib, patients with EGFR mutations respond to icotinib much

better than patients with wild type EGFR

Sun et al. J Clin Oncol 29: 2011; (suppl; abstr 7522)

#7524: A Phase II trial of afatinib (BIBW 2992) in patients (pts) with advanced non-small cell lung cancer previously treated with erlotinib (E) or gefitinib (G) – Nobuyuki Yamamoto et al

•  Study type/design –  Phase II, open-label, multicentre study in Japan –  Patients received a single daily oral dose of afatinib (50 mg/day) (28 days representing

one course of treatment) •  Study endpoints

–  Primary: objective tumour response (RECIST) –  Secondary: clinical benefit (CR, PR, SD, time to objective response, duration of objective

response, duration of clinical benefit, PFS, OS, safety, PK profile, examination of EGFR mutations

•  Patient population –  Patients in Japan with Stage IIIB/IV NSCLC (ECOG PS 0–1) who had progressed

according to RECIST after 1–2 lines of chemotherapy and ≥12 wks of E or G (n=62) –  Median age (range): 65 (33-84); 77% female

•  Key patient inclusion criteria –  Confirmed Stage IIIB/IV adenocarcinoma (with at least one measurable lesion)

Yamamoto et al. J Clin Oncol 29: 2011 (suppl; abstr 7524)

Key results

Independent review Investigator assessment

PR, confirmed (%) 5 (8.2) 8 (13.1)

PR, unconfirmed (%) 9 (14.8) 13 (21.3)

DCR* (CR+PR+SD), confirmed (%)

40 (65.6) 44 (72.1)

DCR (CR+PR+SD), unconfirmed (%)

52 (85.2) 57 (93.4)

Median PFS (months) 4.4 4.6

*Median duration of DCR: 19.9 weeks by independent review and 20.6 weeks by investigator assessment Yamamoto et al. J Clin Oncol 29: 2011 (suppl; abstr 7524)

•  Similar efficacy was seen in those patients meeting acquired resistance criteria (5.9% PR; 69% DCR; median PFS of 4.4 months, by independent review)

•  Two pts had T790M mutations in their primary tumors; one, harbouring L858R+T790M, had a long SD (308 days)

•  Common adverse events included diarrhoea, rash/acne, stomatitis, nail effects and decreased appetite

Conclusions •  Afatinib has demonstrated clinically meaningful efficacy in the overall study

population, with consistent results by investigator and independent review –  8.2% ORR; DCR for at least 8 weeks of 65.6%; median PFS of 4.4

months by independent review –  13.1% ORR; DCR of 72.1%; median PFS of 4.6 months by investigator

assessment •  Almost identical efficacy results to the overall study population were noted

in the patients with acquired resistance to erlotinib or gefitinib •  The predominant adverse events were diarrhoea, acne/rash, nail effects

and stomatitis, which was consistent with previous studies of afatinib

Yamamoto et al. J Clin Oncol 29: 2011 (suppl; abstr 7524)

#7525: Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib – Yelena Janijgian et al

•  Study objective –  To assess the safety and preliminary efficacy of afatinib in combination with cetuximab in

patients with clinically defined acquired resistance to EGFR therapy •  Study type/design

–  Phase Ib, open-label, multicentre study (US and The Netherlands) –  Patients with AR received afatinib 40 mg/day with escalating dose cohorts of biweekly

cetuximab (250 and 500 mg/m2) –  Patients receiving the recommended Phase II dose (RP2D) were evaluated for objective

response –  Acquisition of tumour tissue after emergence of AR was mandatory

•  Patients –  Of 26 patients treated, 22 received the predetermined maximum dose (afatinib 40 mg/day

plus cetuximab 500 mg/m2) –  Median time on prior erlotinib/gefitinib therapy was 2.4 years

•  Study endpoints –  Primary: Occurrence of DLT –  Secondary: Objective response (assessed at weeks 4, 8 and 12, and every 8 weeks

thereafter) Janijgian et al. J Clin Oncol 29: 2011 (suppl; abstr 7525)

Key results

•  Efficacy –  Disease control was achieved in all patients treated at the RP2D

•  Tumour size reduction in 76% of patients •  Confirmed PR in 8/22 evaluable patients, including 4/13 in T790M+ NSCLC

•  Safety –  No DLT was observed –  Common AEs: Grade 1/2 rash 46%, diarrhoea 19% –  Three patients has Grade 3 rash Janijgian et al. J Clin Oncol 29: 2011 (suppl; abstr 7525)

T790M positive

T790M negative

T790M unknown

No EGFR mutation

Total

Total treated 27 15 3 2 47

Evaluable for efficacy 26 14 3 2 45

Best response n (%)

Any PR 13 (50) 8 (57) 2 (67) 23 (51)

Confirmed PR 9 (35) 7 (50) 2 (67) 18 (40)

SD 11 (42) 5 (36) 1 (33) 19 (42)

Clinical response (any PR + SD) 24 (92) 13 (93) 3 (100) 2 (100) 42 (93)

Progression of disease 2 (8) 1 (7) 3 (7)

Conclusions •  In this patient population, RP2D is afatinib 40 mg daily and cetuximab 500

mg/m2 every 2 weeks •  Most patients in the study (>90%) derived clinical benefit from afatinib +

cetuximab therapy •  In this ongoing study, objective responses were observed in T790M-

positive and T790M-negative tumours, with a confirmed objective response rate of 40%

•  These data support that EGFR mutation-positive NSCLC, with acquired resistance to erlotinib and gefitinib, continues to depend on EGFR signaling

Janijgian et al. J Clin Oncol 29: 2011 (suppl; abstr 7525)

#7526: A randomized phase 2 study of pemetrexed vs pemetrexed+erlotinib in second-line treatment for locally advanced or metastatic, non-squamous NSCLC Joachim Von Pawel et al. Asklepios Fachkliniken München–Gauting Hospital, Germany

Study design •  This was a multi-centre, randomized, Phase II, open-label study to evaluate the efficacy

and safety of pemetrexed alone versus pemetrexed + erlotinib as second-line therapy in patients with Stage III or IV non-squamous NSCLC

•  Patients aged ≥18 years with histologically confirmed Stage III or IV non-squamous* NSCLC who had failed 1 prior platinum-based chemotherapy regimen were eligible –  Patients were recruited at 24 centres in five countries

•  Eligible patients were randomized 1:1 to receive either pemetrexed 500 mg/m2 Q3W (Arm A) or pemetrexed 500 mg/m2 Q3W plus erlotinib 150 mg daily (Arm B)

•  Patients were stratified by ECOG PS (0-1 vs 2) and smoking status (never-smoker vs ≤15 pack-year history vs ex-smoker stopped >25 years ago vs >15 pack-year history and smoked in the last 25 years)

•  All patients received vitamin B12 and folic acid supplementation, and prophylactic dexamethasone according to the pemetrexed prescribing information

•  Patients were followed for 12 months after last pemetrexed dose (treatment duration not specified)

•  Primary endpoint: PFS •  Secondary endpoints: RR, DCR, TTTF, OS, 1-year OS rate, safety and AE profile *Histological subtype was restricted to non-squamous NSCLC in a protocol amend, based on results from other studies which showed that the benefits of pemetrexed are greater in patients with other than predominantly squamous NSCLC.1-3 Patients with squamous NSCLC already recruited were allowed to continue treatment if they were receiving benefit, as determined by the study investigator

1.  Ciuleanu et al. Lancet 2009;374:1432-1440 2.  Peterson et al. Eur J Cancer 2007;5(Suppl 4):363-364

3.  Scagliotti et al. J Clin Oncol 2008;26(21):3543-3551

Patient demographics •  165 patients were randomized (pemetrexed, n=86; pemetrexed + erlotinib, n=79) and 159

received at least one dose of study drug •  Baseline and disease characteristics of patients with non-squamous NSCLC are shown below Patient characteristics Pemetrexed (n=83) Pemetrexed + erlotinib (n=76) Mean age, years (SD) 59.8 (10.25) 63.5 (9.7) No of males, n (%) 49 (59.0) 46 (60.5) Ethnic origin, n (%)

Caucasian Hispanic West Asian

82 (98.8)

1 (1.2) 0 (0)

75 (98.7)

0 (0) 1 (1.3)

ECOG PS* 0 1 2

33 (39.8) 39 (47.0) 11 (13.3)

33 (44.0) 33 (44.0) 9 (12.0)

Disease stage IIIA IIIB IV

3 (3.6)

10 (12.0) 70 (84.3)

1 (1.3)

11 (14.5) 64 (84.2)

Smoking status Ex-smoker Current smoker Never smoker

44 (53.0) 25 (30.1) 14 (16.9)

51 (67.1) 15 (19.7) 10 (13.2)

*1 patient in the pemetrexed + erlotinib group had missing data Von Pawel et al. J Clin Oncol 29: 2011; (suppl; abstr 7526)

Efficacy (non-squamous NSCLC only)

PFS rates (%)

Pemetrexed (n=83)

Pemetrexed + erlotinib (n=76)

3 months 42.4 57.2

6 months 22.7 31.5

12 months 3.5 18.8

•  Response rates (CR or PR): •  P: 10.8% •  P+E: 17.1%

•  DCR: •  P: 51.8%

•  P+E: 55.3% •  TTTF:

•  P: 2.4 months (95% CI: 1.7-3.0) •  P+E: 3.0 (95% CI: 2.2-4.1) •  Median OS:

•  P: 7.8 months (95% CI: 5.3-10.4) •  P+E: 11.8 months

(95% CI: 8.2-16.7) •  1-year OS:

•  P: 34.1% •  P+E: 49.4%

0.0

20.0

40.0

60.0

80.0

100.0

Pemetrexed No. of patients Events Censored Median time 95% CI Log rank P-value one-sided 0.0047

83 70 (84.3%) 13 (15.7%) 2.89 months (1.94, 3.38)

76 60 (78.9%) 16 (21.1%) 3.19 months (2.86, 4.70)

Pemetrexed + erlotinib

Prop

ortio

n of

pat

ient

s pr

ogre

ssio

n-fr

ee

Time (months) 83 76

30 38

14 20

6 16

0 5

0 2

0 2

0 2

0 1

0 1

0 0

0 0

0 3 6 9 12 15 18 21 24 27 30 33 36

2 11

PEM PEM + ERLO

Pemetrexed + erlotinib Pemetrexed

Von Pawel et al. J Clin Oncol 29: 2011; (suppl; abstr 7526)

Safety •  TEAEs:

–  Non-squamous: Arm A: 58 (69.9%); Arm B: 72 (94.7%) –  Squamous: Arm A: 14 (73.7%); Arm B: 24 (92.3%)

– 

•  SAEs –  Non-squamous: Arm A: 10 (12.0%); Arm B: 24 (31.6%)

•  30 deaths were reported during the study or within 30 days of discontinuation, mostly due to PD –  One death due to drug-related febrile neutropenia occurred in Arm B

(non-squamous subtype)

*Includes Grade 5 events

Treatment-related Grade 3/4 toxicities occurring in patients with non-squamous NSCLC

Pemetrexed (n=83)

Pemetrexed + erlotinib (n=76)

Ethnic origin, n (%) Rash/desquamation* Diarrhoea Febrile neutropenia

1 (1.2) 1 (1.2) 2 (2.4)

7 (9.2) 4 (5.3)

8 (10.5) Laboratory, n (%)

Anaemia Leukopenia Neutropenia Thrombocytopenia

5 (6.0) 8 (9.6) 8 (9.6) 4 (4.8)

9 (11.8)

18 (23.7) 19 (25.0) 11 (14.5)


Conclusions •  Second-line therapy with pemetrexed + erlotinib was associated with a

significant improvement in PFS and OS versus pemetrexed alone in patients with non-squamous NSCLC –  There were no statistically significant differences in RR or DCR

between groups •  The toxicity profile of combination therapy with pemetrexed + erlotinib

was as expected –  Combination therapy was associated with an increase in TEAEs, SAEs,

and Grade 3/4 laboratory and non-laboratory toxicities compared with pemetrexed monotherapy

•  The benefits of combination therapy with pemetrexed + erlotinib in this setting require confirmation in a Phase III study


#7000: Randomized phase III trial of amrubicin (versus topotecan (Topo) as second-line treatment for small cell lung cancer (SCLC) – Robert Jotte et al

•  Study objective –  To compare safety and efficacy of amrubicin versus Topo in second-line

treatment of SCLC •  Study type/design

–  Randomized Phase III study: patients randomized 2:1 to amrubicin 40 mg/m2 IV (Days 1-3, n=424) or to Topo 1.5 mg/m2 IV (Days 1-5, n=213)

–  24 months of follow up •  Patient population

–  Patients with SCLC (similar baseline characteristics across study groups)

•  Study endpoints –  Primary endpoint: OS –  Secondary endpoints: ORR, TTP, PFS, QoL, safety

Jotte et al. J Clin Oncol 29: 2011 (suppl; abstr 7000)

Key results

•  ORR: 31.1% vs 16.9% (p=0.001) •  OS in refractory patients : 6.2 months vs 5.7

months (HR 0.77, p=0.047)

•  Grade 3/4 AEs in amrubicin vs Topo (all p<0.05) –  Neutropenia (41% vs 53%) –  Thrombocytopenia (21% vs 54%) –  Anaemia (16% vs 30%) –  Infection (16% vs 10%) –  Febrile neutropenia (10% vs 4%)

Amrubicin Topotecan

0 3 6 9 12 15 18 21 24 27 30 33

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

0

Surv

ival

pro

babi

lity

Time (months)

Amrubicin Topotecan HR P Value* N/Events 424/336 213/175 Median OS 7.5 7.8 0.880 0.1701 95% CI 6.8–8.5 6.6–8.5 0.733–1.057

*Unstratified log-rank test

Conclusions •  Amrubicin significantly improved ORR compared with Topo in second-line

treatment of SCLC •  OS trended in favour of amrubicin, particularly in refractory patients •  The safety profile of amrubicin was acceptable

–  Increased infections –  Fewer transfusions –  No evidence of significant cumulative cardiotoxicity

Jotte et al. J Clin Oncol 29: 2011 (suppl; abstr 7000)

METASTATIC NSCLC Elderly

#7547 - Meta-analysis of efficacy and safety of single-agent-and doublet chemotherapy with or without platinum in advanced non small cell lung cancer in the elderly – Gaetan De Guetz et al •  Study objective

–  To assess efficacy and safety of single-agent and doublet chemotherapy (CT) with or without platinum in advanced NSCLC in the elderly

•  Study type/design –  PubMed query, using keywords simultaneously: NSCLC, aged, antineoplastic combined CT,

randomized controlled trial –  Efficacy outcomes: ORR and 1-year OS –  Safety outcomes: All grade and grade 3/4 toxicities

•  Key results –  Twelve eligible studies included 2,530 patients (mean age 74; 1,911 men and 545 women; 591 stage

IIIB and 1,600 stage IV; 796 squamous cell carcinomas, 860 adenocarcinomas) –  One-year OS significantly improved with doublets compared with single-agents –  Doublets including platinum significantly improved OS, but not those without platinum –  HRs for nausea/vomiting, neutropenia, thrombocytopenia and anaemia were significantly higher for

doublets than for single-agents –  For Grade 3/4 toxicity, only HRs for neutropenia, thrombocytopenia and anaemia were significantly

higher for doublets •  Key conclusion(s)

–  Doublet CT significantly improved ORR and OS, specifically when including platinum –  Benefit-to-risk ratio of platinum based doublets in advanced NSCLC appears favourable in the elderly

De Guetz et al. J Clin Oncol 29: 2011 (suppl; abstr 7547)

#7509: Randomized phase III trial comparing weekly docetaxel (D)-cisplatin (P) combination with triweekly D alone in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): An intergroup trial of JCOG0803/WJOG4307L – Tetsuya Abe et al

•  Study objective –  To investigate whether the addition of a modified platinum agent might improve the survival in

elderly patients with advanced NSCLC •  Study type/design

–  Phase III trial comparing weekly DP with tri-weekly D –  Patients were randomized to receive either DP or D by the minimization method, balancing for

site, age (<75 years/≥75 years) and stage (III/IV) –  DP comprised administration of D (20 mg/m2) and P (25 mg/m2) iv on days 1, 8 and 15 every 4

weeks –  D comprised administration of D (60 mg/m2) iv on day 1 every 3 weeks –  Treatment repeated until disease progression

•  Study endpoints –  Primary endpoint: OS (secondary endpoints: toxicity, PFS, response, symptom score)

•  Key patient inclusion –  Chemotherapy-naïve; unfit for bolus P administration; stage III/IV or relapsed NSCLC; age ≥70

years; PS 0-1 •  Patient characteristics

–  First interim analysis performed on 221 assessable pts (D/DP: 108/113, <75/≥75 years: 22/78%, male/female: 70/30%, PS 0/1: 35/65%, III/IV or relapse: 32/68%)

Abe et al. J Clin Oncol 29: 2011; (suppl; abstr 7509)


•  The predictive probability that DP would be superior to D at the time of the final analysis was 0.996%, which led to early termination of the trial.

•  Proportion of patients with an improved symptom score after 3 courses of treatment was higher in the D arm

•  Major grade 3-4 toxicities were (D/DP, %): –  Neutropenia 88/11, anaemia 3/16, anorexia 1/10, febrile neutropenia 17/0%, pneumonitis

3/2% •  Treatment-related death occurred in 3 pts of the DP arm


1.00

0.75

0.50

0.25

0

Prop

ortio

n

0 3 6 9 12 15 18 21 24 27 Months after randomization

MST (months) D 17.3 DP 13.3 HR 1.557 (99.99% CI 0.624–3.884), p=0.969*

*by stratified log-rank with age, one-sided

Conclusions •  This study failed to demonstrate any advantage of the addition of weekly P

to single-agent D in first line chemotherapy for elderly advanced NSCLC patients

•  There were no significant differences between the two arms in PFS and response rate

•  The incidence of haematological toxicity was higher in D, and non-haematological toxicity was adversely higher in DP –  These toxicities were well tolerable

•  Symptom score was more favorable in D than DP •  There were no significant differences in EGFR mutation status and

subsequent chemotherapies between the two arms in the additional analysis


#7014: Platinum-based adjuvant chemotherapy (ACT) in elderly patients with non-small cell lung cancer (NSCLC) in the SEER-Medicare database: Comparison between carboplatin- and cisplatin-based regimens - Fei Gu et al

•  Study objective –  To compare OS and toxicity among elderly patients with stage II-IIIA NSCLC treated with adjuvant

carboplatin (Carbo) versus cisplatin (Cis) •  Study type/design

–  3,324 patients 65 yrs or older identified from the SEER-Medicare database with surgically resected stage II-IIIA NSCLC, diagnosed between 1992 and 2005

–  Among them 636 (19%) received platinum-based ACT (started within 3 months of surgery) –  Propensity score methods were used to assess and compare the association of Carbo versus Cis ACT

with postoperative OS •  Key results

–  105 patients (16.5%) received Cis- and 489 (76.9%) received Carbo-based ACT only (42 [6.6%] received both treatments)

–  636 patients who received platinum ACTs had significantly improved survival (HR 0.79, 95% CI: 0.71-0.89)

–  No difference in survival (HR for Carbo 0.91; 95% CI 0.70-1.18) –  Chemo-related toxicities were mostly comparable between treatments

•  Patients treated with Cis experienced significantly more infections (≤10% vs 5%,p=0.011) and incidences of anaemia (16% vs 8%, p=0.0015) compared with patients treated with Carbo

•  Key conclusions –  The SEER-Medicare data allowed comparison of Carbo versus Cis ACTs in elderly resectable NSCLC –  Carbo is much more commonly used and provides a comparable OS benefit and a slightly better

toxicity profile than Cis Gu et al. J Clin Oncol 29: 2011; (suppl; abstr 7014)

SCLC AND MPM

#7090: Phase II trial of neoadjuvant pemetrexed plus cisplatin followed by surgery and radiation in the treatment of malignant pleural mesothelioma (MPM) – Federico Rea et al •  Objective: to evaluate the efficacy of neoadjuvant pemetrexed + cisplatin prior to

extrapleural pneumonectomy (EPP) and hemithoracic radiation in patients with MPM •  Study design: a Phase II, open-label study •  Primary endpoint: event-free survival (EFS) (secondary endpoints: PFS, OS and

toxicity) •  Treatment:

–  Neoadjuvant pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 Q3W for 3 cycles –  EPP within 3 weeks of CT –  RT within 4-12 weeks of surgery – total dose 54 Gy* –  90 days of follow-up

•  54 patients with Stage I-III MPM were enrolled, of which 52 completed CT, and 22 completed all treatment and follow-up

•  Median EFS: 6.9 months (95% CI: 5.0-10.5) –  18/54 and 13/54 were event-free at 1 and 2 years, respectively

•  Median PFS: 8.6 months (95% CI: 6.3-14.4); median OS: 15.5 months (95% CI: 11.0-NR)

•  36/54 patients experienced ≥1 Grade 3-4 toxicity –  Most common TEAEs: nausea, anaemia, hypertension

•  The combination therapy regimen evaluated is feasible and has a manageable toxicity profile providing that cardiopulmonary function is closely monitored

*Total RT dose reduced to 50.4 Gy after 2 cases of cardiopulmonary failure Rea et al. J Clin Oncol 29: 2011 (suppl; abstr 7090)

#7022: COCIS individual patient data (IPD) meta-analysis: Carboplatin- or cisplatin-based chemotherapy (CT) as first-line treatment of small cell lung cancer (SCLC) – Antonio Rossi et al •  Study objective

–  To compare the efficacy of cisplatin- vs carboplatin-based CT for the first-line treatment of SCLC •  Study type/design

–  Systematic review was performed to identify randomized phase III trials comparing cisplatin- vs carboplatin-based CT in the first-line treatment of SCLC

–  Primary endpoint of meta-analysis was OS –  IPD (baseline characteristics, treatment details, toxicity and outcome measures) were obtained via

collaborating with all groups identified by the systematic review •  Key results

–  Four eligible trials were included with a total of 663 patients (329 cisplatin, 334 carboplatin) –  Baseline characteristics were well balanced between arms –  Median OS was 9.6 months with cisplatin and 9.4 months with carboplatin

(HR 1.08, 95% CI 0.92–1.27; p = 0.69) –  No evidence of treatment difference according to gender, stage, PS or age –  Haematological toxicity was higher with carboplatin, and non-haematologicol toxicity was higher with

cisplatin •  Key conclusions

–  COCIS is the first IPD meta-analysis in the treatment of poor prognosis and/or extensive stage SCLC –  There appears to be no survival difference between cisplatin- and carboplatin-based CT in this settin

Rossi et al. J Clin Oncol 29: 2011; (suppl; abstr 7022)

#7025: Does disease control rate (DCR) at 9 and 18 weeks predict overall survival (OS) in patients with malignant pleural mesothelioma (MPM)? An individual patient data combined analysis of 10 European Organisation for Research and Treatment of Cancer (EORTC) Lung Cancer Group (LCG) studies – Laurent Greiller et al

•  Study objective –  To investigate if DCR could be a better predictor of OS than the RR in MPM patients (pts)

•  Study type/design –  Individual patient data from 10 EORTC LCG studies (9 Phase II and 1 Phase III trials) of first-line

chemotherapy in MPM were pooled –  Response to therapy was assessed according to WHO criteria in all trials except the 2 most recent

trials, which used RECIST –  Landmark analyses (LA) were performed to assess the association of the intermediate endpoints (DCR

and RR) with OS •  All 10 studies (N=523 pts) were included in the LA of DCR, but only 6 studies (N=369 pts) were

suitable for LA of DCR and RR at 9 weeks and 18 weeks •  Key results

–  Based on the data from 6 studies, disease control (vs progression) at 9 and 18 weeks was associated with longer survival times , HR 0.41 (95% CI 0.30-0.55) and 0.52 (95% CI 0.37-0.74)

–  In the same population, response (vs non-response) at 9 and 18 weeks was also associated with longer survival times, HR 0.51 (95% CI 0.36-0.72) and 0.55 (95% CI 0.38-0.78)

–  In the overall population, disease control at 9 and 18 weeks was confirmed as a predictor of OS, HR 0.37 (95% CI 0.30-0.47) and 0.50 (95% CI 0.38-0.65)

•  Key conclusions –  With a smaller HR, DCR at 9 weeks shows some advantage over RR in predicting OS in MPM pts –  DCR should be considered as a primary endpoint when designing future Phase II clinical trials in MPM

Greiller et al. J Clin Oncol 29: 2011; (suppl; abstr 7025)

#7006: A mulitcenter, randomized Phase III maintenance study of thalidomide (arm A) versus observation (arm B) in patients with malignant pleural mesothelioma (MPM) after induction chemotherapy – Paul Baas et al •  Study objective

–  To determine if thalidomide as maintenance therapy improves PFS in patients with MPM who have not progressed following initial therapy with pemetrexed/carboplatin or cisplatin

•  Study design

–  Endpoints: >50% ↑ in TTP (primary); duration of response, OS, toxicity (secondary) •  Results

–  Between May 2004 and December 2009, 222 patients were included (111 in each arm) •  Median age: 64 years (range 41-82), 86% epithelial tumours, 215 WHO PS 0-1

–  Median duration of treatment: 12.0 weeks –  Grade 3/4 toxicities: 21% –  No difference in efficacy between study arms: TTP HR: 1.0 (0.7-1.2; p=0.71); OS HR 1.2 (0.9-1.6;

p=0.30) •  No obvious difference in post-study treatments between treatment arms

•  Conclusions –  This is the largest maintenance study in patients with MPM reported to date –  Thalidomide as switch maintenance therapy in MPM is not effective –  Thalidomide 200 mg/day is associated with limited toxicity

Baas et al. J Clin Oncol 29: 2011 (suppl; abstr 7006)

Pemetrexed (500 mg/m2) Cisplatin (75 mg/m2) or

Carboplatin (AUC=5) q3w X≥4 cycles

SD CR PR

Thalidomide 100–200 mg/day

Observation

ASCO 2011

Supported by Eli Lilly & Company

Developed in association with the European Thoracic Oncology Platform

3-7 June 2011 | Chicago, USA

developed in association with the european thoracic

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