1 ASCO 2012 1-5 June 2012 | Chicago, USADeveloped in association with the European Thoracic Oncology Platform ASCO 2012 1-5 June 2012 | Chicago, USA Sponsored with support from Eli Lilly and Company. Eli Lilly and Company has not influenced the content of this publication

2 Letter from Prof Rolf StahelDear Colleagues It is my pleasure to present this ETOP slide set which has been designed to highlight and summarise key findings in thoracic cancers from the major congresses of ASCO in This scientific slide kit will be offered in 3 languages – English, French and Italian. The area of clinical research in oncology is a challenging and ever changing environment. Within this environment we all value access to scientific data and research which helps to educate and inspire further advancements in our roles as scientists, clinicians and educators. I hope you find this review of the latest developments in thoracic cancers of benefit to you in your practice. If you would like to share your thoughts with us we would welcome your comments. Please send any correspondence to I would like to thank our ETOP members Dr Enriqueta Felip, Dr Solange Peters and Dr Martin Reck for their roles as Editors – for prioritising abstracts and reviewing slide content, also Dr Peters for overseeing translation to French and Dr Serena Ricciardi for overseeing translation to Italian. The slide set you see before you would not be possible without their commitment and hard work. And finally, we are also very grateful to Lilly Oncology for their financial, administerial and logistical support in the realisation of this complex yet rewarding activity. Yours sincerely, Rolf Stahel

3 ETOP Medical Slide Deck Editors 2012Medical Oncology (Early stage I, II & III + biomarkers) Dr Solange Peters Multidisciplinary Oncology Center Lausanne Cancer Center Lausanne, Switzerland Medical Oncology (Stage IV + biomarkers) Dr Enriqueta Felip Oncology Department Vall d'Hebron University Hospital Barcelona, Spain Medical Oncology (SCLC, MPM + rare tumours): Dr Martin Reck Department of Thoracic Oncology Hospital Grosshansdorf Grosshansdorf, Germany

4 Table of contents Biomarkers Early-stage/locally-advanced NSCLCMetastatic NSCLC 1st line Maintenance Later lines SCLC and MPM Rare tumours

5 biomarkers

6 CRA2509: Anti-PD-1 (BMS , MDX-1106) in patients with advanced solid tumors: Clinical activity, safety, and a potential biomarker for response – SL Topalian et al Blockade of programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells may help to overcome immune resistance and mediate tumor regression Aim: Phase 1 multidose trial to describe the activity and safety of BMS , a fully human monoclonal antibody blocking PD-1 Rapid PD or deterioration Off study Key patient inclusion criteria Advanced melanoma, RCC, NSCLC, CRC or CRPC PD after 1–5 systemic therapies (n=296) BMS IV every 2 weeks at doses of 0.1 to 10.0 mg/kg during dose-escalation and/or cohort expansion Unacceptable toxicity Follow-up every 8 weeks x6 Treat to confirmed CR, worsening PD, unacceptable toxic, or 12 cycles CR/PR/SD or PD but clinically stable RCC, renal cell carcinoma; CRC, colorectal cancer; CRPC castration-resistant prostate cancer; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease Topalian et al. J Clin Oncol 30, 2012 (suppl; abstr CRA2509)

7 ORR (CR/PR) No. of pts (%)Efficacy and safety Grade 3/4 AEs in 14% of patients; 5% of patients discontinued treatment due to AEs Grade 3/4 drug-related AEs included diarrhoea, pruritus, ALT/AST, pneumonitis, infusion reaction and increased TSH (each in ≤1% of patients) Tumor Type Dose (mg/kg) No. pts ORR (CR/PR) No. of pts (%) SD≥24 wk No.pts MEL 0.1–10 94 26 (28) 6 (6) NSCLC 1–10 76 14 (18) 5 (7) RCC 1 OR 10 33 9 (27) 236 patients starting therapy before 07/2011 were evaluated for response as of 24 February 2012 20/31 responses lasted ≥1 year in patients with ≥1 year follow-up No ORRs were observed in 19 CRC or 13 CRPC patients ORR, objective response rate Topalian et al. J Clin Oncol 30, 2012 (suppl; abstr CRA2509)

8 7509: Clinical activity and safety of anti-PD1 (BMS , MDX-1106) in patients with advanced non-small-cell lung cancer (NSCLC) – Brahmer JR et al Study objective To assess BMS as a mediator of antitumour activity in pretreated patients (pts) with advanced NSCLC Study type/design BMS was administered IV Q2WK to pts with various solid tumours, including NSCLC, at doses of 0.1 to 10 mg/kg during dose-escalation and/or cohort expansion Pts with advanced NSCLC previously treated with at least 1 prior chemotherapy regimen were eligible Pts received up to 12 cycles (4 doses/cycle) of treatment or until PD or CR Key results Of 240 pts treated, 76 NSCLC pts were treated at 1 (n=18), 3 (n=19), or 10 mg/kg (n=39) Clinical activity was observed at all dose levels (1 mg/kg vs 3 mg/kg vs 10 mg/kg): ORR (%): 6 vs 32 vs 18 Stable disease ≥24 weeks: 6% vs 11% vs 5% Progression free survival rate at 24 weeks: 16% vs 41% vs 24% Key conclusions BMS is well tolerated and has encouraging clinical activity in pts with previously treated advanced NSCLC Further development of BMS in pts with advanced NSCLC is warranted Brahmer et al. J Clin Oncol 30, 2012 (suppl; abstr 7509)

9 FGFR1 amplification in squamous cell lung cancers7041: Amplification of fibroblast growth factor receptor type 1 gene (FGFR1) in samples from 101 NSCLC patients (pts) with squamous cell carcinoma (SCC) histology – Martinez Marti et al 7061: SOX2 and FGFR1 gene copy number in surgically resected non-small cell lung cancer (NSCLC) – Toschi et al 7063: FGFR1 amplification in squamous cell lung cancers – Cote et al 7545: FGFR1 amplification and EGFR mutation in Chinese squamous cell lung cancer – Wei et al Abstract No of cases Histology subtype Disease stage(s) Technique Definition of amplification % amplified % polysomy (if available) 7041 101 Squamous I–IV FISH Median of 6 or more gene copies 6.9 43/94 7061 447 Mean of 6 or more gene copies 8.3 - 7063 119 Quantitative PCR Predicted CNV of ≥2 in ≥1 exon 24.4 7545 177 Copy number >2 and <9 (low); >9 (high) 25.2 Martinez Marti et al. J Clin Oncol 30, 2012 (suppl; abstr 7041) Toschi et al. J Clin Oncol 30, 2012 (suppl; abstr 7061) Cote et al. J Clin Oncol 30, 2012 (suppl; abstr 7063) Wei et al. J Clin Oncol 30, 2012 (suppl; abstr 7545) CNV, copy number variation

10 7006: Comprehensive genomic characterization of squamous cell carcinoma of the lung – Govindan R et al Study objective To characterise the genomic/epigenomic landscape of lung squamous cell carcinoma (SCC) and to identify potential targets for therapy Study type/design DNA, RNA, and miRNA sequencing + DNA copy number profiling, quantification of mRNA expression and promoter methylation on resected samples from untreated patients with stage I–III SCC of the lung Genomic/epigenomic landscape of lung squamous cell carcinoma >30 sites of significant somatic copy number alteration (SCNA) were identified from 178 SCC samples Exome sequencing revealed 13 significantly mutated genes with a False Discovery Rate (FDR) of <0.01 and high expression levels, including TP53, CDKN2A, PTEN, KEAP1, and NFE2L2 Apart from near universal loss of TP53 and CDKN2A, alterations in the NFE2L2/KEAP1 and PI3K/AKT pathways were found in 35% and 43% of tumours analysed mRNA expression profiling revealed four distinct expression subtypes Classical (36%): NFE2L2 and KEAP1 mutations, FGFR kinase alterations, increased global methylation and the highest rate of tobacco use Basal (25%): alterations in FGFR kinases secretory (24%): PDGFRA alterations Primitive (15%): RB1 mutations Govindan et al. J Clin Oncol 30, 2012 (suppl; abstr 7006)

11 Therapeutic targets in squamous cell lung carcinomaGene Event type Frequency CDKN2A Deletion/mutation/methylation 72 PI3KCA Mutation 16 PTEN Mutation/Detection 15 FGFR1 Amplification EGFR 9 PDGFRA Amplification/Mutation CCND1 8 DDR2 4 BRAF ERBB2 FGFR2 3 Govindan et al. J Clin Oncol 30, 2012 (suppl; abstr 7006)

12 Conclusions Squamous cell carcinoma of the lung is a distinct molecular subtype of lung cancer potentially amenable to distinct molecularly targeted therapies Govindan et al. J Clin Oncol 30, 2012 (suppl; abstr 7006)

13 7007: Prognostic and predictive effects of KRAS mutation subtype in completely resected non-small cell lung cancer (NSCLC): A LACE-bio study – Shepherd FA et al Study objective To explore the influence of KRAS mutation subtype in completely resected NSCLC Study type/design Analysis of KRAS subtype in the LACE-Bio study KRAS mutation was determined by direct sequencing and exploratory analyses performed to identify relationships between mutation status and subtype, OS and DFS Key results KRAS subtype was available in 1,532 patients (756 observation, 776 adjuvant chemotherapy) 300 KRAS-mutated NSCLC were identified (275 codon 12, 24 codon 13,1 codon 14) In the observation arm, there was no difference in prognosis for OS for codon 12 (HR for mutation vs wild-type KRAS 1.04, CI: 0.77–1.4) or codon 13 (HR 1.01, CI: 0.47–2.17) mutations A non-significant trend for benefit from adjuvant chemotherapy was observed in wild-type, but not in patients with codon 12 mutations In patients with codon 13 mutations, chemotherapy was deleterious (HR for adjuvant chemotherapy versus observation 5.78, CI: 2.06–16.2, p<0.001), and results were similar for DFS Shepherd et al. J Clin Oncol 30, 2012 (suppl; abstr 7007)

14 Prognostic value of KRAS mutation according to histology (OS)Category No. deaths / No. entered Mutated Wild-type Hazard ratio Adjusted HR (95% CI) Squamous cell carcinoma 20/43 325/662 1.26 [0.80;1.98] p=0.32 Adenocarcinoma 95/203 188/396 1.00 [0.78;1.28] p=0.97 Other NSCLC 30/52 90/176 1.84 [1.21;2.79] p=0.005 Total 145/298 603/1,234 1.17 [0.96;1.42] p=0.12 0.2 1.0 3.0 Test for interaction: p=0.05 Mutated better Wild-type better Shepherd et al. J Clin Oncol 30, 2012 (suppl; abstr 7007)

15 Conclusions KRAS mutations did not reveal prognostic in available NSCLC samples collected in LACE-Bio study Patients with KRAS codon 13 mutations had significantly poorer outcomes with ACT These results require further confirmation and should be interpreted with caution in view of the small number of patients with codon 13 mutations Shepherd et al. J Clin Oncol 30, 2012 (suppl; abstr 7007)

16 7505: Multiplex testing for driver mutations in squamous cell carcinomas of the lung – Paik PK et alStudy objective To characterise the frequency of known driver events in squamous cell lung cancers Study type/design Prospective, multiplex testing of squamous cell lung cancer tumours (Squamous Cell Lung Cancer Mutation Analysis Program, ‘SQ-MAP’) Key results 72 squamous cell lung cancer patient specimens processed through SQ-MAP Stage IV: 76%; female, 33%; median age 67 (range: 44–88) Data are available for 52 patients FGFR1 amplification: 25% (95% CI: 15–38); PTEN mutation: 17% (95% CI: 5–37); PTEN loss: 11% (95% CI: 3–26); PIK3CA mutation: 8% (95% CI: 2–17); KRAS mutation: 2% (95% CI: 1–9); DDR2: 0 (95% CI: 0–15) 1 PTEN mutation overlapped with FGFR1 amplification; all other events were mutually exclusive Key conclusions An actionable driver event was identified in the majority of squamous cell lung cancers Next generation sequencing by MSK-IMPACT is feasible using ‘small biopsy’ and FFPE specimens SQ-MAP serves as a platform supporting both personalized care and research Paik et al. J Clin Oncol 30: 2012 (suppl; abstr 7505)

17 SQ-MAP integrated resultsTarget N Frequency 95% CI FGFR1 amplification 13/52 25% 15–38% PTEN mutation 17% 3/18 17% 5–37% PTEN loss, complete 3/27 11% 3–26% PIK3CA mutation 4/52 8% 2–17% KRAS mutation 1/52 2% 1–9% DDR2 mutation 0/18 0% 0–15% Paik et al. J Clin Oncol 30: 2012 (suppl; abstr 7505)

18 Capelletti et al Dana-Farber Cancer Institute, Boston, MA, USA7510: Discovery of recurrent KIF5B-RET fusions and other targetable alterations from clinical NSCLC specimens Capelletti et al Dana-Farber Cancer Institute, Boston, MA, USA

19 Background Many NSCLCs have driving oncogenic alterations including in EGFR, KRAS, ERBB2, BRAF, ALK and ROS1 Clinically effective drugs are approved for EGFR and ALK and clinical trials are underway for other genomic targets Need a clinical test that can Identify broad range of genomic alterations in existing or new genes Mutations, copy number gains, rearrangements Validate new genomic alterations as potential drug targets Capelletti et al. J Clin Oncol 30, 2012 (suppl; abstr 7510)

20 Methods: cancer genomic profiling workflowFixed sample slides DNA extraction, library construction, and hybrid capture (Agilent SureSelectTM Sequencing (Illumina HiSeqTM 2000) Clinical report Annotation and interpretation dbSNP COSMIC Medical literature Analysis pipeline Point mutations Short insertions/deletions Copy number alterations Rearrangements <21 days 2574 coding exons of 145 cancer relevant genes introns from 14 genes often rearranged in cancer Capelletti et al. J Clin Oncol 30, 2012 (suppl; abstr 7510)

21 Key results: mutated genes found in 24 tested patients with NSCLCNo. of mutated samples Potential therapeutic treatment or clinical trial KRAS 10 Resistance to EGFR kinase inhibitors, clinical trials of P13K and MEK inhibitors STK11 4 Presently unknown JAK2 3 JAK2 inhibitors EGFR 2 Erlotinib or gefitinib BRAF Vemurafenib and GSK CDKN2A CDK inhibitors e.g. PD RET RET inhibitors e.g. Sorafenib or sunitinib CTNNB1 MDM2 Nutlins PIK3CA Pi3 kinase/mTOR inhibitors ATM PARP inhibitors TSC1 1 mTOR inhibitors CONE1 CDK4 inhibitors e.g. PD NF1 RB1 MLH1 MSH6 CDK4 Capelletti et al. J Clin Oncol 30, 2012 (suppl; abstr 7510)

22 Key results: fusion gene found containing domains of KIF5B and the entire RET tyrosine kinase domainAnalysis found an 11,294,741 bp pericentric inversion on chromosome 10 generating a novel gene fusion joining exons 1–15 of KIF5B to exons 12–20 of RET (K15:R12) in a Caucasian never smoker KIF5B EXON KINESIN MOTOR COILED-COIL TAIL 2 RET TYROSINE KINASE 1114 KIF5BRET KINESIN MOTOR COILED-COIL 2 TYROSINE KINASE Capelletti et al. J Clin Oncol 30, 2012 (suppl; abstr 7510)

23 Key results: KIF5B-RET appears to be oncogenic and sensitive to RET kinase inhibitorsK15:R12 was introduced into Ba/F3 cells and IL-3 independent growth was seen (consistent with oncogenic transformation) In 643 additional tumours, 11 fusion+ patients were found Four unique KIF5B-RET variants were found: K15:R12, K16:R12, K22:R12 and K15:R11 KIF5B-RET Ba/F3 cells were sensitive to sunitinib, sorafenib and vandetinib K758M (R10) K758M (R10+IL3+Puro) K758M (R10+IL3) Capelletti et al. J Clin Oncol 30, 2012 (suppl; abstr 7510)

24 Conclusions Both known and novel genomic alterations from NSCLC formalin fixed paraffin embedded specimens were identified using a single test KIF5B-RET was found to be oncogenic and most likely to be sensitive to RET kinase inhibitors A clinical trial is underway investigating sunitinib in 35 patients with advanced NSCLC who are Triple negative for EGFR, KRAS and ALK Never smokers OR who have a known RET arrangement A molecular comparison will be performed of responders and non- responders Capelletti et al. J Clin Oncol 30, 2012 (suppl; abstr 7510)

25 7534: Native and rearranged ALK copy number and rearranged ALK cell count in NSCLC: Implications for ALK inhibitor therapy – Camidge DR et al Study objective To explore the significance of native and rearranged ALK copy number on crizotinib outcomes and whether >15% reflected a clear biological distinction in the frequency of ALK+ cells Study type/design Copy number and genomic status of ALK assessed by FISH: total of 1426 NSCLC clinical specimens, 174 ALK+ and 1252 ALK- by standard criteria, and 26 NSCLC cell lines (2 ALK+ and 24 ALK-) Key results Mean native ALK gene copy number was significantly higher in ALK- than in ALK+ cases (2.8 [range 1.2–11.4] vs 1.8 [range 0.6–5.3]; p<0.0001) Frequency of native ALK copy number gain (≥3 copies/cell in ≥40% cells): 19% in ALK+ vs 62% in ALK- tumours (p<0.0001) Among ALK- cell lines, mean native ALK copy number ranged from 2.1–6.9 and was not correlated with in vitro crizotinib sensitivity (IC –2.8 uM) In ALK+ patients, neither native or rearranged ALK copy number, nor percentage cell count correlated with maximal tumour shrinkage or PFS with crizotinib Key conclusions Baseline mean native and rearranged copy number are not clinically relevant variables with respect to predicting tumour shrinkage or extra-CNS PFS from ALK inhibition in ALK+ tumours Camidge et al. J Clin Oncol 30, 2012 (suppl; abstr 7534)

26 10506: DEAR1, a novel tumor suppressor, negative regulator of epithelial-mesenchymal transition, and prognostic factor in non-small cell lung cancer – Quintas-Cardama A et al Study objective To study the impact of DEAR1 loss in lung cancer Study type/design DEAR1 deficient mice were crossed with mice carrying the latent mutant K-rasG12D allele (K-rasLA1) Key results No survival difference was observed between DEAR1+/─ and DEAR1─/─ mice (729 vs 699 days, p=0.98) but survival was markedly shorter than that of DEAR1 wild-type littermates (803 days, p=0.01) DEAR1-deficient K-rasLA1 mice had reduced life span compared with DEAR1+/+:K-ras+/LA1 littermates (184 vs 291 days, p<0.0001) The survival of DEAR1+/─:K-ras+/LA1 and DEAR1─/─:K-ras+/LA1 mice were similar (180 vs 153 days, p=0.38) Patients with early stage NSCLC and loss of DEAR1 expression have a markedly shorter time to relapse compared to those retaining DEAR1 expression (5.1 vs 2.87 years, p=0.049) and worse 5-year relapse-free and overall survival rates Key conclusions DEAR1 is a novel tumor suppressor that negatively regulates EMT and promotes lung cancer metastasis Loss of DEAR1 progresses in parallel with histological progression of lesions DEAR1 loss impacts outcomes outcomes in human NSCLC Quintas-Cardama et al. J Clin Oncol 30, 2012 (suppl; abstr 10506)

27 Impact of DEAR1 deficiency on survival100 80 60 40 20 Percent survival DEAR1+/+ 803 days DEAR1+/+ 699 days DEAR1+/+ 729 days Time DEAR1+/– vs DEAR1–/– mice (729 vs 699 days, p=0.98; HR for death 1.0, 95% CI: 0.57–1.74) DEAR1+/– or DEAR1–/– vs Wild-Type littermates (803 days, p=0.01; HR=2.30, 95% CI: 1.18–4.47) Quintas-Cardama et al. J Clin Oncol 30, 2012 (suppl; abstr 10506)

28 10542: Serum hepatocyte growth factor and interleukin-6 as prognostic markers for stage III non-small cell lung cancer – Ujiie H et al Study objective To survey prognostic biomarkers for resectable non-small cell lung cancer (NSCLC) Study type/design Levels of hepatocyte growth factor (HGF), interleukin-6 (IL-6), and nicotinamide N–methytransferase (NNMT) were measured in preoperative sera taken from 109 patients using the ELISA method Key results Median HGF and IL-6 contents in sera from 109 patients were 860 pg/mL and 2.7 pg/mL, respectively Analysis of survival curves indicated that: HGF or IL-6 levels higher than the median were associated with poor overall survival (HGF, p=0.019; IL-6, p=0.002), particularly in patients with stage III cancer (HGF, p=0.016; IL-6, p=0.013) Carcinoembryonic antigen (known tumour marker) and NNMT (previously identified as a candidate tumour marker) exhibited no correlation with the prognosis Tumour status (pT factor) and stage were strong prognostic indicators (p<0.001) Key conclusions Serum levels of HGF and IL-6 could be a useful prognostic indicator of the survival of stage III NSCLC patients undergoing surgery and chemotherapy Ujiie et al. J Clin Oncol 30, 2012 (suppl; abstr 10542)

29 10526: Frequency and clinical characterization of NSCLC patients harboring PIK3CA mutations identified within a regional screening network – Gardizi M et al Study objective To assess frequency and clinical characteristics of patients with PIK3CA-mutated lung tumours Study type/design Patients with NSCLC and PIK3CA mutations were identified within a regional Network for Molecular Screening in Lung Cancer PIK3CA-mutated samples were tested for the presence of BRAF, KRAS, EGFR mutations and ALK translocation, ERBB2 and FGFR1 amplifications Key results PIK3CA mutations were detected with a frequency of 3.7% (24% exon 20, 76% exon 9) in patients Squamous cell carcinoma: 32%; adenocarcinoma: 48%; other histological subtypes or NSCLC- NOS: 18% Exon 9 mutations were present in the acinar and lepidic subtype, whereas exon 20 mutations were seen in the papillary and solid subtype Co-occuring genetic lesions were observed in 16% (mutations in KRAS=2, EGFR=1, BRAF=1; FGFR1 amplification=2) Key conclusions Screening for PIK3CA mutations is feasible and a high proportion of patients with PIK3CA-mutated lung cancer have prior malignancies and show a high load of comorbidity PIK3CA mutations are not exclusive to KRAS, EGFR or BRAF mutations or FGFR1 amplifications Gardizi et al. J Clin Oncol 30, 2012 (suppl; abstr 10526)

30 10617: Predictive impact of RRM1 protein expression on vinorelbine efficacy in NSCLC patients randomized in a chemotherapy phase III trial – Vilmar A et al Study objective To explore the predictive role of ribonucleotide reductase subunit M1 (RRM1) in patients with advanced NSCLC Study type/design Phase III, randomised study: 443 patients with advanced NSCLC were randomised to regimen A (paclitaxel and cisplatin with gemcitabine) or regimen B (cisplatin and vinorelbine) Immunohistochemical evaluation of RRM1 was performed on mainly bioptic material and correlated to response rates, progression free survival (PFS) and overall survival (OS) Key results 261 (58.9%) patients had representative tissue samples for RRM1 evaluation Disease control rate, PFS and OS were significantly improved in patients with RRM-negative tumours receiving regimen B as compared with patients with RRM-positive tumors (68.8% vs 31.2%, p=0.046, months (mo) [95% CI: 5.83–7.96] vs 3.93 mo [95% CI: 3.11–4.76], p=0.000 and 11.5 mo [95% CI: 9.65–13.48] vs 7.4 mo [95% CI: 5.37–9.43], p=0.002, respectively) This was not the case for patients receiving regimen A Together with histological subtype, RRM1-positivity emerged as the only other significant prognostic variable with a hazard ratio of 1.56 (95% CI: 1.38–2.35, p=0.033) in multivariate analysis for patients treated with regimen B Key conclusions RRM1 protein expression was without predictive impact in patients treated with cisplatin, paclitaxel and gemcitabine Vilmar et al. J Clin Oncol 30, 2012 (suppl; abstr 10617)

31 Early stage locally advanced nsclc

32 7000: Is consolidation chemotherapy after concurrent chemoradiotherapy beneficial for locally advanced non-small cell lung cancer? A pooled analysis of the literature – Yamamoto S et al Study objective To determine whether consolidation chemotherapy (CCT) is beneficial for patients with locally advanced non-small cell lung cancer (NSCLC) in terms of survival prolongation and toxicity Study type/design Systematic search of PubMed for Phase II/III trials examining survival of locally-advanced NSCLC treated with concurrent chemoradiotherapy between January 1, 1995 and October 31, 2011 Median overall survival (mOS) and corresponding 95% confidence interval (CI) were collected from each study and pooled Collected trial arms were divided into two groups by the presence of CCT: Arm with CCT (CCT+) and without CCT (CCT-) 41 studies identified: 7 Phase III studies and 34 Phase II studies with 45 arms (CCT+: 25, CCT-: 20) Without consolidation chemotherapy (CCT–) Chemotherapy PL+A PL+A Thoracic radiotherapy TRT PL, platinum A, B, cytotoxic agent With consolidation chemotherapy (CCT+) PL+A PL+A Continuation consolidation chemotherapy (CCCT) PL+A TRT B Switch consolidation chemotherapy (SCCT) Yamamoto et al. J Clin Oncol 30, 2012 (suppl; abstr 7000)

33 Key efficacy and safety datamonth CCT– HR=0.98 (95% CI 0.84–1.13) p=0.757 18.1 (95%CI: 16.5–20.2) *Adjusted HR=0.95 (95% CI 0.75–1.21) p=0.515 *Adjusted for period and region CCT+ 18.1 (95%CI: 16.7–20.5) I2 values for assessing heterogeneity were 15.3% in all studies No difference between the two groups for Grade 3/4 pneumonitis, oesophagitis and neutropenia Yamamoto et al. J Clin Oncol 30, 2012 (suppl; abstr 7000)

34 Conclusions The pooled analysis on publication basis failed to provide evidence that consolidation chemotherapy improves overall survival in patients with locally-advanced NSCLC Clinical trials to evaluate the impact of consolidation chemotherapy or new targeted/immunotherapy strategies of consolidation are still warranted Yamamoto et al. J Clin Oncol 30, 2012 (suppl; abstr 7000)

35 R Phase III, double-blind randomised study Endpoints Primary: PFS7001: GILT study: Oral vinorelbine (NVBo) and cisplatin (P) with concomitant radiotherapy (RT) followed by either consolidation (C) with NVBo plus P plus best supportive care (BSC) or BSC alone in stage (st) III non-small cell lung cancer (NSCLC): Final results of a Phase (ph) III study – Huber RM et al Phase III, double-blind randomised study Objective: To assess consolidation with vinorelbine/cisplatin in stage III NSCLC BSC + NVBo 60-80mg/m² days 1, 8 + P 80mg/m² q3w/2cycles N=96 Key patient inclusion criteria Untreated NSCLC Inoperable stage III amenable to radiotherapy (n=288) Concomitant radiotherapy (RT) and oral vinorelbine (NVBo)/ cisplatin (P) (n=279) R Best supportive care (BSC) N=105 Endpoints Primary: PFS Secondary: ORR, OS, safety and QoL ORR, objective response rate, QoL, quality of life Huber et al. J Clin Oncol 30, 2012 (suppl; abstr 7001)

36 Key efficacy and safety dataCT+BSC (N=86) BSC (N=102) P PFS (months)* 6.4 (5.0–8.7) 5.5 (3.8–7.4) 0.63 HR: 093 (0.69–1.28) OS (months)* 20.8 (13.5–25.3) 18.5 (13.6–24.7) 0.87 2 year Survival 41.6 41.1 4 year survival 25.2 21.4 Haematological toxicity (Grade 3/4 AEs) CT+BSC (N=86) BSC (N=102) Anaemia 3.5/– 1.1/– Leucopenia 20.0/5.0 – Neutropenia 11.6/10.5 Thrombocytopenia 1.2/– *Median calculated from time of randomisation CT, chemotherapy; BSC, best supportive care Huber et al. J Clin Oncol 30, 2012 (suppl; abstr 7001)

37 Conclusions OS from this study is in line with previously published results At this time, there is no significant survival in evaluated patients who received consolidation with oral vinorelbine + cisplatin Disease control rate is significantly improved (p=0.0084) Prolongs PFS for patients with stable disease after CT-RT Huber et al. J Clin Oncol 30, 2012 (suppl; abstr 7001)

38 7002: Phase II study of pemetrexed (P) plus carboplatin (Cb) or cisplatin (C) with concurrent radiation therapy followed by pemetrexed consolidation in patients (pts) with favorable-prognosis inoperable stage IIIA/B non-small cell lung cancer (NSCLC) – Choy H et al Study objective To assess P + Cb or C with concurrent radiation therapy followed by pemetrexed consolidation in pts with favorable-prognosis inoperable stage IIIA/B NSCLC Study type/design Open-label randomised Phase II trial Patients (n=98) were randomised (1:1) to P 500 mg/m2 + Cb AUC 5 (PCb) or P 500 mg/m2 plus C 75 mg/m2 (PC) intravenously (IV) every 21 days for 3 cycles All pts received CRT 64–68 Gy (2 Gy/day, 5 days/week, Days 1–45) Consolidation P 500 mg/m2 IV every 21 days for 3 cycles began 3 weeks after completion of CRT Study endpoints Primary: 2-year overall survival (OS) Secondary: median OS, time to progression (TTP), overall response rate (ORR), and toxicity Patient characteristics 98 pts were enrolled (PCb: 46; PC: 52) Choy et al. J Clin Oncol 30, 2012 (suppl; abstr 7002)

39 Key efficacy and safety dataMedian TTP (months): 8.8 versus 13.1 for PCb: versus PC; p=0.057 ORR: 52% (CR 6.5%; PR 46%) with PCb and 46% (CR 4%; PR 42%) with PC Grade 4 treatment-related toxicities (% PCb/% PC) were: anaemia, 0/2; neutropenia, 6.5/4; thrombocytopenia, 4/2; and oesophagitis, 0/2; no drug-related deaths were reported PCb, pemetrexed/carboplatin; PC, pemetrexed/cisplatin TTP, time to progression; ORR, overall response rate CR, complete response; PR, partial response Choy et al. J Clin Oncol 30, 2012 (suppl; abstr 7002)

40 Conclusions Pemetrexed combined with carboplatin or cisplatin in combination with concurrent radiotherapy is well tolerated and feasible for locally advanced NSCLC Data suggest a superior efficacy benefit with pemetrexed and cisplatin, with this combination meeting and exceeding the pre-specified 2-year survival endpoint at 56.4% Pemetrexed can be safely delivered in the consolidation phase after combined chemoradiotherapy at full doses Pemetrexed and cisplatin in combination with concurrent radiotherapy followed by pemetrexed consolidation is being studied in a phase III comparison against standard of care in locally advanced NSCLC Choy et al. J Clin Oncol 30, 2012 (suppl; abstr 7002)

41 Primary endpoint: overall survival (OS) 7017: Updated results of a phase III trial comparing standard thoracic radiotherapy (RT) with or without concurrent daily low-dose carboplatin in elderly patients (pts) with locally advanced non-small cell lung cancer (NSCLC): JCOG0301 – Okamoto H et al Study objective To evaluate whether RT with daily carboplatin would result in longer survival than RT alone in elderly patients alone (RT arm) at a total dose of 60 Gy (in 30 fractions), or CRT arm including the same RT plus concurrent chemotherapy with carboplatin 30 mg/m2/day, 5 days/week × 20 days Study type/design Patients aged >70 years with unresectable stage III NSCLC were randomised to either RT alone (RT arm), a total dose of 60 Gy, or CRT arm including the same RT plus concurrent chemotherapy with carboplatin 30 mg/m2/day, 5 days/week × 20 days Study endpoints Primary endpoint: overall survival (OS) Secondary endpoints: overall response rate (ORR), progression-free survival (PFS), localisation of progression, safety Patient characteristics Baseline characteristics were similar in the RT (n=100) vs CRT (n=100) arms Okamoto et al. J Clin Oncol 30, 2012 (suppl; abstr 7017)

42 Key efficacy and safety dataPatient characteristics RT arm (n=100) CRT arm (n=100) Median age (range), year 77 (71–93) 77 (71–89) Male/Female, n 84/16 80/20 Histological status of tumour, n: Ad/Sq/La/AdSq/Others 41/55/1/0/3 48/42/1/2/7 Performance status (ECOG), n: 0/1/2 41/55/4 41/56/3 Stage of disease, no: IIIA/IIIB 54/46 51/49 Updated OS Updated PFS 1 2 3 4 5 6 7 8 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years after randomisation Proportion 1 2 3 4 5 6 7 8 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years after randomisation Proportion Median OS: 22.4 (CRT) vs 16.5 (RT) mo. (p=0.03) Median PFS: 8.9 (CRT) vs 6.9 (RT) mo. (p=0.03) CRT arm CRT arm RT arm RT arm Okamoto et al. J Clin Oncol 30, 2012 (suppl; abstr 7017)

43 Conclusions Authors conclude that CRT using daily carboplatin is considered to be the standard treatment for elderly patients with locally advanced NSCLC This is the first trial demonstrating the clinically significant benefits of concurrent CRT in the specific and prospective setting of elderly patients with stage III NSCLC Okamoto et al. J Clin Oncol 30, 2012 (suppl; abstr 7017)

44 1st line Metastatic nsclc

45 LBA7500: LUX-Lung 3: A randomised, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations – Yang JC et al Randomised, open-label, Phase III study Objective: To investigate the efficacy and safety of afatinib compared with pemetrexed/cisplatin in patients with EGFR mutation positive advanced lung adenocarcinoma Daily afatinib 40mg (n=230) Key patient inclusion criteria* Stage IIIB/IV PS 0–1 Chemotherapy-naïve (n=345) R Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 every 21 days up to 6 cycles (n=115) Primary endpoint PFS *Central testing was performed for EGFR mutations (companion diagnostic TheraScreen EGFR RGQ PCR kit) Yang et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7500)

46 Cisplatin/ pemetrexed n=115Key efficacy data: PFS Afatinib n=230 Cisplatin/ pemetrexed n=115 PFS event, n (%) 152 (66) 69 (60) Mean PFS (months) 11.1 6.9 Hazard ratio (95% confidence interval) 0.58 (0.43–0.78) p=0.0004 100 80 60 40 20 Progression-free survival (probability) 47% Afatinib Cisplatin/pemetrexed 22% Progression-free survival (months) Yang et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7500)

47 Key efficacy data: objective responseAll patients Common mutations (Del19/L858R) 100 80 60 40 20 100 80 60 40 20 p<0.0001 p<0.001 p<0.0001 p<0.001 % % Independent Investigator Independent Investigator Median duration of response: 11.1 vs 5.5 months (all patients; independent review) Yang et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7500)

48 Key efficacy data: other resultsCancer-related symptoms Significant delay in time to deterioration of cancer-related symptoms with afatinib vs pemetrexed/cisplatin Cough (HR=0.60, p=0.0072) Dyspnoea (HR=0.68, p=0.0145) Quality of life Significant improvements with afatinib versus pemetrexed/cisplatin in Global health status/QoL Physical functioning Role functioning Cognitive functioning QoL, quality of life Yang et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7500)

49 Conclusions LUX-Lung 3 is the largest prospective trial in EGFR mutation positive lung cancer and the first study using pemetrexed/cisplatin as a comparator LUX-Lung met its primary endpoint of PFS (independent review) Overall study population: Median PFS of 11.1 months for afatinib; 6.9 months for chemotherapy HR=0.58 (95% CI: 0.43–0.78), p=0.0004 Patients with common mutations (Del19+L858R): Median PFS of 13.6 months for afatinib; 6.9 months for chemotherapy HR=0.47 (95% CI: 0.34–0.65), p<0.0001 Consistent efficacy in all relevant subgroups AE, adverse event Yang et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7500)

50 Pemetrexed alone (500mg/m2) every 3 weeks for 4 cycles (n=102)7506: A randomised Phase III trial of single-agent pemetrexed (P) versus carboplatin and pemetrexed (CP) in patients with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2 – Lilenbaum R et al Randomised, multicentre, Phase III study in Brazil Objective: To investigate the efficacy and safety of pemetrexed compared with pemetrexed/carboplatin in patients with advanced NSCLC Pemetrexed alone (500mg/m2) every 3 weeks for 4 cycles (n=102) Key patient inclusion criteria Advanced NSCLC Any histology at first, amended to non-squamous only PS 2 No prior chemotherapy Adequate organ function (n=217) Stratification factors included stage (IIIB vs IV) age (≥70 vs <70) weight loss (≥5 kg vs <5kg) R Pemetrexed (500mg/m2) + carboplatin (AUC 5) every 3 weeks for 4 cycles (n=103) Primary endpoint OS Lilenbaum et al. J Clin Oncol 30: 2012 (suppl; abstr 7506)

51 Pemetrexed/carboplatinKey efficacy data: OS Pemetrexed Pemetrexed/carboplatin Median, months 5.6 9.1 OS at 6 months, % 50 65 OS at 12 months, % 18 43 1.0 0.8 0.6 0.4 0.2 HR=0.57 (0.41–0.79); p=0.001 Overall survival Pemetrexed Pemetrexed/carboplatin Time (months) Lilenbaum et al. J Clin Oncol 30: 2012 (suppl; abstr 7506)

52 Key efficacy and safety: other resultsPemetrexed Pemetrexed/ carboplatin P ORR (CR+PR) 10.5% 24.0 <0.029 Median PFS (months) 3.0 5.9 <0.001 PFS at 6 months (%) 17 47 – Grade 3/4 safety % Pemetrexed (n=104) Pemetrexed/ carboplatin (n=107) Anaemia 3.9 11.7 Thrombocytopenia 1.0 Neutropenia 5.8 Febrile neutropenia 2.9 1.9 Nausea/emesis Diarrhoea 2 1 Dyspnoea 10.8 Grade 5 events Lilenbaum et al. J Clin Oncol 30: 2012 (suppl; abstr 7506)

53 Conclusions Combination chemotherapy with carboplatin-pemetrexed significantly improves survival compared with single agent pemetrexed in patients with advanced and a PS of 2 The secondary endpoints of response rate and PFS were also met The survival benefit was maintained in subset populations Toxicity was acceptable in this high-risk group Lilenbaum et al. J Clin Oncol 30: 2012 (suppl; abstr 7506)

54 7519: A randomized placebo-controlled phase III study of intercalated erlotinib with gemcitabine/platinum in first-line advanced non-small cell lung cancer (NSCLC): FASTACT-II – Mok T et al Study objective To investigate the efficacy and safety of intercalated erlotinib with gemcitabine/platinum in first-line advanced NSCLC Study type/design FASTACT-II: confirmatory, randomised, Phase III, placebo-controlled, double-blind study Patients with untreated stage IIIB/IV NSCLC and ECOG PS 0/1 were randomised (1:1) to receive up to 6 cycles of gemcitabine (1250 mg/m2 on d1 and 8) + platinum (carboplatin 5 x AUC or cisplatin 75 mg/m2 on d1) q4w, with either intercalated erlotinib (150 mg/day on d15–28) or placebo Non-progressing patients received maintenance erlotinib or placebo until progression/toxicity/death Primary endpoint: PFS; secondary endpoints: overall response rate (ORR), overall survival (OS), safety, QoL and biomarker analyses Key results 451 patients received erlotinib (n=226) or placebo (n=225) and baseline demographics were well balanced across the arms PFS was significantly prolonged with erlotinib vs placebo: median 7.6 vs 6.0 months, respectively; HR (95% CI 0.46–0.70); p<0.0001 ORR was significantly improved with erlotinib vs placebo: 42.9% vs 17.8%; p<0.0001 Key conclusions Intercalation of erlotinib with CT significantly prolonged PFS in first-line advanced NSCLC Mok et al. J Clin Oncol 30, 2012 (suppl; abstr 7519)

55 Key results 1.0 0.9 Erlotinib Placebo 0.8 0.7 0.6 PFS probability 0.5Log-rank p<0.0001 0.4 0.3 0.2 0.1 6.0 7.6 0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Patients remaining Erlotinib Placebo Time (Months) 226 225 192 185 162 156 136 114 102 57 81 31 65 21 46 13 33 7 23 4 5 2 2 1 1 1 Mok et al. J Clin Oncol 30, 2012 (suppl; abstr 7519)

56 7520: Overall survival (OS) results from OPTIMAL (CTONG0802), a phase III trial of erlotinib (E) versus carboplatin plus gemcitabine (GC) as first-line treatment for Chinese patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) – Zhou C et al Study objective To investigate OS in the OPTIMAL study in first-line advanced NSCLC patients with EGFR activating mutations (Act Mut+) Study type/design Phase III trial of E vs GC as first-line treatment for Chinese patients with Act Mut+ advanced NSCLC Chemotherapy-naive Chinese patients with advanced NSCLC and EGFR Act Mut+, ECOG performance status 0–2 and measurable disease were randomised to E (150 mg/day) or GC (stratified by histology, smoking status and mutation type) Key results 165 patients were randomised to treatment and 154 patients received at least one dose of study drug (ITT population; E, n=82; GC, n=72); 7 patients are still responding to erlotinib in the E arm First-line E significantly prolonged PFS compared with GC: 13.7 mo vs 4.6 mo; HR=0.164 (95% CI: –0.256); p<0.0001) OS did not differ significantly between the two treatment arms (HR=1.04, p=0.69), and no significant difference in OS was observed in the different subgroups A total of 92 deaths were reported (E, n=50; GC, n=42) Key conclusions Significant clinical benefits with E suggest that E should be considered as one of the standard first-line treatments for patients with advanced EGFR Act Mut+ NSCLC Zhou et al. J Clin Oncol 30, 2012 (suppl; abstr 7520)

57 7521: Updated overall survival results of WJTOG 3405, a randomized phase III trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first-line treatment for patients with non-small cell lung cancer harboring mutations of the epidermal growth factor receptor (EGFR) – Mitsudomi T et al Study objective To update overall survival (OS) results of WJTOG3405 following a longer follow-up period Study type/design WJTOG 3405: a randomised Phase III study comparing G with CD as first-line treatment for patients with NSCLC harbouring mutations of EGFR OS was re-evaluated using updated data (data cut off: 31 July, 2011; median follow-up: 34 months) for 172 patients Key results Median survival time (MST) for G arm was 36 mo (95% CI: 26.3–) which was not significantly different from 39 mo (95% CI: 31.2–) for CD arm (HR 1.185, 95% CI 0.767–1.829) Multivariate analysis revealed that treatment arm, smoking status, sex, age, postoperative recurrence or IIIB/IV, and mutation type did not significantly affected OS In the G arm, MST of patients with exon 19 deletion (36 mo) was comparable to that of patients with L858R (35 mo) 130 patients received both platinum doublet and EGFR-tyrosine kinase inhibitor (TKI) and 34 patients received EGFR-TKI without platinum doublet (MST: 36 months [95% CI: 31.2–45.7] and 45 months [95% CI: 25.6–], respectively [no significant difference]) Key conclusions This updated OS analysis revealed that G for advanced NSCLC with EGFR mutation offers distinct survival benefit of 3 years Mitsudomi et al. J Clin Oncol 30, 2012 (suppl; abstr 7521)

58 7530: First-line dacomitinib (PF ), an irreversible pan-HER tyrosine kinase inhibitor, for patients with EGFR-mutant lung cancers – Kris MG et al Study objective To evaluate dacomitinib as first-line treatment (tx) for patients (pts) with lung cancers (and sensitizing EGFR deletions/mutations in exons 19 or 21) Study type/design Open-label Phase II study: pts received dacomitinib once daily continuously at 45 mg or 30 mg with the option to escalate to 45 mg; evaluation was every 28 days Primary endpoint: progression-free survival rate at 4 months (PFS at 4M) Key results 47 pts had EGFR mutation in exons 19 (n=25) or 21 (n=21), 32 were female and 26 Asian Preliminary PFS at 4M was 96% (95% CI: 84–99) Preliminary PFS rate was 77% at 1 year and preliminary median PFS was 17 months 34/46 evaluable pts with EGFR exon 19 or 21 mutations had a PR (PR rate = 74%; 95% CI: 59–86; exon 19 = 72%; exon 21 = 76%) Key conclusions 74% of pts with EGFR exon 19 or 21 mutant lung cancers experienced PR with first-line dacomitinib 77% remained progression free at 1 year and median PFS was 17 months Kris et al. J Clin Oncol 30, 2012 (suppl; abstr 7530)

59 EGFR exon 19 and 21 mutations (n=46) Other EGFR mutations (n=7)Key results Percent progression free at timepoint EGFR exon 19 and 21 mutations (n=46) Other EGFR mutations (n=7) All patients (N=89) 4 months, % (95% CI) 96 (84–99) 63 (14–89) 77 (67–84) 6 months, % (95% CI) 84 (70–92) 42 (6–77) 9 months, % (95% CI) 21 (1–60) 12 months, % (95% CI) 74 (58–85) Median PFS, months % (95% CI) 17 (13–24) Kris et al. J Clin Oncol 30, 2012 (suppl; abstr 7530)

60 Maintenance Metastatic nsclc

61 R 2:1 every 21 days until PD PemetrexedLBA7507: PARAMOUNT: Final overall survival (OS) results of the phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo (plb) plus BSC immediately following induction treatment with pem plus cisplatin (cis) for advanced nonsquamous (NS) non-small cell lung cancer (NSCLC) – L Paz-Ares et al Randomised, placebo-controlled, double-blind Phase III study Pemetrexed 500mg/m2; cisplatin 75mg/m2 Folic acid and vitamin B12 administered to both arms Induction therapy 4 cycles, every 21 days Continuation maintenance therapy every 21 days until PD CR/PR/SD per RECIST Pemetrexed + BSC Pemetrexed + Cisplatin Previously untreated PS 0/1 Stage IIIB-IV NS-NSCLC R 2:1 Placebo + BSC Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD) CR, complete response; PR, partial response; SD, stable disease; BSC, best supportive care Paz-Ares et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7507)

62 Key efficacy data: PARAMOUNT final OS from randomisationPemetrexed Placebo Median OS (mo) 13.9 11.0 (95% CI) (12.8–16.0) (10.0–12.5) Censoring (%) 28.7 21.7 Survival rate (%, 95% CI) 1-year 58 (53–63) 45 (38–53) 2-year 32 (27–37) 21 (15–28) 1.0 0.9 0.8 0.7 0.6 Pemetrexed Survival probability 0.5 0.4 Log-rank P=0.0195 Unadjusted HR: 0.78 (95% CI: 0.64–0.96) 0.3 0.2 Placebo 0.1 0.0 3 6 9 12 15 18 21 24 27 30 33 36 Time from randomisation (Months) Patients at risk Pem + BSC Placebo + BSC Paz-Ares et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7507)

63 Key efficacy data: PARAMOUNT – PFS from randomisationPFS: Primary efficacy endpoint PFS: Reassessed at time of final OS 1.0 1.0 Unadjusted HR: 0.62 (0.49–0.79) Unadjusted HR: 0.60 (0.50–0.73) 0.8 0.8 0.6 0.6 Survival probability Survival probability 0.4 0.4 Pemetrexed Pemetrexed 0.2 0.2 Placebo Placebo 0.0 0.0 3 6 9 12 15 3 6 9 12 15 18 21 24 27 30 33 Time (Months) Time (Months) Patients at risk Patients at risk Pem + BSC Plac + BSC 359 180 132 52 57 17 21 5 4 Pem + BSC Plac + BSC 359 180 215 75 139 33 97 16 67 9 47 7 32 6 22 4 16 2 10 5 Paz-Ares et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7507)

64 Key safety data: PARAMOUNT – possible drug-related CTCAEs*Pemetrexed (N=359) Placebo (N=180) Grade 1/2 % Grade 3/4 % Grade 3/4 % Fatigue† 17.5 4.7 10.6 1.1 Nausea 13.4 0.6 2.2 Anemia† 11.7 6.4 4.4 Vomiting 7.5 0.3 Mucositis/stomatitis‡ 5.8 Neuropathy/sensory 5.3 6.1 Neutropenia† 5.0 Leukopenia 2.8 ALT (SGPT) 2.5 Maintenance safety similar to known profile of single-agent pemetrexed *Data derived from the March 2011 safety update. Toxicities of any grade, occurring in ≥5% of patients in either arm, are listed, along with some select toxicities. †P<0.05 Fisher’s exact test of Grade 3/4 toxicities. ‡Combined term Paz-Ares et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7507)

65 Conclusions These final results show that survival is significantly improved when patients are treated with pemetrexed continuation maintenance therapy compared with placebo (HR=0.78) The survival results were internally consistent across all subgroups, including response to induction (complete/partial response versus stable disease) (data not shown in this summary) PARAMOUNT is the first study to show continuation maintenance has an impact on the disease course of advanced NSCLC (including PFS and OS), supporting a change in the treatment paradigm in this setting Paz-Ares et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7507)

66 Later lines Metastatic nsclc

67 LBA7501: TAILOR: A phase III trial comparing erlotinib with docetaxel as the second-line treatment of NSCLC patients with wild-type (wt) EGFR – Garassino MC et al Randomised, multicentre, Phase III study Objective: To investigate the efficacy and safety of erlotinib compared with docetaxel in the second-line treatment of NSCLC Daily erlotinib 150 mg (n=108) PD or toxicity Key patient inclusion criteria* EGFR NSCLC (exons 19 and 21) at progression Previously treated with a first line platinum-based regimen (n=218) R Docetaxel 75 mg/m2 (3-weekly) or 35 mg/m2 (weekly) (n=110) PD or toxicity Primary endpoint: OS Secondary endpoint: PFS, response rate, QOL *EGFR and KRAS mutational status were assessed by direct sequencing in all eligible patients; PD, progressive disease Garassino et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7501)

68 Progression-free survivalKey efficacy data: PFS Median PFS months 6-month PFS Docetaxel 3.4 28.9% Erlotinib 2.4 16.9% 100 80 60 40 20 HR 0.69 (95% CI 0.52–0.93 p=0.014) Progression-free survival Docetaxel Erlotinib 1 2 3 4 5 6 7 Months Garassino et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7501)

69 Key efficacy and safety data: other resultsDocetaxel (n=104) Erlotinib (n=107) P ORR (CR+PR) 13.9% 2.2 0.004 DCR (CR+PR+SD) 41.5% 22.8 0.007 Safety % Docetaxel (n=104) Erlotinib (n=107) Patients with serious AE ≥1 14.4 13.1 Treatment-related serious AE 3.8 1.8 Treatment-related deaths 0.9 Treatment-related AEs leading to withdrawal 1.0 Grade 3/4 AEs: alopecia, neutropenia and neurological events higher with docetaxel; dermatological toxicity higher with erlotinib AE, adverse event; ORR, objective response rate; CR, complete response; DCR, disease control rate; CR, complete response; PR, partial response; SD, stable disease Garassino et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7501)

70 Conclusions TAILOR is the only prospective head-to-head trial comparing erlotinib versus docetaxel in wild-type EGFR patients Docetaxel significantly improves the PFS, response rate and disease control rate over erlotinib Reported toxicity was as expected Survival will be analysed when 199 deaths will occur Garassino et al. J Clin Oncol 30, 2012 (suppl; abstr LBA7501)

71 7013: MAGE-A3 cancer immunotherapeutic in resected stage IB-III NSCLC patients with or without sequential or concurrent chemotherapy – Pujol J-L et al Study objective To evaluate the safety profile of the MAGE-A3 cancer immunotherapeutic, formulated with the recombinant MAGE-A3 protein and the AS15 immunostimulant, and the induction of specific immune response with or without adjuvant chemotherapy (CT) Study type/design Phase I/II study: MAGE-A3 CI was administered intramuscularly 8q3w in resected MAGE-A3+ stage IB- III NSCLC patients (pts) Three cohorts (C) were evaluated: immunization with concurrent cisplatin plus vinorelbine (C1), sequentially after the same CT (C2) or with no CT (C3) Key results A total of 38/55 treated pts received the 8 doses schedule (15/19 in C1, 14/18 in C2, 9/18 in C3) Immunogenicity results: specific antibodies were detected in all patients after 4 and 8 doses; CD4+ T- cell immune response seen in 4/11 (C1), 4/15 (C2), 2/8 (C3) pts; CD8+ T-cell immune response only seen in 1 pt in C1 cohort and 1 pt in C2 cohort Almost all pts reported at least one AE, mostly general constitutional disorders (e.g. myalgia, back pain) and administration site reactions Key conclusions Data suggested that the MAGE-A3 cancer immunotherapeutic was well tolerated and induced specific antibodies against MAGE-A3 after 4 doses in presence/absence of concurrent or sequential adjuvant CT Pujol et al. J Clin Oncol 30, 2012 (suppl; abstr 7013)

72 7502: SELECT: Randomized phase III study of docetaxel (D) or pemetrexed (P) with or without cetuximab (C) in recurrent or progressive non-small cell lung cancer (NSCLC) after platinum-based therapy – Kim ES et al Study objective To investigate effect of adding C to standard chemotherapy on progression-free survival (PFS) in patients (pts) with recurrent or progressive NSCLC after platinum-based therapy Study type/design SELECT was a multicentre, open-label, randomised Phase III trial; pts received either P (500 mg/m2) or D (75 mg/m2) on day 1 and then were randomised within each group to chemotherapy plus C (400/250 mg/m2) (initial/weekly) or chemotherapy alone Therapy was given for up to six 3-week cycles; pts randomised to C continued weekly monotherapy until disease progression or unacceptable toxicity Preplanned subgroup analyses for epidermal growth factor receptor (EGFR) staining intensity by immunohistochemistry and histology were performed Study endpoints Primary endpoint: PFS Secondary endpoints: overall survival (OS), objective response rate (ORR), duration of response (DOR), safety Patient characteristics 938 total pts were randomised with comparable baseline demographics between PC (n=301) and P (n=304): median age 64 years; male 60%; Caucasian 88%; KPS 80–100/60–70: 84%/16%; squamous/non-squamous: 24%/76% Kim et al. J Clin Oncol 30, 2012 (suppl; abstr 7502)

73 Key efficacy and safety data1.0 Pemetrexed + cetuximab (N=301) Median (95% CI) 2.89 (2.69, 3.22) 0.9 0.8 Pemetrexed (N=304) Median (95% CI) 2.76 (2.53, 3.29) 0.7 0.6 Event-free probability 0.5 0.4 0.3 0.2 0.1 0.0 6 12 18 24 30 36 42 48 54 60 66 72 Time (months) Median OS (months) for PC vs P was 6.93 and 7.79, respectively (HR=1.01 [95% CI: 0.86–1.20], p=0.86) No statistical differences in efficacy based on histology or EGFR staining intensity More drug-related AEs/SAEs were observed in the PC arm, with differences mainly attributable to skin toxicities, GI (diarrhoea/stomatitis), and hypomagnesemia AE, adverse event; SAE, serious adverse event Kim et al. J Clin Oncol 30, 2012 (suppl; abstr 7502)

74 Conclusions The addition of cetuximab to pemetrexed did not improve PFS or OS in patients with recurrent or progressive NSCLC after platinum-based therapy There was no improvement in efficacy with the addition of cetuximab to pemetrexed when analyzed by histology or EGFR staining intensity More adverse events/serious adverse events were observed in the cetuximab group However, the safety profiles were consistent with existing data and no new safety signals were observed H-score analysis is planned Kim et al. J Clin Oncol 30, 2012 (suppl; abstr 7502)

75 7503: Phase II double-blind, randomized study of selumetinib (SEL) plus docetaxel (DOC) versus DOC plus placebo as second-line treatment for advanced KRAS mutant non-small cell lung cancer (NSCLC) – Janne PA et al Study objective To prospectively evaluate SEL + DOC vs DOC + placebo in advanced KRAS mutant NSCLC (based on preclinical observations) Study type/design Phase II double-blind, randomised study Patients (pts) with stage IIIB-IV, KRAS mutant NSCLC, who had received prior chemotherapy, received iv DOC 75 mg/m2, and po SEL 75 mg or placebo BD Primary endpoint: overall survival (OS) Secondary endpoints: progression-free survival (PFS), objective response rate (RR), duration of response, change in tumour size, proportion of patients alive and progression-free at 6 mo, and safety and tolerability Key results Between April 2009 and June 2010, 422 pts were screened across 67 centres in 12 countries; 113 had KRAS mutant NSCLC and 87 were randomised (DOC, 43; SEL/DOC, 44) Baseline characteristics were well balanced (DOC vs SEL/DOC): WHO PS 0, 49% vs 48%; female, 54% vs 52%; KRAS codon 12, 90% vs 93% OS was longer for SEL/DOC vs DOC (9.4 mo vs 5.2 mo; 56 events, median follow-up 219 days; ns) and all secondary endpoints were significantly improved for SEL/DOC vs DOC Key conclusions This is the first prospective study to demonstrate a clinical benefit of a targeted therapy (SEL + DOC) for patients with KRAS mutant cancer of any type Janne et al. J Clin Oncol 30: 2012 (suppl; abstr 7503)

76 7504: Analysis of resistance mechanisms to ALK kinase inhibitors in ALK positive NSCLC patients – Doebele RC et al Study objective To define molecular mechanisms of resistance to anaplastic lymphoma kinase (ALK) kinase inhibitors in ALK+ non-small cell lung cancer (NSCLC) patients Study type/design Of 30 ALK+ crizotinib-treated NSCLC patients experiencing radiologic disease progression, samples were taken from 19/23 patients with accessible extracerebral progression Key results Rebiopsy of patients with progressing tumour lesions successfully yielded tumour in 84% Of these, 81% demonstrated a plausible mechanism of resistance A diverse array of mechanisms of resistance were observed: ALK dominant (50%): ALK kinase domain mutations (31%) and ALK fusion gene copy number gain (19%) ALK non-dominant (50%) Emergence of alternate oncogene (31%): EGFR or KRAS activating mutation Unknown (19%): non-mutated EGFR, HER2 and KIT should be considered Key conclusions ALK kinase inhibitor resistance in ALK+ NSCLC occurs through a diverse array of kinase domain mutations, ALK gene fusion CNG, and emergence of second (same cell) or separate (different cell) oncogenic drivers Doebele et al. J Clin Oncol 30, 2012 (suppl; abstr 7504)

77 Systematic resistance to ALK inhibitorsALK Non-Dominant ALK Dominant Doebele et al. J Clin Oncol 30, 2012 (suppl; abstr 7504)

78 7508: Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement Tsang Shaw et al Massachusetts General Hospital Cancer Center, Boston, MA, USA

79 Molecularly enriched cohortsStudy design Phase I study of crizotinib (PROFILE 1001) ROS1+ NSCLC expansion cohort Cohort 5 (n=6) 300 mg BID Part 1: Dose escalation Cohort 6 (n=9) Cohort 4 (n=7) 250 mg QD MTD/RP2D 200 mg BID Cohort 3 (n=8) 200 mg QD Part 2: Dose expansion Molecularly enriched cohorts (c-MET, ALK, ROS1) Cohort 2 (n=4) 100 mg QD Patients with advanced NSCLC harbouring ROS1 rearrangement recruited into the expansion cohort Patients were treated with crizotinib 250 mg BID Cohort 1 (n=3) 50 mg QD Tsang Shaw et al. J Clin Oncol 30, 2012 (suppl; abstr 7508)

80 Baseline characteristics: patients with advanced ROS1+ NSCLCAge, yrs Median (range) 54 (31, 72) Sex, n Male/Female 8/7 Smoking history, n (%) Never 14 (93) Former 1 (7) Race, n (%) Caucasian 10 (67) Asian 4 (27) Other Histology, n (%) Adenocarcinoma 15 (100) ECOG PS, n (%) 1 5 (33) Prior treatment None 2 (13) ≥1 regimen 12 (80) Not reported Tsang Shaw et al. J Clin Oncol 30, 2012 (suppl; abstr 7508)

81 Key results: antitumour activity of crizotinib in evaluable ROS1+ patientsROS1+ (n=14) Best response† Complete 1 Partial 7 Stable disease 4 Progressive disease 2 Other ORR 57.1 Median duration of treatment (weeks) 25.7 Disease control rate at 8 weeks 79% Pharmacokinetics and safety profile of crizotinib in this group of patients were similar to that observed in patients with ALK-positive NSCLC †RECIST 1.0 Tsang Shaw et al. J Clin Oncol 30, 2012 (suppl; abstr 7508)

82 Key results: summary of tumour responses in patients with advanced ROS1+ NSCLC (n=14*)100 PD SD PR CR 80 60 40 20 † ‡ Decrease or increase from baseline (%) 15+ –20 16+ 18+ –40 4+ 12+ –60 8+ 22+ 18 44+ –80 –100 20+ 35+ 48+ *Response-evaluable population †Tumour ROS1 FISH-positive, but negative for ROS1 fusion gene expression ‡Crizotinib held for >6 wks prior to first scans which showed PD +, treatment ongoing Tsang Shaw et al. J Clin Oncol 30, 2012 (suppl; abstr 7508)

83 Conclusions ROS1 rearrangement defines a distinct subset of NSCLCCrizotinib demonstrates marked antitumour activity in patients with advanced ROS1+ NSCLC This study represents the first clinical validation of ROS as a therapeutic target in cancer Tsang Shaw et al. J Clin Oncol 30, 2012 (suppl; abstr 7508)

84 SCLC / MPM

85 TPS7112: IFCT-GFPC-0701 MAPS trial, a multicenter randomized phase III trial of pemetrexed-cisplatin with or without bevacizumab in patients with malignant pleural mesothelioma (MPM) – G Zalcman et al Accrual 445 patients to be recruited over 48 months, with at least 24 months of follow-up Accrual: 1st patient included in Feb 2008 On January : 257 patients from 85 centres Expected end of accrual: September 2013 Anciliary studies Quality of life PET-CT Pharmacoeconomics Biology on paraffin-embedded specimens: BIO-MAPS IHC: VEGFR2, CD34, VE-statin, ERCC1, TS, b-tubulin 3, IGF-R, c-MET, EGF-R Key conclusions This Phase III study has been designed to demonstrate the efficacy of bevacizumab added to pemetrexed/cisplatin in chemotherapy-naïve patients with MPM Zalcman et al. J Clin Oncol 30, 2012 (suppl; abstr TPS7112)

86 Study design: IFCT-GFPC-0701 MAPS trialFrench Intergroup study to examine pemetrexed/cisplatin with or without bevacizumab Multicentre, randomised Phase III trial Pemetrexed/ cisplatin* plus bevacizumab every 21 days, for 6 cycles Non-progressive patients received bevacizumab maintenance therapy until progression or toxicity Key patient inclusion criteria Unresectable histologically proved MPM No prior chemotherapy ECOG PS 0–2, no thrombosis, nor bleeding (n = approximately 445) R Pemetrexed/ cisplatin* every 21 days, for 6 cycles Primary endpoint OS Secondary endpoint PFS *With vitamin B12 + B9 substitution MPM, malignant pleural mesothelioma Pemetrexed, 500 mg/m2; cisplatin 75 mg/m2; bevacizumab 15mg/kg Zalcman et al. J Clin Oncol 30, 2012 (suppl; abstr TPS7112) 86 86

87 7003: A phase III study comparing amrubicin and cisplatin (AP) with irinotecan and cisplatin (IP) for the treatment of extended-stage small cell lung cancer (ED-SCLC): JCOG0509 – Kotani Y et al Study objective To compare AP with IP for the treatment of ED-SCLC Study type/design Phase III trial comparing AP with IP in patients (pts) with chemotherapy-naïve ED-SCLC, aged 20 to 70, and ECOG PS 0–1: pts were randomised to receive either IP: I (60 mg/m2) iv on days 1, 8, and 15, and P (60 mg/m2) iv on day 1, every 4 weeks; or AP: A (40 mg/m2) iv on day 1–3, and P (60 mg/m2) iv on day 1, every 3 weeks The initial dose of A was decreased from 40 mg/m2 to 35 mg/m2 due to increased FN Study endpoints Primary: overall survival (OS) Secondary: response rate (RR), progression-free survival (PFS), adverse events (AEs), quality of life Patient characteristics IP AP Patients enrolled 142 Male/Female 120/22 119/23 Age yrs, median (range) 63 (39–70) 63 (29–70) Performance status: 0/1 78/64 80/62 Measurable lesion +/- 1/141 2/140 Metastasis (overlapped): lung/bone/brain/liver/others 9/25/32/35/68 14/31/41/45/64 FN, febrile neutropenia Kotani et al. J Clin Oncol 30, 2012 (suppl; abstr 7003)

88 Key efficacy and safety dataPts Event Median (mo) [95% CI] IP 142 82 18.3 [14.6–24.3] AP 100 18.3 [13.6–17.5] 100 80 60 40 20 Proportion survival (%) HR*: % CI: 1.03–1.93 non-inferiority one-sided p=0.681 IP AP Survival time (months) DSMC recommended early publication because the hazard ratio of AP to IP was larger than non-inferiority margin of 1.31. Median PFS: 5.7 (IP) vs 5.1 months (AP) (HR 1.44, 95% CI: 1.13–1.83) Grade 4 neutropenia (22.5% vs 79.3%) and Grade 3–4 febrile neutropenia (10.6% vs 32.1%) was higher in the AP arm, while Grade 3–4 diarrhoea (7.7% vs 1.4%) was higher in IP arm *Stratified Cox regression, with PS and sex as strata Kotani et al. J Clin Oncol 30, 2012 (suppl; abstr 7003)

89 Conclusions Non-inferiority of amrubicin and cisplatin to irinotecan and cisplatin was not demonstrated in this study Irinotecan and cisplatin remains the standard treatment for extended-stage SCLC Kotani et al. J Clin Oncol 30, 2012 (suppl; abstr 7003)

90 Primary: complete response rate (WHO criteria) 7004: Phase III trial of concurrent thoracic radiotherapy (TRT) with either the first cycle or the third cycle of cisplatin and etoposide chemotherapy to determine the optimal timing of TRT for limited-disease small cell lung cancer – Park K et al Study objective To determine the optimal timing of TRT for limited-disease small cell lung cancer Study type/design Phase III randomised study where a total of 219 patients with limited-disease SCLC received four cycles of cisplatin plus etoposide (cisplatin 70 mg/m2 on day 1 and etoposide 100 mg/m2 on days 1 to 3 every 3 weeks) Patients were randomly assigned to receive concurrent TRT, beginning with the first cycle (initial arm) or the third cycle (delayed arm) of chemotherapy In both arms, patients received 2.1 Gy once-daily in 25 fractions over a period of five weeks, with a total dose of 52.5 Gy Study endpoints Primary: complete response rate (WHO criteria) Secondary: ORR, OS, PFS, toxicity (NCI-CTC ver. 2.0) Patient characteristics Patient characteristics were well balanced between treatment arms Park et al. J Clin Oncol 30, 2012 (suppl; abstr 7004)

91 Key efficacy and safety dataInitial arm (n=111) Delayed arm (n=108) 95% CI of the difference CR 40 (36.0%) 41 (38.0%) (-14.7%, 10.9%) PR 62 (55.9%) 56 (51.9%) SD 4 (3.6%) 4 (3.7%) PD 5 (4.5%) 5 (4.6%) Unknown 2 (1.9%) ORR (CR+PR) 91.9% 89.8% Initial arm vs delayed arm: Median OS: 24.1 mo vs 26.8 mo (HR=0.9; 95% CI: 0.18–1.62) Median PFS: 12.4 mo vs 11.2 mo (HR=1.10; 95% CI:0.37–1.84; p=0.60) Grade 3/4 febrile neutropenia: 21.6% vs 10.2% Grade 3/4 neutropenia: 70.3% vs 59.3% Park et al. J Clin Oncol 30, 2012 (suppl; abstr 7004)

92 Conclusions TRT (52.5 Gy, once daily) beginning with the third cycle of chemotherapy showed comparable survival outcomes and complete response rates with TRT beginning with the first cycle of chemotherapy, with a lower frequency of febrile neutropenia This study supports the use of TRT regimen, given concurrently with the third cycle of EP chemotherapy for the treatment of LD-SCLC Park et al. J Clin Oncol 30, 2012 (suppl; abstr 7004)

93 7005: SWOG 0802: A randomized phase II trial of weekly topotecan with and without AVE0005 (aflibercept) in patients with platinum-treated extensive-stage small cell lung cancer (E-SCLC) – Allen JW et al Study objective To evaluate the efficacy and toxicity of weekly IV topetecan (T) (4 mg/m2) with or without aflibercept (A) (6 mg/kg Q21D) in patients with relapsed SCLC following one line of platinum-based chemotherapy for extensive or limited-stage (L) SCLC Study type/design Randomised Phase II study: patients received T or A+T (1:1 ratio) Eligible patients had adequate organ function, ECOG PS 0–1, and no recent bleeding or cardiac events Primary endpoint: 3-month PFS Data shown are for patients stratified as platinum-refractory (PR) Study endpoints Primary: 3-month progression-free survival Secondary: overall survival, toxicity, response in subset of patients with measurable disease Patient characteristics Patient demographics were well balanced between treatment arms 55 patients received A + T: median age 60.9 yrs, 47% male, 89% caucasian 51 patients received T alone: median age 63.6 yrs, 67% male, 84% caucasian Q21D, 21-day dosing Allen et al. J Clin Oncol 30, 2012 (suppl; abstr 7005)

94 Key efficacy and safety dataProgression-free survival Overall survival 100 80 60 40 20 3-month Median in N Events estimate months Aflibercept % Topotecan Topotecan % 1.4 100 80 60 40 20 Median in N Deaths months Aflibercept Topotecan Topotecan p=0.01 p=0.35 Percentage Percentage Months after registration Months after registration Allen et al. J Clin Oncol 30, 2012 (suppl; abstr 7005)

95 Conclusions This study met its primary endpoint of improved 3-month PFS with aflibercept + topetecan (p=0.01), warranting further study in the PR setting Clinical benefit with aflibercept + topetecan was achieved primarily through improved DCR Toxicity was mainly haematologic and was less than seen with standard dose topetecan Topetecan + aflibercept warrants further study in this patient population Allen et al. J Clin Oncol 30, 2012 (suppl; abstr 7005)

96 Primary endpoint: overall survival (OS) Patient characteristics 7028: Randomized phase III study comparing etoposide and cisplatin (EP) with irinotecan and cisplatin (IP) following EP plus concurrent accelerated hyperfractionated thoracic radiotherapy (EP/AHTRT) for the treatment of limited-stage small-cell lung cancer (LD-SCLC): JCOG0202 – Kubota K et al Study objective To compare EP with IP following EP plus concurrent AHTRT for the treatment of LD- SCLC Study type/design Phase III randomised study: eligible patients received one cycle of EP (etoposide 100 mg/m2 on days 1–3 and cisplatin 80mg/m2 on day 1) plus AHTRT (1.5 Gy BID, total 45 Gy/3 weeks) Patients who achieved CR, good PR, PR or SD with induction EP/AHTRT were randomised to receive either 3 cycles of consolidation EP or IP (irinotecan 60 mg/m2 and cisplatin 60 mg/m2 on days 1, 8, 15) Patients with CR or good PR after consolidation chemotherapy received prophylactic cranial irradiation Study endpoints Primary endpoint: overall survival (OS) Patient characteristics 281 patients from 36 institutions were registered: after induction EP/AHTRT, 258 patients were randomised to consolidation EP (n=129) or IP (n=129) Patient demographics were well balanced between the two groups Kubota et al. J Clin Oncol 30, 2012 (suppl; abstr 7028)

97 Key efficacy and safety dataTreatment arm MST (years) 3 years (%) 5 years EP 3.2 52.8 36.8 IP 2.8 46.6 33.7 1 2 3 4 5 6 7 9 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Years after randomisation Proportion 8 EP IP One sided p=0.703, HR=1.086 95% CI: 0.806–1.464 Conclusions Etoposide and cisplatin (EP) + accelerated hyperfractionated thoracic radiotherapy (AHTRT) followed by 3 cycles of irinotecan and cisplatin failed to demonstrate survival advantage over 4 cycles of EP + AHTRT 4 cycles of EP + AHTRT remains the standard treatment for limited- stage small cell lung cancer Kubota et al. J Clin Oncol 30, 2012 (suppl; abstr 7028)

98 7029: Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma (MPM) – Krug LM et al Study objective To assess pemetrexed/cisplatin with or without CBP501, a synthetic duodecapeptide, in patients with advanced malignant pleural mesothelioma Study type/design Open-label, multicentre, randomised Phase II study conducted in four countries (USA, Canada, Argentina and Russia) Chemotherapy-naive patients with unresectable MPM (stratified by histology and performance status) were randomised 2:1 to pemetrexed 500 mg/m2 / cisplatin 75 mg/m2 + CBP mg/m2 IV (Arm A), or pemetrexed/cisplatin alone (Arm B). Patients continued on treatment until progression or intolerance Primary endpoint: progression free survival (PFS) at 4 months (Arm A) Key results 63 pts were treated and patient characteristics in the two treatment arms were similar PFS ≥4 months (preliminary data): 68% (Arm A) vs 61% (Arm B)* Grade 3/4 treatment-related toxicities were uncommon and comparable in the two arms 53% of patients treated with CBP501 had infusion reactions, all Grade 1/2 Key conclusions 68% of patients in treatment arm A were progression free for ≥4 months Response rate and median PFS survival favoured the triplet combination arm The addition of CBP501 did not result in any added toxicity apart from Grade 1–2 infusion reactions *p-value not available Krug et al. J Clin Oncol 30, 2012 (suppl; abstr 7029)

99 Key results: efficacy Arm A N=40 Arm B N=23 Complete response, n (%)0 (0) 1 (4) Partial response, n (%) 16 (40) 3 (13) Objective response rate, n (%) [95% CI] 16 (40) [.25, .57] 4 (17) [.05, .39] Stable disease, n (%) 17 (43) 13 (57) Progressive disease, n (%) 6 (15) PFS ≥4 months, n (%) 27 (68) 14 (61) Median PFS (mo) [95% CI] 5.9 [4.3, 9.1] 4.7 [3.7, 5.9] Median overall survival (mo) [95% CI] 13.2 [9.1, 16.2] 12.7 [6.5, 15.9] PFS, progression-free survival Krug et al. J Clin Oncol 30, 2012 (suppl; abstr 7029)

100 7030: Amatuximab, a chimeric monoclonal antibody to mesothelin, in combination with pemetrexed and cisplatin in patients with unresectable pleural mesothelioma: Results of a multicenter phase II clinical trial – Hassan R et al Study objective To assess the efficacy and safety of amatuximab (MORAb-009) plus pemetrexed (P) and cisplatin (C) in patients (pts) with malignant mesothelioma (MM) Study type/design A single-arm Phase II study of amatuximab plus P and C in pts with MM: pts received amatuximab 5 mg/kg on days 1 and 8 with P 500 mg/m2 and C 75 mg/m2 (PC) given on day 1, of each 21 day cycle for 6 cycles Primary endpoint was progression-free survival (PFS) at 6 months Key results 89 pts enrolled at 26 sites: median age 67 yrs (range 46–80), 78% male, 70% with KPS >90%, 89% epithelial MM, 11% biphasic MM, 88% had stage III/IV disease Median number of PC + amatuximab cycles was 5 (range 1–6) and 56 (63%) pts received single agent amatuximab PFS at 6 months was 52% (95% CI: 39.5–63.5) with a median PFS of 6.1 months (95% CI: 5.4–6.5) Median OS: 14.8 months (95% CI: 12.4–18.5); partial response: 39%; stable disease: 51% Hypersensitivity reactions from amatuximab in 12.4% pts (Grade 3/4: 4.5%) Key conclusions Amatuximab in combination with PC was generally well-tolerated in this study and 90% of pts achieved an objective tumour response or stable disease 23/89 are still alive, 5/89 patients are still receiving Amatuximab (by April ) Hassan et al. J Clin Oncol 30, 2012 (suppl; abstr 7030)

101 7031: Comparison of prognostic impact between metabolic and radiologic response after induction chemotherapy for resectable malignant pleural mesothelioma: A multicenter study – Tsutani Y et al Study objective To evaluate the usefulness of metabolic response on FDG-PET compared with radiologic response (according to modified RECIST criteria) with clinical T1–3 N0–2 M0 MPM (epithelioid: 76%; biphagic: 20%; sarcomatoid: 4%) after induction chemotherapy to predict outcome for patients  Study type/design HRCT and FDG-PET was performed before and after induction platinum-based chemotherapy on 50 patients with clinical T1–3 N0–2 M0 MPM who underwent EPP  postoperative hemithoracic radiation A decrease of more than 30% in tumour maximum standardised uptake value (SUVmax) was defined as a metabolic responder Key results Median overall survival (OS) from diagnosis was 20.5 mo (95% CI: 15.0–26.0 mo) Fourteen patients were classified as metabolic responders (28%) and 36 as non-responders (72%) Metabolic responders significantly correlated to OS with median OS for metabolic responders not reached (3-year OS: 60.0%) vs 18.7 mo (95% CI: 13.3–24.2 mo; 3-year OS: 26.5%) for non-responders (p=0.025) Decreased SUVmax (%) (p=0.010) and epithelioid subtype (p=0.044) were independent factors for OS Key conclusions Metabolic response on FDG-PET has a higher predictive value of prognosis than radiologic response on HRCT after induction chemotherapy for patients with resectable MPM Tsutani et al. J Clin Oncol 30, 2012 (suppl; abstr 7031)

102 7089: Genome-wide association study of survival in small cell lung cancer patients treated with irinotecan and cisplatin chemotherapy Ji-Youn Han et al Center for Lung Cancer, National Cancer Center, Goyang, South Korea

103 Study design and baseline characteristicsProspectively collected blood samples from 139 patients who participated in two Phase II studies of irinotecan and cisplatin (IP) chemotherapy as first-line therapy Patients had ED-SCLC A genome-wide analysis study (GWAS) using overall survival (OS) as the endpoint was conducted Germline DNA was genotyped using Affymetrix 5.0 or 6.0 array sets Adjustments made for age, performance status (PS) and gender Most promising SNPs with p<1 x 10−6 in the GWAS allelic association analyses were selected Associations between OS and single nucleotide polymorphisms (SNPs) were investigated using multivariate Cox regression analysis Characteristics n (%) Age, years Median (range) 64 (33–79) Gender Male 126 (91) Female 13 (9) ECOG PS 0 or 1 103 (74) 2 36 (26) ED-SCLC, extensive-disease small-cell lung cancer Han et al. J Clin Oncol 30, 2012 (suppl; abstr 7089) 103 103

104 Key results: SNPs associated with survivalRisk allele/ control allele Genetic model HR (95% CI) P* rs T/C Dominant 30.2 (8.3–109.0) 2.1 x 10-7 rs G/A Additive 2.5 (1.7–3.5) 3.8 x 10-7 rs 7.6 (3.4–16.6) 4.5 x 10-7 rs C/T Recessive 3.4 (2.1–5.5) 3.5 x 10-7 rs C/G 4.9 (2.7–9.0) 3.1 x 10-7 rs T/G 7.8 (3.4–17.7) 8.0 x 10-7 rs 5.8 (2.9–11.7) 8.4 x 10-7 A total of 426,019 SNPs were genotyped and 343,530 SNPs passed quality control (HWE, p<10-7, minor allele frequency >1%) rs , rs , rs and rs were significantly associated with a refractory relapse *Multivariate Cox proportional hazard regression analysis Adjustments for age (continuous), gender (male or female) and ECOG PS (0, 1 or 2) were made Han et al. J Clin Oncol 30, 2012 (suppl; abstr 7089)

105 Conclusions Seven single nucleotide polymorphisms (SNPs) showed a significant association with OS Patients rs CT, rs AG or GG, rs AG, rs CC, rs CC, rs TT and rs TT genotypes showed shorter OS compared with patients with control alleles This exploratory genome-wide analysis study identified candidate SNPs that might be predictive for outcome of SCLC patients receiving irinotecan and cisplatin chemotherapy Further validation through a replication study is needed Han et al. J Clin Oncol 30, 2012 (suppl; abstr 7089)

106 Rare tumours

107 7033: Phase II study of cixutumumab (IMC-A12) in thymic malignancies – A Rajan et alStudy objective To examine cixutumumab, a fully human IgG1 monoclonal antibody that targets IGF-IR, in patients with recurrent thymoma (T) and thymic carcinoma (TC) Study type/design Patients (n=49) received cixutumumab (20 mg/kg IV every 3 weeks) until progression or toxicity Outcomes: response rate Key results In 37 evaluable T patients, there were 5 (14%) PR, 8 (76%) SD, and 4 (11%) PD Corresponding numbers in 12 TC patients were 0, 5 (42%) and 7 (58%) Median PFS for T and TC was 40 and 6 weeks, respectively Cixutumumab-related Grade 3/4 AEs included hyperglycaemia (8%), hyperuricaemia, weight loss, lipase elevation, chest wall pain (5% each) and AST elevation (3%); Two patients died Autoimmune symptoms developed in 9/33 patients Key conclusions Cixutumumab monotherapy was well tolerated and active in T TC activity is unworthy of further investigation PR, partial response, SD, stable disease; PD, progressive disease Rajan et al. J Clin Oncol 30, 2012 (suppl; abstr 7033)

108 7104: A prospective, phase II trial of induction chemotherapy with docetaxel/cisplatin for Masaoka stage III/IV thymic epithelial tumors Silvia Park et al Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

109 Unresectable Masaoka’s stage III/IV TET patientsStudy design In this open-label, Phase II, non-randomised study, patients with histologically proven, Masaoka stage III/IV TETs at presentation were enrolled Unresectable Masaoka’s stage III/IV TET patients Day 1 Docetaxel 75 mg/m2 Day 1 Cisplatin 75 mg/m2 Every 3 weeks x 3 cycles Surgical resection If PD  Off protocol TET, thymic epithelial tumour Park et al. J Clin Oncol 30, 2012 (suppl; abstr 7104)

110 Baseline characteristicsAge, median (range) 54 (15–68) Sex: Male/Female 16 (59.3) / 11 (40.7) Masaoka stage III 8 (29.6) IVA 17 (63.0) IVB 2 (7.4) WHO Histologic type B1 type B2 type 3 (11.1) B3 type 5 (18.5) C type Park et al. J Clin Oncol 30, 2012 (suppl; abstr 7104)

111 Key results: treatment after induction docetaxel/cisplatinComplete resection (+) n=17 (89.5%) Post op. RT, n=8 Surgical resection (+) n=19 (70.4%) Post op. CT, n=6 Complete resection (–) n=2 (10.5%) Post op. RT + CT, n=2 Total N=27 Palliative RT, n=3 Surgical resection (–)* n=8 (29.6%) Palliative CT, n=4 Follow-up loss, n=1 Response rate after completion of neoadjuvant docetaxel/cisplatin: PR 17 (63.0%) SD 10 (37.0%) Major side effects after neoadjuvant docetaxel/cisplatin: Grade 3 anorexia (n=1), nausea (n=2), alopecia (n=1) *Reason for not undergoing surgical resection in 8 patients: surgeons’ decisions, n=5; patients’ refusal, n=2; RT alone based on minimal residual disease, n=1 Park et al. J Clin Oncol 30, 2012 (suppl; abstr 7104)

112 Key results: OS and PFS 4 year OS: 79.4% 4 year PFS: 40.6%Complete resection (+) Complete resection (–) 100 80 60 40 20 Overall survival (%) Time from initial diagnosis (months) P=0.0589 4 year OS: 79.4% 100 80 60 40 20 Progression-free survival (%) Time from initial diagnosis (months) P=0.2680 4 year PFS: 40.6% Park et al. J Clin Oncol 30, 2012 (suppl; abstr 7104)

113 Conclusions Neoadjuvant docetaxel/cisplatin was well tolerated and feasible Grade 3 anorexia (n=1), nausea (n=2), diarrhoea (n=3), alopecia (n=1) Neoadjuvant docetaxel/cisplatin improved the surgical respectability in patients with advanced thymic epithelial tumours Park et al. J Clin Oncol 30, 2012 (suppl; abstr 7104)

114 ASCO 2012 1-5 June 2012 | Chicago, USADeveloped in association with the European Thoracic Oncology Platform ASCO 2012 1-5 June 2012 | Chicago, USA Sponsored with support from Eli Lilly and Company. Eli Lilly and Company has not influenced the content of this publication