Pooled analysis of clinical outcomes in studies of patients with EGFR mutations treated with either an EGFR TKI or chemotherapy Luis Paz-Ares 1, Denis Soulières 2, Barbara Klughammer 3, Ivan Melezínek 4, Joachim Moecks 5, Tony Mok 6 1 Hospital Universitario Virgen del Rocío, Seville, Spain; 2 Centre Hospitalier de l’Université de Montréal, Montréal, Canada; 3 F. Hoffmann-La Roche Ltd, Basel, Switzerland; 4 Roche Products Ltd, Welwyn Garden City, UK; 5 BIOMCON GmbH, Mannheim, Germany; 6 The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China

EGFR mutations Activating mutations –exon 19 deletion –L858R Overall incidence in population –~10% in Western countries –~30% in Asian countries K Deletion L858R Insertion G719X 3.2% 48.2% 42.7% 3.7% Kinase domain P-loop  C helix A-loop ExonsEGFR Mitsudomi T, et al. Int J Clin Oncol 2006

Biological significance of EGFR mutation-positive NSCLC EGFR TK mutations have significant biological consequences –constitutive activation of receptor –preferential dimerisation with HER3, leading to strong AKT / STAT survival pathway signalling tumours may be ‘addicted’ to this signalling EGFR inhibition may be essential to restore apoptosis Opportunity for personalised treatment of NSCLC Sordella R, et al. Science 2004

Clinical characteristics of EGFR mutation-positive NSCLC – SLCG Data Patients with EGFR Mutations Frequency (%)95% CI All patients (N=2105) –18.3 Gender Female Male – –9.9 Age ≤57 57–69 > – – –25.6 Smoking History Ex-smoker Current smoker Never-smoker –11.6 4–8.6 34–41.7 Histology Adenocarcinoma BAC LCC – – –15

Optimal treatment outcomes: EGFR TKI or chemotherapy? Limited prospective data in EGFR mutation+ NSCLC –most existing data from small, retrospective studies, often limited to single ethnic groups Challenges for prospective studies –relatively low rate of mutations –limited availability of tumour samples Pooled analysis performed to consolidate available data –provide broad overview of data across different clinical settings and ethnicities

Methodology Searches performed using major databases (to 11 June 2009) –PubMed, Embase, Biosis Previews excluded reviews and non-English language –included data from ASCO 2008 and 2009 Inclusion criteria –median PFS/TTP reported for patients with EGFR mutations who received chemotherapy or EGFR TKI monotherapy (any line of treatment), with associated sample size Exclusion criteria –two EGFR TKIs studied in sequence –EGFR TKI given as maintenance or adjuvant therapy –data reported in another publication (latest update was included)

Statistical approach Methods Weighted estimate of pooled median PFS Accuracy interval based on exponential distribution Bootstrap re-sampling to check accuracy interval Permutation testing to compare median PFS estimates between treatments Potential publication bias addressed Limitations of this analysis No individual patient data –only high level information, no account for censored observation Considers only PFS –non-standardised PD assessment across studies Due to reporting differences, individual mutations not considered separately No restriction on study designs or study quality

Summary of search strategy Reports identified from broad literature search (n=564) Studies retained for full paper review (n=175) Studies identified from ASCO 2008–9 search (n=42) Excluded based on abstract or title: no clinical data related to question (n=431) Excluded (n=121) PFS/TTP/n not reported for pts with mutations (n=96) EGFR TKIs given sequentially or as maintenance or adjuvant therapy (n=10) Data duplicated in another publication (n=15) Studies included (n=54)

Summary of data included ErlotinibGefitinibChemotherapy Pts treated in any line; n3651, Pts treated in first-line setting 57% 95% Total number of patients = 1,809 (65% treated in first-line setting)

Median PFS from individual studies 90% accuracy intervals (any line of therapy) Erlotinib Gefitinib Chemotherapy

Pooled analysis (any line of therapy) Pooled median PFS (95% accuracy interval) 13.2 (12.0–14.7) 9.8 (9.2–10.4) 5.9 (5.3–6.5) Permutation test for estimated pooled median PFS (1,000 iterations) EGFR TKI vs chemotherapy p=0.000 (two-sided)

Outcomes according to line of therapy Pooled median PFS (95% accuracy interval); months ErlotinibGefitinibChemotherapy Any line13.2 (12.0–14.7)9.8 (9.2–10.4)5.9 (5.3–6.5) 1st line12.5 (10.0–16.0)9.9 (9.0–10.9)6.0 (5.4–6.7)

Analysis to assess publication bias Spread of data suggests no publication bias Erlotinib ChemotherapyGefitinib

Conclusions This analysis suggests longer PFS with erlotinib (13.2 months) and gefitinib (9.8 months) than chemotherapy (5.9 months) in EGFR mutation+ NSCLC Magnitude of benefit adds to evidence that EGFR TKIs should be the preferred first-line option in EGFR mutation+ disease –avoids toxicity of chemotherapy –many patients do not receive second-line therapy due to worsening condition Prospective studies are essential to confirm these findings

Ongoing prospective first-line studies in patients with EGFR mutation+ NSCLC EURTAC (Europe) –phase III, randomised (n=173) –erlotinib 150mg/day vs platinum doublet OPTIMAL, ML20981 (China) –phase II, randomised (n=150) –erlotinib 150mg/day vs platinum doublet WJTOG 3405 (Japan) –phase III, randomised –gefitinib 250mg/day vs cisplatin/docetaxel Primary endpoint in all trials: PFS