01 Reporting & Interpreting Statistics in Clinical Research Robert Pirker, MD Medical University of Vienna Vienna, Austria

02 Conflict of Interest Honoraria for Advisory Board/Consulting –AstraZeneca –Boehringer Ingelheim –Celgene –MSD –Synta Speaker’s fee –AstraZeneca –Boehringer Ingelheim –Pierre Fabre –Roche

03 Interpretation of Clinical Trials Type of cancer & patient population Aim of the study –Clear (simple) and scientifically & clinically relevant Design of the study –Phase I – IV; superiority, non-inferiority, equality –Experimental arm versus control arm –Endpoints, randomisation, stratification factors –Publication Clear? Conclusion in agreement with aim of the study? Significance & clinical relevance of the outcome –Magnitude of the difference (benefit) –Consistency between endpoints and with other trials –Risk-benefit analysis –Establishment of a novel treatment (procedure)

04 Patient Population Does the study population reflect the real world setting? Balanced between arms? –Age –Gender –Performance status –Histology –Molecular markers Treatment –Number of chemotherapy cycles –Duration

05 LUX-Lung 1: LUX-Lung 1 Miller VA et al. Lancet Oncology. 2012;13:528

06 LUX-Lung 1: Patient Population Miller VA et al. Lancet Oncology. 2012;13:528 Afatinib plus best supportive care (n=390) Placebo plus best supportive care (n=195) Age (years)58 (30-85)59 (32-82) Sex Male Female 159 (41%) 231 (59%) 78 (40%) 117 (60%) ECOG performance status (24%) 268 (69%) 30 (8%) 53 (27%) 127 (65%) 15 (8%) Ethnic origin White Eastern Asian Other Asian Other 121 (31%) 227 (58%) 38 (10%) 4 (1%) 72 (37%) 110 (56%) 12 (6%) 1 (<1%) Clinical stage (at screening) IIIB IV 15 (4%) 375 (96%) 6 (3%) 189 (97%) Smoking history Never-smoker Ex-smoker (since >1 year before diagnosis) with <15 pack-years Current or other ex-smoker 245 (63%) 27 (7%) 118 (30%) 121 (62%) 13 (7%) 61 (31%)

07 Endpoints in Clinical Trials Response rate –RECIST (Response Evaluation Criteria in Solid Tumours) Time-based outcome parameters –Survival –Disease-free survival –Relapse-free survival –Progression-free survival –Time to disease progression –Duration of response –Time to treatment failure Patient reported outcomes (PROs) –Lung cancer symptom scale Safety Cost-effectiveness

08 Endpoints in Phase III Trials Statistically significant Clinically meaningful Ocana A & Tannock I. J Natl Cancer Inst. 2011;103:16 Dependent on the clinical setting –Curative versus palliative Should reflect patient benefit –Survival –Progression-free survival plus some measure of quality of life –Symptom relief and/or quality of life

09 Aim of the Study Examples Phase III trials with superiority design –Bevacizumab trials –Cetuximab trials –Afatinib trials Phase III trials with non-inferiority design –Pemetrexed/cisplatin vs gemcitabine/cisplatin Recent developments –Phase I/II trials with response rates as primary endpoint Clinical relevance? –Master protocols with adaptive design –Risk of withholding of standard treatment (chemotherapy) Afatinib is approved in a number of markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF® and in the U.S. under the brand name GILOTRIF® for use in patients with distinct types of EGFR mutation-positive NSCLC. Registration conditions differ internationally, please refer to locally approved prescribing information. Afatinib is under regulatory review by health authorities in other countries worldwide. Afatinib is not approved in other indications.

010 AVAiL: PFS Reck M et al. J Clin Oncol. 2009;27:1227 Bevacizumab in Advanced Non-Squamous NSCLC ECOG 4599: Survival & PFS Sandler A et al. N Engl J Med. 2006;355:2542

011 Pirker R et al. Lancet. 2009;373:1525 FLEX: Overall Survival

012 LUX-Lung 3: PFS Independent Review ‒ All Randomized Patients Sequist et al. JCO 2013, 31, 3327 *

013 Cisplatin/Pemetrexed versus Cisplatin/Gemcitabine in Advanced NSCLC Scagliotti G et al. J Clin Oncol. 2008;26:3543

014 Cisplatin/Pemetrexed versus Cisplatin/Gemcitabine in Advanced NSCLC Scagliotti G et al. J Clin Oncol. 2008;26:3543 Cisplatin/pemetrexed is superior in non-squamous but inferior in squamous NSCLC compared to cisplatin/gemcitabine

015 Study Design & Study Aim To compare two arms –Superiority –Non-inferiority –Equality To demonstrate a difference of a pre-defined magnitude between the arms Sample size calculation

016 Interpretation of Clinical Outcome Point of view –Science –Investigator –Treating physician –Patient –Industry –Regulatory –Society Endpoints –Survival versus progression-free survival –Consistency –Independent review versus investigator assessment Statistically significant, clinically meaningful, risk-benefit, cost-effectiveness

017 LUX-Lung 1: Interpretation of outcome Miller VA et al. Lancet Oncology. 2012;13:528 Survival (primary endpoint) Progression-free survival HR 1.08 HR 0.38 Improved QoL

018 LUX-Lung 3 and LUX-Lung 6 Study Design Afatinib 40 mg/d b Cisplatin + Pemetrexed 75 mg/m mg/m 2 IV q21d, up to 6 cycles Stage IIIB (wet)/IV lung adenocarcinoma EGFR mutation in tumour (central lab testing; TheraScreen ® EGFR29 a RGQ PCR) Cisplatin + Gemcitabine 75 mg/m mg/m 2 D1, D8 IV q21d, up to 6 cycles Randomisation 2:1 Stratified by EGFR mutation (Del19/L858R/other) Primary endpoint: PFS (RECIST 1.1, independent review) c Secondary endpoints: OS, PRO d, ORR, DCR, DOR, tumour shrinkage, safety a EGFR29: 19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I. b Dose escalated to 50 mg if limited AE observed in cycle 1. Dose reduced by 10-mg decrements in case of related G3 or prolonged G2 AE. c Tumour assessments: q6 weeks until week 48 and q12 weeks thereafter until progression/start of new therapy. d Patient-reported outcomes: EQ-5D, EORTC QLQ-C30 and LC 13 at randomisation and q3 weeks until progression or new anticancer therapy. Note: 24 patients in LUX-Lung 3 and 28 patients in LUX-Lung 6 were still on treatment as of December RGQ = rotor-gene Q; PCR = polymerase chain reaction; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumours; ORR = objective response rate; DCR = disease control rate; DOR = duration of response; OS = overall survival. 1. Sequist et al. J Clin Oncol. 2013;31:3327; 2. Wu et al. Lancet Oncol. 2014;15:213. LUX-Lung 3 1 (n=345) LUX-Lung 6 2 (n=364; Asian pts)

019 LUX-Lung 3: PFS Independent review ‒ all randomized patients Sequist et al. JCO 2013, 31, 3327 *

020 LUX-Lung 6: PFS§ Wu Y-L et al. Lancet Oncology 2014 § Independent review

021 LUX-Lung 3: Quality of life Yang JC-H et al. J Clin Oncol. 2013;31:3342

022 LUX-Lung 3: Quality of life Yang JC-H et al. J Clin Oncol. 2013;31:3342 ACough BDyspnoea CPain ** *

023 Combined OS Analysis of LUX-Lung 3 and 6: Common Mutations (n=631) Presented by: James Chih-Hsin Yang Afatinib n=419 Chemo n=212 Median, months HR (95%CI), p-value 0.81 (0.66–0.99), p= Estimated OS probability Time (months) Afatinib Chemo No of patients

024 Combined OS Analysis of LUX-Lung 3 & 6: Mutation Categories Presented by: James Chih-Hsin Yang Estimated OS probability Time (months) Estimated OS probability Time (months) Afatinib Chemo No of patients Afatinib Chemo No of patients Del19 Afatinib n=236 Chemo n=119 Median, months HR (95%CI), p-value 0.59 (0.45–0.77), p= L858R Afatinib n=183 Chemo n=93 Median, months HR (95%CI), p-value 1.25 (0.92–1.71), p=0.1600

025 LUX-Lung 3 & LUX-Lung 6 Strengths –Second generation TKI broader activity, irreversible binding –Well designed studies Molecularly selected patients Comparison with cisplatin-based chemotherapy –PFS prolongation & symptom relief (QoL benefit) –Survival benefit (del exon 19) –Consistency of results Concerns –Increased adverse events (diarrhea, skin rash) –Costs?

026 Independent Review: A Waste of Resources? Blinded independent central review might not be of help Dodd LE et al. J Clin Oncol. 2008;26:3791 HR 0.38 vs 0.37HR 0.58 vs 0.49HR 0.28 vs 0.26 LUX-Lung 1LUX-Lung 3LUX-Lung 6

027 Clinical outcome Statistical significance versus clinical meaningfulness Examples

028 ECOG 4599: Survival & PFS Sandler A et al. N Engl J Med. 2006;355:2542 Bevacizumab in Advanced Non-Squamous NSCLC AVAiL: PFS Reck M et al. J Clin Oncol. 2009;27:1227

029 Selection based on ICH HR 0.87 FLEX: Survival Pirker R et al. Lancet. 2009;373:1525 BMS 099: Survival Lynch T et al. J Clin Oncol. 2010;28;911 Cetuximab Phase III Trials No selection HR 0.89

030 HR 0.84 (95% CI ) INSPIRE: Survival Paz-Ares L et al. Lancet Oncology Necitumumab: Phase III Trials SQUIRE: Survival Thatcher N et al. Lancet Oncology HR 1.01 (95% CI )

031 PLEN04.02: Discussant - Robert Pirker, Austria Hazard ratioP value Cetuximab FLEXITT0.87 ( )0.04 BMS099 ITT0.89 ( )NS Meta-Analysis ITT0.88 ( )0.009 Adeno0.94 ( ) Squamous0.77 ( ) Other0.88 ( ) Necitumumab SQUIRE Squamous0.84 ( ) 0.01 INSPIREAdeno1.01 ( ) NS Pirker R et al. Lancet. 2009;373:1525; Lynch TJ et al. J Clin Oncol. 2010;28:911; Pujol JL et al. Lung Cancer. 2014; 83:211; Thatcher N et al. Lancet Oncol. 2015;16:763; Paz-Ares L et al. Lancet Oncol. 2015;16:328. 1st line Chemotherapy ± EGFR Antibodies: Survival

032 PLEN04.02: Discussant - Robert Pirker, Austria Pirker R et al. Lancet Oncol. 2012;13:33 HR 0.99 (95% CI ) HR 0.73 (95% CI ) Interaction P value=0.044 Low and High EGFR Expression in FLEX

033 PLEN04.02: Discussant - Robert Pirker, Austria Hazard ratio Cetuximab Meta-Analysis Squamous 0.77 ( ) FLEX ITTHigh H score 0.73 ( ) SquamousHigh H score 0.62 ( ) AdenoHigh H score 0.74 ( ) SWOG S0819 ITTFISH positive 0.83 ( ) SquamousFISH positive 0.56 ( ) Necitumumab SQUIRE SquamousITT 0.84 ( ) High H score 0.75 ( ) FISH positive 0.70 ( ) Survival Based on Biomarkers

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