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Afatinib BIBW 2992LUX-Lung 1: Rationale

Presence of EGFR-activating mutation in NSCLC confers exquisite sensitivity to EGFR TKIsPatients initially sensitive to gefitinib (G) or erlotinib (E) eventually progressResistance T790M mutations are detected in ~50% of patients previously responsive to gefitinib/erlotinibAfatinib is an irreversible EGFR and HER2 inhibitor with preclinical activity against NSCLC with T790M mutations (EC50: 99 nM, NCI-1975)No approved therapy available for locally advanced or metastatic NSCLC in patients who have failed CT and progressed after treatment with EGFR TKI

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Trial design

Randomization2 : 1

Oral BIBW 2992 50 mg once daily plus best supportive care

Oral placebo once daily plus best supportive care

N=585Patients with:• Adenocarcinoma of the lung • Stage IIIB/IV • Progressed after one or two lines of chemotherapy (incl. one platinum-

based regimen) and ≥12 weeks of treatment with erlotinib or gefitinib• ECOG 0–2

Primary endpoint: Overall survival (OS)Secondary: PFS, RECIST response, QoL, safety

Countries: North America, Europe, AsiaCountries: North America, Europe, AsiaStatus: Recruitment complete, DBL for primary analysis 6 July 2010Status: Recruitment complete, DBL for primary analysis 6 July 2010Countries: North America, Europe, AsiaCountries: North America, Europe, AsiaStatus: Recruitment complete, DBL for primary analysis 6 July 2010Status: Recruitment complete, DBL for primary analysis 6 July 2010

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Demographics/prior treatment

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Disease control rate and objective responses

Independent

Investigator

Afatinib (%)

Placebo

(%)

Afatinib (%)

Placebo

(%)

PR, regardless of confirmationPR, confirmed

13.3*7.4

0.5** 0.5

14.110.8

0.5 0.5

SD 50.8 17.9 49.7 21.0

DCR (CR+PR+SD), confirmed

58.2 18.5 60.5 21.5

Median duration of response: 6 monthsMedian duration of response: 6 months

* P < 0.01 compared to placebo** P < 0.0001 compard to placebo* P < 0.01 compared to placebo** P < 0.0001 compard to placebo

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Waterfall plots by independent review

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PFS by independent review

Importante vantaggio sull’aumento del PFSImportante vantaggio sull’aumento del PFS

HR = 0.38

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PFS by subgroups

Hazard ratio

← Favors afatinib Favors placebo →

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Overall survival

Nessun vantaggio in sopravvivenza

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1.0771.1681.0201.1091.0051.0561.1521.1601.0341.0231.2002.1880.8061.0161.1541.2431.0351.1960.8821.1031.0690.8981.190

Hazard ratio

OS by subgroups

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Sopravvivenza e ulteriori trattamentiNessun trattamento ulterioreNessun trattamento ulterioreUlteriori trattamentiUlteriori trattamenti

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Conclusions 1Patient population was enriched as intendedLUX-Lung 1 did not meet its primary endpoint of overall survival

Unprecedented survival in both trial arms Considerable and unexpected use of further systemic treatments

Afatinib significantly improved progression

free survival (HR = 0.38)2 months absolute increase in median PFS

Robust effect across all subgroups

Seen with both independent and investigator

assessments

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Conclusions 2

Significantly higher ORR and DCR on afatinib

Clinically relevant improvement in pre-specified lung cancer related symptoms in the afatinib arm

Safety profile of afatinib as expected: Diarrhea and rash managed effectively by dose interruption/reduction

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