COOL - Community in Oncology On Lung Cancer http://www.esanum.it/cool

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Afatinib BIBW 2992
LUX-Lung 1: Rationale
Presence of EGFR-activating mutation in NSCLC
confers exquisite sensitivity to EGFR TKIs
Patients initially sensitive to gefitinib (G) or
erlotinib (E) eventually progress
Resistance T790M mutations are detected in ~50%
of patients previously responsive to
gefitinib/erlotinib
Afatinib 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
Randomization
2 : 1
Oral BIBW 2992 50 mg once daily
plus best supportive care
Oral placebo once daily
plus best supportive care
N=585
Patients 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, Asia
Status: 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
Afatini
b (%)
Placeb
o
(%)
Afatini
b (%)
Placebo
(%)
PR, regardless of
confirmation
PR, confirmed
13.3*
7.4
0.5**
0.5
14.1
10.8
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

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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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1.077
1.168
1.020
1.109
1.005
1.056
1.152
1.160
1.034
1.023
1.200
2.188
0.806
1.016
1.154
1.243
1.035
1.196
0.882
1.103
1.069
0.898
1.190
Hazard ratio
OS by
subgroups

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Sopravvivenza e ulteriori trattamenti
Nessun trattamento ulteriore Ulteriori trattamenti

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Conclusions 1
Patient population was enriched as intended
LUX-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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