afatinib bibw 2992 nov 2010
DESCRIPTION
COOL - Community in Oncology On Lung Cancerhttp://www.esanum.it/coolTRANSCRIPT
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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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