Beyond Erlotinib: Better EGFR Inhibitors? Gregory J. Riely Memorial Sloan-Kettering Cancer Center

An “Optimal” EGFR TKI Efficacy in EGFR mutant cancer Better than chemotherapy Fewest associated adverse events Targets mechanisms of acquired resistance Effective against clinical acquired resistance

An “Optimal” EGFR TKI Erlotinib Afatinib Efficacy in EGFR mutant cancer Better than chemotherapy Fewest associated adverse events Targets mechanisms of acquired resistance Effective against clinical acquired resistance

Erlotinib Demonstrates Efficacy in EGFR Mutant Lung Cancers Rosell et al, Lancet Oncol 2012

Erlotinib is Better Than Chemotherapy in EGFR Mutant Lung Cancers Rosell et al, Lancet Oncol 2012

An “Optimal” EGFR TKI Erlotinib Afatinib Efficacy in EGFR mutant cancer X Better than chemotherapy Fewest associated adverse events Targets mechanisms of acquired resistance Effective against clinical acquired resistance

Afatinib is Effective in Patients with EGFR Mutant Lung Cancers L858R Exon 19 Deletion Yang et al, Lancet Oncol 2012

Afatinib is Better Than Cisplatin/Pemetrexed in Patients with EGFR Mutant Cancers Yang JC, et al. Sequist et al J Clin Oncol 2013

An “Optimal” EGFR TKI Erlotinib Afatinib Efficacy in EGFR mutant cancer X Better than chemotherapy Fewest associated adverse events Targets mechanisms of acquired resistance Effective against clinical acquired resistance

Danger Zone

Trial Comparisons Ahead Cross Trial Comparisons Ahead

Comparing EGFR TKI Erlotinib Afatinib N= 86 229 RR (%) 58% 56% Median PFS (mo) 10 mo 11 mo Median OS (mo) 19 mo NR Rosell, Lancet Oncol 2012; Sequist J Clin Oncol 2013

Comparing EGFR TKI Erlotinib Afatinib N= 86 229 Grade 3+ Rash 13% 16% Grade 3+ Diarrhea 5% 14% Grade 3+ Paronychia NR 11% Rosell, Lancet Oncol 2012; Sequist J Clin Oncol 2013

An “Optimal” EGFR TKI Erlotinib Afatinib Efficacy in EGFR mutant cancer X Better than chemotherapy Fewest associated adverse events ? Targets mechanisms of acquired resistance Effective against clinical acquired resistance

Pao et al, PLoS Medicine 2005, Yu et al CCR 2013

Afatinib Activity Against EGFR T790M Li et al, Oncogene 2008

Afatinib Activity Against EGFR T790M Li et al, Oncogene 2008

An “Optimal” EGFR TKI Erlotinib Afatinib Efficacy in EGFR mutant cancer X Better than chemotherapy Fewest associated adverse events Targets mechanisms of acquired resistance Effective against clinical acquired resistance

Afatinib in Acquired Resistance to Erlotinib/Gefitinib Miller et al, Lanct Oncol 2012

Afatinib in Acquired Resistance to Erlotinib/Gefitinib Miller et al, Lanct Oncol 2012

Afatinib in Acquired Resistance OS in patients who had no subsequent therapy Miller et al Lancet Oncol 2012

An “Optimal” EGFR TKI Erlotinib Afatinib Efficacy in EGFR mutant cancer X Better than chemotherapy Fewest associated adverse events Targets mechanisms of acquired resistance Effective against clinical acquired resistance - ?

Mutation-targeted EGFR inhibitors Developed to target EGFR T790M, EGFR exon 19 deletion, EGFR L858R Little wild-type EGFR inhibitory activity (i.e. less rash and diarrhea)

Soria et al, WCLC 2013

CO-1686 Soria et al, WCLC 2013

AZD9291 has Activity Against Xenograft Model of L858R/T790M Ranson et al, WCLC 2013

AZD9291 Ranson et al, WCLC 2013

CO-1686 Soria et al, WCLC 2013

AZD9291 Ranson et al, WCLC 2013

Conclusions Erlotinib and Afatinib have similar efficacy and adverse event profile None of the currently approved EGFR TKI adequately target clinical acquired resistance 3rd Generation EGFR TKI that are mutation specific have significant promise