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

2. 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

3. 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

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

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

6. 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

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

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

9. 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

10. Danger
Zone

11. Trial Comparisons Ahead
Cross
Trial Comparisons Ahead

12. 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

13. 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

14. 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

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

16. Afatinib Activity Against EGFR T790M
Li et al, Oncogene 2008

17. Afatinib Activity Against EGFR T790M
Li et al, Oncogene 2008

18. 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

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

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

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

22. 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 - ?

23. 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)

24. Soria et al, WCLC 2013

25. CO-1686
Soria et al, WCLC 2013

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

27. AZD9291
Ranson et al, WCLC 2013

28. CO-1686
Soria et al, WCLC 2013

29. AZD9291
Ranson et al, WCLC 2013

30. 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