Optimizing EGFR TKI Therapy in NSCLC Clinical, pharmacokinetic and molecular features

1. Optimizing EGFR TKI Therapy in NSCLCClinical, pharmacokinetic and molecular features Roman Perez-Soler, M.D. Albert Einstein College of Medicine New York

2. EGFR InhibitorsAre they curing anybody?

3. EGFR Activating MutationsPredictive, Prognostic or Both ? Predictive for reponse to EGFR TKI�s: Yes Predictive for PFS with EGFR TKI�s: Yes Predictive, prognostic, or both for survival with EGFR TKI�s: ???

4. EGFR TKIs:molecular structure

5. Erlotinib : Not rationally designed, selected by screening Structural differences may affect affinity for wt EGFR and its mutant variants plasma, tumour and normal tissue distribution metabolism in-vitro activity clinical efficacy and toxicity

6. Erlotinib is little lipophilic http://books.google.com/books?id=U79HAISvKQQC&pg=PA560&lpg=PA560&dq=drug+lipophilicity+consequence&source=web&ots=gXRmNhmqya&sig=V4JSss2T7iLfHZ85hx-GFywlSmg&hl=en&sa=X&oi=book_result&resnum=1&ct=result#PPA559,M1http://books.google.com/books?id=U79HAISvKQQC&pg=PA560&lpg=PA560&dq=drug+lipophilicity+consequence&source=web&ots=gXRmNhmqya&sig=V4JSss2T7iLfHZ85hx-GFywlSmg&hl=en&sa=X&oi=book_result&resnum=1&ct=result#PPA559,M1

7. Activity of major metabolites

8. Potency in vitro for Erlotinib

9. Erlotinib is a potent inhibitor of mutant EGFR

10. Erlotinib: pharmacokinetic profile

11. Exposure to Erlotinib is greater at standard dosing Erlotinib is administered at a dose close to the maximum tolerated dose

12. At recommended dose, Erlotinib free drug concentrations show sufficient exposure for inhibition of wild-type and mutant EGFR Liu J, Karlsson MO, Brahmer J, et al. CYP3A Phenotyping Approach to Predict Systemic Exposure to EGFR Tyrosine Kinase Inhibitors. J Natl Cancer Inst 2006:98:1714-23 Figure 1e (page 1718)Liu J, Karlsson MO, Brahmer J, et al. CYP3A Phenotyping Approach to Predict Systemic Exposure to EGFR Tyrosine Kinase Inhibitors. J Natl Cancer Inst 2006:98:1714-23 Figure 1e (page 1718)

13. Erlotinib:clinical results Response of EGFR WT NSCLC to EGFR TKIs

14. Pivotal BR.21 study: trial design Primary endpoint: overall survival (OS) Secondary endpoints: progression-free survival (PFS), response rate (RR), safety, quality of life (QoL), duration of response

15. BR.21: significantly improved survival with Erlotinib

16. All patient subgroups derive an OS benefit from Erlotinib: BR.21 study

17. BR.21: Erlotinib is effective in EGFR WT disease

18. SATURN: improved PFS and OS* with Erlotinib

19. BeTa LUNG: PFS in EGFR WT disease

20. Summary: Erlotinib in EGFR WT disease Erlotinib has proven survival benefits in EGFR WT NSCLC Several controlled clinical trials (BR.21, SATURN and BeTa LUNG) demonstrate that Erlotinib has statistically proven efficacy in patients with EGFR WT disease

21. BR.21: could rash be a positive sign for clinical benefit?

22. SummaryErlotinib Molecular and pharmacokinetic differences may explain in part erlotinib efficacy At the recommended doses, erlotinib results in increased exposure levels allowing inhibition of both mutant and wild-type EGFR Erlotinib shows a statistically significant efficacy in patients with wt EGFR Increased rash with erlotinib may be associated with improved clinical outcomes

23. Comparing Erlotinib vs. gefitinib: pooled analysis of patients with EGFR MUT+ disease

24. Possible explanations for the suggested efficacy of erlotinib in mutated tumors

25. Erlotinib binds to the same site of the kinase domain of EGFR as ATP Erlotinib binds much tighter to wt EGFR than ATP, this prevents the phosphorylation, and the signaling cascade cannot start How erlotinib inhibits EGFR

26. Dose intensity No data available on the rash/survival relationship in patients with EGFR mutations If such relationship exists, it would favor that dose intensity is important also in this patient population

27. Delayed emergence of resistance

28. Acquired resistance to erlotinib in EGFR mutated tumors Emergence and predominance of tumor clones carrying theT790 second mutation which has a much higher affinity for ATP A drug used at a higher dose intensity will more effectively compete for ATP Activation of alternative signaling pathways which signal through HER3: cMET (receptor and/or ligand) Other: switch to wt EGFR for tumor growth (non-mutated allele) ?? A drug with effect on wt EGFR would be able to avoid this mechanism

29. T790 Mutations Does not appear to confer tumor virulence (not present in untreated patients) Confers resistance if majority clone as a result of selection pressure (intermittent administration of erlotinib may be more effective by allowing the sensitive clones to reemerge)

30. Treatment of Tumors with T790 as Predominant Clone Main ennemy is ATP high affinity Maximize efficacy by increasing dose, pulse administration, use of drug with higher affinity for T790, use of irreversible inhibitor Because T790 has lower virulence, intermittent administration should allow reemergence of sensitive clones

31. Characteristics of ideal EGFR TKI in the face of emerging resistance to TKI�s in EGFR mutated tumors Higher affinity than ATP for wt EGFR and its mutated variants (broad spectrum) Used at maximum tolerated dose Maximize tumor drug levels Intermittent administration (to allow sensitive clones to re-emerge)