Emerging Algorithm for Optimal Sequencing of EGFR TKIs in EGFR Mutation Positive NSCLC

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1 Emerging Algorithm for Optimal Sequencing of EGFR TKIs in EGFR Mutation Positive NSCLC Keunchil Park, MD, PhD Samsung Medical Center, Sungkyunkwan University School of Medicine

2 Faculty Disclosure Consulting or Advisory Role: Astellas Pharma; AstraZeneca; Boehringer Ingelheim; Clovis Oncology; Hanmi; Kyowa Hakko Kirin; Lilly; Novartis; Ono Pharmaceutical; Roche Speakers' Bureau: Boehringer Ingelheim Research Funding: AstraZeneca 2

3 Key Factors in First-line EGFR TKI Selection Sequence makes survival Not all TKIs are equal Drug-drug interactions Efficacy Adverse event profile 3

4 Key Factors in First-line EGFR TKI Selection Sequence makes survival Not all TKIs are equal Drug-drug interactions Efficacy Adverse event profile 4

5 The Family of EGFR TKIs Wild-type EGFR Intrinsic mutant EGFR ErbB heterodimers (eg, Her2: ErbB3) Acquired T790M EGFR K K K K K K K Erlotinib Gefitinib 1st-generation TKI EGFR inhibition Activity range Reversible binding to wild-type and mutant EGFR Inactive on T790M mutant Afatinib Dacomitinib 2nd-generation TKI ErbB Family blockade Activity range Irreversible covalent binding to EGFR, ErbB2 and ErbB4 to inhibit all ErbB Family signalling Broader activity to overcome EGFR TKI resistant mutations Osimertinib 3rd-generation TKI EGFR mutant specific inhibitor Activity Specificity for EGFR T790M mutant; EGFR wild-type sparing Irreversible covalent binding to mutant EGFR Range K Kinase domain Liao et al. Curr Opin Oncol. 2015;27:94. 5

6 IC 50 (nm) Activity of First-, Second-, and Third-Generation EGFR TKIs Against EGFR Mutations T790M Wild-type Wild-type T790M 1 EGFRm Wild-type EGFRm EGFRm T790M Gefitinib Afatinib Osimertinib Wild-type EGFR T790M EGFR mutant: L858R, exon 19 del IC 50 = half-maximal inhibitory concentration. Li et al. Oncogene. 2008;27:4702; Cross et al. Cancer Discov. 2014;4:1046; Hirano et al. Oncotarget. 2015;6:

7 Key Factors in First-line EGFR TKI Selection Sequence makes survival Not all TKIs are equal Drug-drug interactions Efficacy Adverse event profile 7

8 months First- and Second-Generation EGFR TKIs Are Standard for First-line Treatment of NSCLC With Common EGFR Mutations Better PFS vs platinum-based chemotherapy a a EURTAC ENSURE OPTIMAL WJTOG NJE002 IPASS LL3 LL6 EURTAC ENSURE OPTIMAL WJTOG NJE002 IPASS LL3 LL6 Erlotinib Gefitinib a Afatinib Platinum-based chemotherapy a PFS not reported for common mutations only. NSCLC = non small cell lung cancer. Chen et al. Ann Oncol. 2013;24:1615; Gefitinib Summary of Product Characteristics 2010; Han et al. J Clin Oncol. 2012;30:1122; Maemondo et al. N Engl J Med. 2010;362:2380; Mok et al. N Engl J Med. 2009;361:947; Mitsudomi et al. Lancet Oncol. 2010;11:121; Rosell et al. Lancet Oncol. 2012;13:239; Sequist et al. J Clin Oncol. 2013;31:3327; Wu et al. Lancet Oncol. 2014;15:213; Wu et al. Ann Oncol. 2015;26:1883; Zhou et al. Lancet Oncol. 2011;8:735. 8

9 First- and Second-Generation EGFR TKIs Are Not Equal: Response Rate and PFS in LUX-Lung 7 LUX-Lung 7: Afatinib vs Gefitinib Park et al. Lancet Oncol. 2016;17:577; Corral et al. ELCC Abstract 93PD. 9

10 First- and Second-Generation EGFR TKIs Are Not Equal: PFS in ARCHER 1050 ARCHER 1050: Dacomitinib vs Gefitinib (excluding CNS metastases) CNS = central nervous system; ITT = intent-to-treat; CI, confidence interval. Mok et al. ASCO Abstract LBA

11 First and Third-Generation EGFR TKIs Are Not Equal: PFS in FLAURA FLAURA: Osimertinib vs Gefitinib or Erlotinib 11 Ramalingam et al. ESMO Abstract LBA2.

12 Key Factors in First-line EGFR TKI Selection Sequence makes survival Not all TKIs are equal Drug-drug interactions Efficacy Adverse event profile 12

13 Safety Second- or Third-Generation TKIs vs First-Generation TKIs LUX-Lung 7 1,2 ARCHER FLAURA 4 Afatinib (n=160) Gefitinib (n=159) Dacomitinib (n=227) Gefitinib (n=225) Osimertinib (n=279) Treatment discontinuation rate 6.3% 6.3% 9.7% 6.6% 13.0% (any) Most common grade 3 AEs Diarrhoea: 12% Rash/acne: 9% Liver enzyme elevation: 9% Rash/acne: 3% Acne: 14% Diarrhoea: 9% Paronychia: 8% Liver enzyme elevation: 9% Paronychia: 1% Diarrhoea: 2% Decreased appetite: 3% 1. Park et al. Lancet Oncol. 2016;17:577; 2. Paz-Ares et al. Ann Oncol. 2017;28:270; 3. Mok et al. ASCO Abstract LBA9007; 4. Ramalingam et al. ESMO Abstract LBA2. 13

14 Dose Reduction of Afatinib Reduced Drug-Related AEs Without Compromising Efficacy PFS = progression-free survival; HR = hazard ratio; CI = confidence interval. Hirsch V, et al. ASCO 2016 poster presentation:

15 Key Factors in First-line EGFR TKI Selection Sequence makes survival Not all TKIs are equal Drug-drug interactions Efficacy Adverse event profile 15

16 DDIs of First-, Second-, and Third-Generation EGFR TKIs Enzymes Involved in the Metabolism of Oral EGFR TKIs Drug Metabolised by CYP Enzymes 3A4 3A5 2D6 1A1 1A2 1B1 2C8 2C9 May Inhibit May Induce Gefitinib Erlotinib CYP2C19 (w) CYP2D6 (w) UGT1A9, BRCP CYP3A4 (m) CYP2C8 (m) CYP1A1 (s) UGT1A1 (s) CYP1A1 CYP1A2 Afatinib Dacomitinib CYP2D6 (s) Osimertinib BCRP CYP3A4 CYP1A2 CYP2C DDI = drug-drug interaction; CYP = cytochrome P450 enzyme; BCRP = breast cancer resistance protein; UGT = UDP-glycosyltransferase. Cross et al. Cancer Discov. 2014;4:1046; Li et al. Oncogene. 2008;27:4702; Peters et al. Cancer Treat Rev. 2014;40:917; TAGRISSO Prescribing Information. March

17 Key Factors in First-line EGFR TKI Selection Sequence makes survival Not all TKIs are equal Drug-drug interactions Efficacy Adverse event profile 17

18 OS With Afatinib in EGFR-Mutant NSCLC Common Mutations (del19/l858r) (n=307) a Only 6 patients in the afatinib arm were treated with osimertinib because of lack of availibility (trial recruitment was from August 2009 to February 2011). NSCLC = non small cell lung cancer. Yang et al. Lancet Oncol. 2015;16:

19 Molecular Mechanisms of Acquired Resistance to First-/Second-Generation EGFR TKIs Yu HA et al. Clin Cancer Res. 2013;19:

20 OS in Patients Treated With Third-Generation TKIs Subsequently in LUX-Lung 7 20%/17% who discontinued afatinib/gefitinib received third-generation TKIs (osimertinib, olmutinib, rociletinib) NE = not estimable. Corral et al. ELCC Abstract 93PD. 20

21 Treatment Sequences in EGFR-Mutant NSCLC After First-line EGFR TKI 1st-/2nd-generation TKI T790M + T790M - Osimertinib Chemotherapy Chemotherapy Except if molecular target 1st-/2nd-generation TKI Other MET/HER2 inhibitor Osimertinib Chemotherapy Except if molecular target NEED MATURE OS AND TREATMENT SEQUENCES FROM AURA3 and FLAURA (med PFS = 18.9 months) 21

22 Key Factors in First-line EGFR TKI Selection Sequence makes survival Not all TKIs are equal Drug-drug interactions Efficacy Adverse event profile 22

23 Questions?