IMPORTANT PATHWAYS TO TARGET IN (ADVANCED) NSCLC:

Transcription

1 IMPORTANT PATHWAYS TO TARGET IN (ADVANCED) NSCLC: A focus on EGFR-inhibition and implications for clinical practice Floriana Morgillo, MD PhD and Morena Fasano, MD PhD Faculty of Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples Italy

2 ESMO RECOMMENDATIONS DIAGNOSIS AND PERSONALISED MEDICINE FOR NSCLC Novello S, et al D Angelo SP, et al. J Clin Oncol 2011.

3 EGFR TKIS ROLE IN EGFR MUTATION NSCLC PATIENTS

4 EGFR MUTATIONS: FIRST OBSERVED IN 2004 Lynch TJ, et al (New Eng J Med 350: ) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib Paez JG, et al (Science 304: ) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy Mitsudomi T, et al. J Clin Oncol 23 (11), 2005: Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence Sensitive mutations Resistant mutations G719X (3%) VAIKEL insertion (1%) LREA deletion (45%) L858R (40%) L861X (2%) Exon 18 Exon 19 Exon 20 Exon 21 L747S T790M D761Y T854A Exon 20 insertion (4%) Histology: Adenocarcinoma Well-differentiated Asian Young Women Ohashi K, et al. J Clin Oncol 2013.

5 TIMELINE OF EGFR TKIS AND DEVELOPMENT OF DIFFERENT GENERATIONS OF EGFR TKIS Gandhi L, et al. Clin Cancer Res 2012;18(14):

6 SELECTION OF FIRST-LINE THERAPY FOR PATIENTS WITH EGFR MUTATION- POSITIVE NSCLC

7 1ST LINE EGFR TKIS VS. CT: PHASE 3 TRIALS Trial (n) TKI Chemo Mutation mpfs (TKI vs. C), p PFS HR (95%CI) ORR (TKI vs. C) OS (TKI vs. C) IPASS (n=261) Gefitinib Carbo-Paclitaxel All 9.5 vs. 6.3; p< ( ) 71 vs vs. 22 First Signal (n=42) Gefitinib Cis- Gem All 8.0 vs. 6.3 p< ( ) 84.6 vs NEJ002 (n=230) Gefitinib Carbo-Paclitaxel L858R Ex19D 10.8 vs. 5.4; p< ( ) 74 vs vs. 24 WJTOG 3405 (n=172) Gefitinib Cis-Doce L858R Ex19D 9.2 vs. 6.3; p< ( ) 62 vs vs. 39 OPTIMAL (n=165) Erlotinib Carbo-Gem L858R Ex19D 13.1 vs. 4.6; p< ( ) 83 vs. 36 N EURTAC (n=174) Erlotinib Cis/Carbo- Doce/Gem L858R Ex19D 9.7 vs. 5.2; p< ( ) 58 vs vs. 19) LUX-3 (n=345) Afatinib Cis-Pem All L858R Ex19D 11.1 vs. 6.9; p= vs. 6.9; P= ( ) 0.47 ( ) 56 vs vs. 28 LUX-6 (n=242) Afatinib Cis-Gem All 11.0 vs. 5.6; p=< ( ) 67 vs vs. 24 Mok T, et al. N Engl J Med 2009; Fukuoka T, et al. J Clin Oncol 2011; Han JY, et al. J Clin Oncol 2012; Maemondo M, et al. N Engl J Med 2010; Mitsudomi T, et al. Lancet Oncol 2010; Zhou C, et al. Lancet Oncol 2011; Rosell R, et al. Lancet Oncol 2012; Sequist L, et al. J Clin Oncol 2013; Wu YL, et al. Lancet Oncol 2014.

8 PFS WITH TKIS BETTER FOR DEL19 THAN L858R PFS with TKIs better for del19 than L858R Del19 HR: 0.24 L858R HR: 0.48 p for interaction <0.001 Lee CK, et al. J Clin Oncol 33(17), 2015: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

9 PFS Mok T, et al. N Engl J Med 2009; Inoue A, et al. Ann Oncol 2013; 24:54-59; Rosell R, et al. Lancet Oncol 2012; 13: ; Wu YL, et al. Ann Oncol 2015; 26: ; Yang JC, et al. J Clin Oncol 2013; 20;31(27): ; Yang JC, et al. Lancet Oncol 2015; 16:

10 SECOND GENERATION EGFR-TKI: AFATINIB DACOMITINIB

11 SECOND GENERATION EGFR-TKI: AFATINIB DACOMITINIB

12 AFATINIB OS in Del 19 Subgroup Reprinted from Lancet Oncol, 16(2), Yang JCH, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials, Copyright 2015, with permission from Elsevier.

13 COMBINED OS ANALYSIS: MUTATION CATEGORIES Del19 L858R Reprinted from Lancet Oncol, 16(2), Yang JCH, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials, Copyright 2015, with permission from Elsevier..

14 HR FOR OS IN DEL19 Afatinib Study or subgroup HR (95% CI) LUX-Lung (0.36, 0.79) LUX-Lung (0.44, 0.94) Total 0.59 (0.45, 0.77) Erlotinib Study or subgroup HR (95% CI) ENSURE 0.79 (0.48, 1.30) EURTAC 0.94 (0.57, 1.54) OPTIMAL 1.52 (0.91, 2.52) Total 1.04 (0.71, 1.51) Favours afatinib Favours chemotherapy Gefitinib Study or subgroup HR (95% CI) IPASS 0.86 (0.61, 1.22) NEJ (0.52, 1.34) WJTOG (0.65, 2.18) Total 0.90 (0.70, 1.17) Favours erlotinib Favours chemotherapy Favours gefitinib Favours chemotherapy Kato T, et al. ISPOR 18th Annual European Congress 2015; PCN40.

15 COMBINED OS ANALYSIS: MUTATION CATEGORIES Del19 L858R Reprinted from Lancet Oncol, 16(2), Yang JCH, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials, Copyright 2015, with permission from Elsevier.

16 TRIALS Trial OS HR (95% CI) Crossover from CT to TKI LUX-Lung 3 1 Del19 L858R 0.54 ( ) 1.30 ( ) 75% LUX-Lung 6 2 Del19 L858R IPASS 3 5 Del19 L858R NEJ002 6,7 Del19 L858R WJTOG Del19 L858R EURTAC 9,10 Del19 L858R OPTIMAL 11 Del19 L858R ENSURE 12 Del19 L858R Favours TKI Favours chemotherapy 0.64 ( ) 1.22 ( ) 0.79 ( ) 1.44 ( ) 0.83 ( ) 0.82 ( ) NA NA 0.94 ( ) 0.99 ( ) NA NA NA NA 53% 52% 95% 76% Adapted from West J, ASCO 2014.

17 HR FOR OS IN L858R Afatinib Study or subgroup HR (95% CI) LUX-Lung (0.80, 2.11) LUX-Lung (0.81, 1.83) Total 1.25 (0.91, 1.71) Erlotinib Study or subgroup HR (95% CI) ENSURE 1.05 (0.60, 1.84) EURTAC 1.00 (0.56, 1.79) OPTIMAL 0.92 (0.55, 1.54) Total 0.98 (0.72, 1.35) Gefitinib Study or subgroup HR (95% CI) IPASS 1.40 (0.91, 2.15) NEJ (0.49, 1.38) WJTOG (0.60, 2.05) Total 1.11 (0.81, 1.54) 0.1 Favours afatinib 1 10 Favours chemotherapy 0.1 Favours erlotinib 1 10 Favours chemotherapy Favours gefitinib Favours chemotherapy Kato T, et al. ISPOR 18th Annual European Congress 2015; PCN40.

18 SECOND GENERATION EGFR-TKI: AFATINIB DACOMITINIB

19 SECOND GENERATION EGFR-TKI: AFATINIB DACOMITINIB

20 DACOMITINIB ARCHER 1009 Dacomitinib vs. erlotinib in pre-treated patients 1 BR.26 Dacomitinib vs. placebo in pre-treated patients 2 1. Reprinted from Lancet Oncol, 15(1 2), Ramalingam SS, et al. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial, Copyright 2014, with permission from Elsevier. 2. Reprinted from Lancet Oncol, 15(12), Ellis PM, et al. Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial, Copyright 2014, with permission from Elsevier.

21 ARCHER 1009 PFS for independent review for all patients (A) and patients with KRAS WT (B) OS for all patients (A) and patients with KRAS WT (B) NEGATIVE TRIAL Reprinted from Lancet Oncol, 15(1 2), Ramalingam SS, et al. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial, Copyright 2014, with permission from Elsevier.

22 EGFR MUTATION: TREATMENT OPTIONS

23 ARCHER 1050: PHASE III TRIAL OF DACOMITINIB VS. GEFITINIB Patients with Advanced Adenocarcinoma NSCLC Documented common EGFR mutations (del19 or L858R ± T790M) First line (no prior treatment) PS 0-1 N = 440 Randomization Dacomitinib 45 mg Gefitinib 250 mg Primary endpoint: PFS Wu YL, et al. Lancet Oncol. 2017;18:

24 ARCHER 1050: PFS (ITT POPULATION) Reprinted from The Lancet Oncol, 18, Wu YL, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial, , Copyright 2017, with permission from Elsevier.

25 PHASE III STUDY (WJOG 5108L): GEFITINIB VS. ERLOTINIB Urata Y, et al. J Clin Oncol 34(27), 2016: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

26 LUX LUNG 7: PHASE IIB TRIAL OF AFATINIB VS. GEFITINIB Patients with Advanced lung adenocarcinoma Documented common EGFR mutations (del19 or L858R) First line (no prior treatment) PS 0-1 N = 264 Randomization Afatinib 40 mg Gefitinib 250 mg Primary endpoint: PFS and disease control rate at 12 months Park K, et al. Lancet Oncol 2016.

27 AFATINIB VS. GEFITINIB IN PATIENTS WITH EGFR MUT+NSCLC Del 19 megfr Afatinib Gefitinib N ORR 73% 66% Median PFS 12.7 mo mo. HR 0.76 ( ) L858R megfr Afatinib Gefitinib N ORR 66% 42% Median PFS 10.9 mo mo. HR 0.71 ( ) Overall population Afatinib (n=160) Gefitinib (n=159) HR (95%CI) p-value Median 0S 27.9 mo mo (0.66, 1.12)

28 COMBO TREATMENTS ERLOTINIB + BEVACIZUMAB: EGFR NSCLC (PHASE IIR) Best RECIST (Response Evaluation Criteria in Sold Tumours) response, as determined by independent review committee Erlotinib + Bevacizumab group (n=75) Erlotinib alone group (n=77) Complete response 3 (4%) 1 (1%) Partial response 49 (65%) 48 (62%) Stable disease 2 (29%) 19 (25%) Progressive disease 0 6 (8%) Non-evaluable 1 (1%) 3 (4%) Reprinted from The Lancet Oncol, 15, Seto T, el al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study, Copyright 2014, with permission from Elsevier.

29 ACQUIRED RESISTANCE TO EGFR-TKIS

30 HETEROGENEOUS ACQUIRED RESISTANCE MECHANISMS TO EGFR-TKIS T790M Exon 20 substitution 2 Camidge, et al 1 1. Reprinted by permission from Springer Nature: Nat Rev Clin Oncol, Acquired resistance to TKIs in solid tumours: learning from lung cancer. Camidge DR, et al. Copyright Reprinted from Bioorg Med Chem, 16(7), Michalczyk A, et al. Important pathways to target in (advanced) NSCLC: A focus on EGFR-inhibition and implications for clinical practice, Copyright 2008, with permission from Elsevier. Cross DAE, et al. Cancer Discovery 2014

31 THIRD-GENERATION EGFR TKIS: ROCILETINIB (CO-1686), OSIMERTINIB (AZD9291)AND OLMUTINIB (HM 61713) EGFR TKI Selectivity Reversible/ Irreversible Osimertinib (AZD9291) Mutant EGFR Irreversible Rociletinib (CO-1686) Mutant EGFR Irreversible Olmutinib (BI /HM61713) Status in lung cancer FDA-approved, T790M+ only No longer in development Mutant EGFR Irreversible Investigational Select clinical trials NCT (Ph 3 first-line) NCT (Ph 3 adjuvant) NCT (Ph 2) NCT (Ph 2) NCT (Ph 2) Olmutinib 1. TAT congress. Rociletinib (CO-1686), an irreversible EGFR-mutant selective inhibitor. Available at: Jean-Charles-Soria.pdf (accessed October 2015). 2. TAT congress. AZD9291 a novel EGFR-TKI that overcomes T790M-mediated resistance in NSCLC. Available at: (accessed October 2015).

32 TREATMENT STRATEGIES FOR PATIENTS DEVELOPING EGFR T790M MUTATION: Rociletinib (CO-1686), Osimertinib (AZD9291) and Olmutinib (HM 61713) Osimertinib Rociletinib Olmutinib FDA and EMA approved Discontinued for poor efficacy

33 TREATMENT STRATEGIES FOR PATIENTS DEVELOPING EGFR T790M MUTATION: Rociletinib (CO-1686), Osimertinib (AZD9291) and Olmutinib (HM 61713) Osimertinib Rociletinib Olmutinib FDA and EMA approved Discontinued for poor efficacy

34 TREATMENT STRATEGIES FOR PATIENTS DEVELOPING EGFR T790M MUTATION: Osimertinib (AZD9291) Clinical trials AURA (NCT ) Available Data Single-arm, dose escalation and expansion (Phase I, completed) and Phase II extension (N=~175) 2 Phase I: Safety, tolerability, PK and antitumour activity of ascending doses of AZD Phase II: Assessment of efficacy and tolerability of AZD mg QD in T790M NSCLC 2 AURA 2 (NCT ) Available Data AURA 3 (NCT ) Available Data Confirmatory global Phase II assessment of efficacy and tolerability of AZD mg QD in patients with T790M+ NSCLC Phase III AZD92921 vs. platinum-based doublet chemotherapy in second-line patients with T790M+ advanced/metastatic NSCLC who have progressed following prior therapy with an EGFR-TKI FLAURA (NCT ) Available Data Phase III AZD92921 vs. standard of care EGFR-TKI as first-line treatment in naïve patients with EGFR mutation positive, locally advanced or metastatic NSCLC

35 TREATMENT STRATEGIES FOR PATIENTS DEVELOPING EGFR T790M MUTATION: Osimertinib (AZD9291) Clinical trials AURA (NCT ) Available Data Single-arm, dose escalation and expansion (Phase I, completed) and Phase II extension (N=~175) 2 Phase I: Safety, tolerability, PK and antitumour activity of ascending doses of AZD Phase II: Assessment of efficacy and tolerability of AZD mg QD in T790M NSCLC 2 AURA 2 (NCT ) Available Data AURA 3 (NCT ) Available Data Confirmatory global Phase II assessment of efficacy and tolerability of AZD mg QD in patients with T790M+ NSCLC Phase III AZD92921 vs platinum-based doublet chemotherapy in second-line patients with T790M+ advanced/metastatic NSCLC who have progressed following prior therapy with an EGFR-TKI FLAURA (NCT ) Available Data Phase III AZD92921 vs standard of care EGFR-TKI as first-line treatment in naïve patients with EGFR mutation positive, locally advanced or metastatic NSCLC

36 OSIMERTINIB: ORR, DOR, MPFS AURA Ph I (80 mg) N=61 AURA pooled Ph II (80 mg) N=397 Confirmed ORR 71% (95% CI 57, 82) 66% (95% CI 61, 71) Disease control rate 93% (95% CI 84, 98) 91% (95% CI 88, 94) Best objective response Complete response Partial response Stable disease 6 weeks Progressive disease AURA Ph I (80 mg) N=43 AURA pooled Ph II (80 mg) N=262 Median DoR,* months (95% CI) 9.6 (7.7, 15.6) 12.5 (11.1, NC) Maximum DoR, months 26.3 ongoing 15.3 ongoing Remaining in response, % (95% CI) 12 months 18 months 24 months 44 (29, 58) 32 (19, 46) 20 (8, 35) 53 (46, 59) NC NC AURA Ph I (80 mg) N=63 AURA pooled Ph II (80 mg) N=411 Median PFS,* months (95% CI) 9.7 (8.3, 13.6) 11.0 (9.6, 12.4) Remaining in response, % (95% CI) 12 months 18 months 24 months 41 (29, 53) 29 (18, 41) 17 (8, 30) 48 (42, 53) NC NC Jänne PA, et al. New Engl J Med Goss G, et al. Lancet Oncol 2016.

37 TREATMENT STRATEGIES FOR PATIENTS DEVELOPING EGFR T790M MUTATION: Osimertinib (AZD9291) Clinical trials AURA (NCT ) Available Data Single-arm, dose escalation and expansion (Phase I, completed) and Phase II extension (N=~175) 2 Phase I: Safety, tolerability, PK and antitumour activity of ascending doses of AZD Phase II: Assessment of efficacy and tolerability of AZD mg QD in T790M NSCLC 2 AURA 2 (NCT ) Available Data AURA 3 (NCT ) Available Data Confirmatory global Phase II assessment of efficacy and tolerability of AZD mg QD in patients with T790M+ NSCLC Phase III AZD92921 vs. platinum-based doublet chemotherapy in second-line patients with T790M+ advanced/metastatic NSCLC who have progressed following prior therapy with an EGFR-TKI FLAURA (NCT ) Available Data Phase III AZD92921 vs. standard of care EGFR-TKI as first-line treatment in naïve patients with EGFR mutation positive, locally advanced or metastatic NSCLC

38 TREATMENT STRATEGIES FOR PATIENTS DEVELOPING EGFR T790M MUTATION: Osimertinib (AZD9291) Clinical trials AURA (NCT ) Available Data Single-arm, dose escalation and expansion (Phase I, completed) and Phase II extension (N=~175) 2 Phase I: Safety, tolerability, PK and antitumour activity of ascending doses of AZD Phase II: Assessment of efficacy and tolerability of AZD mg QD in T790M NSCLC 2 AURA 2 (NCT ) Available Data AURA 3 (NCT ) Available Data Confirmatory global Phase II assessment of efficacy and tolerability of AZD mg QD in patients with T790M+ NSCLC Phase III AZD92921 vs. platinum-based doublet chemotherapy in second-line patients with T790M+ advanced/metastatic NSCLC who have progressed following prior therapy with an EGFR-TKI FLAURA (NCT ) Available Data Phase III AZD92921 vs standard of care EGFR-TKI as first-line treatment in naïve patients with EGFR mutation positive, locally advanced or metastatic NSCLC

39 AURA3: PFS N=419 patients T790M + NSCLC progressing after TKI-anti-EGFR (R 2:1) With CNS metastases Without CNS metastases From New Engl Jour Med, Mok TS, et al. Osimertinib or Platinum Pemetrexed in EGFR T790M Positive Lung Cancer, 376, 7: Copyright Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

40 AURA3: PFS From New Engl Jour Med, Mok TS, et al. Osimertinib or Platinum Pemetrexed in EGFR T790M Positive Lung Cancer, 376, 7: Copyright Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

41 AURA3: DURATION OF RESPONSE BY INVESTIGATOR ASSESSMENT Osimertinib (n=279) Platinum-pemetrexed (n=140) Response rate (95% CI) 71% (65-76) 31% (24-40) Disease control rate 93% (90-96) 74% (66-81) Median DoR,* months (95% CI) 9.7 (8.3, 11.6) 4.1 (3.0, 5.6) Estimated remaining in response,* % (95% CI) 9 months 12 months 53 (45, 61) 38 (28, 48) 16 (6, 29) 11 (3,25) Mok TS, et al. NEJM 2017;376:

42 AURA3: DURATION OF RESPONSE BY INVESTIGATOR ASSESSMENT From New Engl Journ Med, Mok TS, et al. Osimertinib or Platinum Pemetrexed in EGFR T790M Positive Lung Cancer, 376, 7: Copyright Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

43 TREATMENT STRATEGIES FOR PATIENTS DEVELOPING EGFR T790M MUTATION: Osimertinib (AZD9291) Clinical trials AURA (NCT ) Available Data Single-arm, dose escalation and expansion (Phase I, completed) and Phase II extension (N=~175) 2 Phase I: Safety, tolerability, PK and antitumour activity of ascending doses of AZD Phase II: Assessment of efficacy and tolerability of AZD mg QD in T790M NSCLC 2 AURA 2 (NCT ) Available Data AURA 3 (NCT ) Available Data Confirmatory global Phase II assessment of efficacy and tolerability of AZD mg QD in patients with T790M+ NSCLC Phase III AZD92921 vs. platinum-based doublet chemotherapy in second-line patients with T790M+ advanced/metastatic NSCLC who have progressed following prior therapy with an EGFR-TKI FLAURA (NCT ) Available Data Phase III AZD92921 vs. standard of care EGFR-TKI as first-line treatment in naïve patients with EGFR mutation positive, locally advanced or metastatic NSCLC

44 TREATMENT STRATEGIES FOR PATIENTS DEVELOPING EGFR T790M MUTATION: Osimertinib (AZD9291) Clinical trials AURA (NCT ) Available Data Single-arm, dose escalation and expansion (Phase I, completed) and Phase II extension (N=~175) 2 Phase I: Safety, tolerability, PK and antitumour activity of ascending doses of AZD Phase II: Assessment of efficacy and tolerability of AZD mg QD in T790M NSCLC 2 AURA 2 (NCT ) Available Data AURA 3 (NCT ) Available Data Confirmatory global Phase II assessment of efficacy and tolerability of AZD mg QD in patients with T790M+ NSCLC Phase III AZD92921 vs platinum-based doublet chemotherapy in second-line patients with T790M+ advanced/metastatic NSCLC who have progressed following prior therapy with an EGFR-TKI FLAURA (NCT ) Available Data Phase III AZD92921 vs. standard of care EGFR-TKI as first-line treatment in naïve patients with EGFR mutation positive, locally advanced or metastatic NSCLC

45 FLAURA: OSIMERTINIB VS. STANDARD OF CARE From N Engl J Med, Soria JC, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer, 378: Copyright 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

46 FLAURA: OSIMERTINIB VS. STANDARD OF CARE From N Engl J Med, Soria JC, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer, 378: Copyright 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

47 TREATMENT STRATEGIES FOR PATIENTS DEVELOPING EGFR T790M MUTATION: Rociletinib (CO-1686), Osimertinib (AZD9291) and Olmutinib (HM 61713) Osimertinib Rociletinib Olmutinib FDA and EMA approved Discontinued for poor efficacy

48 TREATMENT STRATEGIES FOR PATIENTS DEVELOPING EGFR T790M MUTATION: Rociletinib (CO-1686), Osimertinib (AZD9291) and Olmutinib (HM 61713) Osimertinib Rociletinib Olmutinib FDA and EMA approved Discontinued for poor efficacy

49 TRIALS ENROLLING IN 2014 Treatment strategies for patients developing EGFR T790M mutation: Rociletinib (CO-1686) TIGERX Expansion Cohorts TIGER Trials 2nd line PD upon 1 immediate prior TKI T790M+ biopsy upon progression >2nd line PD upon 2 TKI or chemotherapy T790M+ biopsy upon progression 500 mg BID 625 mg BID 750 mg BID 500 mg BID 625 mg BID 750 mg BID TIGER 1 (Phase 2/3) Randomised CO-1686 vs. erlotinib 1st-line, treatment-naïve Mutant EGFR (not screened for T790M status) TIGER 2 (Phase 2) Single-arm 2nd-line mutant EGFR NSCLC, T790M+ Patients progressing on 1 st -line EGFR TKI TIGER 3 (Phase 3) Randomised CO-1686 vs. chemotherapy 2nd-line mutant EGFR NSCLC, T790M+ Patients progressing on 1 st -line EGFR TKI TIGER 4 (Phase 2) (TIGER 2 like; pts T790M plasma)

50 TRIALS ENROLLING IN 2014 Treatment strategies for patients developing EGFR T790M mutation: Rociletinib (CO-1686) TIGERX Expansion Cohorts TIGER Trials 2nd line PD upon 1 immediate prior TKI T790M+ biopsy upon progression >2nd line PD upon 2 TKI or chemotherapy T790M+ biopsy upon progression 500 mg BID 625 mg BID 750 mg BID 500 mg BID 625 mg BID 750 mg BID TIGER 1 (Phase 2/3) Randomised CO-1686 vs. erlotinib 1st-line, treatment-naïve Mutant EGFR (not screened for T790M status) TIGER 2 (Phase 2) Single-arm 2nd-line mutant EGFR NSCLC, T790M+ Patients progressing on 1 st -line EGFR TKI TIGER 3 (Phase 3) Randomised CO-1686 vs. chemotherapy 2nd-line mutant EGFR NSCLC, T790M+ Patients progressing on 1 st -line EGFR TKI TIGER 4 (Phase 2) (TIGER 2 like; pts T790M plasma)

51 SLD change from baseline (%) BEST RESPONSE TO ROCILETINIB All Doses 1 Maturing PFS at 500mg or 625mg BID mg 625m g 750mg Total n ORR (%) DCR (%) mg BID HBr 625mg BID HBr 750mg BID HBr + Ongoing 1. Goldman JW, et al. J Thor Oncol 2015;10(Supl 2):S318. Presented at WCLC 2015; abstract MINI16.03; Courtesy of Dr JW Goldman. 2. Sequist LV, et al. ASCO 2015.

52 TREATMENT STRATEGIES FOR PATIENTS DEVELOPING EGFR T790M MUTATION: Rociletinib (CO-1686), Osimertinib (AZD9291) and Olmutinib (HM 61713) Osimertinib Rociletinib Olmutinib FDA and EMA approved Discontinued for poor efficacy

53 TREATMENT STRATEGIES FOR PATIENTS DEVELOPING EGFR T790M MUTATION: Rociletinib (CO-1686), Osimertinib (AZD9291) and Olmutinib (HM 61713) Osimertinib Rociletinib Olmutinib FDA and EMA approved Discontinued for poor efficacy

54 STUDY DESIGN Olmutinib (HM 61713): study design Recommended dose: 800 mg (400 mg BID) Kim DW, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8011). Presented at ASCO Courtesy of Prof Kim

55 OLMUTINIB (HM 61713): EXPANSION PART Best Overall Response PFS (T790M+ vs. T790M-) Kim DW, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8011). Presented at ASCO Courtesy of Prof DW Kim

56 TYPE OF PROGRESSION DRIVES THERAPY

57 TYPE OF PROGRESSION DRIVES THERAPY Sacher AG, et al. Cancer 2014;120(15): Published by Wiley Online Library American Cancer Society.

58 ASPIRATION TRIAL: ERLOTINIB BEYOND PROGRESSION IN EGFR+ Is it possible to continue gefitinib beyond progression according to RECIST criteria? Patients received erlotinib 150 mg/d orally until disease progression, after which erlotinib therapy could be continued at patient and/or investigator discretion Park K, et al. JAMA Oncol 2016r;2(3): Courtesy of Prof K Park

59 ASPIRATION TRIAL: ERLOTINIB BEYOND PROGRESSION IN EGFR+ In patients receiving post-pd erlotinib (n=93) PFS1 was 11.0 months and PFS2 was 14.1 months, providing an additional 3.1 months of PFS Park K, Abstract 12230, ESMO Park K, et al. JAMA Oncol Gandara DR, et al. Clin Lung Cancer Courtesy of Prof K Park.

60 CHEMOTHERAPY IN EGFR TKI RESISTANCE: LUX-LUNG 5 TRIAL Schuler M, et al. Ann Oncol 2016;27(3): By permission of Oxford University Press/ on behalf of the European Society for Medical Oncology (ESMO)

61 LUX-LUNG 5 (LL5) PFS OS Schuler M, et al. Ann Oncol 2016;27(3): By permission of Oxford University Press/ on behalf of the European Society for Medical Oncology (ESMO)

62 RESISTANCE TO FIRST- SECOND AND THIRD GENERATION EGFR-TKI

63 RESISTANCE TO TKI ANTI-EGFR: FIRST-SECOND AND THIRD GENERATION Schuler M, et al. Ann Oncol 2016;27(3): By permission of Oxford University Press/ on behalf of the European Society for Medical Oncology (ESMO)

64 RESISTANCE MECHANISMS FOUND ON TUMOUR NGS 119 T790M+ patients treated with single-agent osimertinib for acquired resistance 29 remain on therapy without progression 10 off due to AE without progression 80 patients eligible for resistance analysis 35 without post-progression biopsy 12 without complete tissue testing 33 patients with progression tumour NGS 11 maintained T790M 7 C797S 1 PIK3CA mutation *Patient with both PIK3CA + SCLC transformation 22 lost T790M 5 SCLC histologic transformation* 3 MET amplification 1 BRAF V600E 2 PIK3CA mutation* 1 KRAS Q61K 1 CCDC6-RET fusion 1 FGFR3-TACC fusion EGFR C797S was detected only in patients with maintained T790M Competing resistance mechanisms were detected in patients with loss of T790M T790M Maintained (n=11) T790M loss (n=22) Sex, number (%) Female 10 (91) 12 (55) Male 1 (9) 10 (45) Race/ethnicity, number (%) White 8 (73) 15 (68) p-value Asian 2 (18) 3 (14) Black 0 (0) 3 (14) 0.71 Hispanic 1 (9) 1 (5) EGFR driver mutation, number (%) Exon 19 del 7 (64) 16 (73) L858R 4 (36) 6 (27) 0.7 Number of prior TKIs, number (%) 1 9 (82) 16 (73) 2 2 (18) 6 (27) 0.69 Pretreatment T790M detection method, number (%) Plasma 2 (18) 5 (23) Tumor 9 (82) 17 (77) 1 Time-to-treatment failure, months, median (range) 15.2 ( ) 3.2 ( ) <0.001 Pathogenic TP53 mutation, number (%) No 6 (55) 5 (23) Yes 5 (45) 17 (77) Oxnard GR, et al. J Thorac Oncol 2017;12(11; Suppl 2):S Presented at WCLC Abstract OA Courtesy of Prof GR Oxnard

65 LOSS OF T790M AND EARLY RESISTANCE TO OSIMERTINIB PIK3CA R88Q EGFR C797S EGFR C797S Median TTF for 33 patients = 6.9 months Resistance due to loss of T790M is often seen early on osimertinib EGFR C797S 1 EGFR C797S EGFR C797S EGFR C797S 1 EGFR C797S EGFR C797S EGFR C797S MET amplification PIK3CA N345K SCLC transformation Resistance due to EGFR C797S is often seen later on osimertinib KRAS Q61K FGFR3-TACC fusion BRAF V600E SCLC transformation MET amplification CCDC6-RET rearrangement SCLC transformation SCLC transformation MET amplification SCLC transformation + PIK3CA E545K T790M+ at resistance T790M- at resistance T790M- in tumor/ T790M+ in plasma at resistance 1 EGFR C797S detected in plasma but not tumor TTF (months) Oxnard GR, et al. J Thorac Oncol 2017;12(11; Suppl 2):S Presented at WCLC Abstract OA Courtesy of Prof GR Oxnard

66 Copies/mL of plasma Copies/mL of plasma SERIAL PLASMA GENOTYPING ON OSIMERTINB Acquired EGFR C797S Small cell transformation Start of osimertinib Biopsy date Start of osimertinib EGFR exon 19 del EGFR T790M EGFR C797S TA EGFR C797S GC Biopsy date EGFR exon 19 del EGFR T790M 10 N/D Time on osimertinib (months) 10 N/D Time on osimertinib (months) Emergence of C797S mutation with the re-emergence of exon 19 del and T790M after initial response to osimertinib Rapid loss of T790M with continued increase in driver mutation in a patient with small cell transformation on biopsy Oxnard GR, et al. J Thorac Oncol 2017;12(11; Suppl 2):S Presented at WCLC Abstract OA Courtesy of Prof GR Oxnard

67 Copies/mL of plasma ACQUIRED KRAS MUTATION IS A NOVEL MECHANISM OF ACQUIRED EGFR TKI RESISTANCE N/D Start of osimertinib EGFR exon 19 del EGFR T790M KRAS Q61K Biopsy date Time on osimertinib (months) 65-year-old female never smoker with acquired resistance to osimertinib after 7.8 months Post-osimertinib tumour NGS detected known driver (19 del) and a new KRAS Q61K mutation, with loss of T790M Plasma ddpcr confirms the emergence of the KRAS mutation and also detects re-emergence of the T790M mutation Oxnard GR, et al. J Thorac Oncol 2017;12(11; Suppl 2):S Presented at WCLC Abstract OA Courtesy of Prof GR Oxnard

68 Percent without treatment failure Number of patients VALIDATION COHORT: LOSS OF T790M ASSOCIATED WITH EARLY RESISTANCE Plasma available for 157 subjects on the first-in-human AURA trial, 110 with a detectable driver at time of osimertinib resistance N = 110 T790M+/C797S+ Median: 12.4 T790M+/C797S- Median: 12.6 T790M loss Median: N = 38 N = 36 N = 36 T790M+/ C797S+ T790M+/ C797S T790M loss TTF (months) 0 <=5.5 >5.5 to <=13 >13 TTF (months) Those with T790M loss had shorter TTF compared with those with maintained T790M Among those with early resistance (TTF 5.5 months), 68% had loss of T790M Oxnard GR, et al. J Thorac Oncol 2017;12(11; Suppl 2):S Presented at WCLC Abstract OA Courtesy of Prof GR Oxnard

69 Relative T790M allelic fraction (AF) LOSS OF T790M IS DIFFICULT TO PREDICT FROM BASELINE PLASMA GENOTYPING Maintained T790M (n=33) T790M loss (n=17) N/D Baseline Progression Baseline and progression plasma genotyping available for 50 AURA subjects Relative T790M allelic fraction (AF) = T790M AF / EGFR driver AF Relative T790M AF for patients with loss of T790M trended only slightly lower (0.29 median) compared with patients with maintained T790M (0.38 median) Oxnard GR, et al. J Thorac Oncol 2017;12(11; Suppl 2):S Presented at WCLC Abstract OA Courtesy of Prof GR Oxnard

70 Change in driver (%) Change in T790M (%) Change difference (%) EARLY PLASMA RESPONSE ON OSIMERTINIB Pretreatment and 1 3 week follow-up plasma genotyping available for 19 DFCI patients T790M response similar in both groups Less driver response in those with eventual T790M loss Those with eventual T790M loss had more response in their T790M than in their driver (median difference = 16%) Those with maintained T790M had a similar response in their T790M and their driver (median difference = 0%) T790M maintained T790M loss Oxnard GR, et al. J Thorac Oncol 2017;12(11; Suppl 2):S Presented at WCLC Abstract OA Courtesy of Prof GR Oxnard

71 ROLE OF RE-BIOPSY AND ROLE OF LIQUID BIOPSY

72 ROLE OF RE-BIOPSY Table 2 Re-biopsy methods Surgery n=82 Adrenalectomie 1 Lung surgery 3 Node surgery 1 Biopsy Bronchial + E-BUS 43 Pulmonary under CT 19 Liver 2 Bone 6 Skin 2 Cytology Nodes 3 Results: from May 2012 to May 2013, 18 centres enrolled 100 patients (males: 44%; median age: 64.8 years; PS 0/1:88%; adenocarcinoma:89%; EGFR mutated: 50%; no initial biological profile: 16,4%). Re-biopsy was not possible in 19.5% of cases and provided no or too few tumour cells in 25.6% of cases. Repeat biopsy was useful for guiding treatment in 30.4% (25/82) of cases. Complications were infrequent (2 cases of moderate bleeding and 1 case of pneumothorax). Conclusions: Re-biopsy of advanced NSCLC is feasible in the realworld setting, with acceptable adverse events. Guidelines are needed on the indications of re-biopsy, the choice of procedure, the sampling site and laboratory analysis. Pleura 2

73 ADEQUACY AND COMPLICATIONS OF RE-BIOPSY Detailed circumstances of ineligible cases for re-biopsy and gene study in 32 patients Characteristic No of Patients* Adjacent large central bronchus or vessels 14 (44) Prominent internal airbronchograms with little solid portion 3 (9) Prominent peribronchovascular crowding 3 (9) Progressive disease by nontarget lesions 6 (19) 126 patients referred for repeat biopsy with NSCLC resistant to conventional chemotherapy or EGFR-TKI 94 patients (31 men, 63 women) selected for re-biopsy (75%) (25% of case it was not possible) Technical success rate for biopsy was 100% (80% suitable for mutational analyses) Post-procedural complications occurred in 13 (14%) patients Progressive disease by bone metastasis 1 (3) Total necrosis or mainly nonviable tumour component at CT 2 (6) Basal lung lesion with severe respiratory compromise 1 (3) Probable benign lesion rather than malignancy 1 (3) Severe pleural effusion 1 (3) *Numbers in parentheses are percentages. Percentages were rounded. Busy bronchi and vascular structure associated with traction bronchiectasis and lobar or segmental volume decrease. Fissural or pleural dissemination or innumerable small metastatic nodules smaller than 5 mm in diameter without main mass lesion. Yoon HJ, et al. Radiology 2012;265(3):

74 ROLE OF LIQUID BIOPSY Intra-tumour and Inter-tumour Heterogeneity Mutational monitoring though Liquid Biopsy Circulating free (cf) DNA Microvesicules exosomes Circulating Tumor Cells (CTCs) Tumour heterogeneity and the evolution of polyclonal drug resistance, Burrell RA, et al. Mol Oncol. 2014;8(6): Published under a Creative Commons Attribution (CC BY) License. Available at:

75 HOW TO IDENTIFY THE EMERGING MECHANISMS OF ACQUIRED RESISTANCE- ANALYSIS OF CIRCULATING TUMOUR DNA Oxnard GR, et al. J Clin Oncol 34(28), 2016: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

76 RESPONSE RATE IN T790M+: TUMOUR=PLASMA Oxnard GR, et al. J Clin Oncol 34(28), 2016: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

77 RESPONSE RATE IN T790M+: TUMOUR=PLASMA Oxnard GR, et al. J Clin Oncol 34(28), 2016: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

78 HOW TO DEFINE THE EMERGING MECHANISMS OF ACQUIRED RESISTANCE- WHICH METHODS? 38 patients enrolled in the AURA trial 72 patients enrolled in the AURA trial Exon 19 deletion Cobas EGFR mutation test therascreen ddpcr EGFR ARMS-PCR ddpcr BEAMingdP CR Sensitivity 86% (24/28) 82% - 93% Specificity 100% (10/10) 100% (10/10) - 100% (10/10) Concordance 89% 87% - 95% L858R Sensitivity 90% (9/10) 78% (7/9) 90% (9/10) 100% (10/10) Specificity 100% (28/28) 100% (28/28) 100% (28/28) 93% (26/28) Concordance 97% 95% 97% 95% T790M Sensitivity 41% (7/17) 29% (5/17) 71% (12/17) 71% (12/17) Specificity 100% (6/6) 100% (6/6) 83% (5/6) 67% (4/6) Concordance 57% 48% 74% 70% Exon 19 deletion Cobas EGFR mutation test BEAMingdPCR Sensitivity 82% (23/28) 82% (23/28) Specificity 97% (30/31) 97% (30/31) L858R Sensitivity 87% (20/23) 87% (20/23) Specificity 97% (35/36) 97% (35/36) T790M Sensitivity 73% (30/41) 81% (33/41) Specificity 67% (16/24) 58% (14/24) EGFR mutation Cobas EGFR mutation test Exon 19 deletion 90% (65/72) L858R 93% (67/72) T790M 90% (65/72) Digital platforms are more sensitive and quantitative, allowing quantification of longitudinal plasma samples BUT CONSIDER biological FALSE POSITIVE Thress KS, et al. Lung Cancer 2015.

79 HOW TO DEFINE THE EMERGING MECHANISMS OF ACQUIRED RESISTANCE- WHICH METHODS? Oxnard GR, et al. J Clin Oncol 34(28), 2016: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

80 TREATMENT ALGORITHM FOR ADVANCED NSCLC WITH EGFR-ACTIVATING MUTATION-EGFR Reprinted from Crit Rev Oncol Hematol, 117, Russo A, et al. Third generation EGFR TKIs in EGFR-mutated NSCLC: Where are we now and where are we going, Copyright 2017 with permission from Elsevier.

81 TAKE HOME MESSAGE In patients with activating EGFR mutations, EGFR TKIs therapy statistically significantly delays disease progression and should be considered as front-line therapy In EGFR WT patients, EGFR TKIs are not recommended in first line, being inferior to chemotherapy and no better than placebo At the time of progression patients on EGFR TKIs should undergo additional molecular testing to select the optimal therapy Blood based testing may be considered in patients where a biopsy is not always possible: If blood is negative a biospy should be performed Consider both plasma and tumour analysis to confirm presence or absence of T790M mutation Osimertinib is preferred to chemotherapy in patients with T790M positive tumours at the time of progression (osimertinib resulted in a significant improvement in PFS) Switch to chemotherapy is standard of care for T790M negative patients Consider clinical trials for T790M negative population to assess new agents e.g. Axl, MET, HER2 etc.

82 THANK YOU!