Resistência aos inibidores de tirosina quinases (TKIs): estratégias de

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1 Acquired resistance to EGFR and other tyrosine kinase inhibitors (TKIs) Resistência aos inibidores de tirosina quinases (TKIs): estratégias de tratamento Daniel B. Costa, MD, PhD, MMSc Division i i of Hematology/Oncology l Beth Israel Deaconess Medical Center Harvard Medical School

2 Non-small-cell lung cancer (NSCLC) Adapted from: American Cancer Society (2014) Adapted from: Imielinski M. et al. Cell 150, (2012) non-small-cell lung cancer (NSCLC) unselected cytotoxic chemotherapies (1990s) Adapted from: Shaw AT et al. N Engl J Med;368: (2013) squamous cell carcinoma adenocarcinoma histology-based cytotoxic chemotherapies (2000s) other/unknown EGFR mutations (~15%) KRAS mutations (~25%) ALK rearrangements ROS1 (~5%) rearrangements (~2%) genomics-driven precision therapies ( ) ( ) (2010s)

3 Outline Initial development of EGFR tyrosine kinase inhibitors (TKIs) for unselected NSCLC EGFR mutations as preclinical and clinical biomarkers for EGFR TKIs in NSCLC Registration clinical trials of EGFR TKIs for EGFR mutated NSCLC Challenges and limitations of genotype-driven therapies for EGFR mutated t NSCLC due to acquired resistance to EGFR TKIs

inhibitors (TKIs) gefitinib i ib AstraZeneca

4 Epidermal growth factor receptor (EGFR) pathway Initial EGFR tyrosine kinase inhibitors (TKIs) gefitinib i ib AstraZeneca erlotinib OSI Pharmaceuticals Genentech - Roche Ciardiello F, et al. N Engl J Med; 358: (2008) Side-effect profile in humans: 1) Skin rash ~ 50-80% of patients 2) Diarrhea ~ 20-50% 3) Anorexia ~ 10-15% 4) Interstitial Lung Disease <1-5%

5 EGFR TKIs: registration trials in unselected NSCLC ISEL (gefitinib) ib) and BR.21(erlotinib) ib) ISEL (gefitinib 250 mg daily) BR.21 (erlotinib 150 mg daily) Thatcher N, et al. Lancet. 4;366(9496): (2005) Shepherd FA, et al. N Engl J Med.: (2005)

6 EGFR TKIs: unusual rapid and durable responses seen during initial clinical development of gefitinib and erlotinib ib baseline erlotinib sense EGFR c.2573t>g p.l858r

7 Outline Initial development of EGFR tyrosine kinase inhibitors (TKIs) for unselected NSCLC EGFR mutations as preclinical and clinical biomarkers for EGFR TKIs in NSCLC Registration clinical trials of EGFR TKIs for EGFR mutated NSCLC Challenges and limitations of genotype-driven therapies for EGFR mutated t NSCLC due to acquired resistance to EGFR TKIs Presented by: Daniel B. Costa, MD, PhD, MMSc

8 Celebrating a decade since the initial discovery of EGFR mutations in EGFR TKI-responsive NSCLCs ( ) Pasi Jänne Matthew Meyerson Bruce Johnson Kwok-Kin Wong Michael Eck Nathanael Gray Geoffrey Oxnard David Jackman Paez JG, Janne PA, et al. Science 304:1497 (2004) Susumu Kobayashi Balazs Halmos Thomas Daniel Jeffrey Lecia Jeffrey Tony Rafael Tetsuya Daniel Daniel Lynch Jr. Haber Engelman Sequist Settleman Mok Rosell Mitsudomi Tenen Costa Lynch TJ, et al. New Engl J Med 350:2129 (2004) William Pao Harold Varmus Mark Kriss Vincent Miller Mark Ladanyi Gregory Riely Katerina Politi Pao W, et al. Proc Natl Acad Sci 101: (2004) Adi Gazdar John Minna The presenter would like to apologize to those who were instrumental in the first decade of EGFR mutation research but not included as a result of space constraints

9 EGFR mutations in NSCLC cluster around the tyrosine kinase domain (ATP binding pocket) of EGFR (1) G719X N-lobe exon 19 T790M deletions/ insertions C-helix P-loop exon 20 erlotinib insertions L858R L861Q activation loop C-lobe Lancet Oncology; 13(1):e (2012) Adapted from Yasuda, Kobayashi, Costa DB. Lancet Oncology; 13(1):e23 31 (2012)

EGFR mutations in NSCLC cluster around the tyrosine kinase domain (ATP binding pocket) of EGFR (2) exon 2-4 5-7 8-12 13-16 17 18-24 25-28 Ligand binding domain Cystein rich domain Ligand binding

10 EGFR mutations in NSCLC cluster around the tyrosine kinase domain (ATP binding pocket) of EGFR (2) exon Ligand binding domain Cystein rich domain Ligand binding domain Cystein rich domain Transmembrane region Tyrosine kinase domain Regulatory domain exon AA P-loop C-helix A-loop 875 frequency (%) G719X (3%) exon 19 insertions (1%) exon 19 exon 20 T790M L858R L861Q deletions insertions (45%) (5-10%) (40%) (2%) Adapted from Yasuda, Kobayashi, Costa DB. Lancet Oncology;13(1):e (2012)

EGFR mutations in NSCLC: Correlation with clinicopathologic

adenocarcinomas; (almost all cases of squamous cell carcinomas and

Women with lung adenocarcinomas; - East-Asian racial groups with lung

CAP, IASLC and AMP recommend rapid testing for EGFR mutations and ALK

regardless of sex, race, smoking history or other clinical risk factors

11 EGFR mutations in NSCLC: Correlation with clinicopathologic characteristics EGFR mutations are more prevalent on: - Lung adenocarcinomas; (almost all cases of squamous cell carcinomas and small cell lung cancers with EGFR mutations have mixed histology) - Women with lung adenocarcinomas; - East-Asian racial groups with lung adenocarcinomas; - Never smokers with NSCLC. CAP, IASLC and AMP recommend rapid testing for EGFR mutations and ALK rearrangements in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history or other clinical risk factors (Lindeman NI, et al. J Thorac Oncol 8:823 [2013]) lung adenocarcinomas of former/current smokers lung adenocarcinomas of never smokers

EGFR mutated NSCLC and their oncogenic potential (genetically-engineered mouse models [GEMM]) (structural mechanisms) (preclinical models of signaling) GEMM:

lung adenocarcinomas - tumors respond to EGFR TKI - favors active conformation - decreases affinity for ATP - increased inhibitor binding - EGFR TKIs induce apoptosis

12 EGFR mutated NSCLC and their oncogenic potential (genetically-engineered mouse models [GEMM]) (structural mechanisms) (preclinical models of signaling) GEMM: Structural ral model: EGFR signaling cascade: EGFR-L858R L858R bound to gefitinib L858R and exon 19 deletions gefitinib 1 M (EGFR dele746_a750) (EGFR L858R) - induces lung adenocarcinomas - tumors respond to EGFR TKI - favors active conformation - decreases affinity for ATP - increased inhibitor binding - EGFR TKIs induce apoptosis Ji H et al. Cancer Cell ;9(6): Yun CH et al. Cancer Cell. (2007) Costa DB et al. PLoS Medicine ; 4(10): e315. ; ( ) (2006) Eck MJ. Biochim Biophys Acta. (2010) (2007)

13 EGFR TKIs and EGFR mutated NSCLC: understanding the concept of oncogene addiction

14 Heterogeneity of different EGFR mutations: EGFR exon 20 insertion mutations cluster within or following the regulatory C-helix of EGFR and most, outside A763_Y764insFQEA, are insensitive to reversible EGFR TKIs. Structure and enzyme kinetic studies studies, shows that a typical exon 20 insertion mutant binds EGFR TKIs with a binding mode and apparent affinity similar to that of wild-type (WT) EGFR Yasuda H, et al. Sci Transl Med; 5(216):216ra177 (20013)

EGFR mutations in NSCLC: Preclinical pattern of sensitivity to EGFR TKIs T790M N-lobe exon 19 insertions exon 19 deletions G719X P-loop erlotinib C-helix exon 20

erlotinib, afatinib G719X (3%) exon 19 insertions (1%) sensitive sensitive exon 19 deletions (45%) sensitive exon 20 insertions (5-10%) resistant* *(A763_Y764insFQEA

15 EGFR mutations in NSCLC: Preclinical pattern of sensitivity to EGFR TKIs T790M N-lobe exon 19 insertions exon 19 deletions G719X P-loop erlotinib C-helix exon 20 insertions L858R L861Q A-loop C-lobe exon AA P-loop C-helix A-loop 875 EGFR mutation (frequency %) sensitivity to gefitinib, erlotinib, afatinib G719X (3%) exon 19 insertions (1%) sensitive sensitive exon 19 deletions (45%) sensitive exon 20 insertions (5-10%) resistant* *(A763_Y764insFQEA sensitive) T790M resistant L858R (40%) sensitive L861Q (2%) sensitive Greulich H, et al. PLoS Med; 2(11):e313(2005) Yasuda H, et al. Sci Transl Med; 5(216):216ra177 (20013)

16 Outline Initial development of EGFR tyrosine kinase inhibitors (TKIs) for unselected NSCLC EGFR mutations as preclinical and clinical biomarkers for EGFR TKIs in NSCLC Registration clinical trials of EGFR TKIs for EGFR mutated NSCLC Challenges and limitations of genotype-driven therapies for EGFR mutated t NSCLC due to acquired resistance to EGFR TKIs

EGFR TKIs and EGFR mutated NSCLC (clinical

retrospective studies EGFR mutated (exon 19

17 EGFR TKIs and EGFR mutated NSCLC (clinical experience with EGFR TKIs) EGFR mutated (G719X, exon 19 insertions, exon 20 insertions, L861Q) NSCLC: most data from retrospective studies EGFR mutated (exon 19 deletions or L858R) NSCLC: prospective studies ( ) Yamamoto H. Lung Cancer; 63:315. (2009) Gaughan EM, Costa DB. Ther Adv Med Oncol; 3(3):113. (2011) Yey H. Clin Can Res; 19:1894. (2013) Yang JC. 15 th WCLC Australia Oct 28, (2013)

18 IP PASS (ge efitinib) Gefitinib as first line therapy for EGFR mutated NSCLC: Legacy of the IPASS (IRESSA Pan-Asia Study) trial Mok TS, et al. N Engl J Med.; 361: (2009) Mok T. Ann Oncol.19(Supplement 8):abstr LBA2. (2008)

19 EURTAC (erlotinib) N 002 NEJ (g gefitinib) EGFR TKIs as first line therapy for EGFR mutated NSCLC: gefitinib (NEJ 002) and erlotinib (EURTAC) vs chemotherapy Maemondo M., et al. N Engl J Med;362(25): (2010) Rossel R., et al. Lancet Oncol;13(3):239.(2012)

LU UX-Lung (a afatinib) 3 Summary: (EGFR-L858R and

EGFR TKIs - PFSs were 42-84% longer with EGFR TKIs

20 EGFR TKIs as first line therapy for EGFR mutated NSCLC: afatinib (LUX-Lung Lung 3) vs chemotherapy LU UX-Lung (a afatinib) 3 Summary: (EGFR-L858R and exon 19 deletions) - ORRs significantly higher for EGFR TKIs - PFSs were 42-84% longer with EGFR TKIs - No detriment in OS with EGFR TKIs (cross over) Gerber D, Gandhi L, Costa DB. Am Soc Clin Oncol Educ Book. (2014) Sequist LV. J Clin Oncol; 31:3327 (2014)

Evidence-based use of EGFR TKIs (gefitinib, erlotinib and afatinib) for EGFR-L858R or exon 19 deletions mutated advanced NSCLCs as first line systemic therapy April 23 rd, 2009 (European Medicines i

Erlotinib (Tarceva) is approved by European Union for the treatment of NSCLC with EGFR mutations (mostly exon 19 deletions and L858R) May 14 th, 2013 (Food and Drug Administration/US): Erlotinib

21 Evidence-based use of EGFR TKIs (gefitinib, erlotinib and afatinib) for EGFR-L858R or exon 19 deletions mutated advanced NSCLCs as first line systemic therapy April 23 rd, 2009 (European Medicines i Agency): Gefitinib (Iressa) is approved by European Union for the treatment of NSCLC with EGFR mutations (mostly exon 19 deletions and L858R) September 1 st, 2011 (European Medicines i Agency): Erlotinib (Tarceva) is approved by European Union for the treatment of NSCLC with EGFR mutations (mostly exon 19 deletions and L858R) May 14 th, 2013 (Food and Drug Administration/US): Erlotinib (Tarceva) is approved by European Union for the treatment of NSCLC with EGFR mutations (exon 19 deletions and L858R) July 12 th, 2013 (Food and Drug Administration/US): Afatinib (Gilotrif) is approved by European Union for the treatment of NSCLC with EGFR mutations (exon 19 deletions and L858R)

22 Outline Initial development of EGFR tyrosine kinase inhibitors (TKIs) for unselected NSCLC EGFR mutations as preclinical and clinical biomarkers for EGFR TKIs in NSCLC Registration clinical trials of EGFR TKIs for EGFR mutated NSCLC Challenges and limitations of genotype-driven therapies for EGFR mutated t NSCLC due to acquired resistance to EGFR TKIs Presented by: Daniel B. Costa, MD, PhD, MMSc

23 Kinase inhibitors in driver oncogene mutant cancers: EGFR TKIs in comparison to other approved inhibitors Cong CR, Jänne PA. Nat Med;19:1389. (2013)

24 EGFR TKIs and EGFR mutated NSCLC: acquired resistance to EGFR TKIs (EGFR-T790M and MET) July 2002 (baseline) resistant mutation (EGFR-T790M) Nov 2003 (gefitinib) July 2004 (gefitinib) oncogene bypass track (MET amplification) EGFR-delL747_S752+T790M Kobayashi S. N Engl J Med;352:786. (2005) Yun CH. Proc Natl Acad Sci; Engelman JA. Science: 316:1039. (2007) y g ; ( ) Pao W. PLoS Med; 2(3):e73 105:2070. (2008) Pao W. Proc Natl Acad Sci; 104: (2007)

25 EGFR TKIs and EGFR mutated NSCLC: major mechanisms of resistance to EGFR TKIs (1)

26 EGFR TKIs and EGFR mutated NSCLC: major mechanisms of resistance to EGFR TKIs (2) EGFR- T790M Ohashi K, Maruvka YE, Michor F, Pao W. J Clin Oncol; 31:1070. (2013)

27 Therapies for acquired resistance to EGFR TKIs in EGFR mutated NSCLC (awaiting evidence-based recommendations) EGFR- T790M Gerber D, Gandhi L, Costa DB. Am Soc Clin Oncol Educ Book. (2014)

Cumulative incidence of central nervous system progression in patients with pre-existing brain metastases (BM) versus no prior

28 Mechanisms of acquired resistance to EGFR TKIs in EGFR mutated NSCLC: cases with central nervous system progression (pharmacokinetic failure) - use radiotherapy when possible - limited role for pulsatile high dose (1500 mg/weekly) erlotinib Cumulative incidence of central nervous system progression in patients with pre-existing brain metastases (BM) versus no prior BM Adapted from Heon et al Clinical Cancer Res 2010 December 1; 16(23): Adapted from Grommes et al Neuro Oncology 2011 Dec;13(12):1364-9

29 How to treat acquired resistance to EGFR TKIs in EGFR mutated NSCLC outside of a clinical trial: (clinical practice pearl no.1) - understand clonal - understand the concept of evolution of the tumor disease flare with acute and role of continued discontinuation of EGFR use of EGFR TKI TKIs Adapted from Chaft et al Clinical Cancer Res (19): 6298.

30 How to treat acquired resistance to EGFR TKIs in EGFR mutated NSCLC outside of a clinical trial: (clinical practice pearl no.2a) -understand the concept of oligoprogressive disease in the setting of acquired resistance to EGFR TKIs and ALK TKIs; -oligopogressive disease = nonleptomeningeal CNS and/or four sites or fewer of extra- CNS progression. Treat with local l modality (radiation i or surgery) Adapted from Weickhardt et al Journal of Thoracic Oncology 2012; December, 7(12): 1807.

31 How to treat acquired resistance to EGFR TKIs in EGFR mutated NSCLC outside of a clinical trial: (clinical practice pearl no.2b) -understand the concept of oligoprogressive disease in the setting of acquired resistance to EGFR TKIs and ALK TKIs; +/- continue TKI Adapted from Weickhardt et al Journal of Thoracic Oncology 2012; December, 7(12): 1807.

32 Therapies for acquired resistance to EGFR TKIs in EGFR mutated NSCLC (awaiting evidence-based recommendations) EGFR- T790M Gerber D, Gandhi L, Costa DB. Am Soc Clin Oncol Educ Book. (2014)

33 How to treat acquired resistance to EGFR TKIs in EGFR mutated NSCLC outside of a clinical trial: (clinical i l practice pearl no.3a) -use of systemic cytotoxic chemotherapy chemotherapy with continuation of EGFR TKIs - 70 EGFR mutated NSCLCs with acquired resistance to gefitinib/erlotinib; -RR was higher with chemotherapy/erlotinib compared to chemotherapy alone (41% vs 18%; OR 0.31, 95% CI 0.09, 1.04; p=0.08); -Median PFS was 4.4 months in the chemotherapy/erlotinib group and 4.2 months in the chemotherapy alone group (adjusted HR 0.79, 95% CI 0.48, 1.29; p=0.34); -There was no significant difference in OS in the crude or adjusted analyses 1 st line chemotherapies: platinum-doublets 2 nd line chemotherapies: pemetrexed, docetaxel 3 rd line chemotherapies: gemcitabine, vinorelbine Adapted from ASCO 2012 (Goldberg S et al) J Clin Oncol 30, 2012 (suppl; abstr 7524) Goldberg SB. Oncologist; 18:1214. (2013)

34 How to treat acquired resistance to EGFR TKIs in EGFR mutated NSCLC outside of a clinical trial: (clinical i l practice pearl no.3b) -use of systemic cytotoxic chemotherapy chemotherapy with continuation of EGFR TKIs (clinical i l trials are required to prove this treatment strategy) PREFER: Post progression Erlotinib For Erlotinib Resistance N = 180 Stage IV/recurrent NSCLC EGFR activating mutation Progression on 1 st -line erlotinib (Tarceva) ECOG PS 0-2 R Chemotherapy x 4 cycles + Erlotinib (Tarceva) Maintenance chemotherapy + Erlotinib (Tarceva) Stratification EGFR mutation type (exon 19 del vs. exon 21 L858R) ECOG PS (0 vs. 1 vs. 2) PD Primary endpoint Progression free survival Secondary endpoints Objective response rate Non-progression rate at 12 weeks Overall survival Safety Exploratory biomarkers Chemotherapy x 4 cycles Maintenance chemotherapy PD Chemotherapy: Carboplatin (AUC 5 or 6) + pemetrexed 500 mg/m 2 q 21 days Maintenance chemotherapy: Pemetrexed 500 mg/m 2 IV q 21 days until PD or intolerable toxicity Erlotinib (Tarceva): Given daily at 150 mg or at previously tolerated dose Courtesy of Drs. Leora Horn and Geoffrey Oxnard

Therapies for acquired resistance to EGFR TKIs in EGFR mutated NSCLC (ongoing clinical trials) cytotoxic chemotherapy with continued EGFR TKI dual

second generation irreversible EGFR TKIs third generation irreversible EGFR TKIs (covalent pyrimidine idi EGFR-T790M inhibitors) Goldberg SB.

35 Therapies for acquired resistance to EGFR TKIs in EGFR mutated NSCLC (ongoing clinical trials) cytotoxic chemotherapy with continued EGFR TKI dual EGFR inhibition (cetuximab + afatinib) afatinib 40 mg/day + cetuximab 500 mg/m2 every 2 weeks: phase Ib trial (significant cutaneous adverse events) second generation irreversible EGFR TKIs third generation irreversible EGFR TKIs (covalent pyrimidine idi EGFR-T790M inhibitors) Goldberg SB. Oncologist; 18:1214. (2013) Horn L. J Clin Oncol 29 :abstr7525). (2011) Miller V. Lancet Oncol ;13(5):528. (2012) Zhou W. Janne PA. Nature; 462:1070. (2009)

36 Afatinib versus placebo for patients with advanced, metastatic nonsmall-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-LungLung 1): a phase 2b/3 trial. -Negative trial. Did not meet primary outcome of improvement in overall survival (OS) -Response rate (RR) on single agent afatinib <10% and PFS <3.5 months RR afatinib 7% RR placebo 1% PFS Adapted from Miller et al. Lancet Oncol 2012 May;13(5): OS afatinib (achievable serum concentration:<0.07 M) EGFR-T790M and the most common EGFR exon 20 insertion mutants have inhibitory IC 50 s that exceed the achievable serum/plasma concentrations of three second generation irreversible EGFR TKIs undergoing clinical trials/clinical development (including afatinib) for EGFR mutated NSCLC when compared to the wild type receptor Yasuda et al. Lancet Oncology 2013

37 Use of irreversible EGFR TKIs and EGFR monoclonal antibodies (dual EGFR targeting) for acquired resistance to EGFR TKIs Preclinical rational for dual targeting of EGFR to overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer Irreversible EGFR TKIs in combination with EGFR monoclonal l antibodies for EGFR mutated t NSCLC (example of afatinib 40 mg/day + cetuximab 500 mg/m2 q2 weeks phase Ib trial) Adapted from Regales et al J Clin Invest 2009 Oct;119(10): (significant skin adverse events!) courtesy of Leora Horn ASCO 2011

38 Therapies for acquired resistance to EGFR TKIs in EGFR mutated NSCLC (awaiting evidence-based recommendations) EGFR- T790M Gerber D, Gandhi L, Costa DB. Am Soc Clin Oncol Educ Book. (2014)

39 Mechanisms of acquired resistance to EGFR TKIs in EGFR mutated NSCLC: rare cases with SCLC transformation (or small cell histology in poorly differentiated t d mixed samples) <5% cases Adapted from Sequist et al Science Trans Med 2011

EGFR TKIs third generation irreversible EGFR TKIs (covalent pyrimidine idi EGFR-T790M inhibitors) Goldberg SB.

40 Therapies for acquired resistance to EGFR TKIs in EGFR mutated NSCLC (ongoing clinical trials) cytotoxic chemotherapy with continued EGFR TKI dual EGFR inhibition (cetuximab + afatinib) (significant skin adverse events) second generation irreversible EGFR TKIs third generation irreversible EGFR TKIs (covalent pyrimidine idi EGFR-T790M inhibitors) Goldberg SB. Oncologist; 18:1214. (2013) Horn L. J Clin Oncol 29 :abstr7525). (2011) Miller V. Lancet Oncol ;13(5):528. (2012) Zhou W. Janne PA. Nature; 462:1070. (2009)

41 Identification of covalent pyrimidine EGFR inhibitors against EGFR-T790M (preclinical compounds) WZ4002 is 100 fold more potent against EGFR-T790M and 100 fold less potent against EGFR WT Zhou W. Jänne PA. Nature; 462:1070. (2009)

42 Therapies for acquired resistance to EGFR TKIs in EGFR mutated NSCLC (covalent EGFR-T790M AZD9291) Phase I study of AZD9291 (clinicaltrials.gov - NCT ) The AURA Study Courtesy of Pasi Jänne Santa Monica Conference (2014) Ranson M. 15 th WCLC: abstract t (2013) Ranson M. European Cancer Congress: abstr33lba. (2013) Cross. AACR-NCI-EORTC: abstract A109.(2013)

43 Therapies for acquired resistance to EGFR TKIs in EGFR mutated NSCLC (covalent EGFR-T790M CO-1686) Phase I study of CO-1686 (clinicaltrials.gov - NCT ) The TIGER Study Courtesy of Thomas Harding - Clovis Oncology, Inc. (2014) Wakelee H. ELCC March Geneva (2014)

44 Therapies for acquired resistance to EGFR TKIs in EGFR mutated NSCLC (awaiting evidence-based recommendations) EGFR- T790M Gerber D, Gandhi L, Costa DB. Am Soc Clin Oncol Educ Book. (2014)

45 Outline What about other kinase inhibitors? Development of the MET/ALK/ROS1 TKI (crizotinib) for ALK rearranged NSCLC Development of the MET/ALK/ROS1 TKI (crizotinib) for ROS1 rearranged NSCLC Challenges and limitations of genotype-driven therapies for NSCLCs due to acquired resistance to TKIs Presented by: Daniel B. Costa, MD, PhD, MMSc

PI3K STAT3/5 RAS PLC- Y AKT mtor MEK PIP 2 BAD S6K ErK IP 3 Cell survival Tumor cell

46 ALK is an oncogene in NSCLC: Identification of ALK rearrangements/translocations in 2007 ALK rearrangements activate signaling pathways Inversion Or Translocation ALK ALK fusion protein* PI3K STAT3/5 RAS PLC- Y AKT mtor MEK PIP 2 BAD S6K ErK IP 3 Cell survival Tumor cell proliferation Soda M., et al. Nature Aug Adapted from: Bang Y et al. Proc ASCO 2;448(7153): ;Abstract 3.

Response to the ALK inhibitor crizotinib:

(A8081001) crizotinib (µm) A549 H3122 (KRAS

crizotinib 250 mg BID Hiroyuki Yasuda/Daniel

47 Response to the ALK inhibitor crizotinib: initial patients with ALK rearranged NSCLC (A ) crizotinib (µm) A549 H3122 (KRAS G12S) (EML4 ALK E13;A20) palk ALK 120kDa pakt AKT actin 60kDa 45kDa crizotinib 250 mg BID Hiroyuki Yasuda/Daniel Costa/Susumu Kobayashi J Thorac Oncol Jul;7(7): Kwak, E. et al. N Engl J Med 2010 Oct28; 363(18):

48 Best radiographic response in expanded cohort of ALK rearranged NSCLC A (crizotinib 250 mg BID) RR (CR+PR) = 60.8% (87/143) 95% CI: 52 68% DCR (CR+PR+SD) = 82.5% (118/143) Camidge DR., et al. Lancet Oncol 2012 Oct;13(10):

49 ALK TKI crizotinib as second line therapy for ALK rearranged NSCLC: PROFILE1007 results Shaw AT et al. N Engl J Med 2013;368: courtesy of Alice Shaw: presented at ESMO 2012

rearrangements ROS1 (~5%) rearrangements (~2%) _ ~ 2% of all NSCLC _ ~ 6% of never smokers

50 ROS1 rearrangements define a novel actionable oncogene in NSCLC: clinical significance elucidated in 2012 EGFR mutations (~15%) other/unknown KRAS mutations (~25%) ALK rearrangements ROS1 (~5%) rearrangements (~2%) _ ~ 2% of all NSCLC _ ~ 6% of never smokers with NSCLC _ Mutually exclusive with other driver oncogenes Adapted from: Bergethon K et al. JCO 2012;30:

51 Response of an ROS1-positive patient with advanced NSCLC to crizotinib 250 mg twice daily pros1 crizotinib (µm) HCC78 H3255 (SLC34A2 ROS1)(EGFR L858R) ROS1 70kDa pakt AKT 60kDa perk ERK actin 44kDa 42kDa 45kDa Hiroyuki Yasuda/Daniel Costa/Susumu Kobayashi J Thorac Oncol Jul;7(7): crizotinib 250 mg BID Bergethon K et al. JCO 2012;30:

52 ALK/ROS1 TKI crizotinib as systemic therapy for ROS1 rearranged NSCLC: PROFILE1001 study crizotinib 250 mg BID (PROFILE1001) RR 60% (95%CI 42-76%) [n=35] DCR 80% at 8 weeks and 66% at 16 weeks courtesy of Dr. Ou, presented at ASCO J Clin Oncol 31, 2013 (suppl; abstr 8032)

54 Mechanisms of acquired resistance to the ALK inhibitor crizotinib in ALK translocated NSCLC biological resistance: mutation ALK TK domain (30% cases) ALK amplification (<10% cases) crizotinib pharmacokinetic failures: - CNS - Systemic Activation of other oncogenes: EGFR (>30% cases)

55 Novel ALK/ROS1 kinase inhibitors for ALK or ROS1- positive advanced NSCLCs with resistance to crizotinib Drug Name(s) Clinicaltrials.gov Identifier Phase Description of the Trial Ceritinib LDK378 NCT ALK+ tumors NCT ALK+ NSCLC, crizotinib-naïve patients NCT ALK+ NSCLC, previously treated with chemotherapy and crizotinib NCT ceritinib vs. standard chemotherapy in previously untreated ALK+ NSCLC NCT ceritinib vs. standard chemotherapy in ALK+ NSCLC previously treated with chemotherapy and crizotinib NCT ROS1+ NSCLC, previously treated with chemotherapy Alectinib RO / CH NCT ALK+ NSCLC, previously treated with crizotinib NCT ALK+ NSCLC, previously treated with chemotherapy & crizotinib NCT /2 ALK+ NSCLC, previously treated with crizotinib courtesy of falice Shaw 2014

56 Initial results of the novel ALK/ROS1 kinase inhibitor alectinib (similar results with ceritinib)

57 Initial results of the novel ALK/ROS1 kinase inhibitor ceritinib

58 Therapies for acquired resistance to crizotinib in ALK rearranged NSCLC (awaiting evidence-based recommendations) crizotinib isolated brain- CNS progression local therapy + continue crizotinib ALK rearranged NSCLC acquired resistance a. pharmacokinetic (brain-cns) (systemic) b. biologic (30% ALK mutations) (>30% bypass tracks [EGFR, KIT]) (>40% unknown mechanisms) single site, oligoprogressive asymptomatic, indolent growth, multiple sites symptomatic, multiple sites consider biopsy (research) (clinical trial) local therapy + continue crizotinib continue crizotinib alone cytotoxic chemotherapy +/- crizotinib; or clinical i l trial (novel ALK TKIs: ceritinib,alectinib, others)

Molecular Targets in Lung Cancer

Molecular Targets in Lung Cancer Robert Ramirez, DO, FACP Thoracic and Neuroendocrine Oncology November 18 th, 2016 Disclosures Consulting and speaker fees for Ipsen Pharmaceuticals, AstraZeneca and Merck