EGFR and ALK TKI Therapy in Advanced NSCLC: Molecular Basis and When and Why to Stop or Change

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1 EGFR and ALK TKI Therapy in Advanced NSCLC: Molecular Basis and When and Why to Stop or Change Paul A. Bunn, Jr, MD, Dudley Chair and Professor, Univ. of Colorado Cancer Center, Aurora, CO, USA Consultant: Amgen, Astellas, AstraZeneca, Bayer, Biodesix, Boehringer- Ingelheim, BMS, Celegene, Daiichi- Sankyo, Eli Lilly, Eisai, GSK, Merck, Merck-Serono, Novartis, Roche, Sanofi

2 2012 Treatment Algorithm

3 Imatinib: Tyrosine Kinase Inhibitor IMATINIB Imatinib

4 Positions of Mutations Detected in EGFR Tyrosine Kinase Domain in NSCLC EGF ligand binding Tyrosine kinase Autophosphorylation TM K DFG Y Y Y Y Exon: Paez: GXGXXG K R H DFG L L Y Lynch: Pao: G719 L858 Tumor with point mutation (amino acid substitution) Tumor with in-frame deletion Activation loop EGF = endothelial growth factor; TM = transmembrane. Adapted from: Pao et al. Proc Natl Acad Sci U S A. 2004;101:13306; Lynch et al. N Engl J Med. 2004;350:2129; Paez et al. Science. 2004;304:1497.

5 Gandhi J. PLoS ONE 2009;e4576 EGFR TKI Sensitivity in NSCLC Cell Lines Correlates with Mutational Status

6 Randomized Trials of EGFR TKI vs CT in 1st Line Rx Study Response Rate PFS EURTAC 58.1% vs 14.9% 9.7 vs 5.2 mo (HR 0.37) OPTIMAL 83% vs 36% 13.1 vs 4.6 mo (HR 0.16) NEJ % vs 31% 10.8 vs 5.4 mo (HR 0.30) WJTOG % vs 31% 9.2 vs 6.3 mo (HR 0.49) IPASS 71% vs 47% 9.5 vs 5.5 mo (HR 0.19) LUX LUNG 3 56% vs 23% 11.1 vs 6.9 mo (HR 0.58) Mitsudomi T. Lancet Oncol 2010;11: Maemondo M. N Engl J Med 2010;362: Zhou C. Lancet Oncol 2011;12: Rosell R. Lancet Oncol. 2012; 13: Mok T. N Engl J Med 2009;361: Yang JCH. J Clin Oncol 2012 (Proc ASCO Annual Meeting) ;30:LBA7500

7 Crizotinib: Small Molecule TKI of c-met, ALK and ROS1 Co-crystal structure of crizotinib (PF ) bound to c-met Anaplastic Lymphoma Kinase: Initially identified in Anaplastic Large Cell Lymphoma (ALCL):2;5 translocation fusing NPM to ALK Point mutations in neuroblastoma Novel fusion identified in 2007 in NSCLC; EML4-ALK Cui et al. J Med Chem 54: , 2011 and Pfizer data on file

8 ALK Rearrangement and FISH ALK EML4 3 ALK EML4 5 ALK EML4 Camidge DR. Clin Cancer Res 2010; 16:

9 ALK-Positive NSCLC Study A OR, PFS, OS with Crizotinib Best Response (N*=106) Retrospective comparison in ALK-positive patients Treated: from 1001 study Naïve: patient series from study sites OS PFS OS Median PFS = 10.0 mo Median OS: NR (79% pts still in f/u) Survival probability 6 months: 90.0% 12 months: 80.5% Kwak EL. N Engl J Med 2010;363: Shaw AT. Lancet Oncol. 2011;12:

10 Ongoing randomized trials of crizotinib in ALK+ NSCLC PROFILE 1007 (N=318) ALK-FISH positive 1 prior chemotherapy (platinum-based) R A N D O M I Z E Crizotinib 250 mg BID (n=159) [continuous] pemetrexed 500 mg/m 2 or docetaxel 75 mg/m 2 (n=159) infused on day 1 of a 21-day cycle PROFILE 1014 (N=334) ALK-FISH positive, non-squamous NSCLC No prior treatment for advanced disease Clinicaltrials.gov R A N D O M I Z E Crizotinib 250 mg BID (n=167) [continuous] Crossover on PD pemetrexed/cisplatin or pemetrexed/carboplatin (n=167) infused on day 1 of a 21-day cycle

11 EGFR/ALK TKI Duration Continue until symptomatic progression Consider local RX (eg brain RT) for single site progression Consider continuing or resuming after next line of therapy at symptomatic progression

12 Results of the BFR14 Trial of Imatinib in GIST Long-Term Survival The rates of patients with relapse at 2 y post-randomization decreased with treatment duration: 38%, 20%, and 0% of patients randomized after 1, 3, and 5 years of imatinib treatment in the C-arm Comparison of PFS in continuation arm Reduced relapse rate with longer treatment Le Cesne. J Clin Oncol 2011 (Proc ASCO Annual Meeting);29 (suppl): Abstract 10015

13 Mok T. Proc IASLC Santa Monica Worshop, 2011 RECIST Criteria for Progression A Signal to Stop the EGFR TKI?

14 Patient Treated with Gefitinib Since 2005 Exon-19 Mutation Positive Lung Cancer Aug 2008 Oct 2008 Apr 2009 Aug 2009 Dec 2009 May 2010

15 MSKCC FDG PET and CT Effects of Discontinuation and Re-Initiation of Gefitinib or Erlotinib in Patients With Acquired Resistance Riely G. Clin Cancer Res 2007;13:

16 Changes in Tumor Diameter (RECIST) After Discontinuation and Re-introduction of EGFR TKI Riely G. Clin Cancer Res 2007;13:

17 ALK+ Tumor Progression Within Brain Shaw AT. Lancet Oncol 2011;12: * Brain metastases at any point in course of disease 52% ALK+ crizotinib naive 47% ALK+ crizotinib treated Brain metastases on treatment Weickhardt AJ. J Clin Oncol 2012 (Proc ASCO Annual Meeting);30(suppl): Abstract 7526* Costa DB. J Clin Oncol 2011;29:e % as site of first progression, (85% of whom had CNS as sole site of first progression) At CNS progression: CSF:plasma ratio = (i.e. <0.3% gets into brain) *Retrospective series, CNS imaging/timing not mandated

18 Treatment of Isolated CNS Progression and Continuation of Relevant TKI in Oncogene Addicted NSCLC is Associated with >7 months Prolonged Disease Control Number of patients 10 PFS1 (95% CI) 10.9 months PFS2 (95% CI) 7.1 months = Monitor CNS on therapy = CNS progression may not mean failure of drug (just of drug delivery) Weickhardt AJ. J Clin Oncol 2012 (Proc ASCO Annual Meeting);30(suppl): Abstract 7526

19 Continuation of TKI + Local Rx for TKI PD on Erlotinib or Crizotinib study N pts PFS1 PFS2 Colorado MSKCC Weickhardt AJ. J Clin Oncol 2012 (Proc ASCO Annual Meeting);30(suppl): Abstract 7526 Yu A. J Clin Oncol 2012 (Proc ASCO Annual Meeting);30(suppl): 7527

20 SELECT: Adjuvant Erlotinib Neal J. J Clin Oncol 2012 (Proc ASCO Annual Meeting);30(suppl):abstr 7010

21 Randomized Study on Treatment-Beyond- Progression EGFR TKI EGFR TKI till PD By doctor Discretion* Advance stage NSCLC with EGFR Mutation PD By RECIST Primary endpoint: OS Platinum-based Doublet Chemotherapy *Doctor Discretion: Symptomatic progression, multiple progression Threat to major organ etc

22 EGFR/ALK TKI: What to Do at SX PD Rebiopsy to determine cause. Select therapy based on established cause or standard chemotherapy if no cause can be established. Consider continuing TKI through next line of chemo or reinstituting TKI after PD on chemo.

23 Determination of Biological Resistance Mechanisms: Analysis of Growing Lesions Following TKI ffailure Doebele RC. J Clin Oncol 2012 (Proc ASCO Annual Meeting);30(suppl):7504

24 Tyrosine Kinase Inhibitor Resistance TKI TKI x TKR TKR TKR Adenoca. Adenoca. Adenoca.

25 Defined Mechanisms of Acquired Resistance to EGFR TKIs Sequist L. Sci Transl Med 2011; 3(75):75ra26

26 EGFR TKI-Resistant EGFR Mutant NSCLC: Afatinib(BIBW2992) + Cetuximab NOTE: Preliminary Efficacy Appears Equivalent in T790M cancers Horn L. J Thor Oncol 2011;6(Suppl 2): S361-S36 (Proc of the 14th WCLC: abstract O19.07).

27 CO-1686 Causes Tumor Shrinkage in L858R/T790M (Double Mutant) Model CO-1686 and erlotinib administered PO QD for 24 days; BIBW administered IP QD for 24 days

28 Clovis Launching 2 Global Phase 1/2 Trials Parallel US/EU/AU and Asia Pacific trials Targeted patient population EGFR mutation positive patients in escalation phase EGFR mutation positive and T790M positive patients in phase II expansion phase Tumor tissue and blood collected for T790M diagnostic evaluation

29 Mechanisms of Crizotinib Resistance Doebele R. Clin Cancer Res 2012;18:

30 ALK Mutations/CNG: ALK Dominant Mechanisms of Resistance Doebele R. Clin Cancer Res 2012;18:

31 Differential Sensitivity of ALK Mutations to Next Generation ALK Kinase Inhibitors. Clinically Relevant: Systemically or CNS? Zhang S. Proc 101st Annual Meeting of the AACR 2010; Abstract LB.298. Katayama R. Sci Transl Med 2012;4:120ra17

32 LDK378 Shows Antitumor Activity in ALK+ NSCLC Initial dose (mg) Patients (n) Responses NSCLC < (25) (67) Other diseases Response rate 81% (21/26) in NSCLC patients treated at 400 mg who progressed following crizotinib Responses include confirmed + unconfirmed per RECIST 1.0 (6 patients with PR awaiting confirmatory scans) Mehra R. J Clin Oncol 2012 (Proc ASCO Annual Meeting);30(suppl):abstr 3007

33 Antitumor Activity in Brain Metastases at the MTD, 750 mg Baseline After 6 weeks on LDK378

34 EGFR as a Mechanism of Resistance: Ligand-Driven Clinical Data *compared to baseline Increased* Decreased* Unchanged* Mixed* 3/9 increased (one overlapping with ALK mutation) 2/9 decreased 3/9 unchanged 1/9 mixed patchy increased and unchanged Katayama R. Sci Transl Med 2012;4:120ra17

35 Clinical Data on HSP90 in Crizotinib naïve ALK+ NSCLC Wong K. J Clin Oncol 2011 (Proc ASCO Annual Meeting); 29 (suppl):abstr 7500 (Synta STA9090) Sequist L. J Clin Oncol 2010; 28: (Infinity IPI-504)

36 15th World Conference on Lung Cancer