1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

3. EML4-ALK translocations and crizotinib Heather Wakelee, MD Assistant Professor of Medicine, Oncology Stanford University/Stanford Cancer Center

4. Soda et al. Nature 2007

5. ALK Pathway Translocation Or ALK ALK fusion protein Tumor cell proliferation Inversion Cell survival PI3K BAD AKT STAT3/5 mTOR S6K RAS MEK ErK PLC- Y PIP 2 IP 3 With permission from Bang ASCO 2010

6. ~250 kb~300 kb t(2;5) ALK gene breakpoint region 2p23 regionTelomere Centromere 3’ 5’ FISH Assay for ALK Rearrangement* Break-apart FISH assay for ALK-fusion genes ALK 29.3 EML4 42.3 ALK break-apart FISH assay [Courtesy John Iafrate, Massachusetts General Hospital] q36.1 q36.3 q37.2 q34 q32.1 q32.3 q33.2 q31.3 q24.3 q24.1 q23.2 q22.2 q22.1 q21.2 q14.3 q14.1 q12.3 q12.1 p12 p13.2 p14 p16.1 p16.3 p22.1 p23.2 p22.3 p24.1 p24.3 p25.2 q36.1 q36.3 q37.2 q34 q32.1 q32.3 q33.2 q31.3 q24.3 q24.1 q23.2 q22.2 q22.1 q21.2 q14.3 q14.1 q12.3 q12.1 p12 p13.2 p14 p16.1 p16.3 p22.1 p23.2 p22.3 p24.1 p24.3 p25.2 Split signal Non-split signal *Assay is positive if rearrangements can be detected in ≥15% of cells FISH = fluorescence in situ hybridization With permission from Bang ASCO 2010

7. Crizotinib: First-in-human ALK Inhibitor Potent and selective ATP competitive oral inhibitor of ALK and MET tyrosine kinases and their oncogenic variants Safety and activity of crizotinib examined in an expanded cohort of patients with advanced ALK-positive NSCLC 1 Crizotinib administered at the MTD of 250 mg PO twice daily 1 Kwak et al. NEJM 2010;363:1693-703 Shaw ASCO 2011, Lancet Oncology 12:1004, 2011

8. Clinical and Demographic Features of ALK- Positive and ALK-Negative NSCLC Patients ALK Controls N=36 WT/WT Controls N=253 p-value Age, yrsMedian 5164 <0.001 Range 32–7827–87 Sex, nM/F 16/20108/145 0.86 Race, n (%)Caucasian 31 (86)231 (92) 0.47 Asian 3 (8)15 (6) Smoking history, n (%)Never smoker 24 (67)63 (25) <0.001 ≤ 10 pack-years 7 (19)32 (13) > 10 pack-years 5 (14)158 (62) Histology, n (%)Adenocarcinoma 34 (94)223 (88) 0.39 Squamous 1 (3)10 (4) Other 1 (3)20 (8) Brain metastases*No/Yes 19/17147/105 0.59 * At any time Shaw ASCO 2011, Lancet Oncology 12:1004, 2011

9. 60 40 20 0 –20 –40 –60 –80 –100 Progressive disease Stable disease Confirmed partial response Confirmed complete response Maximum change in tumor size (%) –30% Tumor Responses to Crizotinib for Patients with ALK-positive NSCLC * With permission from Bang ASCO plenary 2010 N= 76

10. Treatment-related Grade 3/4 Adverse Events in ALK-positive NSCLC Adverse event Grade 3 n (%) Grade 4 n (%) Any adverse event10 (12)1 (1) ALT elevation*4 (5)1 (1) AST elevation5 (6)0 Lymphopenia2 (2)0 Hypophosphatemia1 (1)0 Neutropenia1 (1) 0 Hypoxia1 (1)0 Dyspnea1 (1) 0 Pulmonary embolism1 (1)0 * Based on laboratory data (n=71), ALT increase to grade 1, 52%; to grade 2, 4%; 1 patient discontinued for ALT elevation Bang ASCO 2010

11. Crizotinib Survival Analysis: Study Objectives Examine overall survival of crizotinib-treated ALK-positive NSCLC patients Compare the survival outcomes of crizotinib- treated vs crizotinib-naïve, ALK-positive NSCLC patients Explore the prognostic significance of ALK rearrangement by comparing the survival outcomes of crizotinib-naïve ALK-positive and ALK-negative NSCLC patients Shaw ASCO 2011, Lancet Oncology 12:1004, 2011

12. Study Populations ALK CRIZOTINIB ALK-positive Crizotinib-treated N=82 US/Australia N=56 2 nd /3 rd line N=30 ALK CONTROLS US/Australia N=36 2 nd line N=23 Never/light smoker AdenoCA N=21 ALK-positive Crizotinib-naïve WT/WT CONTROLS US (MGH) N=253 2 nd line N=125 Never/light smoker AdenoCA N=48 ALK-negative EGFR- wildtype Never/light smoker AdenoCA N=28 Shaw ASCO 2011, Lancet Oncology 12:1004, 2011

13. Clinical and Demographic Features of Crizotinib- Treated and Control ALK-Positive NSCLC Patients ALK Crizotinib N=56 ALK Controls N=36 p-value Age, yrsMedian 51 0.90 Range 28–7832–78 Sex, nM/F 30/2616/20 0.52 Race, n (%)Caucasian 48 (86)31 (86) 1.00 Asian 4 (7)3 (8) Smoking history, n (%)Never smoker 46 (82)24 (67) 0.25 ≤ 10 pack-years 7 (13)7 (19) > 10 pack-years 3 (5)5 (14) Histology, n (%)Adenocarcinoma 54 (96)34 (94) 0.64 Squamous 1 (2)1 (3) Other 1 (2)1 (3) Brain metastases*No/Yes 27/2919/17 0.83 * At any time Shaw ASCO 2011, Lancet Oncology 12:1004, 2011

14. Treatment Histories of Crizotinib-Treated and Control ALK-Positive NSCLC Patients ALK Crizotinib N=56 ALK Controls N=36 p-value Lines of therapy*Median 22 0.68 Range 0–70–71–41–4 Types of therapies, n (%)Platinum 44 (79)30 (83) 0.79 Pemetrexed 30 (54)24 (67) 0.28 Erlotinib 27 (48)16 (44) 0.83 * For metastatic disease Shaw ASCO 2011, Lancet Oncology 12:1004, 2011 Pemetrexed may lead to prolonged PFS in ALK+ pts Camidge et al. JTO 6:774, 2011 Balanced for age, gender, but more with smoking history in control group

15. ALK Crizotinib (n=30) ALK Control (n=23) Median Survival, moNR 6 1-yr Survival, %70 44 WT/WT Control (n=125) 11 47 From 2 nd /3 rd line crizotinib 2-yr Survival, %55 12 32 HR = 0.49, p = 0.02 Overall Survival 2 nd Line Subset Shaw ASCO 2011, Lancet Oncology 12:1004, 2011

16. Limitations of the Study Retrospective nonrandomized study design with potential imbalances among the study populations Potential confounding of survival outcomes by post-crizotinib therapies Small numbers in subset analyses Shaw ASCO 2011, Lancet Oncology 12:1004, 2011

17. Resistance to Crizotinib Resistance to crizotinib develops, usually in < 1yr Cell line work of acquired resistance revealed 1 : –Amplification of EML4-ALK, secondary mutation (L1196M - gatekeeper) Analysis of pts with secondary resistance revealed 2 : –Secondary resistance mutations in ALK TK domain 3 –Increase in ALK CNG –Growth of other NSCLC clones (EGFR, KRAS) HSP90 inhibitors show promise 1-Katayama Proc NAS 108:7535, 2011 2-Doebele Clin Ca Res Epub, 2012 3-Choi NEJM 363:1734, 2010

18. Research To Practice could not obtain permission to reproduce this slide at the time of publication. For further information, please see the following: Ramalingam S et al. Heat Shock Protein 90 Inhibitors in Lung Cancer: Shock and Awe? Presentation. ASCO 2011. No abstract available

19. Crizotinib Summary Crizotinib highly effective in pts w/ ALK FISH+ NSCLC Better diagnostics under development Survival benefit demonstrated Role as 1 st line therapy under investigation –Currently in NCCN guidelines Resistance in < 1 yr a major issue –Mechanisms, 2 nd mutations, growth of other clones HSP90 inhibitors, other strategies in development

20. Saturday, February 11, 2012 Hollywood, Florida Faculty Co-Chairs Rogerio C Lilenbaum, MD Mark A Socinski, MD Co-Chair and Moderator Neil Love, MD Chandra P Belani, MD John Heymach, MD, PhD Pasi A Jänne, MD, PhD Thomas J Lynch Jr, MD Heather Wakelee, MD