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.

2. Faculty Geoffrey R Oxnard, MD Gregory J Riely, MD, PhD David R Spigel, MD Moderator Consensus or Controversy? Clinical Investigators Provide Perspectives on Targeted Treatment of Non-Small Cell Lung Cancer Saturday, September 24, 2016 7:00 AM – 8:00 AM Chicago, Illinois Joel W Neal, MD, PhD

3. Agenda Module 1 – Clinical Algorithms for Biomarker Testing Module 2 – Management of Patients with EGFR Tumor Mutations Module 3 – Management of Patients with ALK and ROS1 Alterations Module 4 – Identification of Other Potentially Targetable Tumor Mutations (MET Exon 14, BRAF V600E, HER2, RET, et cetera) and Implications for Clinical Practice and Ongoing Research

4. In preparation for this meeting, we conducted a survey of 8 lung cancer clinical investigators: Dana-Farber Cancer Institute Memorial Sloan Kettering Cancer Center Sarah Cannon Research Institute Stanford Cancer Institute University of Colorado Cancer Center Jonsson Comprehensive Cancer Center, UCLA Abramson Cancer Center, University of Pennsylvania The Chinese University of Hong Kong

5. Module 1: Clinical Algorithms for Biomarker Testing

6. What type of mutation testing, if any, should be ordered in the first-line treatment of a patient with nonsquamous cell carcinoma of the lung who is a… Multiplex/NGS EGFR, ALK and ROS1; if negative, multiplex/NGS FISH (ALK/ROS1/RET/MET) and NGS Multiplex/NGS EGFR, ALK and ROS1; if negative, multiplex/NGS EGFR, ALK and ROS1 EGFR, ALK and ROS1; if negative, multiplex/NGS Multiplex/NGS EGFR, ALK and ROS1; if negative, multiplex/NGS FISH (ALK/ROS1/RET/MET) and NGS Multiplex/NGS EGFR, ALK and ROS1; if negative, multiplex/NGS EGFR, ALK and ROS1 SmokerNonsmoker

7. What type of mutation testing, if any, should be ordered in the first-line treatment of a patient with squamous cell carcinoma of the lung who is a… None SmokerNonsmoker Multiplex/NGS None FISH (ALK/ROS1/RET/MET) and NGS None EGFR, ALK and ROS1; if negative, multiplex/NGS Multiplex/NGS EGFR, ALK and ROS1; if negative, multiplex/NGS FISH (ALK/ROS1/RET/MET) and NGS Multiplex/NGS EGFR, ALK and ROS1; if negative, multiplex/NGS

8. Frequency of Oncogenic Drivers in Lung Adenocarcinoma Cancer Genome Atlas Research Network. Nature 2014;511(7511):543-50.

9. For patients with metastatic NSCLC who experience disease progression after having exhausted all available treatment options and still have at least a fair performance status, should multiplex/NGS testing be ordered to evaluate for potentially targetable mutations? Not if it would require a new biopsy or if pt already is known to have a genotype (like KRAS or EGFR) Yes

10. Have you observed patients with negative EGFR and/or ALK standard assays obtain “positive” multiplex/NGS test results and then respond to targeted treatment? Yes No

11. Next-Generation Sequencing (NGS) to Identify Actionable Genomic Alterations in “Pan-Negative” Lung Adenocarcinomas from Patients with No Smoking or a Light Smoking History Genomic alteration/s identified with no targeted therapy option No genomic alteration identified Genomic alteration with targeted therapy in NCCN guidelines EGFR G719A BRAF V600E SOCS5-ALK HIP1-ALK CD74-ROS1 KIF5B-RET CCDC6-RET Genomic alteration with targeted agent available on or off a clinical trial CDKN2A loss EGFR L747P EGFR exon 18 del (n = 2) EGFR exon 20 ins ERBB2 L755F FGFR1 T141R KRAS G12C KRAS Q61H MDM2 amp (n = 3) 39% (n = 12/31) 29% (n = 9/31) 6% (n = 2/31) 26% (n = 8/31) Drilon A et al. Clin Cancer Res 2015;21(16):3631-9.

12. Module 2: Management of Patients with EGFR Tumor Mutations

13. In general, what is your usual first-line treatment recommendation for a patient with metastatic NSCLC and an EGFR… Erlotinib Exon 19 deletion mutation Erlotinib Afatinib Gefitinib Exon 21 L858R mutation Exon 20 insertion mutation Erlotinib Gefitinib Chemotherapy +/- bevacizumab Erlotinib for A763_Y764insFQEA, platinum doublet for all others Chemotherapy +/- bevacizumab

14. Meta-Analysis of PFS Benefit Observed with EGFR TKIs: Exon 19 Deletion and Exon 21 L858R Substitution Lee CK et al. J Clin Oncol 2015;33(17):1958-65. TrialHR95% CIHR95% CI Exon 19 deletionsExon 21 L858R substitution ENSURE0.200.12 to 0.330.540.32 to 0.91 EURTAC0.270.17 to 0.430.530.29 to 0.97 LUX-Lung 30.280.18 to 0.440.730.46 to 1.16 LUX-Lung 60.200.13 to 0.320.320.19 to 0.54 NEJ0020.240.15 to 0.380.330.20 to 0.54 OPTIMAL0.130.07 to 0.240.260.14 to 0.48 WJTOG 34050.420.26 to 0.660.690.44 to 1.07 All0.240.20 to 0.290.480.39 to 0.58

15. LUX-Lung 7: Efficacy of Afatinib versus Gefitinib for EGFR- Mutant NSCLC Efficacy Afatinib (n = 160) Gefitinib (n = 159)HR, p-value Median PFS 11.0 mo10.9 mo0.73, 0.017 Median TTF13.7 mo11.5 mo0.73, 0.0073 Median OS*27.9 mo25.0 mo0.87, 0.33 * Data not mature Park K et al. Lancet Oncol 2016;17(5):577-89.

16. For a patient with EGFR mutation-positive NSCLC who initially responds to an EGFR TKI and is now experiencing disease progression, should the patient be evaluated for a T790M mutation? Yes

17. Do you generally perform plasma or tissue biopsy when evaluating for a T790M mutation? Plasma first; if negative, tissue Tissue unless not easy or high risk, then plasma Plasma first; if negative, tissue

18. Do you generally use urine mutation assays when evaluating for a T790M mutation? No, too early for clinical application No No, too early for clinical application No Yes, sometimes, concurrent with plasma No, too early for clinical application

19. Association between Plasma Genotyping and Outcomes with Osimertinib Outcome Tumor T790M+ Tumor T790M- Plasma T790M+ Plasma T790M- ORR (n = 173, 58, 164, 102)62%26%63%46% Median PFS (n = 179, 58, 169, 104)9.7 mo3.4 mo9.7 mo8.2 mo Sensitivity of plasma genotyping for detection of EGFR mutations: –T790M: 70% –Exon 19 del: 82% –Exon 21 L858R: 86% Plasma positive for T790M in 31% of cases negative for T790M in tumor Oxnard GR et al. J Clin Oncol 2016;34(28):3375-82.

20. Plasma and Urine Detection Is Sensitive and Complements Tissue T790M Testing Wakelee HA et al. Proc ASCO 2016;Abstract 9001. In T790M-positive patients, response was similar whether status was identified by plasma, tissue or urine. Plasma vs tissue T790M Tissue Total PositiveNegativeInadequate Plasma (BEAMing) Positive3132338374 Negative7417 108 Total3874055482 Urine vs tissue T790M Tissue Total PositiveNegativeInadequate Urine Positive1421116169 Negative315642 Inadequate2002 Total1751622213 Tissue as reference, urine sensitivity = 81.1% (142/175) Tissue as reference, plasma sensitivity = 80.9% (313/387)

21. Plasma, Tissue and Urine Identify Unique and Overlapping Subsets of T790M-Positive Patients Wakelee HA et al. Proc ASCO 2016;Abstract 9001. 181 samples with matched pretreatment T790M results in plasma, tissue and urine 57% were positive by all 3 sample types

22. In general, what would be your most likely systemic therapy recommendation for a patient with EGFR mutation-positive nonsquamous NSCLC who responded to erlotinib and is now experiencing disease progression and has a biopsy-proven T790M mutation? Osimertinib

23. Change in Tumor Size with Osimertinib (AZD9291) in EGFR TKI-Resistant T790M-Mutation Positive and Negative NSCLC D = study discontinuation EGFR T790M-PositiveORR = 61% N = 127 evaluable EGFR T790M-NegativeORR = 21% N = 61 evaluable Jänne PA et al. N Engl J Med 2015;372(18):1689-99.

24. Select Adverse Events with Osimertinib (AZD9291) Osimertinib (N = 253) Any gradeGrade 3-5 Diarrhea47%2% Nausea22%<0.5% Rash40%1% Pruritus19%0% Decreased appetite21%1% Constipation16%0% Hyperglycemia6 (2.4%) QT prolongation11 (4.3%) Pneumonitis-like event6 (2.4%) Jänne PA et al. N Engl J Med 2015;372(18):1689-99.

25. Osimertinib Platinum-based doublet chemotherapy www.clinicaltrials.gov. NCT02151981 Target accrual (N = 410) Locally advanced or metastatic, EGFR mutation-positive NSCLC Disease progression after first-line EGFR TKI therapy T790M-positive Primary Endpoint: Progression-free survival Key Secondary Endpoints: Objective response rate, overall survival and safety AURA3: A Phase III Study of Osimertinib versus Platinum- Based Doublet Chemotherapy for Locally Advanced or Metastatic NSCLC R 2:1

26. Press Release — July 18, 2016 Osimertinib met primary endpoint in Phase III second-line lung cancer trial "The AURA3 Phase III trial met its primary endpoint, demonstrating superior progression-free survival (PFS) compared to standard platinum- based doublet chemotherapy. In addition to PFS, the objective response rate (ORR), disease control rate (DCR) and duration of response (DoR) also achieved clinically meaningful improvement versus chemotherapy." https://www.astrazeneca-us.com/content/az-us/media/press-releases/2016/TAGRISSO-osimertinib-met- primary-endpoint-in-phase-III-2nd-line-lung-cancer-trial-18072016.html

27. Osimertinib Erlotinib OR gefitinib www.clinicaltrials.gov. NCT02296125 Eligibility (N = 650) Advanced EGFR mutation-positive NSCLC Primary Endpoint: Progression-free survival Key Secondary Endpoints: Overall response rate, overall survival and quality of life 1:1 FLAURA: A Phase III Study of Osimertinib versus a Standard-of-Care EGFR TKI as First-Line Treatment for EGFR Mutation-Positive Locally Advanced or Metastatic NSCLC R

28. Osimertinib Placebo www.clinicaltrials.gov. NCT02511106 Eligibility (N = 700) Stage IB-IIIA EGFR mutation-positive NSCLC Primary Endpoint: Disease-free survival Key Secondary Endpoints: Overall survival and quality of life ADAURA: A Phase III Study of Osimertinib versus Placebo for EGFR Mutation-Positive Stage IB-IIIA NSCLC After Complete Tumor Resection with or without Adjuvant Chemotherapy 1:1 R

29. BLOOM Study Design Yang JC et al. Proc ASCO 2016;Abstract 9002; Ahn MJ et al. Proc ASCO 2016;Abstract 9003.

30. BLOOM: Time on Treatment with Osimertinib for Patients with Leptomeningeal Carcinomatosis Yang JC et al. Proc ASCO 2016;Abstract 9002. Response (n = 21): Confirmed 33%; unconfirmed 5% Neurological improvement: n = 5 Clearance of tumor cells from CSF: n = 2 Adverse events: As expected, manageable

31. * * PD * BLOOM: Antitumor Activity of AZD3759 Ahn MJ et al. Proc ASCO 2016;Abstract 9003. Response (n = 21): Confirmed 3; unconfirmed 3 8/22 pts with measurable extracranial lesions had tumor shrinkage Adverse events similar to other approved EGFR inhibitors, mainly rash and diarrhea * Confirmed PR

32. Summary of Third-Generation EGFR TKIs Currently in Development AgentKey active studies HM61713 (BI 1482694) NCT01588145: Phase I/II trial to evaluate safety, tolerability and pharmacokinetic profile of HM61713 (BI 1482694) in NSCLC patients NCT02444819: Phase II trial to evaluate the efficacy and safety of HM61713 (BI 1482694) as 1 st -line NSCLC anticancer therapy NCT02485652: Phase II trial of HM61713 (BI 1482694) for the treatment of ≥2 nd -line T790M mutation- positive adenocarcinoma of the lung ASP8273 NCT02500927: A study of ASP8273 in EGFR TKI-naïve patients with NSCLC harboring EGFR mutations NCT02192697: An open study of ASP8273 in patients with NSCLC who have EGFR mutations NCT02113813: A dose-escalation study of ASP8273 in subjects with NSCLC who have EGFR mutations NCT02588261: A study of ASP8273 vs erlotinib or gefitinib in first-line treatment of patients with Stage IIIB/IV NSCLC with EGFR activating mutations (SOLAR) EGF816 NCT02323126: Study of efficacy and safety of nivolumab in combination with EGF816 in patients with previously treated NSCLC NCT02335944: Study of safety and efficacy of EGF816 in combination with INC280 in NSCLC patients with EGFR mutation NCT02108964: A Phase I/II, multicenter, open-label study of EGFRmut-TKI EGF816, administered orally in adult patients with EGFRmut solid malignancies PF-06747775NCT02349633: Study for patients with NSCLC EGFR mutations (Del 19 or L858R +/- T790M) www.clinicaltrials.gov

33. Efficacy of ASP8273 Best Improvement from Baseline in Sum of Tumor Diameters Yu HA et al. Proc ASCO 2016;Abstract 9050. All patients (n = 63)T790M (n = 58) ORR30%31% PFS6.0 mo

34. ASP8273: Select Adverse Events Adverse event (n = 63)Grade 1 or 2Grade 3 or 4 Diarrhea46%2% Nausea27%0% Hyponatremia6%13% Paresthesia14%0% Six subjects experienced serious treatment-related AEs: anaphylactic reaction, hyponatremia, pancreatitis, squamous cell carcinoma of the skin, urinary tract infection and vertigo Yu HA et al. Proc ASCO 2016;Abstract 9050.

35. In general, what would be your most likely systemic therapy recommendation for a patient with EGFR mutation-positive nonsquamous NSCLC who responded to erlotinib and is now experiencing disease progression and is T790M mutation- negative? Chemotherapy

36. In general, how do you sequence immune checkpoint inhibitors for patients with metastatic NSCLC with tumor mutations? After targeted therapy and platinum chemo, sometimes after second chemo if PD-L1-negative After targeted therapy and 1-2 lines of chemo After targeted therapy and after or before chemo, depending on status Third or fourth line after EGFR TKIs and chemo Salvage therapy After targeted agents and first-line chemo exhausted Fourth line after targeted agents and chemo After targeted agents and chemo options exhausted

37. Association between Overall Survival and EGFR Mutation Status in Response to PD-1 Pathway Blockade Borghaei H et al. N Engl J Med 2015;373(13):1627-39; Herbst RS et al. Lancet 2016;387(10027):1540-50. CheckMate 057: Nivolumab vs docetaxel KEYNOTE-010: Pembrolizumab vs docetaxel SubgroupNo. of patientsUnstratified hazard ratio EGFR mutation status Positive821.18 Not detected3400.66 Not reported1600.74 Mutant46/860.88 Wild-type447/8750.66 Favors docetaxel Nivolumab betterDocetaxel better Favors pembrolizumab

38. Association between Response Rates to PD-1 Pathway Blockade and EGFR and ALK Status in NSCLC Gainor JF et al. Clin Cancer Res 2016;22(18):4585-93. ORR EGFR-mutant or ALK-positive EGFR WT/ALK- negative P = 0.053

39. Module 3: Management of Patients with ALK and ROS1 Alterations

40. What would be your preferred first-line systemic therapy recommendation for a patient with metastatic nonsquamous NSCLC that is demonstrated to have an ALK rearrangement (cost and reimbursement issues aside)? Crizotinib Alectinib Crizotinib Alectinib Crizotinib

41. J-ALEX Study: Progression-Free Survival (ITT) Nokihara H et al. Proc ASCO 2016;Abstract 9008. Consistent benefit observed with alectinib in all subgroups Patients with brain metastases: HR 0.08 favoring alectinib Events, n (%)25 (24.3%)58 (55.8%) Median, moNR10.2 p-value<0.0001 HR0.34

42. ALEX Phase III Study Design In comparison to crizotinib, alectinib demonstrated statistically significant improvement in PFS in the Japanese Phase III parallel trial J-ALEX (HR = 0.34, p < 0.0001). Ou SHI et al. Proc ASCO 2015;Abstract 8008; Nokihara H et al. Proc ASCO 2016;Abstract 9008. R ALK+ Stage IIIB/IV or recurrent NSCLC Chemotherapy naïve ECOG PS 0-2 Alectinib 600 mg BID (n = 143) Crizotinib 250 mg BID (n = 143) Until PD* or premature withdrawal (eg, due to toxicity) Subsequent therapy and survival follow-up 1:1 * Determined by investigators, based on RECIST v1.1

43. In general, what would be your preferred choice of second-line therapy for a patient with ALK-rearranged metastatic nonsquamous cell cancer of the lung who experiences disease progression on crizotinib? Alectinib Ceritinib or alectinib — coin flip Alectinib Ceritinib (alectinib not available in Hong Kong)

44. N Engl J Med 2014;370(13):1189-97. Phase I dose-escalation study (50 to 750 mg)

45. Reduction in Tumor Size in Patients Receiving Ceritinib Overall response rate (ORR): 58% ORR, prior crizotinib: 56% Shaw AT et al. N Engl J Med 2014;370(13):1189-97.

46. Select Adverse Events Suspected to Be Related to Ceritinib Therapy 750 mg/day (n = 81) Adverse eventAny gradeGrade ≥3 Diarrhea83%7% Nausea83%7% Vomiting65%6% Abdominal pain38%Not reported Constipation36%Not reported Elevated ALT level41%23% Elevated AST level27%12% Hypophosphatemia11%2% Maximum tolerated dose of ceritinib was 750 mg once daily. Dose-limiting toxicities included diarrhea, vomiting, dehydration, elevated AST level and hypophosphatemia. Shaw AT et al. N Engl J Med 2014;370(13):1189-97.

47. Phase II Study: Activity of Alectinib in Patients with Crizotinib-Resistant ALK-Positive NSCLC Ou SHI et al. Proc ASCO 2015;Abstract 8008. Objective response rate: Chemo naïve (n = 26): 69% Prior chemo (n = 96): 45% All patients (n = 122): 50% * Chemotherapy-naïve patients Sum of longest diameter, maximum decrease from baseline (%) Systemic best OR: PD (n = 22)SD (n = 35)PR (n = 61)

48. Activity of Alectinib in Patients with ALK-Positive NSCLC and Measurable CNS Metastases Ou SHI et al. Proc ASCO 2015;Abstract 8008. 27.4% complete CNS response in all pts 43.5% complete CNS response in pts with untreated CNS metastases 57.1% objective CNS response in pts with measurable disease Prior CNS radiation: Yes (N = 24) No (N = 11) Sum of longest diameter, maximum decrease from baseline (%)

49. Treatment-Related Adverse Events (AEs) with Alectinib (8% discontinued due to AEs) AE in ≥5% patientsGrade 1-2Grade 3-4 Myalgia16%1% Constipation14%0% Fatigue13%1% Asthenia10%1% AST elevation9%2% ALT elevation8%2% Photosensitivity9%0% Rash9%0% Peripheral edema8%1% Bilirubin elevation6%1% Nausea6%0% Diarrhea4%1% Ou SHI et al. Proc ASCO 2015;Abstract 8008.

50. In general, what would be your preferred choice of second-line therapy for a patient with metastatic nonsquamous cell cancer of the lung and a ROS1 rearrangement who experiences disease progression on crizotinib? Chemotherapy Ceritinib or brigatinib (if available on compassionate use) Chemotherapy

51. Module 4: Identification of Other Potentially Targetable Tumor Mutations (MET Exon 14, BRAF V600E, HER2, RET, et cetera) and Implications for Clinical Practice and Ongoing Research

52. Outside of a protocol setting, do you generally use targeted therapy for patients with NSCLC and a MET exon 14 skipping mutation? Crizotinib in second or third line Crizotinib in first line Have not yet but would use crizotinib in first line Crizotinib in second or third line Crizotinib in first line Crizotinib after first line Crizotinib in first line Crizotinib in second or third line

53. Antitumor Activity of Crizotinib in Advanced MET Exon 14- Altered NSCLC Drilon AE et al. Proc ASCO 2016;Abstract 108. Maximum Response to Crizotinib in Patients with MET Exon 14-Altered Lung Cancers (n = 16 with measurable disease at baseline and ≥1 response assessment scan) Partial response (PR), confirmed Stable disease: includes 4 unconfirmed PRs Stable disease and 0% change from baseline 20 0 -20 -40 -60 -80 -100 % change from baseline ** *

54. Which targeted therapy, if any, do you use for a patient with metastatic NSCLC with a BRAF V600E tumor mutation? At what point during treatment do you generally use a BRAF inhibitor, with or without a MEK inhibitor, for patients with metastatic NSCLC and a BRAF V600E mutation? Dabrafenib with trametinib Targeted therapyLine of treatment Dabrafenib with trametinib Vemurafenib Dabrafenib with trametinib Second line First line Second line First line Second line First line Second line

55. Dabrafenib and Trametinib in BRAF V600E-Mutant Metastatic NSCLC Planchard D et al. Lancet Oncol 2016;17:984-93. Overall response rate: 63% Disease control rate: 79% 40 20 0 -20 -40 -60 -80 -100 Patients Maximum reduction from baseline measurement, % Best confirmed response CR PR SD PD NE NE patients did not have a follow-up scan required for confirmation.

56. Outside of a protocol setting, do you generally use targeted therapy for patients with metastatic NSCLC and a tumor RET rearrangement? No, lots of trials available for these patients Cabozantinib in second line No Cabozantinib in second line or beyond Cabozantinib in second line Cabozantinib after first line Cabozantinib or vandetanib in second or third line Alectinib, vandetanib or sorafenib in second or third line

57. Response to Cabozantinib Drilon AE et al. Proc ASCO 2015;Abstract 8007. PR = partial response; SD = stable disease; ORR = overall response rate Confirmed PR SD Best response% (n) PR44% (7/16) Confirmed Unconfirmed 38% (6/16) 6% (1/16) SD56% (9/16) ORR 38% (95% CI 15%-65%) ORR 12wks 36% (95% CI 13%- 65%) (5 PRs of 14 evaluable at 12 wks)

58. Outside of a protocol setting, do you generally use targeted therapy for patients with metastatic NSCLC and a tumor HER2 mutation or amplification? Afatinib in second or third line No Afatinib in second line or beyond Trastuzumab in second line Afatinib after first line Trastuzumab/afatinib in second or third line Afatinib in second or third line