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Prior to the start of the program, please check your syllabus to ensure you have the following printed program materi

METHOD OF PARTICIPATION. Prior to the start of the program, please check your syllabus to ensure you have the following printed program materials: Pre-activity Survey Located at the front of your syllabus CME Evaluation with Post-activity Survey Located at the back of your syllabus.

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Prior to the start of the program, please check your syllabus to ensure you have the following printed program materi

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  1. METHOD OF PARTICIPATION • Prior to the start of the program, please check your syllabus to ensure you have the following printed program materials: • Pre-activity Survey • Located at the front of your syllabus • CME Evaluation with Post-activity Survey • Located at the back of your syllabus

  2. Disclosures All relevant financial relationships with commercial interests reported by faculty speakers, steering committee members, non-faculty content contributors and/or reviewers,or their spouses/partners have been listed on page 5 of your program syllabus. Off-label Discussion Disclosure This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

  3. Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: • Review strategies for molecular evaluation of NSCLC • Discuss formulation of treatment plans for patients with NSCLC based on biomarker expression • Review quality measures associated with personalizing treatment for NSCLC • Discuss emerging strategies for the management of NSCLC

  4. Pre-activity Survey • Please remove the Pre-activity Survey from the front of your packet • Your answers are vital to our understanding of the effectiveness of this CME program, and will help shape future educational activities and topics • Please fill in the most appropriate answer(s) for the questions below: • Degree:  MD/DO Nursing Professional PharmD Other: _____________________________ • Specialty: Oncology/Hematology  Thoracic Surgery Pulmonology Internal Medicine Other: ___________

  5. Pre-activity Survey Question 1 Please rate your level of confidence in personalizing treatment strategies for non-small cell lung cancer (NSCLC): 1 2 3 4 5 Not confident Expert

  6. Pre-activity Survey Question 2 Do you routinely order histologic and molecular tests for diagnosing patients and base your treatment decisions on the results from these tests: 1 2 3 4 5 Never Always

  7. Pre-activity Survey Question 3 A 47- year-old patient with stage IIA NSCLC received cisplatin and pemetrexed for 2 years after which she experiences dyspenia and has a pleural effusion. A PET and brain MRI reveal disease limited to the left lung with extensive pleural involvement and mediastinaladenopathy. EGFR testing was repeated and she is found to have an EGFR exon 19 deletion. What is the best therapeutic option at this stage (assuming her effusion is controlled)? • Carboplatin/pemetrexed • Carboplatin/paclitaxel/bevacizumab • Erlotinib or afatinib • Crizotinib

  8. Pre-activity Survey Question 4 A 55-year-old patient is asymptomatic until a routine chest CT revealed diffuse pleural-based lesions on the right hemithorax and a right upper lobe lung mass. A CT guided biopsy of the pleural-based mass revealed TTF-1 positive adenocarcinoma which was negative for EGFR mutation. What is the most appropriate next step for this patient? • Start the patient on chemotherapy • Order testing for ALK • Repeat testing for EGFR • Order testing for ERCC1

  9. Pre-activity Survey Question 5 Which of the following statements are true regarding EGFR mutations in NSCLC? • NSCLC patients with the most common somatic mutations of EGFR are hyper-responsive to EGFR TKIs such as afatinib and erlotinib • The most common NSCLC-associated EGFR mutations are the in-frame deletion in exon 19 and point mutation in exon 21 • EGFR mutational testing should be conducted to personalize therapy • All of the above

  10. Pre-activity Survey Question 6 A 72-year-old male with 40 pack years of smoking history was found to have squamous cell NSCLC which was P63 positive. He was treated with carboplatin and paclitaxel for 4 cycle, had stable disease, but developed peripheral neuropathy. He refuses further chemotherapy but is willing to try a novel agent. Which of the following promising agents would you recommend now? • PD-1 targeted therapy • PARP inhibitor • Heat shock protein 90 inhibitors • EGFR TKI

  11. Annual Cancer Deaths, USMore Deaths Than Breast, Colon and Prostate Cancer Combined Siegel et al, 2013; CA Cancer J Clin 2013;63:11-30.

  12. Lung Cancer : Death Rates & Smoking First Surgeons Generals Report (1964) NCI Cancer Bulletin, 2005.; Vol 2 iss 7.

  13. Screening: NLST trial overview • Eligibility • Age 55-74 • 30 pack year smoking history (quit w/in preceding 15 years • 1:1 randomization of CXR vs low-dose CT annually x 3 • 53,345 patients screened and followed for 2 years • 95% of positive screens were “false positives” • 20% relative mortality reduction-354 vs 442 lung CA deaths • Number needed to screen to prevent one lung cancer death: 320 Clinicaltrials.gov; NCT00047385.

  14. NLST Survival CurvesKaplan-Meier curves for all-cause mortality Lung Cancer Mortality All Mortality Relative reduction in all-cause mortality of 6.7%, p=0.02 1877 deaths in CT group. 2000 in CXR group. NLST, NEJM, 2011;365:395-409.

  15. NSCLC detected at an early stage, with an EGFR mutation Case# 1

  16. Case 1 • A 45 yo never-smoking woman originally from India presents with increasing cough. She has no response to antibiotics. After 1 month a CXR shows a LUL mass. • A CT scan confirms a 3 cm LUL mass • A PET shows uptake in the mass + in the left hilum • She tolerates a left upper lobectomy without complications with final pathology confirming a 2.5 cm adenocarcinoma with 3 positive hilar LNs, 0/14 mediastinal nodes: T2bN1M0 stage IIA CXR = chest x-ray; LUL = left upper lobe; CT = computed tomography; PET = positron emission tomography; LN = lymph node.

  17. Case 1: Question 1 • Would you obtain testing to guide choice of adjuvant chemotherapy? If so, which biomarkers would you test for? A. Yes, ERCC1 B. Yes, ERCC1 / RRM1 C. Yes, ERCC1 / RRM1 / TS D. No

  18. Case 1: Question 1 - Answer • Would you obtain testing to guide choice of adjuvant chemotherapy? If so, which biomarkers would you test for? A. Yes, ERCC1 B. Yes, ERCC1 / RRM1 C. Yes, ERCC1 / RRM1 / TS D. No – recent trials question the utility even further, though never clearly established

  19. Predictive Markers in NSCLC • To date, these prognostic + predictive factors in early stage are retrospective analyses • 15 gene signature from JBR.10 +/- chemo • New gene and miRNA signatures being explored • Potentially PREDICTIVE markers in advanced NSCLC • ERCC1 low: platinum sensitive • RRM1 low: gemcitabine sensitive • Thymidylate synthase (TS) low: pemetrexed sensitive • EGFR mutation: EGFR-TKI sensitive • ALK translocation: ALK TKI sensitive NCCN v.1.2014.

  20. IALT Bio - ERCC1 Old/New • 761 tumors (589) of 1867 total pts on trial • Old 44%: New 77% ERCC1 positive 2008:HR 1.20 [0.91-1.59] New: HR 0.96 [0.74-1.25; P=0.78] • Old 56%: New 23% ERCC1 negative 2008:HR 0.76 [0.59-0.98] New: HR 0.81 [0.50-1.31 P=0.39] • ERCC1 Analysis Conclusions : • Technical biases interfered with prior use of ERCC1 IHC as a predictive marker for platinum chemotherapy • Current antibodies cannot adequately discriminate the ERCC1-202 isoform which is the only active isoform • Highlights importance of assessing multiple isoforms and function in biomarker studies • Functional assays required for better predictive capacity Olaussen KA. NEJM; 355: 983, 2006; Friboulet NEJM, 368:1101, 2013.

  21. Prospective Biomarker Adjuvant Trials Clinicaltrials.gov.

  22. Case 1: Question 2 Which of the following is NOT an appropriate choice of adjuvant chemotherapy for this patient? A. 4 cycles of cisplatin/vinorelbine B. 4 cycles of cisplatin/pemetrexed C. 4 cycles of cisplatin/docetaxel D. 4 cycles of carboplatin/paclitaxel

  23. Case 1: Question 2 - Answer Which of the following is NOT an appropriate choice of adjuvant chemotherapy for this patient? A. 4 cycles of cisplatin/vinorelbine B. 4 cycles of cisplatin/pemetrexed C. 4 cycles of cisplatin/docetaxel D. 4 cycles of carboplatin/paclitaxel Strongest data for A, but B or C are acceptable choices of adjuvant chemotherapy) NCCN v.1.2014.

  24. Lung Adjuvant Cisplatin Evaluation (LACE) Meta-analysis • 5 trials - 4,584 patients • Median follow-up: 5.1 years • OS HR 0.89 [0.82-0.96], p= .005 • Stage IA HR 1.40 [0.95, 2.06] • Stage IB HR 0.93 [0.78, 1.10] • Stage II/III HR 0.83 [0.73, 0.95] Overall, about 5-10% survival benefit at 5 years with chemo therapy in stage II and greater. Strongest data with cisplatin/vinorelbine Pignon et al, JCO 2008, 26(21): 3552-3559.

  25. EGFR Mutation Testing

  26. BR.19 Overall Survival by EGFR Mutation Status and Treatment Sensitizing mutation Wild type 100 Gefitinib Placebo 100 Gefitinib Placebo 80 80 60 Percentage 60 40 Low N Percentage 40 20 20 0 # at Risk 0 1 2 3 4 5 6 Time (Years) 0 Placebo 40 38 32 30 26 6 1 # at Risk 0 1 2 3 4 5 6 Gefitinib 36 29 26 21 17 7 0 Time (Years) Placebo 145 126 118 101 77 34 2 Gefitinib 136 121 105 89 74 21 2 HR (95% C.I.) Gefitinib/Placebo: 1.21 (0.84, 1.73) Log Rank: p=0.301 HR (95% C.I.) Gefitinib/Placebo: 1.58 (0.83, 3.00) Log Rank: p=0.160 Goss ASCO 2010, Abstr 7005.

  27. SELECT: Disease-Free Survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 • 69% of patients completed >90% of therapy • 39% of patients had one or more dose reductions Median follow-up time: 2.7 years Survival Probability 94% 2-Year DFS Censored observation 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 Time from initiating adjuvant erlotinib (Years) Patients at Risk 36 35 34 34 33 19 7 3 1 0 N=36, expanded to 100 pts Neal ASCO 2012; Abstr 7010.

  28. RADIANT : Adjuvant NSCLC +/-Erlotinib RANDOM I Z E • ELIGIBLE: • N=945 • Resected I-IIIA • Lobectomy Required IHC/FISH for EGFR Chemo optional Erlotinib 150 mg poqd X 2 yrs 974 pts enrolled 17% w/ EGFR mut 16% KRAS mut Placebo poqd X 2 yrs DFS as primary endpoint 2:1 Richardson et al WCLC 2011; O28.01.

  29. ALCHEMIST: Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial

  30. Case 1 (continued) • The 45-year-old NS woman with stage IIA NSCLC receives 4 cycles of cisplatin/pemetrexed on the control arm of E1505. She tolerates it reasonably well and does well for 2 years. • Unfortunately 2 years later she develops increasing dyspnea and is found to have a pleural effusion. • Analysis of the effusion is consistent with recurrent adenocarcinoma. NS = never-smoking

  31. Case 1: Question 3 • The patient is now 47 years old. A PET and brain MRI reveal disease limited to the left lung with extensive pleural involvement and mediastinaladenopathy. EGFR testing was repeated and she is found to have an EGFR exon 19 deletion. • What would be your choice of therapy (assuming her effusion is controlled)? A. Erlotinib B. Afatinib C. Carboplatin/pemetrexed D. Carboplatin/paclitaxel/bevacizumab E. Erlotinib or Afatinib

  32. Case 1: Question 3 - Answer • What would be your choice of therapy (assuming her effusion is controlled)? A. Erlotinib B. Afatinib C. Carboplatin/pemetrexed D. Carboplatin/paclitaxel/bevacizumab E. Erlotinib or Afatinib - both are FDA approved in this setting

  33. Detecting EGFR Mutations in NSCLC • NSCLC patients with the somatic mutation of EGFR have been shown to be hyper-responsive to the EGFR TKIs • The most common NSCLC-associated EGFR mutations are: – in-frame deletion in exon 19 (E746-A750del) – point mutation in exon 21 (L858R) • These account for 85-90% of EGFR mutations Yu et al; 2008 Molecular Markers Meeting; Abstract No 64.

  34. IPASS: PFS and OS by EGFR Mutation Status OS (2010) PFS (2008) Probability of Survival Probability of Progression-Free Survival 1.0 1.0 Gefitinib EGFR M+ Gefitinib EGFR M- 0.8 0.8 C/P EGFR M+ Mutation + C/P EGFR M- 0.6 0.6 0.4 0.4 0.2 0.2 Mutation - 0.0 0.0 40 48 4 52 8 16 28 12 20 32 36 44 0 24 4 8 16 20 12 24 0 Mos Mos Fukuoka M, et al. J Clin Oncol. 2011;29(21):2866-2874; Yang C-H, et al. European Society of Medical Oncology. 2010. Abstract LBA2.

  35. Treatment Naïve EGFRmut PatientsEGFR TKIs vs Chemotherapy *Approved July 2013 for first-line treatment of lung cancer patients with EGFR mutations. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388; Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128; Mitsudomi T, et al. ASCO 2012. Abstract 7521; Zhou C, et al. Lancet Oncol. 2011;12:735-742; Zhou et al. ASCO 2012. Abstract 7520; Rosell R, et al. Lancet Oncol. 2012;13:239-246; Sequist LV, et al. J Clin Oncol. 2013. [epub ahead of print].

  36. Case 1: Question 4 • She starts on erlotinib and does well for 14 months before her dyspnea returns and she is found to have recurrent pleural disease. • After repeating a biopsy, which of the following steps will NOT be appropriate for this patient? A. Switch to doublet chemotherapy (+/- bevacizumab)…Stop erlotinib – preferred under most circumstances unless a trial is available B. Add doublet chemotherapy (+/- bevacizumab)…Cont erlotinib – can consider but still a trial question C. Switch to a 2nd generation EGFR-TKI or trial D. Switch to crizotinib E. All of the above

  37. Case 1: Question 4 - Answer Which of the following steps will NOT be appropriate for this patient? A. Switch to doublet chemotherapy (+/- bevacizumab)…Stop erlotinib – preferred under most circumstances unless a trial is available B. Add doublet chemotherapy (+/- bevacizumab)…Cont erlotinib – can consider but still a trial question C. Switch to a 2nd generation EGFR-TKI or trial D. Switch to crizotinib E. All of the above

  38. Repeat Biopsies for Patients with Acquired Resistance to EGFR inhibitors SequistSciTransl Med 3:75ra26, 2011

  39. Tumor Regression by T790M Mutation StatusAfatinib + Cetuximabat Recommended Dose Median PFS 4.7 months and median duration of response 7.7 months Horn et al, WCLC 2011, Abstr O19.07.

  40. CO-1686 Summary • 42 pts (74% T790M+) treated w/ CO-1686 up to 1800mg/day • CO-1686 is well tolerated with no evidence of dose related diarrhea or rash • Encouraging activity has been observed in heavily pretreated T790M+ EGFR mutant patients resistant to erlotinib , especially at higher doses • Metastasis shrinkage has been observed at multiple organ sites, including in the CNS • 3 of 4 T790M+ evaluable patients on 900mg bid achieved PRs to date Sequist, abstr 2524 ASCO 2013.

  41. A patient with an EML4-ALK transformation Case # 2

  42. Case 2: History • A 55-year-old male presented with right chest pain, dyspnea and cough. • Chest CT revealed diffuse pleural-based lesions on the right hemithorax and right upper lobe lung mass • 2 cm liver lesion was noted • PMH significant for hypertension and stable coronary artery disease • 10 pack years prior smoking history • CT guided biopsy of a pleural-based mass revealed adenocarcinoma • TTF-1 positive • Tumor specimen was negative for EGFR mutation • ECOG PS=1

  43. Case 2: Question 1 • Which of the following would you do next? • Start the patient on chemotherapy • Order testing for ALK • Order testing for ROS1 • Order testing for ALK and ROS1

  44. Case 2: Question 1 - Answer • Which of the following would you do next? • Start the patient on chemotherapy • Order testing for ALK • Order testing for ROS1 • Order testing for ALK and ROS1 – It is preferable to perform both ALK and ROS1 testing by FISH

  45. Potent oncogenic activity Present in approximately 4-5% of NSCLC More common in Never-smokers Adenocarcinoma Signet ring morphology ALK Fusion Gene Yuan et al J HematolOncol, 2011, 4, 1-16; Shaw et al, 2009, J ClinOncol 27:4247-4253.

  46. ROS1 Rearrangements in NSCLC • Present in ~1% of NSCLC cases (also found in some GBMs and cholangiocarcinomas) • Enriched in younger never or light smokers with adenocarcinoma histology • No overlap with other oncogenic drivers TPM3-ROS1 SDC4-ROS1 SLC34A2-ROS1 CD74-ROS1 EZR-ROS1 LRIG3-ROS1 ROS1 Bergethon et al., JCO 30(8): 863-70, 2012; Takeuchi et al., Nat Med 18(3): 378-81, 2012.

  47. Summary of Tumor Responses in Patients with Advanced ROS1+ NSCLC (N=14*) 100 80 60 40 20 † ‡ Decrease or Increase From Baseline (%) 0 15+ –20 16+ 18+ –40 4+ 12+ 8+ –60 22+ 18 44+ –80 –100 PD SD PR CR 20+ 35+ 48+ Shaw et al, J ClinOncol 30, 2012 (suppl; abstr 7508).

  48. CAP / IASLC / AMP Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK TKIs (Released on April 3, 2013) • Main Issues Addressed: • Timing of molecular testing, performance of testing, should other genes be tested, and the implementation/operationalization of molecular testing • Who Should Be Tested for EGFR and ALK?: • 1.1a /1.1b Recommendations. EGFR (1.1a)/ALK (1.1b) molecular testing to be used to select patient for EGFR/ALK-targeted TKI therapy, and patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics. • Using Clinical Criteria is Not Optimal: • Using clinical characteristics to exclude patients for EGFR mutation or ALK rearrangement testing is not recommended Lindeman et al, 2013, J Thoracic Oncol, 8(7): 823-859.

  49. IHC as a Screening Tool for ALK Detection Cagle et al, 2013, IASLC webinar.

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