SURGICAL GRAND ROUNDS

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1 SURGICAL GRAND ROUNDS David H. Harpole, Jr., M.D. New Options for Achieving Individualized Approaches to Non-small Cell Lung Cancer Management Dr. Harpole has financial relationships with the following companies: GlaxoSmithKline Consultant GlaxoSmithKline spouse, Shareholder **To be determined following presentation review: ** Vanderbilt CME has determined there is no conflict of interest. SPONSORED BY THE VANDERBILT SCHOOL OF MEDICINE DEPARTMENT OF SURGERY DEPARTMENT OF THORACIC SURGERY

2 New Options for Achieving Individualized Approaches to Non-Small Cell Lung Cancer (NSCLC) Management David H. Harpole Jr, MD Professor of Surgery Division of Thoracic Surgery Department of Surgery Associate Professor of Pathology Department of Pathology Duke Institute for Genome Science and Policy Duke University Medical Center Durham, North Carolina

3 Educational Activity Learning Objectives List barriers that hinder optimal care for NSCLC patients and establish methods to achieve improved outcomes Define strategies to better include patients and their families in a shared decision making process for the management of their NSCLC Assess the latest data from newer oncologic therapies to determine future strategies for improving the significant failure rate seen among current approaches for NSCLC management Determine individualized NSCLC patient scenarios where novel targeted therapies may apply and assess how these options may integrate into existing regimens, taking into account potential safety issues Examine the potential role of biomarkers in the individualized management of NSCLC patient and identify new knowledge and skill sets required for their incorporation into clinical practice

4 > 85% of Lung Cancer is Caused by Cigarette Smoking Decrease in risk seen 5 years after stopping, never reaches baseline Cessation after diagnosis improves treatment tolerance and outcome Videtic GM, et al. J Clin Oncol. 2003;21(8): Fox JL, et al. Lung Cancer. 2004;44(3):

5 Non-small Cell Lung Cancer (NSCLC) NSCLC accounts for ~135,000 cases of lung cancer annually Approximately 30 40% of these patients will have metastatic disease Untreated patients have a median survival of ~4 5 months

6 Estimated New Cancer Cases United States, 2009 Males Females Jemal A, et al. CA Cancer J Clin. 2009;59(4):

7 Estimated Cancer Deaths United States, 2009 Males Females Jemal A, et al. CA Cancer J Clin. 2009;59(4):

8 Survival by Clinical and Pathologic Stage Proposed IASLC Stage Groupings Clinical Pathological Detterbeck FC, et al. Chest. 2009;136: Goldstraw P, et al. J Thorac Oncol. 2007;2:

9 Lung Cancer: Symptoms Related to Primary Lesion Cough, often dry Shortness of breath Hemoptysis Wheezing Related to Spread within Chest Shortness of breath Hoarseness Superior vena cava syndrome Horner s syndrome Related to Distant Metastasis Brain Bone Liver Adrenal glands

10 Lung Cancer Assessment History and Physical Exam: Assess weight loss and Performance status Labs: CBC, comprehensive metabolic panel Smoking cessation counseling CXR CT Chest with IV contrast (includes liver and adrenal glands) Biopsy: Bronchoscopy CT guided Mediastinoscopy Endoscopic Ultrasonography (EUS-FNA, EBUS-FNA) Thoracentesis +/- FDG-PET scan or PET/CT +/- MRI Brain/Spine (Suggestive Symptoms)

11 Overview of NSCLC Treatment Stage I Surgery (Poor risk: RFA, SBRT) Stage II Adjuvant Chemotherapy Stage III Surgery or Radiation With Chemotherapy Stage IV or Recurrent Disease Chemotherapy Targeted Therapy

12 Therapy in Stage IV Disease Goals Palliative Improve symptoms Improve quality of life Control disease Improve progression free survival Improve overall survival

13 Non-Small Cell Lung Cancer: Stage IV Disease GENERAL PRINCIPLES: Baseline factors predict survival Age Weight loss Gender Performance status Age does not predict worse outcome Elderly patients with a good performance status should be offered systemic treatment Older patients are more susceptible to toxic side effects of chemotherapy

14 Common Chemotherapy for Stage IV NSCLC Platinum Cisplatin Carboplatin Taxanes Paclitaxel Docetaxel Gemcitabine Vinca Alkaloids Vinorelbine Vinblastine Pemetrexed Mitomycin

15 Non-Small Cell Lung Cancer: Chemotherapy Side Effects Neutropenia Anemia Hair loss Nausea & vomiting Mouth sores Loss of appetite Neuropathy Hearing loss Renal failure Death Neutropenic fevers Thrombocytopenia Fatigue Diarrhea/constipation Allergic reaction Rash Muscle aches Edema Eye tearing

16 Survival After 1, 2, or 3 Cytotoxic Chemotherapies Delbaldo C, et al. JAMA. 2004;292: drugs are better than 1

17 Survival After 1, 2, or 3 Cytotoxic Chemotherapies Delbaldo C, et al. JAMA. 2004;292: cytotoxic drugs are not better than 2

18 What Treatment? Chemotherapy Individualization Balance agent toxicity with tumor sensitivity Schiller et al., New Engl J Med 346: 92, 2002

19 Randomization Factors Stage Performance status Gender Histologic vs cytologic diagnosis History of brain metastases Recent Advances: Cis /Gem vs Cis /Pem R A N D O M I Z A T I O N Vitamin B 12, folate, and dexamethasone given in both arms Cisplatin 75 mg/m 2 day 1 + Gemcitabine 1250 mg/m 2 days 1,8 (n = 863) Each cycle repeated q 3 wk up to 6 cycles Cisplatin 75 mg/m 2 day 1 + Pemetrexed 500 mg/m 2 day 1 (n = 862) Primary Endpoint Overall Survival Scagliotti GV, et al. J Clin Oncol. 2008;26:

20 Recent Advances: Cis /Gem vs Cis /Pem: Survival Survival Probability Median (95% CI) Cisplatin/pemetrexed 10.3 ( ) Cisplatin/gemcitabine 10.3 ( ) CP vs CG Adjusted HR (95% CI) 0.94 ( ) Survival Time, mo Scagliotti GV, et al. J Clin Oncol. 2008;26:

21 Recent Advances: Pemetrexed/Cisplatin vs Gemcitabine/Cisplatin: Results Endpoint Pem/Cisplatin Gem/Cisplatin P Value or HR (95% CI) ORR 30.6% 28.2% P = DOR, mos P = Median PFS, mos HR = 1.04 ( ) Median PFS, mos (adeno or large cell carcinoma) HR = 0.90 ( ) Median OS, mos HR = 0.94 ( ) Median OS, mos (adeno or large cell carcinoma) HR = 0.81 ( ) P = 0.03 Median OS, mos (squamous cell carcinoma) HR = 1.3 P = 0.05 Scagliotti GV, et al. Eur J Cancer. 2009;45(13):

22 Maintenance Therapy Continuing the same combination therapy Crossing over to a different combination regimen Continuing a targeted agent after 4-6 cycles of chemotherapy Instituting early second-line Continuing one of the 2 agents administered as front-line combination Instituting a non-cross resistant agent after initial chemotherapy

23 Maintenance Pemetrexed vs Placebo Pemetrexed + BSC (N = 441)* Stage IIIB/IV NSCLC ECOG PS prior cycles of gem, doce, or tax + cis or carbo, with CR, PR, or SD 2:1 Randomization Primary Endpoint = PFS Placebo (d1, q21d) + BSC (N = 222)* Ciuleanu T, et al. Lancet. 2009;374(9699):

24 Progression-free Survival PFS Probability HR = 0.60 (95% CI: ) P < Pemetrexed 4.0 mos Placebo 2.0 mos Time (months) Ciuleanu T, et al. Lancet 2009;374(9699):

25 Overall Survival (ITT) HR = 0.79 (95% CI: ) 1.0 P = Survival Probability Placebo 10.6 mos Pemetrexed 13.4 mos Time (months) Ciuleanu T, et al. Lancet 2009;374(9699):

26 Overall Survival Adenocarcinoma vs Squamous Adenocarcinoma (n = 481) Squamous (n = 182) 1.0 HR = 0.70 (95% CI: ) P = HR = 1.07 (95% CI: ) P = Survival Probability Placebo 10.3 mos Pemetrexed 15.5 mos Placebo 10.8 mos Pemetrexed 9.9 mos Time (months) Time (months) Ciuleanu T, et al. Lancet 2009;374(9699):

27 Maintenance Chemotherapy To be considered maintenance chemotherapy, patient must not have had progressive disease on first line therapy PFS benefit OS benefit 1 st line bevacizumab combo? 1 st line pemetrexed? Histology Pemetrexed Yes Yes No No Non-squam Docetaxel Yes No No No All Erlotinib Yes No No All Erlotinib + bevacizumab Yes Yes No Non-squam (bevacizumab)?? Yes No Non-squam

28 Second Line Chemotherapy To be considered second (or third line) chemotherapy, patient must have had progressive disease during or after first line therapy Previously there were no studies as few patients responded to first line therapy. Several agents have FDA approval for second line

29 Initial second line trial TAX 317: Docetaxel vs. Supportive Care for Salvage Therapy in Adv NSCLC Schema Shepherd, JCO 18: , Stage IIIB/IV > 1 prior platinum-based Rx No paclitaxel PS 0-2 N = 204 R A N D O M I Z E Docetaxel 100 mg/m 2 IV q 3 wk (protocol amendment) Docetaxel 75 mg/m 2 IV q 3 wk Best Supportive Care (no chemo) Shepherd FA et al. J ClinOncol 2000: 18;

30 Second-line Docetaxel in Advanced NSCLC Cumulative probability 1.0 Docetaxel 75 mg/m 2 (n = 55) Best supportive care (n = 49) Response(%) Median survival (months) 1-year-survival (%) Doc BSC p = 0.01 (log rank) Survival time (months) Shepherd FA et al. J ClinOncol 2000: 18;

31 Comparing to other agents: TAX 320: Second-Line Docetaxel Monotherapy for Advanced NSCLC Stage III or IV locally advanced or metastatic NSCLC Stratified by: Response to previous platinum-based therapy PS N = 373 R A N D O M I Z E Docetaxel 75 mg/m 2 q3w n = 125 Control q3w Vinorelbine 30 mg/m 2 days 1, 8, 15 or ifosfamide 2 mg/m 2 days 1-3 n = 123 End Points Primary: overall survival Secondary: overall response rate, duration of response, TTP, safety, quality of life Fossella FV, et al. J Clin Oncol. 2000;18:

32 Second-Line Docetaxel Monotherapy for Advanced NSCLC: Survival % Survival Median Survival (mo) 1-y Survival (%) Docetaxel 75 mg/m Vinorelbine or ifosfamide P = NS P = Months Fossella FV, et al. J Clin Oncol. 2000;18:

33 Second Agent approved: Pemetrexed vs. Docetaxel in 2 nd -line NSCLC Stratified by: ECOG PS 0/1 vs. 2 Stage III vs. IV # of prior chemo Best response to prior chemo Time since last chemo Prior platinum Prior taxane Homocysteine level Center R A N D O M I Z E D Pemetrexed 500 mg/m 2 i.v. q3wks (n = 2 83) (folic acid 350-1,000 µg daily + vitamin B 12 1,000 µg q 9wks; dexamethasone 4mg bid on d-1,d0,d+1) Docetaxel 75 mg/m 2 i.v. q3wks (n = 288) (dexamethasone 8 mg bid on d-1,d0,d+1) Powered for equivalency Hanna N, et al. J Clin Oncol. 2004;22:

34 Second Line Therapy of Pemetrexed vs. Docetaxel Survival (ITT); Hanna, ASCO, 2003 Survival Distribution Function ITT = intent to treat HR = hazard ratio CI = confidence interval MST = median survival time MST 7.9 mos 1-yr OS: 29.7% Months HR 0.99 Pemetrexed (n = 283) Docetaxel (n = 288) 95% CI of HR (0.82, 1.20) MST 8.3 mos 1-yr OS: 29.7% Hanna N, et al. J Clin Oncol. 2004;22:

35 Hematological Toxicities (Grade ¾ - % Patient) Pemetrexed Docetaxel (n = 265) (n = 276) p-value Neutropenia < Febrile Neutropenia < Infection w/ gr 3/4 Neutropenia Anemia Thrombocytopenia 1.9 < Hanna N, et al. J Clin Oncol. 2004;22:

36 Hospitalizations, Transfusions & Growth Factors Pemetrexed Docetaxel (n = 276) (n = 265) p-value Patients with > 1 hosp 31.7% 40.6% due to an adverse event Total hospitalizations 1.5% 13.4% < due to febrile neutropenia G-CSF/GM-CSF 2.6% 19.2% < Erythropoietin 6.8% 10.1% Red blood cell 16.6% 11.6% Transfusions Hanna N, et al. J Clin Oncol. 2004;22:

37 Phase III Trial of Pemetrexed Vs. Docetaxel in Pretreated NSCLC: Efficacy by Histology Non- Squamous* Squamous Hazard Ratio: Non-Squam Treated with Pem Vs. Other P - Value Pem Doc Pem Doc n = 176 n = 173 n = 78 n = 94 OS 9.2m 8.2m 6.2m 7.4m PFS 3.4m 3.0m 2.3m 2.7m *Adeno/Large Cell Peterson et al., IASLC 2007, abstract P2-328

38 Pemetrexed in 2 nd line NSCLC 100 Peterson et al, Eur J Ca 2007 (suppl 4):363 Percent Surviving 50 Non-squamous: Median = 9.2 Squamous: Median = Overall Survival (months) Peterson et al., IASLC 2007, abstract P2-328

39 Patients Randomized to Docetaxel Overall Survival (months) 100 Non-squamous: Median = Percent Surviving 0 Squamous: Median = 7.4 Overall Survival (months) Peterson et al., IASLC 2007, abstract P2-328

40 Why might pemetrexed be more effective in non-squamous NSCLC? Hanna, ASCO, 2008 Primary target of pemetrexed is thymidylate synthase (TS) TS expression is significantly higher in squamous cell vs adenocarcinoma Ceppi et al 2006;107(7): Pemetrexed is more active in tumors with low levels of TS, DHFR, GARFT Hanauske et al 2007;25(5):417-23

41 BR.21: Erlotinib vs. Placebo in 2nd or 3rd Line NSCLC Eligibility Locally advanced or metastatic NSCLC 1 or 2 prior chemotherapy regimen(s) failed Stratification Center PS (0/1 vs 2/3) Response to prior therapy Prior regimens Prior platinum N = 731 R A N D O M I Z E Erlotinib: 150 mg/d + best supportive care n = 488 Placebo + best supportive care n = 243 Primary endpoint: improvement in overall survival of 33% Secondary endpoints include progression-free survival, overall response rate, duration of response, quality of life, and safety 2:1 randomization to the experimental arm. Shephard FA, et al. N Engl J Med. 2005;353:

42 BR.21: Selected Patient Characteristics % of Patients Erlotinib (n = 488) Placebo (n = 243) Characteristic 65 years of age Female PS 0/1 13/52 14/54 PS 2/3 26/9 23/9 Adenocarcinoma Prior regimens 1/2/3 50/49/1 50/49/1 Current or ex-smoker Patient characteristics were balanced between the arms of the study Shephard FA, et al. N Engl J Med. 2005;353:

43 BR.21: Erlotinib Significantly Improved Overall Survival Survival Distribution Function *From Cox regression model. From 2-sided log-rank test. CI=confidence interval; HR=hazard ratio. Erlotinib 150 mg/day (n = 488) HR (OS) = 0.70 (95% CI, )* P < Erlotinib Placebo Months Placebo (n = 243) Median Survival 6.7 mo 4.7 mo 1-Year Survival 31.2% 21.5% Shepherd FA, et al. J Clin Oncol. 2004;22(suppl):14S. Abstract 7022 and oral presentation; Shepherd et al. N Engl J Med. 2005;353:123.

44 Toxicity of Small Molecular Agents 1. Cavitation and/or bleeding common (VEGF) Clearly a class effect Seems limited to primary lung cancer 2. Hypertension Due to INOS effect Usually treatable with medications 3. Other unique toxicities (especially with the multitargeted agents) Rash Hand-foot syndrome Fatigue Slightly increased neutropenia (effect of VEGF on lymphoid cells)

45 Targeted Therapy in Oncology Target Present in tumor tissue Critical for tumor growth/progression Druggable Dispensable or absent in normal cells Drug Discovery and Development Agent Targets tumor cells Spares normal cells Decreased toxicity

46 Agents Targeting the VEGF Pathway Anti-VEGF antibodies (bevacizumab) VEGF Soluble VEGFRs (VEGF-Trap) P P P P VEGFR-1 P P P P VEGFR-2 Endothelial cell Anti-VEGFR antibodies (IMC-1121b) Podar K, Anderson K. Blood. 2005;105: Small-molecule VEGFR inhibitors Vatalanib (PTK 787) Sunitinib (SU11248) Sorafenib (Bay ) ZD6474

47 Phase III Trial of Bevacizumab in Non-Squamous NSCLC: ECOG 4599 N = 855 (eligible) Eligibility: Non-squamous NSCLC No Hx of hemoptysis No CNS metastases Stratification Variables: RT vs no RT Stage IIIB or IV vs recurrent Wt loss < 5% vs 5% Measurable vs non-measurable Sandler A, et al. New Engl J Med. 2006;355: (PC) Paclitaxel 200 mg/m 2 Carboplatin AUC = 6 (q 3 weeks) x 6 cycles (PCB) PC x 6 cycles + Bevacizumab (15 mg/kg q 3 wks) to PD No crossover to Bevacizumab permitted

48 Patients With PFS (%) Carboplatin/Paclitaxel +/- Bevacizumab: Key Clinical Outcomes Progression-Free Survival Carboplatin/paclitaxel Carboplatin/paclitaxel + bevacizumab P < 0.001; HR = 0.66 Median PFS: 6.2 months vs 4.5 months 6-Month PFS: 55% vs 33% 1-Year PFS: 15% vs 6% Patients Surviving (%) Overall Survival Carboplatin/paclitaxel Carboplatin/paclitaxel + bevacizumab P = 0.003; HR = 0.79 Median OS: 12.3 months vs 10.3 months 1-Year OS: 51% vs 44% 2-Year OS: 23% vs 15% Months Months HR = hazard ratio; OS = overall survival; PFS = progression-free survival Response rate = carboplatin/paclitaxel 15%; carboplatin/paclitaxel + bevacizumab 35%; P < Sandler A, et al. N Engl J Med. 2006;355: Sandler A, et al. J Clin Oncol. 2005;23(16S):4.

49 Grade 3 5 Non-Hematologic Toxicity CP (N = 441) BvCP (N = 427) P Value Hemorrhage Hemoptysis 0.5% 2.1% CNS 0.2% 0.7% GI 0.5% 1.2% Other 0.2% 1.2% Hypertension 0.7% 7.7% < Proteinuria % < Venous thromb 3.2% 5.6% Arterial thromb 1.6% 2.8% Sandler A, et al. New Engl J Med. 2006;355:

50 AVAiL Trial Study Design Previously untreated, stage IIIb, IV or recurrent non-squamous NSCLC R A N D O M I Z E Bevacizumab 7.5 mg/kg + CG Placebo CG Placebo 15 + CG Bevacizumab 15 mg/kg + CG Bevacizumab Bevacizumab PD PD PD Stratification factors: disease stage, ECOG, PS, region, gender Reck M, et al. J Clin Oncol. 2009;27(8): CG: cisplatin-gemcitabine

51 AVAiL Primary Endpoint: PFS Bevacizumab 7.5 mg Group Bevacizumab 15 mg Group Toxicity was similar to that of E4599 Reck M, et al. J Clin Oncol. 2009;27(8): CG: cisplatin-gemcitabine

52 Probability of OS AVAiL: Overall Survival (secondary endpoint) HR (95% CI) Placebo + CG Bev 7.5 mg/kg + CG 0.93 ( ) Bev 15 mg/kg + CG 1.03 ( ) P value Median OS (months) No. at risk Placebo + CG Bev 7.5 mg/kg + CG Bev 15 mg/kg + CG Time (months) Reck M, et al. Ann Oncol Feb 11. [Epub ahead of print] *ITT (intent-to-treat) population CG: cisplatin-gemcitabine

53 Oral VEGF-TKIs Agent Target/MOA Company ZD6474 VEGFR-2, EGFR AstraZeneca Sunitinib VEGFR-1/2, PDGFR, Kit, FLT-3 Sugen/Pfizer Inc Sorafenib VEGFR-2/3, FLT-3, Kit Onyx/Bayer Vatalanib VEGFR-1/2/3, PDGFR, Kit Novartis AG VEGFR-1/2, PDGFR, Kit Pfizer Inc AMG 706 VEGFR, PDGFR, Kit, Ret Amgen AEE-788 VEGFR, EGFR, erb Novartis

54 Adenocarcinoma Molecular Subtypes KRAS Pending EGFR BRAF PIK3CA MEK FGFR4 EML4-ALK HER2

55 Epidermal Growth Factor Receptor (EGFR) as a Target Expression in many cancers; NSCLC (> 80%) EGFR expression is associated with tumor growth, metastasis and poor prognosis Blocking EGFR has the potential to improve outcome in NSCLC

56 EGFR Signaling gefitinib erlotinib Adapted from Ciardiello F, Tortora G. N Engl J Med. 2008;358:

57 EGFR Mutations Found in 350 of 2105 patients with advanced NSCLC(16.6%) Mutation distribution Women > men (70% vs 30%) Never smokers > smoking history (67% vs 33%) Those with adenocarcinomas (80.9%) (P < for all comparisons). Deletions in exon 19 (62.2%) and L858R (37.8%) Adverse events Mild rashes Diarrhea Grade 3 cutaneous toxic effects in 16 patients (7.4%) Grade 3 diarrhea in 8 patients (3.7%) Rosell R, et al; Spanish Lung Cancer Group. N Engl J Med. 2009;361(10):

58 EGFR Mutations Rosell R, et al; Spanish Lung Cancer Group. N Engl J Med. 2009;361(10):

59 IPASS Study Design Patients Chemonaïve Age 18 years Adenocarcinoma histology Never or light exsmokers Life expectancy 12 weeks PS 0-2 Measurable stage IIIB/ IV disease Gefitinib (250 mg/day) 1:1 randomisation Carboplatin (AUC 5 or 6) / paclitaxel (200 mg/m 2 ) 3 weekly # Endpoints Primary Progression-free survival (non-inferiority) Secondary Objective response rate Overall survival Exploratory EGFR mutation Mok TS, et al. N Engl J Med. 2009;361(10):

60 First-line Gefitinib vs Carboplatin- Paclitaxel Mok TS, et al. N Engl J Med. 2009;361(10):

61 First-line Gefitinib vs Carboplatin- Paclitaxel Gefitinib Advantage Systemic Chemotherapy Advantage Mok TS, et al. N Engl J Med. 2009;361(10):

62 A Phase II, Multicenter, Randomized Clinical Trial to Evaluate the Efficacy and Safety of Bevacizumab in Combination With Either Chemotherapy (Docetaxel Or Pemetrexed) or Erlotinib Hydrochloride Compared With Chemotherapy Alone for Treatment of Recurrent or Refractory Non-Small Cell Lung Cancer Herbst RS, et al. J Clin Oncol. 2007;25(30):

63 Efficacy and Safety Summary EFFICACY SUMMARY SAFETY SUMMARY Herbst RS, et al. J Clin Oncol. 2007;25(30): *Proteomics pending

64 Bevacizumab + Erlotinib for Advanced NSCLC After Failure of Standard First-line Chemotherapy Patients (N = 636) randomized 1:1 Bevacizumab (15 mg/kg IV Q3 weeks) + Erlotinib (150 mg daily) or Placebo + Erlotinib (150 mg daily) Responses assessed every 6 weeks to week 24; then every 12 weeks Bevacizumab + Erlotinib Placebo + Erlotinib P Value Median Overall Survival (months) HR = 0.97 (95% CI: ) Median Progression Free Survival (months) < HR = 0.62 (95% CI: ) Objective Response Rate Hainsworth J, Herbst R. IASLC Chicago IL. Nov , 2008.

65 EML4-ALK Fusion Product in NSCLC A receptor tyrosine kinase (anaplastic lymphoma kinase [ALK] fuses to the echinoderm microtubule-associated protein-like 4 (EML-4) Multiple variants of the translocation have been identified Oncogenic (transforms cell lines and transgenic mice develop lung cancer) EML4 ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined Soda M, et al. Nature. 2007;448(7153):

66 Frequency of EML4/ALK translocations Author Total Number Pos % Notes Shaw ASCO 2009 Inamura, JTO 2008 Takeuchi, CCR 2008 Koivuner, CCR 2008 Wong, Cancer 2009 Takahashi, ASO % More likely in adenocarcinoma, light or never smokers, didn t overlap with EGFR or KRAS, younger patients % No overlap with EGFR or KRAS % % More common in never or light smokers % Mostly adenocarcinoma, never smokers, younger % Only looked at surgical cases. No overlap with EGFR, KRAS, HER2, 4 never smokers, 1 <1py smoker, all adenocarcinomas.

67 Is the EML4-ALK Transcript Specific for NSCLC? PCR in 120 NSCLC specimens 1 Controls: Non-neoplastic lung tissues ALK protein levels assayed from 662 NSCLC specimens Results EML4-ALK transcripts (variants 1 and 3) detected in 9/120 NSCLC samples Also found in noncancerous lung tissues No transcripts were detected in matching tumor samples from these patients Analysis of EML4-ALK+ cases Only a minority of cells harbored the EML4-ALK gene (FISH) None of these cases was found to express the EML4-ALK protein Conclusion: EML4-ALK transcript cannot be regarded as a specific diagnostic tool for NSCLC Findings challenged by Mano et al 2 Martelli MP, et al. Am J Pathol. 2009;174: Mano H, Takeuchi K. Am J Pathol Jan 14. [Epub ahead of print]

68 Tumor Responses to PF for NSCLC Evaluable Patients With ALK Fusions Tumor Size Change Duration of Response (Weeks) Kwak EL, et al. ASCO

69 Molecular Analysis and NSCLC ERCC1 (excision repair cross complementation) Expression prognostic for improved survival Expression predictive of reduced response to platinum-based therapy RRM1 (regulatory subunit of ribonucleotide reductase) Expression prognostic for improved survival Expression predictive of reduced response to gemcitabine therapy BRCA1 (breast cancer 1) Low level of expression prognostic for long survival Low level of expression may be predictive of good platinum efficacy and poor taxane efficacy EGFR (epidermal growth factor receptor) EGFR mutations and gene copy number prognostic of survival Predictive for EGFR tyrosine kinase inhibitor efficacy Oligonucleotide-based Gene Expression Profiles Promising strategy for risk assessment and prediction of therapeutic efficacy Bepler G, et al. Cancer Control. 2008;15(2):

70 NSCLC Management Guidelines 1 Recommendations for the treatment of patients with stage IV NSCLC, based on 162 publications Chemotherapy and biologicals Strategies that improve overall survival First-line therapy Patients with performance status of 0 or 1 Platinum-based two-drug combination of cytotoxic drugs is recommended Nonplatinum cytotoxic doublets are acceptable for patients with contraindications For patients with performance status of 2, single cytotoxic drug is sufficient Azzoli CG, et al. J Clin Oncol. 2009;27:

71 NSCLC Management Guidelines 2 Stop first-line cytotoxic chemotherapy at disease progression or after 4 cycles in patients who are not responding to treatment Stop two-drug cytotoxic chemotherapy at 6 cycles in all patients EGFR mutations First-line gefitinib may be recommended for patients with known mutation Otherwise, cytotoxic chemotherapy is preferred Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by IHC Bevacizumab is generally recommended with carboplatinpaclitaxel Azzoli CG, et al. J Clin Oncol. 2009;27:

72 NSCLC Management Guidelines 2 Second-line therapy Docetaxel Erlotinib Gefitinib or Pemetrexed Third-line therapy Erlotinib for erlotinib or gefitinib naive patients Data are insufficient to recommend the routine thirdline use of cytotoxic drugs Data are insufficient to recommend routine use of molecular markers to select chemotherapy

73 Nursing Considerations Assessment Geriatric Patient Planning Histology, Stage, Intervention Patient Education Knowledge base Caregiver Support Resources

74 Multidisciplinary Patient Management Medical Oncology Thoracic Surgery Pulmonology Radiation Therapy Pathology Nursing Pharmacy Medical Director Case Manager Clinical Research Team

75 Communication With Patients Goals Compliance (especially with po medications) Smoking cessation Patient self evaluation and reporting Manage disease symptoms, disease burden, and treatment side effects Offer Web resources

76 Case Scenario 1 55-year-old person with Stage IV NSCLC Adenocarcinoma histology Good performance status Hemoptysis on 3 occasions, total ~15 cc blood What is the most appropriate chemotherapy? A. Cisplatin and gemcitabine B. Cisplatin and pemetrexed C. Carboplatin, paclitaxel, bevacizumab D. Carboplatin and paclitaxel E. Cisplatin, vinorelbine, cetuximab

77 Case Scenario 2 55-year-old woman with Stage IV NSCLC Adenocarcinoma Good performance status EGFR exon 19 deletion What is the optimal chemotherapy? A. Carboplatin, paclitaxel, bevacizumab B. Carboplatin, paclitaxel C. Cisplatin, pemetrexed, bevacizumab D. Erlotinib

78 Case Scenario 3 55-year-old woman with Stage IV adenocarcinoma of the lung, completes 6 cycles of cisplatin, paclitaxel, and bevacizumab with stable disease, grade 1 neuropathy, and continues to work full time What is the most appropriate next step? A. Continue cisplatin, paclitaxel, and bevacizumab until progression B. Continue paclitaxel and bevacizumab until progression C. Begin docetaxel until progression D. Begin pemetrexed until progression E. Discontinue therapy and monitor until progressive disease

79 Case Scenario 4 55-year-old man with Stage IV squamous cell carcinoma completes 6 cycles of cisplatin and vinorelbine with stable disease, grade 1 neuropathy, and continues to work full time What is the most appropriate next step? A. Continue cisplatin and vinorelbine until progression B. Start cetuximab and continue until progression C. Start docetaxel and continue until progression D. Start pemetrexed until progression E. Discontinue therapy and monitor until progressive disease

80 Summary Chemotherapy Two agents > one Three agents no better than two Role for maintenance therapy? Still under evaluation Targeted Therapy Agents targeting the EGFR and VEGF pathways have proved successful Further study will include Earlier stage NSCLC The small molecule VEGF inhibitors appear promising in phase II trials and are being studied in phase III trials Combining targeted agents appears promising Targeting the insulin-like growth factor pathway Promising candidates in development

81 Lung Cancer: Conclusions Smoking remains primary cause of lung cancer Screening remains controversial Staging helps determine treatment Clinical trial participation may be attractive Multiple options in non-small cell lung cancer The future: Treat lung cancer based on molecular characteristics of tumors

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