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Moderator Neil Love, MD

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Moderator Neil Love, MD

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  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.

  2. Challenging Cases in Lung CancerOncologist and Nurse Investigators Consult on Actual Patients from the Practices of the Invited FacultyFriday, May 2, 20146:00 AM – 7:30 AM Faculty Geoffrey R Oxnard, MD Karen L Reckamp, MD, MS Rebecca Lynn Sipples, MSN, APRN, ACNP, AOCNP Alison J Holmes Tisch, MSN, RN, ANP-BP, AOCNP ModeratorNeil Love, MD

  3. Oncology 6-Part Case Series: Key Themes • Mechanisms of action of novel agents and tissue assays to predict response • Side effects and toxicities of novel agents; dose adjustments • Assessment and management of adherence • Specific goals of therapy and likely outcomes; sequencing of agents in advanced disease • Local and systemic complications of cancer: Fatigue, pain, CNS involvement • Care of older, frail patients and those with comorbidities

  4. Oncology 6-Part Case Series: Key Themes • Clinical trials as a means to access new treatments earlier • Management of anxiety and depression • Key determinants of patient satisfaction: What do people with cancer want and need? • Quality, value and cost: Investing resources optimally • End-of-life care and planning • Impact of the cancer experience on family and loved ones, including minor children • Impact of the oncology experience on oncology health professionals

  5. Agenda Two Patients with Adenocarcinoma and EGFR Tumor Mutations • 54 yo woman with advanced EGFR-mutant NSCLC with progressive disease after responding to erlotinib (Ms Sipples) • 36 yo Afghani woman with advanced EGFR-mutant NSCLC currently receiving afatinib/cetuximab (Ms Tisch) A Patient with Metastatic Adenocarcinoma Who Received Front-Line Chemobiologic Therapy Followed by Maintenance • 41 yo woman with advanced “pan-wild-type” NSCLC with 2 young children (Ms Tisch)

  6. Agenda A Patient Who Received Immunotherapy on a Clinical Trial • 77 yo woman with advanced NSCLC who went on a clinical trial of nivolumab and is currently receiving nanoparticle albumin-bound (nab) paclitaxel (MsSipples) Two Patients with Tumor Mutations: ROS1 and HER2 • 70 yo man with advanced, ROS1-mutant NSCLC receiving crizotinib (MsSipples) • 64 yo woman with advanced NSCLC with a HER2 insertion who has requested help with assisted suicide (MsTisch)

  7. Two Patients with Adenocarcinoma and EGFR Tumor Mutations • 54 yo woman with advanced EGFR-mutant NSCLC with progressive disease after responding to erlotinib (Ms Sipples) • 36 yo Afghani woman with advanced EGFR-mutant NSCLC currently receiving afatinib/cetuximab (Ms Tisch)

  8. Case 1 (from the practice of Ms Sipples) • A 54-year-old woman was diagnosed 9 months ago with advanced non-small cell lung cancer (NSCLC) (adenocarcinoma with EGFR L858R exon 21 point mutation) and multiple ring-enhancing brain metastases • She responded to erlotinib but then developed progressive disease

  9. Discussion Point Incidence of tumor driver mutations in patients with NSCLC; algorithms for tissue testing

  10. Incidence of Single Driver Mutations in Metastatic Lung Adenocarcinoma N = 733 Kris MG et al. JAMA 2014;311(19):1998-2006.

  11. Discussion Point Selection of first-line therapy for patients with EGFR activating mutations; similarities and differences between erlotinib and afatinib

  12. Select Trials of First-Line Treatment with EGFR TKIs vs Chemotherapy in EGFR-Mutant NSCLC 1 Mok TS et al. N Engl J Med 2009;361(10):947–57. 2 Fukuoka M et al. J Clin Oncol2011;29(21):2866–74. 3 Maemondo M et al. N Engl J Med 2010;362(25):2380–8. 4 Zhou C et al. Lancet Oncol 2011;12(8):735–42. 5 Zhou C et al. Proc ASCO 2012;Abstract LBA7520. 6 Rosell R et al. Lancet Oncol 2012;13(3):239–46.

  13. Possible Erlotinib-Associated Side Effects Most Common AEs • Rash • Fatigue • Diarrhea • Appetite loss

  14. Afatinib: An Irreversible ErbB Family Blocker EGF ligands Heregulins EGFR inhibitors ErbB Family Blockade EGFR (ErbB1) HER2 (ErbB2) ErbB3 ErbB4 Afatinib is an orally available, irreversible ErbBfamily blocker, with high efficacy potential Inhibition of ErbB family receptor heterodimerization In vitro activity against EGFR-resistant T790M mutation Adapted from Li D et al. Oncogene 2008;27:4702-11.

  15. Stage IIIB/IV lung adenocarcinoma EGFR mutation in tumor R2:1 Afatinib Cisplatin + Pemetrexed Phase III LUX-Lung 3 Study for Patients with Treatment-Naïve Advanced Lung Cancer Primary endpoint: PFS Secondary endpoints: ORR, DCR, DoR, tumor shrinkage, OS, patient-reported outcomes, safety, PK Yang JC et al. Proc ASCO 2012;Abstract LBA7500.

  16. LUX-Lung 3: Response and PFS (Independent Review) Sequist LV et al. J Clin Oncol 2013;31(27):3327-34.

  17. Possible Afatinib-Related AEs Most Common AEs • Diarrhea • Rash/acne • Stomatitis/mucositis • Paronychia • Dry skin Sequist LV et al. J Clin Oncol 2013;31(27):3327-34.

  18. Discussion Point Mechanisms of resistance to EGFR TKI therapy

  19. LUX-Lung 1 Phase IIb/III Study of Afatinib After Failure of Erlotinib, Gefitinib or Both and Chemotherapy • N = 585 patients with Stage IIIB/IV adenocarcinoma of the lung • Afatinib/best supportive care (BSC) vs placebo/BSC • All received prior EGFR TKI and chemotherapy No complete responses Miller VA et al. Lancet Oncol 2012;13(5):528-38.

  20. Phase II Study of Afatinib/Cetuximab ORR: 30% Median PFS: 4.7 mo Median DoR: 8 mo Grade 3 Rash: 18% Grade 3 Diarrhea: 7% Janjigian YY et al. Proc ESMO 2012;Abstract 1227O.

  21. Afatinib + cetuximab at MTD: Responses by T790M mutation T790M+ T790M– EGFR wt Uninformative for T790M 50 40 30 20 10 0 –10 –20 –30 –40 –50 –60 –70 –80 –90 –100 –110 Maximum percentage decrease from baseline (%) 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Patient index sorted by maximum % decrease With permission from Janjigian YY et al. Proc ESMO 2012;Abstract 12007O.

  22. Best Response Rates Janjigian YY et al. Proc ESMO 2012;Abstract 12007O.

  23. Case 2 (from the practice of Ms Tisch) • A 36-year-old Afghani woman was initially diagnosed in June 2005 with bronchoalveolar carcinoma that has since been categorized as adenocarcinoma with lepidic features • The patient’s disease has progressed through multiple treatments including chemotherapy, erlotinib, bevacizumab and 2 clinical trials, one of a single-agent investigational tyrosine kinase inhibitor (TKI) and one of erlotinib combined with cabozantinib • She was later enrolled on a clinical trial of CO-1686 and experienced a life-threatening tumor flare reaction after discontinuation of the drug, which was reversed by restarting erlotinib • She is currently receiving cetuximab and afatinib • The patient is a married mother of young children • Her Muslim faith plays a strong role in her desires concerning possible future end-of-life care

  24. Progressive Disease on a Trial of CO-1686

  25. Partial Response After Retrial with Erlotinib

  26. Progressive Disease After Retrial of Erlotinib

  27. Partial Response to Cetuximab and Afatinib

  28. CO-1686 • Mutation-specific TKI targeting activating mutations and T790M • Theoretically offers key advantage by not inhibiting wild-type EGFR • 45 2nd-line TKI patients, 74% T790M+ • Notably absent was rash and diarrhea • Clinical responses have been observed in 3 of 4 patients who received the highest dose • Phase II and III studies are under development Soria JC et al. Proc WCLC 2013;Abstract O03.06.

  29. Skin Rash from Tyrosine Kinase Inhibitors • Most frequent dermatologic side effect reported is acneiform eruption. • Affects mainly face, upper chest and/or back. • Also known as acne, acneiform skin reaction/rash, follicular rash and maculopapular skin rash. Ricciardi S et al. Clin Lung Cancer 2009;10(1):28-35.

  30. Clinical Grades of Erlotinib-Induced Rash • Mild • Generally localized papulopustular reaction • Minimally symptomatic • No impact on daily activities • No sign of superinfection • Moderate • Generalized papulopustular reaction • Mild pruritus or tenderness • Minimal impact on daily activities • No sign of superinfection • Severe • Generalized papulopustular reaction • Severe pruritus or tenderness • Significant impact on daily activities • Potential for or has become superinfected Saif MW et al. JOP 2008;9(3):267-74.

  31. Case 3 (from the practice of Ms Tisch) • A 41-year-old woman was diagnosed in 2010 with a Stage IIIA adenocarcinoma that was treated with cisplatin/pemetrexed followed by right upper lobectomy and then consolidative chemoradiation therapy • In 2011 she experienced systemic disease recurrence and was started on carboplatin/paclitaxel/bevacizumab followed by maintenance bevacizumab • The patient is married with 2 young children

  32. 2011: Systemic Disease Recurrence

  33. Response to Carboplatin/Paclitaxel/Bevacizumab Prior to Maintenance Therapy

  34. Discussion Point Systemic treatment of metastatic “pan-wild-type” NSCLC: Choice of chemotherapy regimen and role of bevacizumab

  35. Chemotherapeutic Regimens Commonly Employed in the Front-Line Management of Metastatic Pan-Wild-Type NSCLC • Carboplatin/paclitaxel ± bevacizumab • Carboplatin/nab paclitaxel ± bevacizumab • Carboplatin/pemetrexed ± bevacizumab • Cisplatin/chemotherapy ± bevacizumab NCCN NSCLC Clinical Practice Guidelines v 3.2014

  36. ECOG-E4599: Bevacizumab in Nonsquamous NSCLC Sandler A et al. N Engl J Med 2006;355(24):2542-50.

  37. Discussion Point Recognition and management of hypertension and proteinuria with bevacizumab; risk of cardiovascular events

  38. Discussion Point Maintenance strategies in NSCLC: biologic therapy, chemotherapy or both

  39. What Is Maintenance Therapy? • Use of systemic therapy following 1st-line therapy, for patients with CR/PR/SD, before documentation of progression • Continuation of a targeted agent • Continuation of one of the agents used in the 1st-line combination regimen • Switch to a new agent after 1st-line therapy Rogerio C Lilenbaum, MD, Winter Lung Cancer Conference 2014

  40. PointBreak: Phase III Trial Design Maintenance Phase Induction Phase • Inclusion: • - No prior systemic therapy for lung cancer • - PS 0/1 • - Stage IIIB-IV NS-NSCLC • - Stable tx’t brain mets • Exclusion: • Peripheral neuropathy • ≥Grade 1 • - Uncontrolled pleural effusions Pemetrexed + Carboplatin + Bevacizumab Pemetrexed + Bevacizumab R Bevacizumab Paclitaxel + Carboplatin + Bevacizumab Patel JD et al. J Clin Oncol 2013;31(34):4349-57.

  41. ECOG-E5508: A Phase III Study of Maintenance Bevacizumab, Pemetrexed or the Combination in Advanced NSCLC Target Accrual: 1,282 Study is currently recruiting participants Study Start Date: August 2010 Maintenance therapy Bevacizumab R Pemetrexed Bevacizumab + Pemetrexed Primary Endpoint: Overall survival Induction therapy: Carboplatin, paclitaxel and bevacizumab www.clinicaltrials.gov, May 2014

  42. Case 4 (from the practice of Ms Sipples) • A 77-year-old woman diagnosed in 1982 with early-stage NSCLC experienced disease recurrence in the right upper lobe in 2011, for which she underwent a segmentectomy followed by adjuvant cisplatin/pemetrexed • Her disease recurred in May 2012, at which time she received carboplatin/gemcitabine • After further disease progression, in April 2013 she was enrolled on a clinical trial of an immune checkpoint inhibitor but 2 months later developed brain metastases, which were resected • Since June 2013 she has been receiving nab paclitaxel 3 out of 4 weeks and has responded well but has developed neuropathy within the past month

  43. Discussion Point Adjuvant therapy for NSCLC: Choice of platinum doublet in older patients

  44. Discussion Point Available data with nab paclitaxel in lung cancer

  45. Phase III Nab P/C vs P/C Study Design Nab Paclitaxel 100 mg/m2 d1, 8, 15 Carboplatin AUC 6 d1 q3wk No Premedication n = 521 Chemo-naïve PS 0-1 Stage IIIb/IV NSCLC N = 1,052 1:1 Paclitaxel 200 mg/m2 d1 q3wk Carboplatin AUC 6 d1 q3wk With Premedication of Dexamethasone + Antihistamines n = 531 Stratification factors: • Stage (IIIbvs IV) • Age (<70 vs >70) • Histology (squamous vsnonsquamous) Socinski MA et al. J Clin Oncol 2012;30(17):2055-62.

  46. Common Treatment-Related ≥Grade 3 Adverse Events Socinski MA et al. J Clin Oncol 2012;30(17):2055-62.

  47. Objective Responses by Histology Squamous Nonsquamous P < 0.001 P = 0.060 P = 0.808 P = 0.069 Nab P/C Percent Responses P/C n = 292 n = 310 n = 228 n = 221 Socinski MA et al. J Clin Oncol 2012;30(17):2055-62; Socinski MA et al. ASCO 2010;Abstract 7511.

  48. Response and Survival in Elderly Patients (≥70) Socinski MA et al. Ann Oncol 2013;24(2):314-21.

  49. Discussion Point Anti-PD-1 and anti-PD-L1 antibodies: Mechanisms of action, predictors of response, time sequence of antitumor benefit, side effects and toxicities

  50. Role of PD-1 in Suppressing Antitumor Immunity Tumor cell Patient’s T cells MHC TCR T cell PD-1 PD-L1 T-cellblockade B7.1 Tumor cell growth T cells MHC TCR PD-1 PD-L1 T-cellactivation Tumor cell death EngineeredFc-domain B7.1 Granzymes and perforin + Anti-PD-L1 • Blocking PD-L1 restores T-cell activity, resulting in tumor regression in preclinical models • Binding to PD-L1 leaves PD-1/PD-L2 interaction intact and may enhance efficacy and safety Adapted from Spigel et al. Proc ASCO 2013;Abstract 8008.

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