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New Perspectives on Second-Line Therapy for NSCLC

New Perspectives on Second-Line Therapy for NSCLC. Tony Mok, MD (Moderator) Professor, Department of Clinical Oncology, Chinese University of Hong Kong; Honorary Consultant, Prince of Wales Hospital, Hong Kong, China. Overview.

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New Perspectives on Second-Line Therapy for NSCLC

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  1. New Perspectives on Second-Line Therapy for NSCLC Tony Mok, MD (Moderator) Professor, Department of Clinical Oncology, Chinese University of Hong Kong; Honorary Consultant, Prince of Wales Hospital, Hong Kong, China

  2. Overview • Discuss the current standards of care for second-line therapy in patients with advanced NSCLC • Examine the unique and unmet needs of patients without targetable activating mutations • Review emerging research findings on second-line therapy in NSCLC and their implications for clinical practice NSCLC = non-small cell lung cancer

  3. Panelists Martin Reck, MD, PhD Head, Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, Germany Luis Paz-Ares Rodríguez, MD, PhD Chair, Department of Oncology, Seville University Hospital, Seville, Spain

  4. Single-Driver Mutations in NSCLC Lovly C, et al. http://www.mycancergenome.org/content/disease/lung-cancer. Pao W, Girard N. Lancet Oncol. 2011;12:175-180.

  5. NSCLC Without Targetable Mutations: An Unmet Need Lovly C, et al. http://www.mycancergenome.org/content/disease/lung-cancer. Pao W, Girard N. Lancet Oncol. 2011;12:175-180.

  6. NSCLC Histology Howlader N, et al (eds). SEER Cancer Statistics Review, 1975-2010, National Cancer Institute. Bethesda, MD, 2013.

  7. Single-Driver Mutations in NSCLC Lovly C, et al. http://www.mycancergenome.org/content/disease/lung-cancer. Pao W, Girard N. Lancet Oncol. 2011;12:175-180.

  8. Outcomes With First-Line Doublet Therapy: ECOG 1594 Months OS = overall survival; PFS = progression-free survival Schiller JH, et al. New Engl J Med. 2002;346:92-98.

  9. Outcomes With First-Line Triplet Therapy: ECOG 4599 Months CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio Sandler A, et al. New Engl J Med. 2006;355:2542-2550.

  10. Second-Line Therapy: Options & Outcomes a. Shepherd FA, et al. J Clin Oncol. 2000;18:2095-2103.b. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.c. Kim ES, et al. Lancet. 2008;372:1809-1818.d. Ciuleanu T, et al. Lancet Oncol. 2012;13:300-308.

  11. Second-Line Therapy: Grade 3/4 Toxicities Erlotinib[a] ≈ Pemetrexed[a,b] << Docetaxel[b] 40.2% Percent Reporting Adverse Event a. Vamvakas L, et al. ASCO 2010.b. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.

  12. Selecting Second-Line Therapy • Patient Factors • PS • Age • Patient preference • Treatment History • First-line regimen • Duration of response to first-line treatment • Tumor Characteristics • Tumor burden • Histology • EGFR? • ALK? • KRAS? Good PS + good response to first-line chemo Chemotherapy Targeted therapy (erlotinib, gefitinib,crizotinib) Adenocarcinoma + targetable mutation/rearrangement Wild-type or KRAS mutations Chemotherapy PS = performance status

  13. Second-Line Therapy: Outstanding Needs • Options for patients with wild-type mutations (EGFR, etc) • Predictive biomarkers • New agents with efficacy in the second-line setting

  14. Second-Line Therapy: Research To Date In pre-treated patients, only 2 out of 15 trials to date have shown an improvement in OS All of these trials are against placebo only (no active comparator arm). Direct comparison is not possible. List contains examples and is not exhaustive.

  15. Angiogenesis Inhibitors in NSCLC * Currently approved for first-line therapy of NSCLC, in combination with a platinum and taxane Ellis PM & Al-Saleh K. Critical Rev Onc/Hem. 2012;84:47-58.

  16. Angiogenesis Inhibitors in NSCLC: Nintedanib • Investigational oral agent • Can be combined with chemotherapy • Docetaxel[a] • Pemetrexed[b] • Paclitaxel/carboplatin[c] • Gemcitabine/cisplatin[d] a. Bousquet G, et al. Br J Cancer. 2011;105:1640-1645.b. Ellis PM, et al. Clin Cancer Res. 2010;16:2881-2889.c. Doebele RC, et al. Ann Oncol. 2012;23:2094-2102.d. http://clinicaltrials.gov/show/NCT01346540.

  17. LUME-Lung 1: Trial Design Patients with NSCLC who have failed first-line chemotherapy Randomization Oral nintedanib +Chemotherapy (docetaxel) Placebo +Chemotherapy (docetaxel) Second-line treatment Number of docetaxel cycles not restricted Monotherapy with nintedanib/placebo allowed after ≥ 4 cycles Primary endpoint: PFS Key secondary endpoint: OS Results presented at ASCO 2013 Reck M, et al. ASCO 2013.

  18. LUME-Lung 1: Inclusion Criteria • Inclusion criteria: • Male or female patients, aged ≥ 18 years • Patients with IIIB/IV or recurrent NSCLC (all histologies) • Progression after prior first-line chemotherapy • ECOG score of 0 and 1 • 1314 patients: recruitment completed Reck M, et al. ASCO 2013.

  19. LUME-Lung 1: PFS (All Patients) 100 80 60 Probability of survival without progression (%) 40 20 0 0 2 4 6 8 10 12 14 16 18 Time (months) Reck M, et al. ASCO 2013.

  20. LUME-Lung 1: OS (All Patients) 100 80 60 Probability of survival (%) 40 20 0 0 4 8 12 16 20 24 28 32 36 Time (months) Reck M, et al. ASCO 2013.

  21. LUME-Lung 1: OS (Adenocarcinoma Patients) 100 80 60 52.7% Probability of survival (%) 40 25.7% 44.7% 20 19.1% 0 0 4 8 12 16 20 24 28 32 36 Time (months) Reck M, et al. ASCO 2013.

  22. LUME-Lung 1: Adverse Events of Special Interest Patients Reporting (%) Adverse Events, Grade ≥ 3 (incidence ≥ 1%) Adverse Events, All Grades(incidence ≥ 15%) Reck M, et al. ASCO 2013.

  23. LUME-Lung 1: Summary • Met primary endpoint of delaying tumour growth following failure of first-line therapy • Showed a significant survival benefit in patients with adenocarcinoma compared with an active comparator • Well tolerated with manageable safety profile

  24. Combination Therapy With Angiogenesis Inhibitors: First-Line vs Second-Line Outcomes OS (mo) HR, 0.79; 95% CI, 0.67 to 0.92P = .003 HR, 0.83; P = .0359 LUME-Lung 1(Adenocarcinoma subset) [b] [a] a. Sandler A, et al. New Engl J Med. 2006;355:2542-2550. b. Reck M, et al. J Clin Oncol. 2013;31(suppl): LBAS011.

  25. LUME-Lung 1: OS by Histology 100 80 60 Probability of survival (%) 40 20 0 0 4 8 12 16 20 24 28 32 36 0 4 8 12 16 20 24 28 32 36 All patients Adenocarcinoma subset Reck M, et al. ASCO 2013.

  26. Nintedanib in Squamous Cell Carcinoma: Outstanding Issues • Benefit demonstrated regarding PFS • OS benefit seen in patients with large tumors • Role of FGFR amplification in squamous cell carcinoma requires further investigation

  27. LUME-Lung 1: Toxicities Associated with VEGF/VEGFR Inhibitors ATE = arterial thromboembolism; GI = gastrointestinal; VTE = venous thromboembolism Reck M, et al. ASCO 2013.

  28. Looking Forward: Research Needs • Combination vs monotherapy • Biomarkers to assist in patient selection • Role of clinical factors, histology, etc

  29. LUME-Lung 1: Characteristics Associated With Improved OS in Nintedanib-Treated Adenocarcinoma Patients CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease Reck M, et al. ASCO 2013.

  30. Angiogenesis Inhibitors in the Second-Line Setting: LUME-Lung 1 vs ZODIAC OS (mo) HR, 0.94 95% CI, 0.83 to 1.05P = .2720 HR, 0.91 97.52% CI, 0.78 to 1.07P = .196 LUME-Lung 1[a] [b] a. Reck M, et al. J Clin Oncol. 2013;31(suppl): LBAS011. b. Herbst RS, et al. Lancet Oncol. 2010;11:619-626.

  31. Angiogenesis Inhibitors in the Second-Line Setting: LUME-Lung 2 • Entry Criteria • Stage IIB/IV or recurrent NSCLC • Non-squamous histology • Relapsed/failed one prior line of chemotherapy • Measurable lesion(s) • ECOG PS 0 or 1 Randomization 1:1 Target enrollment: 1300 Nintedanib + pemetrexed (N = 353) Placebo + pemetrexed (N = 360) Disease Progression Disease Progression • Study was halted after interim analysis suggested the primary endpoint of PFS would not be met • Ongoing patients were unblinded and follow-up continued per protocol Hanna NH, et al. ASCO 2013.

  32. LUME-Lung 2: Centrally-Reviewed PFS Estimated patients alive and progression-free (%) Time from randomization (months) Hanna NH, et al. ASCO 2013.

  33. Docetaxel in the Second-Line Setting: Survival Trends OS (mo) Hanna et al. 2004[b] LUME-Lung 1[e] INTEREST[c] TAX 317[a] ZODIAC[d] a. Shepherd FA, et al. J Clin Oncol. 2000;18:2095-2103.b. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597. c. Kim ES, et al. Lancet. 2008;372:1809-1818. d. Herbst RS, et al. Lancet Oncol. 2010;11:619-626. e. Reck M, et al. ASCO 2013.

  34. LUME-Lung 1: Patient Characteristics Reck M, et al. ASCO 2013.

  35. Clinical Questions • Sequencing of therapy? • Treatment beyond progression? • Impact of maintenance therapy on subsequent treatment decisions?

  36. LUME-Lung 1: Characteristics Associated With Improved OS in Nintedanib-Treated Adenocarcinoma Patients Reck M, et al. ASCO 2013.

  37. Take Home Messages • A majority of NSCLC patients do not have targetable mutations • Second-line treatment options for these patients have historically been limited • Combination therapy with the angiogenesis inhibitor bevacizumab has been successful in the first-line setting • In the second-line setting, combination therapy with the angiogenesis inhibitor nintedanib has recently been shown to • Prolong PFS in patients with NSCLC, regardless of histology • Improve OS in patients with adenocarcinoma

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