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New Perspectives on Second-Line Therapy for NSCLC Tony Mok, MD (Moderator) Professor, Department of Clinical Oncology, Chinese University of Hong Kong;

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Presentation on theme: "New Perspectives on Second-Line Therapy for NSCLC Tony Mok, MD (Moderator) Professor, Department of Clinical Oncology, Chinese University of Hong Kong;"— Presentation transcript:

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

4 Single-Driver Mutations in NSCLC Lovly C, et al. Pao W, Girard N. Lancet Oncol. 2011;12:

5 NSCLC Without Targetable Mutations: An Unmet Need Lovly C, et al. Pao W, Girard N. Lancet Oncol. 2011;12:

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

7 GeneIncidence KRAS 15%  25% EGFR 10%  35% ALK 3%  7% MET 2%  4% HER2 2%  4% BRAF 1%  3% PIK3CA 1%  3% AKT11% MAP2K11% NRAS1% ROS11% RET1% Single-Driver Mutations in NSCLC Lovly C, et al. Pao W, Girard N. Lancet Oncol. 2011;12:

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

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

10 StudyTreatment Arms Median OS (mos)1-Year Survival TAX 317 [a] Docetaxel (N = 103) % Best supportive care (N = 100) % Hanna et al [b] Pemetrexed (N = 283) % Docetaxel (N = 288) % INTEREST [c] Gefitinib (N = 723) % Docetaxel (N = 710) % TITAN [d] Erlotinib (N = 203) % Chemotherapy (N = 221: 116 docetaxel, 105 pemetrexed) % Second-Line Therapy: Options & Outcomes a. Shepherd FA, et al. J Clin Oncol. 2000;18: b. Hanna N, et al. J Clin Oncol. 2004;22: c. Kim ES, et al. Lancet. 2008;372: d. Ciuleanu T, et al. Lancet Oncol. 2012;13:

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

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 Adenocarcinoma + targetable mutation/rearrangement Targeted therapy (erlotinib, gefitinib, crizotinib) 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 All of these trials are against placebo only (no active comparator arm). Direct comparison is not possible. List contains examples and is not exhaustive. In pre-treated patients, only 2 out of 15 trials to date have shown an improvement in OS StudyTreatmentMedian OS (mo) Tax 317Docetaxel (D75/100) vs BSC7.5 (D75) vs 4.6 BR.21Erlotinib vs placebo6.7 vs 4.7 JMEIPemetrexed vs docetaxel FAILED Tax 320Docetaxel (D75/100) vs ifosfamide or vinorelbine ISELGefitinib vs placebo ZODIACVandetanib + docetaxel vs docetaxel ZEALVandetanib + pemetrexed vs pemetrexed ZESTVandetanib vs erlotinib VITALAflibercept + docetaxel vs docetaxel BETABevacizumab + erlotinib vs erlotinib TAILORDocetaxel vs erlotinib, non-EGFR mutations TITANDocetaxel/pemetrexed vs erlotinib VinflunineVinflunine vs docetaxel TopotecanOral topotecan vs docetaxel SUN1087Sunitinib + erlotinib vs erlotinib

15 Drug Target EGFRFGFRPDGFRVEGFVEGFR Axitinib β R-1, 2, 3 Bevacizumab* BMS Brivanib R-1 R-2 Cediranib α/βα/β R-1, 2, 3 Linifanib R-1, 2, 3 MGCD265 Motesanib R-1, 2, 3 Nintedanib R-1, 2, 3α/βα/β Pazopanib R-1, 3α/βα/β R-1, 2, 3 Sorafenib β R-2, 3 Sunitinib α/βα/β R-1, 2, 3 Vandetanib R-2, 3 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: b. Ellis PM, et al. Clin Cancer Res. 2010;16: c. Doebele RC, et al. Ann Oncol. 2012;23: d.

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

18 LUME-Lung 1: Inclusion Criteria Reck M, et al. ASCO 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 patients: recruitment completed

19 LUME-Lung 1: PFS (All Patients) Probability of survival without progression (%) Time (months) Nintedanib + docetaxel (n = 655) Placebo + docetaxel (n = 659) Median, mo HR (95% CI)0.79 (0.68 to 0.92) P.0019 Reck M, et al. ASCO 2013.

20 Time (months) Probability of survival (%) LUME-Lung 1: OS (All Patients) Reck M, et al. ASCO Nintedanib + docetaxel (n = 655) Placebo + docetaxel (n = 659) Median, mo HR (95% CI)0.94 (0.83 to 1.05) P.2720

21 % 44.7% 25.7% 19.1% LUME-Lung 1: OS (Adenocarcinoma Patients) Probability of survival (%) Time (months) Reck M, et al. ASCO Nintedanib + docetaxel (n = 322) Placebo + docetaxel (n = 336) Median, mo HR (95% CI)0.83 (0.70 to 0.99) P.0359

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

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 a. Sandler A, et al. New Engl J Med. 2006;355: b. Reck M, et al. J Clin Oncol. 2013;31(suppl): LBAS011. OS (mo) LUME-Lung 1 (Adenocarcinoma subset) HR, 0.79; 95% CI, 0.67 to 0.92 P =.003 HR, 0.83; P =.0359 [a] [b]

25 LUME-Lung 1: OS by Histology Adenocarcinoma subset Nintedanib + docetaxel (n = 655) Placebo + docetaxel (n = 659) Median, mo HR (95% CI)0.94 (0.83 to 1.05) P.2720 Reck M, et al. ASCO Nintedanib + docetaxel (n = 322) Placebo + docetaxel (n = 336) Median, mo HR (95% CI)0.83 (0.70 to 0.99) P.0359 All patients Probability of survival (%)

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

27 LUME-Lung 1: Toxicities Associated with VEGF/VEGFR Inhibitors Adverse event Nintedanib + docetaxelPlacebo + docetaxel All grades % Grade ≥ 3 % All grades % Grade ≥ 3 % Bleeding Thromboembolism Hypertension VTE ATE GI perforation Reck M, et al. ASCO ATE = arterial thromboembolism; GI = gastrointestinal; VTE = venous thromboembolism

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

29 LUME-Lung 1: Characteristics Associated With Improved OS in Nintedanib-Treated Adenocarcinoma Patients CharacteristicHR (95% CI)P value Prior bevacizumab.241 Yes0.61 (0.31, 1.20) No0.85 (0.71, 1.01) Best response to first-line therapy.189 CR/PR/SD0.90 (0.73, 1.10) PD0.62 (0.41, 0.94) Time since start of first-line therapy.419 < 9 months0.75 (0.60, 0.92) ≥ 9 months0.89 (0.66, 1.19) Reck M, et al. ASCO CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease

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

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 Target enrollment: 1300 Nintedanib + pemetrexed (N = 353) Placebo + pemetrexed (N = 360) 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 Randomization 1:1

32 LUME-Lung 2: Centrally-Reviewed PFS Nintedanib + pemetrexed (n = 353) Placebo + pemetrexed (n = 360) Median PFS, mo HR (95% CI)0.83 (0.70 to 0.99) Log-rank p value.0435 Hanna NH, et al. ASCO Time from randomization (months) Estimated patients alive and progression-free (%)

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

34 LUME-Lung 1: Patient Characteristics Characteristic Nintedanib + docetaxel (N = 655) Placebo + docetaxel (N = 659) Age < 65 years69.5%67.5% Current/former smoker74.8%75.6% Histology Adenocarcinoma49.2%51.0% Squamous cell carcinoma42.1%42.2% Other8.7%6.7% Prior therapy Platinum95.9%96.5% Bevacizumab4.1%3.5% Reck M, et al. ASCO 2013.

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

36 LUME-Lung 1: Characteristics Associated With Improved OS in Nintedanib-Treated Adenocarcinoma Patients CharacteristicHR (95% CI)P value Prior bevacizumab.241 Yes0.61 (0.31, 1.20) No0.85 (0.71, 1.01) Best response to first-line therapy.189 CR/PR/SD0.90 (0.73, 1.10) PD0.62 (0.41, 0.94) Time since start of first-line therapy.419 < 9 months0.75 (0.60, 0.92) ≥ 9 months0.89 (0.66, 1.19) Reck M, et al. ASCO 2013.

37 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 Take Home Messages

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