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 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

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

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.

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.

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

Single-Driver Mutations in NSCLC Gene Incidence KRAS 15%  25% EGFR 10%  35% ALK 3%  7% MET 2%  4% HER2 BRAF 1%  3% PIK3CA AKT1 1% MAP2K1 NRAS ROS1 RET Lovly C, et al. http://www.mycancergenome.org/content/disease/lung-cancer. Pao W, Girard N. Lancet Oncol. 2011;12:175-180.

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.

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.

Second-Line Therapy: Options & Outcomes Study Treatment Arms Median OS (mos) 1-Year Survival TAX 317[a] Docetaxel (N = 103) 7.0 37.0% Best supportive care (N = 100) 4.6 12.0% Hanna et al. 2004[b] Pemetrexed (N = 283) 8.3 29.7% Docetaxel (N = 288) 7.9 INTEREST[c] Gefitinib (N = 723) 7.6 32.0% Docetaxel (N = 710) 8.0 34.0% TITAN[d] Erlotinib (N = 203) 5.3 26.0% Chemotherapy (N = 221: 116 docetaxel, 105 pemetrexed) 5.5 24.0% 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.

Erlotinib[a] ≈ Pemetrexed[a,b] << Docetaxel[b] 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.

Tumor Characteristics 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

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

Second-Line Therapy: Research To Date Study Treatment Median OS (mo) Tax 317 Docetaxel (D75/100) vs BSC 7.5 (D75) vs 4.6 BR.21 Erlotinib vs placebo 6.7 vs 4.7 JMEI Pemetrexed vs docetaxel FAILED Tax 320 Docetaxel (D75/100) vs ifosfamide or vinorelbine ISEL Gefitinib vs placebo ZODIAC Vandetanib + docetaxel vs docetaxel ZEAL Vandetanib + pemetrexed vs pemetrexed ZEST Vandetanib vs erlotinib VITAL Aflibercept + docetaxel vs docetaxel BETA Bevacizumab + erlotinib vs erlotinib TAILOR Docetaxel vs erlotinib, non-EGFR mutations TITAN Docetaxel/pemetrexed vs erlotinib Vinflunine Vinflunine vs docetaxel Topotecan Oral topotecan vs docetaxel SUN1087 Sunitinib + erlotinib vs erlotinib 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.

Angiogenesis Inhibitors in NSCLC Drug Target EGFR FGFR PDGFR VEGF VEGFR Axitinib   β R-1, 2, 3 Bevacizumab*  BMS-690514 Brivanib R-1 R-2 Cediranib α/β Linifanib MGCD265 Motesanib Nintedanib Pazopanib R-1, 3 Sorafenib R-2, 3 Sunitinib Vandetanib * 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.

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.

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.

LUME-Lung 1: 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.

LUME-Lung 1: PFS (All Patients) 100 80 60 40 20 0 2 4 6 8 10 12 14 16 18 Nintedanib + docetaxel (n = 655) Placebo + docetaxel (n = 659) Median, mo 3.4 2.7 HR (95% CI) 0.79 (0.68 to 0.92) P .0019 Probability of survival without progression (%) Time (months) Reck M, et al. ASCO 2013.

LUME-Lung 1: OS (All Patients) 100 80 60 40 20 0 4 8 12 16 20 24 28 32 36 Nintedanib + docetaxel (n = 655) Placebo + docetaxel (n = 659) Median, mo 10.1 9.1 HR (95% CI) 0.94 (0.83 to 1.05) P .2720 Probability of survival (%) Time (months) Reck M, et al. ASCO 2013.

LUME-Lung 1: OS (Adenocarcinoma Patients) 100 80 60 40 20 0 4 8 12 16 20 24 28 32 36 52.7% 44.7% 25.7% 19.1% Nintedanib + docetaxel (n = 322) Placebo + docetaxel (n = 336) Median, mo 12.6 10.3 HR (95% CI) 0.83 (0.70 to 0.99) P .0359 Probability of survival (%) Time (months) Reck M, et al. ASCO 2013.

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

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

LUME-Lung 1 (Adenocarcinoma subset) Combination Therapy With Angiogenesis Inhibitors: First-Line vs Second-Line Outcomes OS (mo) HR, 0.79; 95% CI, 0.67 to 0.92 P = .003 HR, 0.83; P = .0359 LUME-Lung 1 (Adenocarcinoma subset) [a] [b] 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.

LUME-Lung 1: OS by Histology Nintedanib + docetaxel (n = 655) Placebo + docetaxel (n = 659) Median, mo 10.1 9.1 HR (95% CI) 0.94 (0.83 to 1.05) P .2720 Nintedanib + docetaxel (n = 322) Placebo + docetaxel (n = 336) Median, mo 12.6 10.3 HR (95% CI) 0.83 (0.70 to 0.99) P .0359 100 80 60 40 20 0 4 8 12 16 20 24 28 32 36 Probability of survival (%) 0 4 8 12 16 20 24 28 32 36 All patients Adenocarcinoma subset Reck M, et al. ASCO 2013.

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

Nintedanib + docetaxel LUME-Lung 1: Toxicities Associated with VEGF/VEGFR Inhibitors Adverse event Nintedanib + docetaxel Placebo + docetaxel All grades % Grade ≥ 3 % Bleeding 14.1 2.3 11.6 1.8 Thromboembolism 5.1 2.1 4.6 3.1 Hypertension 3.5 0.2 0.9 VTE 2.8 1.2 1.5 1.1 ATE 0.6 0.5 1.4 GI perforation ATE = arterial thromboembolism; GI = gastrointestinal; VTE = venous thromboembolism Reck M, et al. ASCO 2013.

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

LUME-Lung 1: Characteristics Associated With Improved OS in Nintedanib-Treated Adenocarcinoma Patients Characteristic HR (95% CI) P value Prior bevacizumab .241 Yes 0.61 (0.31, 1.20) No 0.85 (0.71, 1.01) Best response to first-line therapy .189 CR/PR/SD 0.90 (0.73, 1.10) PD 0.62 (0.41, 0.94) Time since start of first-line therapy .419 < 9 months 0.75 (0.60, 0.92) ≥ 9 months 0.89 (0.66, 1.19) CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease Reck M, et al. ASCO 2013.

Angiogenesis Inhibitors in the Second-Line Setting: LUME-Lung 1 vs ZODIAC OS (mo) HR, 0.94 95% CI, 0.83 to 1.05 P = .2720 HR, 0.91 97.52% CI, 0.78 to 1.07 P = .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.

Nintedanib + pemetrexed 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.

LUME-Lung 2: Centrally-Reviewed PFS Time from randomization (months) Estimated patients alive and progression-free (%) Nintedanib + pemetrexed (n = 353) Placebo + pemetrexed (n = 360) Median PFS, mo 4.4 3.6 HR (95% CI) 0.83 (0.70 to 0.99) Log-rank p value .0435 Hanna NH, et al. ASCO 2013.

Docetaxel in the Second-Line Setting: Survival Trends OS (mo) TAX 317[a] Hanna et al. 2004[b] INTEREST[c] ZODIAC[d] LUME- Lung 1[e] 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.

Nintedanib + docetaxel LUME-Lung 1: Patient Characteristics Characteristic Nintedanib + docetaxel (N = 655) Placebo + docetaxel (N = 659) Age < 65 years 69.5% 67.5% Current/former smoker 74.8% 75.6% Histology Adenocarcinoma 49.2% 51.0% Squamous cell carcinoma 42.1% 42.2% Other 8.7% 6.7% Prior therapy Platinum 95.9% 96.5% Bevacizumab 4.1% 3.5% Reck M, et al. ASCO 2013.

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

LUME-Lung 1: Characteristics Associated With Improved OS in Nintedanib-Treated Adenocarcinoma Patients Characteristic HR (95% CI) P value Prior bevacizumab .241 Yes 0.61 (0.31, 1.20) No 0.85 (0.71, 1.01) Best response to first-line therapy .189 CR/PR/SD 0.90 (0.73, 1.10) PD 0.62 (0.41, 0.94) Time since start of first-line therapy .419 < 9 months 0.75 (0.60, 0.92) ≥ 9 months 0.89 (0.66, 1.19) Reck M, et al. ASCO 2013.

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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