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:
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
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
Single-Driver Mutations in NSCLC Lovly C, et al. Pao W, Girard N. Lancet Oncol. 2011;12:
NSCLC Without Targetable Mutations: An Unmet Need Lovly C, et al. Pao W, Girard N. Lancet Oncol. 2011;12:
NSCLC Histology Howlader N, et al (eds). SEER Cancer Statistics Review, , National Cancer Institute. Bethesda, MD, 2013.
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:
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
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
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:
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:
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
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 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
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.
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.
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
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
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.
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
% 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
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
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
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]
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 (%)
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
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
Combination vs monotherapy Biomarkers to assist in patient selection Role of clinical factors, histology, etc Looking Forward: Research Needs
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
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]
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
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 (%)
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]
Sequencing of therapy? Treatment beyond progression? Impact of maintenance therapy on subsequent treatment decisions? Clinical Questions
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.
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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