Presentation on theme: "New Perspectives on Second-Line Therapy for NSCLC"— Presentation transcript:
1New 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
2OverviewDiscuss the current standards of care for second- line therapy in patients with advanced NSCLCExamine the unique and unmet needs of patients without targetable activating mutationsReview emerging research findings on second-line therapy in NSCLC and their implications for clinical practiceNSCLC = non-small cell lung cancer
3Panelists Luis Paz-Ares Rodríguez, MD, PhD Martin Reck, MD, PhD Chair, Department of Oncology,Seville University Hospital,Seville, SpainMartin Reck, MD, PhDHead, Department of Thoracic Oncology,Hospital Grosshansdorf,Grosshansdorf, Germany
4Single-Driver Mutations in NSCLC Lovly C, et al. Pao W, Girard N. Lancet Oncol. 2011;12:
5NSCLC Without Targetable Mutations: An Unmet Need Lovly C, et al. Pao W, Girard N. Lancet Oncol. 2011;12:
6NSCLC HistologyHowlader N, et al (eds). SEER Cancer Statistics Review, , National Cancer Institute. Bethesda, MD, 2013.
7Single-Driver Mutations in NSCLC GeneIncidenceKRAS15% 25%EGFR10% 35%ALK3% 7%MET2% 4%HER2BRAF1% 3%PIK3CAAKT11%MAP2K1NRASROS1RETLovly C, et al.Pao W, Girard N. Lancet Oncol. 2011;12:
8Outcomes With First-Line Doublet Therapy: ECOG 1594 MonthsOS = overall survival; PFS = progression-free survivalSchiller JH, et al. New Engl J Med. 2002;346:92-98.
9Outcomes With First-Line Triplet Therapy: ECOG 4599 MonthsCI = confidence interval; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratioSandler A, et al. New Engl J Med. 2006;355:
10Second-Line Therapy: Options & Outcomes StudyTreatment ArmsMedian OS (mos)1-Year SurvivalTAX 317[a]Docetaxel (N = 103)7.037.0%Best supportive care (N = 100)4.612.0%Hanna et al. 2004[b]Pemetrexed (N = 283)8.329.7%Docetaxel (N = 288)7.9INTEREST[c]Gefitinib (N = 723)7.632.0%Docetaxel (N = 710)8.034.0%TITAN[d]Erlotinib (N = 203)5.326.0%Chemotherapy (N = 221: 116 docetaxel, 105 pemetrexed)5.524.0%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:
11Erlotinib[a] ≈ Pemetrexed[a,b] << Docetaxel[b] Second-Line Therapy: Grade 3/4 ToxicitiesErlotinib[a] ≈ Pemetrexed[a,b] << Docetaxel[b]40.2%Percent ReportingAdverse Eventa. Vamvakas L, et al. ASCO b. Hanna N, et al. J Clin Oncol. 2004;22:
12Tumor Characteristics Selecting Second-Line TherapyPatient FactorsPSAgePatient preferenceTreatment HistoryFirst-line regimenDuration of response to first-line treatmentTumor CharacteristicsTumor burdenHistologyEGFR?ALK?KRAS?Good PS + good response to first-line chemoChemotherapyTargeted therapy (erlotinib, gefitinib, crizotinib)Adenocarcinoma + targetable mutation/rearrangementWild-type or KRAS mutationsChemotherapyPS = performance status
13Second-Line Therapy: Outstanding Needs Options for patients with wild-type mutations (EGFR, etc)Predictive biomarkersNew agents with efficacy in the second-line setting
14Second-Line Therapy: Research To Date StudyTreatmentMedian OS (mo)Tax 317Docetaxel (D75/100) vs BSC7.5 (D75) vs 4.6BR.21Erlotinib vs placebo6.7 vs 4.7JMEIPemetrexed vs docetaxelFAILEDTax 320Docetaxel (D75/100) vs ifosfamide or vinorelbineISELGefitinib vs placeboZODIACVandetanib + docetaxel vs docetaxelZEALVandetanib + pemetrexed vs pemetrexedZESTVandetanib vs erlotinibVITALAflibercept + docetaxel vs docetaxelBETABevacizumab + erlotinib vs erlotinibTAILORDocetaxel vs erlotinib, non-EGFR mutationsTITANDocetaxel/pemetrexed vs erlotinibVinflunineVinflunine vs docetaxelTopotecanOral topotecan vs docetaxelSUN1087Sunitinib + erlotinib vs erlotinibIn pre-treated patients, only 2 out of 15 trials to date have shown an improvement in OSAll of these trials are against placebo only (no active comparator arm). Direct comparison is not possible. List contains examples and is not exhaustive.
15Angiogenesis Inhibitors in NSCLC DrugTargetEGFRFGFRPDGFRVEGFVEGFRAxitinibβR-1, 2, 3Bevacizumab*BMSBrivanibR-1R-2Cediranibα/βLinifanibMGCD265MotesanibNintedanibPazopanibR-1, 3SorafenibR-2, 3SunitinibVandetanib* Currently approved for first-line therapy of NSCLC, in combination with a platinum and taxaneEllis PM & Al-Saleh K. Critical Rev Onc/Hem. 2012;84:47-58.
16Angiogenesis Inhibitors in NSCLC: Nintedanib Investigational oral agentCan be combined with chemotherapyDocetaxel[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.
17LUME-Lung 1: Trial Design Patients with NSCLC who have failed first-line chemotherapyRandomizationOral nintedanib + Chemotherapy (docetaxel)Placebo + Chemotherapy (docetaxel)Second-line treatmentNumber of docetaxel cycles not restrictedMonotherapy with nintedanib/placebo allowed after ≥ 4 cyclesPrimary endpoint: PFSKey secondary endpoint: OSResults presented at ASCO 2013Reck M, et al. ASCO 2013.
18LUME-Lung 1: Inclusion Criteria Male or female patients, aged ≥ 18 yearsPatients with IIIB/IV or recurrent NSCLC (all histologies)Progression after prior first-line chemotherapyECOG score of 0 and 11314 patients: recruitment completedReck M, et al. ASCO 2013.
19LUME-Lung 1: PFS (All Patients) 10080604020Nintedanib + docetaxel (n = 655)Placebo + docetaxel (n = 659)Median, mo3.42.7HR (95% CI)0.79 (0.68 to 0.92)P.0019Probability of survival without progression (%)Time (months)Reck M, et al. ASCO 2013.
20LUME-Lung 1: OS (All Patients) 10080604020Nintedanib + docetaxel (n = 655)Placebo + docetaxel (n = 659)Median, mo10.19.1HR (95% CI)0.94 (0.83 to 1.05)P.2720Probability of survival (%)Time (months)Reck M, et al. ASCO 2013.
21LUME-Lung 1: OS (Adenocarcinoma Patients) 1008060402052.7%44.7%25.7%19.1%Nintedanib + docetaxel (n = 322)Placebo + docetaxel (n = 336)Median, mo12.610.3HR (95% CI)0.83 (0.70 to 0.99)P.0359Probability of survival (%)Time (months)Reck M, et al. ASCO 2013.
22LUME-Lung 1: Adverse Events of Special Interest Nintedanib + docetaxelPlacebo + docetaxelPatients Reporting (%)Adverse Events, All Grades (incidence ≥ 15%)Adverse Events, Grade ≥ 3 (incidence ≥ 1%)Reck M, et al. ASCO 2013.
23LUME-Lung 1: SummaryMet primary endpoint of delaying tumour growth following failure of first-line therapyShowed a significant survival benefit in patients with adenocarcinoma compared with an active comparatorWell tolerated with manageable safety profile
24LUME-Lung 1 (Adenocarcinoma subset) Combination Therapy With Angiogenesis Inhibitors: First-Line vs Second-Line OutcomesOS (mo)HR, 0.79;95% CI, 0.67 to 0.92 P = .003HR, 0.83;P = .0359LUME-Lung 1 (Adenocarcinoma subset)[a][b]a. Sandler A, et al. New Engl J Med. 2006;355:b. Reck M, et al. J Clin Oncol. 2013;31(suppl): LBAS011.
25LUME-Lung 1: OS by Histology Nintedanib + docetaxel (n = 655)Placebo + docetaxel (n = 659)Median, mo10.19.1HR (95% CI)0.94 (0.83 to 1.05)P.2720Nintedanib + docetaxel (n = 322)Placebo + docetaxel (n = 336)Median, mo12.610.3HR (95% CI)0.83 (0.70 to 0.99)P.035910080604020Probability of survival (%)All patientsAdenocarcinoma subsetReck M, et al. ASCO 2013.
26Nintedanib in Squamous Cell Carcinoma: Outstanding Issues Benefit demonstrated regarding PFSOS benefit seen in patients with large tumorsRole of FGFR amplification in squamous cell carcinoma requires further investigation
27Nintedanib + docetaxel LUME-Lung 1: Toxicities Associated with VEGF/VEGFR InhibitorsAdverse eventNintedanib + docetaxelPlacebo + docetaxelAll grades %Grade ≥ 3 %Bleeding14.12.311.61.8Thromboembolism22.214.171.124.1Hypertension126.96.36.199VTE188.8.131.52.1ATE0.60.51.4GI perforationATE = arterial thromboembolism; GI = gastrointestinal; VTE = venous thromboembolismReck M, et al. ASCO 2013.
28Looking Forward: Research Needs Combination vs monotherapyBiomarkers to assist in patient selectionRole of clinical factors, histology, etc
29LUME-Lung 1: Characteristics Associated With Improved OS in Nintedanib-Treated Adenocarcinoma PatientsCharacteristicHR (95% CI)P valuePrior bevacizumab.241Yes0.61 (0.31, 1.20)No0.85 (0.71, 1.01)Best response to first-line therapy.189CR/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)CR = complete response; PD = progressive disease; PR = partial response; SD = stable diseaseReck M, et al. ASCO 2013.
30Angiogenesis Inhibitors in the Second-Line Setting: LUME-Lung 1 vs ZODIAC OS (mo)HR, 0.9495% CI, 0.83 to 1.05 P = .2720HR, 0.9197.52% CI, 0.78 to 1.07 P = .196LUME-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:
31Nintedanib + pemetrexed Angiogenesis Inhibitors in the Second-Line Setting: LUME-Lung 2Entry CriteriaStage IIB/IV or recurrent NSCLCNon-squamous histologyRelapsed/failed one prior line of chemotherapyMeasurable lesion(s)ECOG PS 0 or 1Randomization 1:1Target enrollment: 1300Nintedanib + pemetrexed(N = 353)Placebo + pemetrexed(N = 360)Disease ProgressionDisease ProgressionStudy was halted after interim analysis suggested the primary endpoint of PFS would not be metOngoing patients were unblinded and follow-up continued per protocolHanna NH, et al. ASCO 2013.
32LUME-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, mo4.43.6HR (95% CI)0.83 (0.70 to 0.99)Log-rank p value.0435Hanna NH, et al. ASCO 2013.
33Docetaxel 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: 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 2013.
35Clinical Questions Sequencing of therapy? Treatment beyond progression?Impact of maintenance therapy on subsequent treatment decisions?
36LUME-Lung 1: Characteristics Associated With Improved OS in Nintedanib-Treated Adenocarcinoma PatientsCharacteristicHR (95% CI)P valuePrior bevacizumab.241Yes0.61 (0.31, 1.20)No0.85 (0.71, 1.01)Best response to first-line therapy.189CR/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.
37Take Home MessagesA majority of NSCLC patients do not have targetable mutationsSecond-line treatment options for these patients have historically been limitedCombination therapy with the angiogenesis inhibitor bevacizumab has been successful in the first-line settingIn the second-line setting, combination therapy with the angiogenesis inhibitor nintedanib has recently been shown toProlong PFS in patients with NSCLC, regardless of histologyImprove OS in patients with adenocarcinoma
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