Anti-angiogenic agents: where we are? Martin Reck Department of Thoracic Oncology Hospital Grosshansdorf Germany Angiogenesis and tumor growth Journal of experimental Medicine 1972; 133: 275-88 1
Angiogenesis is a tightly regulated balance The angiogenic switch On Off = Pro-angiogenic factors (e.g. VEGF, PlGF, bfgf, IL-8) = Anti-angiogenic factors (e.g. thrombospondin-1, angiostatin, IFN-a/b) Hanahan, Folkman. Cell 1996 Targets of Antiangiogenic Therapy VEGF Antibodies VEGF Receptor TKI Vascular Damaging Agents (VDA) Scappaticci, F. A. J Clin Oncol; 20:3906-3927 2002 2
Antiangiogenic Treatment of NSCLC Front-line treatment VEGF-Antibodies Bevacizumab VEGF-TKI Sorafenib Cetiranib Motesanib Other pathways Thalidomide Vascular Disrupting Agents ASA404 Antiangiogenic Treatment of NSCLC Front-line treatment VEGF-Antibodies Bevacizumab VEGF-TKI Sorafenib Cetiranib Motesanib Other pathways Thalidomide Vascular Disrupting Agents ASA404 3
E4599 trial design 1 Bevacizumab in NSCLC Previously untreated stage IIIB/IV non-squamous NSCLC (n=878) CP x 6 (n=444) Bev (15mg/kg) every 3 weeks + CP x 6 (n=434) Bev PD* PD AVAiL trial design 2 Placebo + CG x 6 (n=347) PD* Previously untreated, stage IIIB, IV or recurrent nonsquamous NSCLC (n=1,043) *No cross over permitted CP=carboplatin + paclitaxel CG=cisplatin + gemcitabine PD=progression of disease Bev (15mg/kg) every 3 weeks + CG x 6 (n=351) Bev (7.5mg/kg) every 3 weeks + CG x 6 (n=345) Bev Bev PD PD 1. Sandler, et al. N Engl J Med 2006;355:2542-2550. 2. Reck, et al. J Clin Oncol 2009;27:1227-1234. Bevacizumab in Nonsquamous NSCLC Key Results ECOG 4599 AVAIL PCB PC CGB (7.5) CGB (15) CG RR 35% 15% 34.1% 30.4% 20.1% p-value <0.001 <0.0001 (7.5) 0.0023 (15) PFS (m) 6.2 4.5 6.7 6.5 6.1 HR / p-value 0.66 (<0.001) 0.75 (0.003) / 7.5 0.82 (0.03) / 15 OS (m) 12.3 10.3 13.6 13.4 13.1 HR / p-value 0.79 (0.003) 0.93 (ns) / 7.5 1.03 (ns) / 15 Sandler, et al. N Engl J Med 2006;355:2542-2550. Reck, et al. J Clin Oncol 2009;27:1227-1234. Manegold, et al. ESMO 2008. 4
SAiL: Safety of Avastin in Lung First-line, advanced non-squamous NSCLC (n=2,172) Bevacizumab (7.5mg/kg or 15mg/kg) every 3 weeks + standard of care chemotherapy (up to 6 cycles) Bevacizumab to progression PD Primary endpoint: safety of Bevacizumab when combined with chemotherapy Secondary endpoints: efficacy of Bevacizumab (OS, TTP); safety of Bevacizumab in patients who develop CNS metastases CNS = central nervous system SAIL - Safety Patients (%) 30 20 10 0 Grade 3 AEs of special interest in E4599, AVAiL and SAiL 4,4 5,0 4,0 3,6 Bleeding (all types) *Includes haemoptysis AE = adverse event E4599 Bev 15mg/kg + CP AVAiL Bev 15mg/kg + CG AVAiL Bev 7.5mg/kg + CG SAiL Bev 7.5 or 15mg/kg + chemotherapy 1,9 0,9 0,9 0,7 Pulmonary haemorrhage* 7,0 9,0 Median TTP: 7.8 months Median OS: 14.6 months 7,0 5,7 Hypertension 3,0 3,0 2,0 Proteinuria 3,1 Sandler, et al. NEJM 2006 Hirsh, et al. ASCO 2009 Dansin, et al. ECCO-ESMO 2009 5
Bevacizumab Predictive Marker? Selection driven by safety factors (histology, cardiovascular comorbidity, bleeding risk) No predictive marker for efficacy Conclusion Biomarker Avail-Trial: Biomarker involved in angiogenic pathways may play a prognostic role in patients with advanced NSCLC. The role of angiogenic biomarker will be further evaluated (Leighl N et al, ESMO-ECCO 2009) ABIGAIL (BO21015): phase II biomarker trial Previously untreated stage IIIB/IV non-squamous NSCLC (n=300) Bevacizumab 7.5mg/kg + carboplatin/gemcitabine or carboplatin/paclitaxel Bevacizumab 15mg/kg + carboplatin/gemcitabine or carboplatin/paclitaxel Bevacizumab every 3 weeks until progression Bevacizumab every 3 weeks until progression PD PD Primary endpoint: correlation of biomarkers with RR Primary markers: VEGF-A, svegf receptor 1, svegf receptor 2, PlGF, E- selectin Other markers: ICAM, VCAM, bfgf, oestrogen and related receptors, tissue factors 6
Efficacy for patients with HTN versus those without Survival Median OS (lower upper limit), months Patients without HTN event N=1,586 12.9 (12.4 14.6) Patients with HTN event N=580 18.8 (17.0 20.4) Patients with event (%) 40.9 33.8 Censored patients (%) 59.1 66.2 Progression Median TTP (lower upper limit), months 7.2 (7.0 7.6) 8.7 (8.3 9.2) Progressive disease (%) 56.0 64.7 Censored patients (%) 44.0 35.3 Thatcher N et al, WCLC 2009 Choice of chemotherapy? Shaked Y et al, Cancer Cell 2008 7
Antiangiogenic Treatment of NSCLC Front-line treatment VEGF-Antibodies Bevacizumab VEGF-TKI Sorafenib Cetiranib Motesanib Other pathways Thalidomide Vascular Disrupting Agents ASA404 VEGFR-TKI Drug VEGFR 1-3 PDGFR RET C-KIT FLT-3 EGFR RAF Vandetanib ü - ü - - ü - Cediranib ü ü - ü - - - Motesanib ü ü - ü - - - Sunitinib ü ü - ü ü - - Sorafenib ü ü ü ü ü - ü BIBF 1120 ü ü - - - - - Axitinib ü ü - ü - - - Wedge SR, Clin Cancer Res 2002; Laurie SA, J Clin Oncol 2008; Rosen L, J Clin Oncol 2005; Chow LQ, J Clin Oncol 2005; Wilhelm SM, Cancer Res 2004; Hilberg F, Cancer Res 2008; Schiller J, J Clin Oncol 2007 8
Study Design ESCAPE Chemotherapy phase Maintenance phase Stratification: Geographic region ECOG PS 0 vs 1 Squamous vs non-squamous cell Stage IIIb (with effusion) vs Stage IV n=900 R A N D O M I Z E Carboplatin AUC 6 d1 + Paclitaxel 200 mg/m 2 d1 + Sorafenib 400 mg bid d2-19, q3w (CPS) Carboplatin AUC 6 d1 + Paclitaxel 200 mg/m 2 d1 + Placebo d2-19, q3w (CPP) Sorafenib 400 mg bid Placebo Primary endpoint: Overall survival (Improvement of 30%) Secondary endpoints: Response rate, duration of response, progression free survival, PRO, biomarkers Scagliotti G, J Clin Oncol 2010 (in press) Escape Key results Sorafenib + CP CP Alone P-value Patients 464 462 Histology Squamous cell 109 (23%) 114 (25%) Response rate 27% 24% ns Median OS (m.) 10.7 10.6 0.915 HR 1.15 Median PFS (m.) 4.6 5.4 0.433 HR 0.99 Drug related AE 390 (84%) 314 (68%) <0.001 Drug related SAE 78 (17%) 39 (9%) <0.001 Scagliotti G, J Clin Oncol 2010 (in press) 9
Overall Survival by Histology Survival Probability 1.00 0.75 0.50 0.25 HR = 1.81 95% CI: 1.19, 2.74 Squamous Cell CPS Median: 8.9 months 95% CI: 6.1, 13.9 CPP Median: 13.6 months 95% CI: 9.6, Survival Probability 1.00 0.75 0.50 0.25 Non-Squamous Cell HR = 0.98 95% CI: 0.78, 1.24 CPS Median: 11.5 months 95% CI: 9.7, 14.8 CPP Median: 10.3 months 95% CI: 9.3, 11.5 0 0 4 8 12 16 20 0 0 4 8 12 16 20 Months Months Patients at Risk Patients at Risk CPS 107 73 24 9 2 CPS 357 281 173 38 5 CPP 112 97 41 12 3 CPP 350 280 168 22 2 Scagliotti G, J Clin Oncol 2010 (in press) Nexus Trial - Amendments Cisplatin/Gemcitabine +/- Sorafenib in patients with stage IIIb/IV NSCLC 10/07 Introduction of OS as Co-Primary Endpoint Patient number: 350 900 pat. 25.03.08 DMC: Interim Safety Analysis Recommendation of Exclusion of Squamous Cell Cancer patient due to higher toxicity 04/08 Exclusion of Squamous Cell Cancer patients 07/08 OS only primary endpoint, PFS secondary endpoint, Introduction of two futility interim analyses 02/09 904 randomised patients 10
Cediranib CP + Cediranib (45 / 30 mg) CP P-value Patients 126 123 Response 38% 16% P<0.001 PFS 5.6 5.0 OS (m) 10.5 10.1 HR 0.77, p = 0.13 HR 0.78 P = 0.11 Currently randomized trials using a dose of 20 mg Cediranib on the way Goss GD et al, J Clin Oncol 2010 Motesanib (AMG 706) Randomized, Placebo-controlled, Double-Blind Trial of AMG 706 + Paclitaxel/Carboplatin v Placebo + Paclitaxel/Carboplatin 11/2008 1.100 patients enrolled (33% Squamous Cell Histology) stop of recruitment due to safety reasons (squamous cell histology) 03/2009 Amendment Exclusion of patients with Squamous Cell Histology, reopening of recruitment 11
Thalidomide 722 patients No interim futility analysis No translational research Lee SM et al, J Clin Oncol 2009 Antiangiogenic Treatment of NSCLC Front-line treatment VEGF-Antibodies Bevacizumab VEGF-TKI Sorafenib Cetiranib Motesanib Other pathways Thalidomide Vascular Disrupting Agents ASA404 12
Tumor-VDAs vs Antiangiogenic Agents Disrupt established blood vessels Cause vessel occlusion and inhibition of blood flow Tumor necrosis, major effect on central part of tumor Interfere with new blood vessels Inhibit endothelial proliferation and migration Major effect on peripheral part of tumor Tozer, et al. Nat Rev Cancer 2005;5:423-435. Patterson and Rustin. Clin Oncol (R Coll Radiol) 2007;19:443-456. Baguley. Lancet Oncol 2003;4:141-148. ASA404 + Chemotherapy Surviving 1.0 0.9 0.8 0.7 0.6 0.5 0.4 ASA404 1200 + P/C P/C 0.3 Treatment ASA404 1200 + P/C P/C 0.2 Median (months) 14.0 8.8 0.1 HR (95% CI): 0.73 (0.39, 1.38) Reduction in risk of death: 27% 0.0 0 3 6 9 12 Time (months) ASA404 1200 + P/C P/C Response n = 32 n = 27 PR 10 (31.3%) 6 (22.2%) SD 21 (65.6%) 19 (70.4%) PD 1 (3.1%) 2 (7.4%) 15 McKeage, et al. Br J Cancer 2008;99(12):2006-2012. 13
ASA404: Attract 1 - Study Design Stage IIIB/IV NSCLC All histologies First-line CT naïve PS 0 or 1 Stratification: gender squamous vs non-squamous 08/09 Recruitment finished (1200 pat.) 47% from Europe Results expected 2011 N=1200 Randomization 1:1 Paclitaxel + carboplatin + ASA404 Primary endpoint: overall survival Paclitaxel + carboplatin + placebo Paclitaxel 200 mg/m 2, carboplatin AUC 6, and ASA404 1800 mg/m 2 or placebo Day 1, q3w, up to six cycles Study drug maintenance treatment (after completion of six cycles of study drug + P/C up to progression) Conclusion Improved efficacy by combination of bevacizumab and chemotherapy in non-squamous cell NSCLC Difficult research for predictive markers Role of VEGFR-TKI in front-line treatment of NSCLC under investigation Squamous cell histology associated with higher risk for toxicity Phase III data for ASA404 pending 14