Angiogenesi nel NSCLC: stato dell arte

Transcription

1 Angiogenesi nel NSCLC: stato dell arte Andrea Camerini Oncologia Medica - Ospedale Versilia Investigator Meeting Study GOIRC

2 Overview Neoangiogenesis in NSCLC (among others) Lots of targets lots of drugs Bevacizumab in first-line treatment Some criticisms (pts selection, predictive factors, toxicities)

3 Neoangiogenesis in NSCLC (among others)

4 Angiogenesi: a hallmark of cancer Activating invasion & metastasis Genome instability mutation Tumourpromoting inflammation Resisting cell death Enabling replicative immortality Degrading cellular energetics Sustaining proliferative signalling Avoiding immune destruction Evading growth suppressors Inducing angiogenesis Anti-VEGF therapy Regression of existing tumour vasculature Inhibition of new vessel growth No bone marrow suppression No cumulative toxicities Improved efficacy in combination with a well-established safety profile Hanahan & Weinberg. Cell 2011

5 Angiogenesis is a key element in the development of different types of tumors 1 A tumor mass larger than mm 2 has outgrown its capacity to acquire nutrients by simple diffusion and must initiate angiogenesis through host vessel initiation of capillary sprouts in the direction of the tumor 1 1. Folkman. In: Kufe, Pollock, Weichselbaum, eds. Cancer Medicine (Holland). 6th ed. Hamilton, Ontario: BC Decker; 2000; 2. Bergers, Benjamin. Nat Rev Cancer. 2003;3:401-10; 3. *Folkman. N Engl J Med. 1971;285:1182-6; 4. J Natl Cancer Inst. 1990;82:4-6 *«This article is copyrighted by the Massachusetts Medical Society. All rights reserved. It is provided for your personal informational use only»

6 Jain NEJM 2009

7 TYPE OF MOLECULES MOLECULES RECEPTOR FUNCTION ANGIOGENIC MOLECULES VEGF Family VEGF-A VEGFR-1 VEGFR-2 FGF Family FGF-2 FGFR-1 FGFR-2 FGFR-3 FGFR-4 Angiopoietin (Ang) Metalloproteinases (MMP) Cytokines Ang-1* Ang-2 MMP-2 MMP-9 TNF-α TGF-β CXC Chemokines CXC-ELR + CXCR2 CXCR4 CXCR7 Tie-1 Tie-2 None Substrate: Basement Membrane (BM) Extracellular Matrix (ECM) TNFR TβRI TβRII Proliferation (EC, P) Migration (EC) Formation of tubular structures Proliferación (EC, F) Migration (EC) VEGF Expression Formation of capillary structure Inflammation- related genes Sprouting*, proliferation, migration, vessel stabilization* (EC) Recruitment and activation of mural cells Degradation of BM and ECM Migration (EC) Migration (EC) Tube formation Vessel stabilization Inflammation Tube formation Proliferation, migration, inflammation (EC) Secretion and activation of MMPs Transcription factors HIF-1α* NF-κB** AP-1*** *Expression of VEGF, VEGFR, CXCL8 bfgf **Expression of CXCR2, CCL5, CXCL8 ***CXCL8 ANGIOSTATIC MOLECULES Angiostatin --- None. Proliferación (EC) Angiosotatin binds several proteins: Angiomotin ATP synthase Integrins Annexin II NG2 proteoglycan Endostatin --- None Endostatin binds several proteins Migration (EC) Formation of capillary structure VEGF Expression Proliferación (EC) Apoptosis Migration (EC) Inhibition MMPs Acivation VEGF Expression CXC Chemokines CXC-ELR - CXCR3B Migratory form Proliferation Formation of capillary structures Cytokines INF-γ INFgammaRI INFgammaRII *Expression of angiostatic chemokines Angiogenesis MMPs Inhibitors: TIMP TIMP-2 TIMP-3 Inhibition of MMPs Migratory form Proliferation Formation of capillary structures Abbreviations: AP-1, Activator Protein 1;BM, Basement Membrane; EC, Endothelial Cells; EpC Ephitelial Cells, ECM, Extracellular Matrix; FGF, Fibroblast Growth Factor; F, Rivas-Fuentes J Cancer 2015

8 Epigenetic induction Hypoxia, cytokines, sex hormones, growth factors, chemokines Genetic induction Mutant p53, VHL, PTEN-suppressor genes, and activated oncogenes (e.g., ras, src, EGFR, and erbb-2/her2) VEGF B PlGF VEGF A 121 VEGF A 165 VEGF C VEGF D S S S S Plasma membrane VEGFR-1 (flt-1) NRP-1 NRP-2 PLCγ VEGFR-2 (flk-1/kdr) VEGFR-3 (flt-4) Endothelial cell Raf PKC Host VEGF PI3K Akt MEK Vascular permeability MAPK Proliferation Survival Migration Mobilization (e.g., of VEGFR-2+ endothelial progenitor cells) Kerbel NEJM 2008

9 urthermore, chemokines and their receptors hemokine ligand/receptor axis involved in the pathophysiology of NSCLC. The pathophysiology of NSCLC involve Rivas-Fuentes J Cancer 2015

10 VEGF is an early and persistent promoter of tumour angiogenesis 1 4 VEGF VEGF bfgf TGFβ-1 VEGF bfgf TGFβ-1 PLGF VEGF bfgf TGFβ-1 PLGF PD-ECGF VEGF bfgf TGFβ-1 PLGF PD-ECGF Pleiotrophin Continued VEGF expression 3 Tumours continually require VEGF to recruit new vasculature 5 Graphical elaboration from text data VEGF continues to be expressed throughout tumor progression, even as secondary pathways emerge 2,3,6,7 1. Bergers, Benjamin. Nat Rev Cancer. 2003;3:401-10; 3; 2. Kim, et al. Nature ;362:841-4; 3. Folkman. In: DeVita, Hellman, Rosenberg, eds. Cancer: Principles & Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins;2005; 4. Ferrara, et al. Nat Med. 2003;9:669-76; 5. Inoue, et al. Cancer Cell ;2: ; 6. Mesiano, et al. Am J Pathol ;153: ; 7. Melnyk, et al. J Urol. 1999;161:960-3

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12 1. Avastin Summary of Product Characteristics; 2. Presta, et al. Cancer Res. 1997;57: Bevacizumab precisely targets VEGF to inhibit angiogenesis, for continuous tumour control 1,2 VEGF VEGF receptor Bevacizumab Bevacizumab prevents binding of VEGF to receptors 1,2 Bevacizumab has a long elimination half life (approximately 20 days) 1

13 Bevacizumab exerts multiple effects that contribute to increased treatment efficacy compared to conventional treatments 1 20 Graphical elaboration from text data Regression of existing tumour vasculature 1 3 Inhibition of new vessel growth 1 3,8 Anti-permeability of surviving vasculature Consistently increased response rates 4 7 Continuous control of tumour growth 8 10 Reduction of ascites and effusions 2,3,11, Baluk, et al. Curr Opin Genet Dev. 2005; 15:102-11; 2. Willett, et al. Nat Med. 2004;10:145-7; 3. O Connor, et al. Clin Cancer Res. 2009;15: ; 4. N Engl J Med. 2004; 350: ; 5. Sandler, et al. N Engl J Med ;355: ; 6. Escudier, et al. Lancet ;370: ; 7. Miller, et al. N Engl J Med ;357: ; 8. Mabuchi, et al. Clin Cancer Res ; 14:7781-9; 9. Wild, et al. Int J Cancer ;110(3):343-51; 10. Gerber, Ferrara. Cancer Res ;65:671-80; 11. Prager, et al. Mol Oncol. 2010;4:150-60; 12. Yanagisawa, et al. Anticancer Drugs. 2010;21:687-94; 13. Dickson, et al. Clin Cancer Res ;13: ; 14. Hu, et al. Am J Pathol ;161: ; 15. Ribeiro, et al. Respirology ;14: ; 16. Watanabe, et al. Hum Gene Ther ;20: ; 17. Mesiano, et al. Am J Pathol. 1998;153: ; 18. Bellati, et al. Invest New Drugs ;28:887-94; 19. Huynh, et al. J Hepatol ;49:52-60; 20. Ninomiya, et al J. Surg Res ;154:

14 Lots of targets lots of drugs

15 TABLE 1 Recent phase III trials assessing antiangiogenic agents in a first-line setting Agent and study name [ref.] Target (s) Study design Overall response rate Progression-free survival Overall survival Monoclonal antibodies Bevacizumab; ECOG 4599 [14] Bevacizumab; AVAiL [21, 22] Multi-targeted antiangiogenic orally administered TKIs Cediranib; BR24 [23] Cediranib; BR29 [24] Sorafenib; ESCAPE [25] Sorafenib; NExUS [26] Motesanib; MONET1 [27] Vascular disrupting agents Vadimezan; ATTRACT-1 [28] VEGF VEGF VEGFR-1 3, PDGFR-b, FGFR-1 and c-kit VEGFR-1 3, PDGFR-b, FGFR-1 and c-kit VEGFR-2 3, PDGFR-b, c-kit, Raf and flt-3 VEGFR-2 3, PDGFR-b, c-kit, Raf and flt-3 VEGFR-1 3, PDGFR-b, c-kit and RET Stage IIIB/IV non-squamous NSCLC Patients randomised to: carboplatin/paclitaxel (n5444) or carboplatin/paclitaxel + bevacizumab (15 mg?kg -1 ;n5434) Primary end-point: overall survival Stage IIIB/IV non-squamous NSCLC Patients randomised to: cisplatin/ gemcitabine (n5347), cisplatin/ gemcitabine + bevacizumab (7.5 mg?kg -1 ;n5345) or cisplatin/ gemcitabine + bevacizumab (15 mg?kg -1 ;n5351) Primary end-point: progression-free survival Stage IIIB/IV NSCLC all histologies Patients randomised to: carboplatin/paclitaxel (n5125) or carboplatin/paclitaxel + cediranib (30 mg?day -1 ;n5126) Primary end-point: progressionfree survival Stage IIIB/IV NSCLC all histologies Patients randomised to: carboplatin/paclitaxel or carboplatin/ paclitaxel + cediranib (20 mg?day -1 ) Primary end-point: overall survival Stage IIIB/IV NSCLC all histologies Patients randomised to: carboplatin/paclitaxel (n5462) or carboplatin/paclitaxel + sorafenib (400 mg; n5464) Primary end-point: overall survival Stage IIIB/IV non-squamous NSCLC Patients randomised to: gemcitabine/cisplatin (n5387) or gemcitabine/cisplatin + sorafenib (400 mg; n5385) Primary end-point: overall survival Stage IIIB/IV non-squamous NSCLC Patients randomised to: carboplatin/paclitaxel (n5549) or carboplatin/paclitaxel + motesanib (125 mg; n5541) Primary end-point: overall survival Stage IIIB/IV NSCLC all histologies Patients randomised to: carboplatin/paclitaxel (n5650) or carboplatin/paclitaxel + vadimezan (1800 mg?m -2 ;n5649) Primary end-point: overall survival Carboplatin/paclitaxel: 15% Carboplatin/paclitaxel + bevacizumab: 35% (p,0.001) Cisplatin/gemcitabine: 20.1% Cisplatin/gemcitabine + bevacizumab (7.5 mg?kg -1 ): 34.1% Cisplatin/gemcitabine + bevacizumab (15 mg?kg -1 ): 30.4% (p, and p , respectively) Carboplatin/paclitaxel: 16% Carboplatin/paclitaxel + cediranib: 38% (p,0.0001) Carboplatin/paclitaxel: 34% Carboplatin/paclitaxel + cediranib: 52% (p50.001) Carboplatin/paclitaxel: 27% Carboplatin/paclitaxel + sorafenib: 24% (p50.102) Gemcitabine/cisplatin: 26% Gemcitabine/cisplatin + sorafenib: 28% (p50.27) Carboplatin/paclitaxel: 26% Carboplatin/paclitaxel + motesanib: 40% (p,0.001) Carboplatin/paclitaxel: 25% Carboplatin/paclitaxel + vadimezan: 25% (p51.0) Carboplatin/paclitaxel: 4.5 months Carboplatin/paclitaxel + bevacizumab: 6.2 months HR 0.66 (95% CI ); p,0.001 Cisplatin/gemcitabine: 6.1 months Cisplatin/gemcitabine + bevacizumab (7.5 mg?kg -1 ): 6.7 months Cisplatin/gemcitabine + bevacizumab (15 mg?kg -1 ): 6.5 months HR 0.75 (95% CI ); p and HR 0.92 (95% CI ); p50.03, respectively Carboplatin/paclitaxel: 5.0 months Carboplatin/paclitaxel + cediranib: 5.6 months HR 0.77 (95% CI ); p50.13 Carboplatin/paclitaxel: 5.5 months Carboplatin/paclitaxel + cediranib: 5.5 months HR 0.91 (95% CI ); p50.5 Carboplatin/paclitaxel: 5.4 months Carboplatin/paclitaxel + sorafenib: 4.6 months HR 0.99 (95% CI ); p Gemcitabine/cisplatin: 5.5 months Gemcitabine/cisplatin + sorafenib: 6.0 months HR 0.83 (95% CI ); p Carboplatin/paclitaxel: 5.4 months Carboplatin/paclitaxel + motesanib: 5.6 months HR 0.79 (95% CI ); p,0.001 Carboplatin/paclitaxel: 5.5 months Carboplatin/paclitaxel + vadimezan: 5.5 months HR 1.04 (95% CI ); p Carboplatin/paclitaxel: 10.3 months Carboplatin/paclitaxel + bevacizumab: 12.3 months HR 0.79 (95% CI ); p Cisplatin/gemcitabine: 13.1 months Cisplatin/gemcitabine + bevacizumab (7.5 mg?kg -1 ): 13.6 months Cisplatin/gemcitabine + bevacizumab (15 mg?kg -1 ): 13.4 months HR 0.92 (95% CI ); p and HR 1.03 (95% CI ); p50.761, respectively Carboplatin/paclitaxel: 10.1 months Carboplatin/paclitaxel + cediranib: 10.5 months HR 0.78 (95% CI ); p50.11 Carboplatin/paclitaxel: 12.1 months Carboplatin/paclitaxel + cediranib: 12.2 months HR 0.95 (95% CI ); p50.74 Carboplatin/paclitaxel: 10.6 months Carboplatin/paclitaxel + sorafenib: 10.7 months HR 1.15 (95% CI ); p Gemcitabine/cisplatin: 12.5 months Gemcitabine/cisplatin + sorafenib: 12.4 months HR 0.98 (65% CI ); p Carboplatin/paclitaxel: 11.0 months Carboplatin/paclitaxel + motesanib: 13.0 months HR 0.90 (95% CI ); p50.14 Carboplatin/paclitaxel: 12.7 months Carboplatin/paclitaxel + vadimezan: 13.4 months HR 1.01 (95% CI ); p Crinò L, Eur Respir Rev 2014

16 TABLE 2 Recent phase III trials assessing antiangiogenic agents in a second- or third-line setting Agent and study name [ref.] Target (s) Study design Overall response rate Progression-free survival Overall survival Multi-targeted antiangiogenic orally administered TKIs Nintedanib; LUME-Lung 1[44] Nintedanib; LUME-Lung 2 [45] Vandetanib; ZODIAC [46] Vandetanib; ZEAL [47] Vandetanib; ZEPHYR [48] Vandetanib; ZEST [49] Sorafenib; MISSION [50] Sunitinib [51] VEGF-1 3, PDGF-a and b, andfgfr-1 3 VEGF-1 3, PDGF-a and b, andfgfr-1 3 VEGFR-1 and -2, RET and EGFR VEGFR-1 and -2, RET and EGFR VEGFR-1 and -2, RET and EGFR VEGFR-1 and -2, RET and EGFR VEGFR-2 3, PDGFR-b, c-kit, Raf and flt-3 VEGF-1 3, PDGFR-a and b, andret Stage IIIB/IV NSCLC all histologies Patients randomised to: docetaxel (n5659) or docetaxel + nintedanib (200 mg twice daily; n5655) Primary end-point: progressionfree survival Stage IIIB/IV non-squamous NSCLC Patients randomised to: pemetrexed (n5360) or pemetrexed + nintedanib (200 mg twice daily; n5353) Primary end-point: progressionfree survival Stage IIIB/IV NSCLC all histologies Patients randomised to: docetaxel (n5697) or docetaxel + vandetanib (100 mg?day -1 ;n5694) Primary end-point: progressionfree survival Stage IIIB/IV NSCLC all histologies Patients randomised to: pemetrexed (n5278) or pemetrexed + vandetanib (100 mg?day -1 ;n5256) Primary end-point: progressionfree survival Stage IIIB/IV NSCLC all histologies Pre-treated with EGFR inhibitor and one or two chemotherapy regimens Patients randomised to: placebo (n5307) or vandetanib (300 mg?day -1 ;n5617) Primary end-point: overall survival Stage IIIB/IV NSCLC all histologies Patients randomised to: erlotinib (150 mg?day -1 ;n5617) or vandetanib (300 mg?day -1 ;n5623) Primary end-point: progressionfree survival Stage IIIB/IV non-squamous NSCLC Patients randomised to: placebo (n5353) or sorafenib (400 mg twice daily; n5350) Primary end-point: overall survival Stage IIIB/IV NSCLC all histologies Patients randomised to: erlotinib (150 mg?day -1 ;n5480) or erlotinib + sunitinib (37.5 mg?day -1 ;n5480) Primary end-point: overall survival Monoclonal antibodies, decoy receptors Bevacizumab; BeTa [52] VEGF StageIIIB/IV NSCLC all histologies Patients randomised to: erlotinib (150 mg?day -1 ;n5317) or erlotinib + bevacizumab (n5319) Primary end-point: progressionfree survival Aflibercept; VITAL [53] VEGF Non-squamousNSCLC Patients randomised to: docetaxel (n5457) or docetaxel + aflibercept (6 mg?day -1 ;n5456) Primary end-point: overall survival Overall response rate not reported DCR was significantly greater in the docetaxel + nintedanib arm in patients with adenocarcinoma (p,0.0001) No difference in overall response rate between pemetrexed and pemetrexed + nintedanib (9%) Pemetrexed: DCR 53% Pemetrexed + nintedanib: DCR 61% (p50.039) Docetaxel: 10% Docetaxel + vandetanib: 17% (p ) Pemetrexed: 8% Pemetrexed + vandetanib: 19% (p,0.001) Placebo: 0.7% Vandetanib: 2.6% (p50.028) Erlotinib: 12% Vandetanib: 12% (p50.98) Placebo: 0.9% Sorafenib: 4.9% (p,0.001) Erlotinib: 6.9% Erlotinib + sunitinib: 10.6% (p50.048) Erlotinib: 6% Erlotinib + bevacizumab: 13% (p-value NR) Docetaxel: 8.9% Docetaxel + aflibercept: 23.3% (p,0.001) Docetaxel: 2.7 months Docetaxel + nintedanib: 3.4 months HR 0.79 (CI ); p Pemetrexed: 3.6 months Pemetrexed + nintedanib: 4.4 months HR 0.83 (95% CI ); p50.04 Docetaxel: 3.2 months Docetaxel + vandetanib: 4.0 months HR 0.79 (97.6% CI ); p, Pemetrexed: 11.9 weeks Pemetrexed + vandetanib: 17.6 weeks HR 0.86 (97.6% CI ); p Placebo: 1.8 months Vandetanib: 1.9 months HR 0.63 (95.2% CI ); p,0.001 Erlotinib: 2.0 months Vandetanib: 2.6 months HR 0.98 (95.2% CI ); p Placebo: 43 days Sorafenib: 84 days HR 0.61; p, Erlotinib: 2.0 months Erlotinib + sunitinib: 3.6 months HR 0.81 (95% CI ); p Erlotinib: 1.7 months Erlotinib + bevacizumab: 3.4 months HR 0.62 (95% CI ); p-value NR Docetaxel: 4.1 months Docetaxel + aflibercept: 5.2 months HR 0.82 (95% CI ); p In patients with adenocarcinoma: Docetaxel: 10.3 months Docetaxel + nintedanib: 12.6 months HR 0.83; p In overall population: Docetaxel: 9.1 months Docetaxel + nintedanib: 10.1 months HR 0.94; p No significant difference (median values NR) Docetaxel: 10.0 months Docetaxel + vandetanib: 10.6 months HR 0.91 (97.5% CI ); p Pemetrexed: 9.2 months Pemetrexed + vandetanib: 10.5 months HR 0.86 (97.5% CI ); p Placebo: 7.8 months Vandetanib: 8.5 months HR 0.95 (95.2% CI ); p Erlotinib: 7.8 months Vandetanib: 6.9 months HR 1.01 (95.1% CI ); p Placebo: 253 days Sorafenib: 248 days HR 0.99; p Erlotinib: 8.5 months Erlotinib + sunitinib: 9.0 months HR 0.92 (95% CI ); p Erlotinib: 9.2 months Erlotinib + bevacizumab: 9.3 months HR 0.97 (95% CI ); p Docetaxel: 10.4 months Docetaxel + aflibercept: 10.1 months HR 1.01 (95% CI ); p50.9 Crinò L, Eur Respir Rev 2014

17 Bevacizumab in first-line treatment

18 Bevacizumab-based therapy extends survival beyond historical benchmark of 1 year* 2006 Carboplatin + paclitaxel + bevacizumab: 12.3 months 5 E4599 Non- squamous histology 2006 Carboplatin + paclitaxel: 10.3 months 5 E s Cisplatin + pemetrexed: 11 months s Platinum doublets: 8 months 3 All comers 1980s Single-agent platinum: 6 8 months s BSC: 2 5 months 1 0 3,5 7 10,5 14 Graphical elaboration from text data Median survival (months) *data are not directly comparable because of differences in criteria between trials 1. Ganz, et al. Cancer 1989, 63: ; 2. Bunn, et al. Clin Cancer Res 1998;4: ; 3. **Schiller, et al. N Engl J Med 2002;346:92-8; 4. Scagliotti, et al. The Oncologist 2009, 14: ; 5. **Sandler A et al. N Engl J Med. 2006;355:

19 E4599: trial design Previously untreated stage IIIB, IV or recurrent predominantly non-squamous NSCLC (n=878) CP q3w x 6 (n=444) Bevacizumab (15mg/kg) + CP q3w x 6 (n=434) Bevacizumab PD* PD Graphical elaboration from text data Primary endpoint - overall survival (OS) *No crossover permitted CP = carboplatin/paclitaxel PD = progressive disease Secondary endpoints - objective response rate - progression-free survival (PFS) - duration of response - safety Sandler A et al. N Engl J Med. 2006;355:

20 Bevacizumab-based therapy extends survival beyond historical benchmark of 1 year E4599 overall patient population HR (95% CI) CP (n=444) Bevacizumab 15mg/kg + CP (n=434) 0.79 ( ) p value Median OS (months) Graphical elaboration from text data Sandler A et al. N Engl J Med. 2006;355:

21 E4599: OS benefit in pre-planned analysis of adenocarcinoma histology 1.0 CP (n=302) Bev 15mg/kg + CP (n=300) Estimated probability HR (95% CI) 0.69 ( ) Median OS (months) months (95% Cl) 24 months (95% Cl) 0,565 (0,508 0,621) 0,271 (0,216 0,326) 0,433 (0,376 0,490) 0,168 (0,121 0,216) Adapted from Sandler A et al. J Thorac Oncol. 2010;5:

22 AVAiL: trial design 2 Bevacizumab (15mg/kg) + CG q3w x 6 (n=351) Bevacizumab PD Previously untreated, stage IIIB, IV or recurrent non-squamous NSCLC (n=1,043) RA ND OM I SE 1 1 Placebo (15mg/kg) + CG q3w x 6 (n=347) Placebo (7.5mg/kg) + CG q3w x 6 Placebo PD 2 Bevacizumab (7.5mg/kg) + CG q3w x 6 (n=345) Bevacizumab PD CG = cisplatin/gemcitabine; PD = progressive disease Graphical elaboration from text data Primary endpoint progression-free survival (PFS) Secondary endpoints overall survival (OS) objective response rate safety Reck, et al J Clin Oncol. 2009;27:

23 AVAiL: primary endpoint PFS bevacizumab7,5 mg/kg bevacizumab 15 mg/kg Median PFS = 6,8 months HR=0,75 (CI 95% 0,64-0,87) p=0,0003 Median PFS = 6,6 months HR=0,85 (CI 95% 0,73-1,00) p=0,0456 bevacizumab 15 mg/kg + GC Plot of Kaplan-Meier estimates for progression-free survival (intent-totreat population) for the (A) 7.5 mg/kg bevacizumab (Bev) arm and (B) 15 mg/kg bevacizumab arm compared with placebo. CG, cisplatin plus gemcitabine; HR, hazard ratio. Reck, et al J Clin Oncol. 2009;27:

24 AVAiL: trend towards improved OS in bevacizumab-treated patients not receiving post-protocol therapies* Median OS (95% CI) No 2nd-line Bev groups 8.7 ( ) Placebo 7.3 ( ) HR (p value) Bev to placebo 0.84 (0.20) Graphical elaboration from text data *Exploratory analysis Reck, et al, Ann Oncol ;21: Plots of Kaplan Meier estimates for OS (ITT population) for the bevacizumab 7.5 mg/kg group and the bevacizumab 15 mg/kg group relative to placebo, together with time to event data for the subgroup of patients who did not receive post study therapy

25 A Overall Survival (proportion) Randomly assigned treatment PI + CP B + CP Median OS 17.7 v 24.3 months HR, 0.68; 95% CI, 0.50 to 0.93 P = Time of Study (month) No. at risk PI + CP B + CP Zhou C, JCO 2015

26 100 HR 0 54 (95% CI ) Progression-free survival (%) Number at risk Erlotinib plus bevacizumab group Erlotinib alone group Erlotinib plus bevacizumab group (median 16 0 months [95% CI ]; 46 events) Erlotinib alone group (median 9 7 months [95% CI ]; 57 events) Time (months) Figure 2: Progression-free survival, as determined by independent review committee, in the modified A Erlotinib plus bevacizumab group Responder (CR or PR) Non-responder (SD, PD, or NE) 20 Change in SLD (%) B Erlotinib alone group Change in SLD (%) Seto T, Lancet Oncol Figure 4: Waterfall plot of best percentage change from baseline in the sum of longest tumour diameters

27 Improved outcomes with bevacizumab: meta-analysis of data from RCTs OS PFS Costa Lima BC, PLOS ONE, August 2011; Vol 6,Issue 8, e22681

28 Improved outcomes with bevacizumab: meta-analysis of data from RCTs Meta-analysis confirmed that both OS and PFS in non-squamous NSCLC patients are significantly improved by bevacizumab OS PFS Forest plots of hazard ratios (HRs) for (A) overall survival (OS) and (B) progression-free survival (PFS) from four randomised trials of bevacizumab (7.5 mg/kg or 15 mg/kg) added to standard chemotherapy, compared with chemotherapy alone, as first-line therapy in patients with advanced non-small-cell lung cancer (NSCLC; ECOG 4599, AVAiL, AVF-0757g and JO19907). Pooled HRs were computed using fixed-effect models. The bars indicate 95% confidence intervals (CI). The chi-squared test showed no significant heterogeneity between the trials. (OE, observed-expected). Soria, et al. Annals of Oncology 24: 20 30, 2013

29 Real-world effectiveness of treatment options in NSCLC: SEER analysis Owonikoko, et al. Oncologist :

30 ¼ Sheng J, Medicine 2015

31 SAiL: trial design (Phase IV study) First-line, advanced non-squamous NSCLC (n=2,212) Bevacizumab (7.5mg/kg or 15mg/kg) q3w + standard of care chemotherapy (up to 6 cycles) Bevacizumab to progression PD Graphical elaboration from text data Primary endpoint safety profile 86% of the population had adenocarcinoma histology Secondary endpoints time to disease progression (TTP) overall survival (OS) safety in CNS metastases Crinò L et al; Lancet Oncol. 2010;11:733-40

32 SAiL: confirmed efficacy of bevacizumab OS and TTP: secondary endpoints Months n=2,212 n=2,211* Median OS 1 Median TTP 1 *One patient was reported to have had disease progression before first treatment and was therefore not included in the TTP analysis Graphical elaboration from text data Crinò L et al; Lancet Oncol. 2010;11:733-40

33 SAiL: high disease control rate (DCR) with first-line bevacizumab-based therapy in clinical practice % CR/PR/SD/DCR* (%) 50 48% 37% 0 3% CR PR *Percentage is based on the number of patients with tumour assessment (n=2,036 [92.0%]) CR = complete response; PR = partial response; SD = stable disease Crinò L et al; Lancet Oncol. 2010;11: SD DCR Graphical elaboration from text data

34 TABLE 2. ARIES NSCLC (n = 1967) SAiL 7 (n = 2212) E (n = 434 ITT) AVAiL 4,5 7.5 mg/kg (n = 345 ITT) (n = 307 PP) AVAiL 4,5 15 mg/kg (n = 351 ITT) (n = 285 PP) Chemotherapy Regimen Investigator s choice Investigator s choice Paclitaxel + carboplatin Gemcitabine + cisplatin Gemcitabine + cisplatin Median follow-up, months (range) Median PFS, months (95% CI) 12.5 ( ) 12.5 (SD, ) 19 (for n = 851) 7 for PFS 12.5 for OS 7 for PFS 12.5 for OS 6.6 ( ) 7.8 ( ) a 6.2 (range N/A) 6.7 (range N/A) 6.5 (range N/A) Median OS, 13.0 ( ) 14.6 ( ) 12.3 ( ) 13.6 ( ) 13.4 ( ) months (95% CI) ORR b (%) a The SAiL study reported time to progression (TTP) outcomes instead of PFS. b Patients experiencing a complete response or a partial response; responses were assessed by investigators in ARIES. ARIES, Avastin Regimens: Investigation of Effectiveness and Safety; AVAiL, Avastin in Lung; CI, confidence interval; E4599, Eastern Cooperative Oncology Group 4599; ITT, intent-to-treat; N/A, not available; NSCLC, non small-cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PP, per protocol. Lynch TJ, JTO 2014

35 AVAPERL: trial design and patients disposition CR/PR/SD by RECIST Arm A: bevacizumab (n=125) Patients screened (n=414) First-line induction with Bev-cis-pem* (n=376) Patients randomised to maintenance* (n=253) 5 patients not treated PD Not eligible for randomisation (n=123) 123. patients not randomised 50 discontinued due to AEs 49 discontinued due to PD 9 patients died 7 withdrew consent 5 discontinued for other reasons 3 did not start treatment Arm B: bevacizumab + pemetrexed (n=128) 3 patients not treated Graphical elaboration from text data Barlesi, et al. J Clin Oncol. 2013;31:

36 AVAPERL: PFS from randomization Barlesi F et al. Annals Oncol May;25(5):

37 AVAPERL: OS from induction Barlesi F et al. Annals Oncol May;25(5):

38 POINTBREAK: phase III trial of bevacizumab with pemetrexed 4 cycles Previously untreated, stage IIIB or IV, non-squamous NSCLC, treated CNS mets, PS 0 1 (n=939) R 1:1 Pemetrexed + carboplatin + bevacizumab 15 mg/kg q3w Paclitaxel + carboplatin + bevacizumab 15 mg/kg q3w Pemetrexed + bevacizumab 15 mg/kg q3w Bevacizumab 15 mg/kg q3w Treat to PD Treat to PD Graphical elaboration from text data Primary endpoint OS Secondary endpoints ORR and DCR PFS and TTP safety and QoL Patel, et al. Clin Lung Cancer. 2009;10:252-6

39 POINTBREAK: OS (ITT population) Patel, et al. Clinical Lung Cancer, 2009; 4:

40 PRONOUNCE: Study Design Induction Phase q21d, 4 cycles Maintenance Phase q21d until PD Inclusion: Chemo-naïve patients PS 0/1 Stage IV, nonsquam Stable treated CNS mets R 1:1 Pemetrexed (folic acid & vitamin B 12 ) + Carboplatin Paclitaxel + Carboplatin + Bevacizumab Pemetrexed (folic acid & vitamin B 12 ) Bevacizumab Primary objective: Progression free survival without Grade 4 AE (G4PFS) Zinner et al, J Clin Oncol 31, 2013 (suppl; abstr LBA8003) ASCO Identifier: NCT Graphical elaboration from text data Secondary objectives Progression free survival (PFS) Overall survival (OS) Response rates (RR) and disease control rates (DCR) Safety and tolerability

41 PRONOUNCE: Primary endpoint: G4PFS (ITT) Proportion Pem+Cb: median G4PFS = 3.9 months Pac+Cb+Bev: median G4PFS = 2.9 months Log-rank p-value = HR (90% CI) = 0.85 ( ) Zinner et al, J Clin Oncol 31, 2013 (suppl; abstr LBA8003); ASCO 2013 Months Patients at risk Pem+Cb Pac+Cb+Bev

42 AvaALL: phase IIIb study of bevacizumab continued beyond progression in NSCLC Primary endpoint: OS Stage IIIB/IV non-squamous NSCLC treated with platinumdoublet (4 6 cycles) + bevacizumab PLUS > 2 cycles of bevacizumab maintenance PD 1 Randomise 1:1 SOC2* + bevacizumab PD 2 SOC3 + bevacizumab PD 3 SOC4 ± bevacizumab SOC2* SOC3 SOC4 n=600 Enroll Primary endpoint: OS Graphical elaboration from text data Secondary endpoints include PFS, safety, QoL and biomarker analysis *SOC2: labelled agents for second-line treatment of NSCLC SOC3 and beyond: choice of labelled agents is the investigator s choice Gridelli C, et al. Clin Lung Cancer. 2011;12:407-11

43 Beva troubles (the story of its short use) Is it a matter of toxicity? Is it a matter of costs? Is it a matter of patient selection?

44 Incidence of grade 3/4 AEs across trials Bevacizumab has a safe and tolerable profile 1 Planchard D., Expert Rev. Anticancer Ther. 11(8), (2011)

45 No increased bleeding risk in bevacizumabtreated patients with centrally located tumours Baseline risk factor for PH Central tumour location Yes No Total pts Pts who developed PH (n=13) 9 4 Matched control pts (n=42) Odds ratio (95% CI) 2.1 ( ) PH = pulmonary haemorrhage Graphical elaboration from text data While central tumor location was common, there was no correlation between this and the risk of pulmonary hemorrhage Sandler et al, J Clin Oncol 2009, 27:

46 Hypertension is manageable in bevacizumab-treated patients In SAiL, 85% of HTN events resolved or improved 85% and bevacizumab therapy was continued after 89% of HTN events 89% Resolved or improved Persisted Bevacizumab therapy continued Bevacizumab therapy interrupted or discontinued Crinò L et al; Lancet Oncol. 2010;11: Graphical elaboration from text data

47 SAiL: No increased bleeding risk with concomitant bevacizumab and anticoagulation The incidence of bleeding events, including grade 3 PH, was similar in patients receiving anticoagulants versus those not receiving anticoagulation therapy Dansin et al, Lung Cancer 2012; 76: Reck et al, Annals of Oncology 23: , 2012 CNS, central nervous system. a Pulmonary hemorrhage/hemoptysis. b Cerebral hemorrhage/hematoma. c Percentages are based on number of patients in each subgroup

48 Patients with CNS metastases can receive bevacizumab-based therapy Low risk of CNS bleeding across tumour types (>13,000 patients) Dataset 1 No. of enrolled patients No. of patients with CNS metastases A: 13 phase II/III trials 8,443 Bevacizumab: n=91 Non-bevacizumab: n=96 B: 2 open-label trials (ATHENA and SAiL) C: 2 prospective studies (ATLAS & PASSPORT) Rate of CNS bleeding (%) Bevacizumab arm Non-bevacizumab arm ,382 Bevacizumab: n= Bevacizumab: n= Graphical elaboration from text data 25 March 2009: EMA removed label restriction to allow patients with untreated CNS metastases to receive bevacizumab 2 1. Besse, et al. Clin Cancer Res ;16:

49 Global TL Consensus on bevacizumab safety Exclusion factors for bevacizumab Squamous histology Haemoptysis grade 2 Invalid exclusion factors Central tumour location Cavitation Full-dose anticoagulation Elderly Major vessel invasion = individual assessment No clinical or radiological features (including cavitation and central tumour location) have been shown to be reliable predictive factors for severe PH in bevacizumab-treated patients. Major blood vessel infiltration and bronchial vessel infiltration, encasement and abutting, may predict PH. However, standardized radiological criteria for defining infiltration have not been established. Hypothetically, dilation of the bronchial artery could be a risk factor for PH, but no data exist to support this. Reck et al, Annals of Oncology 23: , 2012

50 No molecular selection (no party) Clinical selection FIT for CTX & BEVA FIT for CISPLATIN FIT for CBDCA UNFIT for a Doublet Courtesy - F De Marinis

51 Conclusions (pills of) Neoangiogenesis is a leading driver in NSCLC Reloaded interest with newer drugs Bevacizumab in a real first-line option with sound data No reliable predictive factors Need for careful clinical selection