Antiangiogénesis Sigue siendo una alternativa? Javier de Castro Carpeño

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1 Antiangiogénesis Sigue siendo una alternativa? Javier de Castro Carpeño Formigal, 24 de junio de 2016

2 Antiangiogénesis Sigue siendo una alternativa?

3 Angiogenesis: A hallmark of cancer leading to malignant growth Sustaining proliferative signaling Resisting cell death Evading growth suppressors Canc er Inducing angiogenesis Enabling replicative mortality Activating invasion and metastasis Hanahan & Weinberg. Cell 2011

4 Agents Targeting the VEGF Pathway Anti-VEGF antibodies Bevacizumab VEGF Soluble VEGFRs Aflibercept Small-molecule VEGFR TKIs Sorafenib (Bay ) Sunitinib (SU11248) Axitinib Motesanib BIBF1120 Cediranib Pazopanib Vandetanib Tivozanib Etc.. P P P P P P P P VEGFR-1 VEGFR-2 Endothelial cell Anti-VEGFR antibodies Ramucirumab Podar K, et al. Blood. 2005:105: Gori B, et al. Ther Clin Risk Manag. 2011;7:

5 CÁNCER DE PULMÓN DE CÉLULAS NO PEQUEÑAS (CPCNP) ESTADIO IV NO ESCAMOSO ESCAMOSO DETERMINAR EGFR Y ALK + - INHIBIDORES EGFR o ALK QUIMIOTERAPIA +/- bevacizumab QUIMIOTERAPIA

6 First-line induction therapy in NSCLC Overall goals of therapy Prolong OS and preserve QoL Diagnosis Treatment selection Induction Maintenance? Goals of induction Shrink the tumour and prevent early progression Control symptoms Favourable tolerability during induction allows therapy continuation

7 Phase III 1L clinical trials in nsnsclc E JMDB (non-sq) 2 Induction Carbo/pac + bev (15mg/kg) x6 Maintenance (to PD) OS from induction (months) Bev 15mg/kg 12.3 Carbo/pac x6 BSC 10.3 Cis/pem x Cis/gem x HR AVAiL 3 Cis/gem/bev (7.5/15mg/kg) x6 Bev 7.5mg/kg Bev 15mg/kg Cis/gem x6 Placebo 13.1 POINTBREAK 4 Carbo/pac+bev x4 Bev 15 mg/kg Carbo/pem+bev x4 Bev 15mg/kg+pem 12.6 PRONOUNCE 5 Carbo/pac+bev x4 Bev 15 mg/kg 11.7 Carbo/pemx4 Pem Sandler, et al. N Engl J Med Scagliotti, et al. Oncologist 2009; 3. Reck, et al. Ann Oncol 2010; 4.Patel IASLC 2012; 5. Zinner ASCO 2013

8 OS estimate E4599: 14-month OS in patients with adenocarcinoma histology E4599 adenocarcinoma population 1.0 Pac + Carbo + Bev Bev Pac + Carbo 0.8 HR=0.69 ( ) Histology n Median OS (months) HR 0.6 Non-squamous Adenocarcinoma Time (months) Bev = bevacizumab; Carbo = carboplatin; Pac = paclitaxel Sandler, et al. J Thorac Oncol 2010

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10 OS estimate POINTBREAK: OS (primary endpoint) ITT population HR (95% CI) Pem + Carbo + Bev Pem + Bev (n=472) Pac + Carbo + Bev Bev (n=467) 1.00 ( ) p value Median OS (months) Time (months) Patel, et al. J Clin Oncol 2013

11 OS estimate AVAPERL: OS from randomisation* Bev Bev+pem NR (34 events) 15.7 months (42 events) HR=0.75 ( ); p= Cont. maintenance bev+pem (n=128) Cont. maintenance bev (n=125) Patients at risk Bev+pem Bev Time (months) *Randomised patients, Intent-to-treat population Median follow-up time: 11 months (8 months, excluding induction) 30% of events at the time of analysis Barlesi, for overall et al. JCO survival 2013

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13 CÁNCER DE PULMÓN DE CÉLULAS NO PEQUEÑAS (CPCNP) ESTADIO IV NO ESCAMOSO ESCAMOSO TTO 2ª L TTO 2ª L PEMETREXED DOCETAXEL ERLOTINIB DOCETAXEL NIVOLUMAB NIVOLUMAB DOCETAXEL+ NINTEDANIB DOCETAXEL + RAMUCIRUMAB

14 Ramucirumab (IMC-1121B) Ramucirumab is a fully human IgG1 monoclonal antibody that binds with high affinity to human VEGFR-2 (Kd ~ 50 pm) 1 Ramucirumab is specific for the human VEGFR-2 receptor 2 Ramucirumab potently blocks binding of VEGF-A to VEGFR-2 (IC 50 = 0.8 nm) 1 Ramucirumab blocks binding of VEGF- C and VEGF-D to VEGFR Lu et al. J Biol Chem 2003;278(44): Data on file, ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company. 3. Data on file, ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company.

15 Revel Study

16 OVERALL SURVIVAL (ITT) Revel Study

17 Revel Study OVERALL SURVIVAL (SUBGROUP ANALYSIS)

18 Revel Study OVERALL SURVIVAL BY HISTOLOGY (ITT)

19 Revel Study PROGRESSION-FREE SURVIVAL

20 Revel Study RESPONSE RATES (RECIST 1.1)

21 Revel Study RESPONSE RATES (HISTOLOGY SUBTYPES)

22 Revel Study HEMATOLOGICAL ADVERSE EVENTS

23 Revel Study ADVERSE EVENTS (ANTIANGIOGENIC THERAPY)

24 Revel Study QUALITY OF LIFE (LCSS, ASBI)

25 Nintedanib Nintedanib, a triple angiokinase inhibitor Mode of action By targeting the 3 major angiogenesis signaling pathways Nintedanib prevents further tumor growth and related tumor escape mechanisms Ligands VEGFs Stimulation Cell type/receptors Endothelial cells VEGFRs, FGFRs FGFs Pericytes PDGFRs PDGFs Smooth muscle cells FGFRs, PDGFRs a Angiokinase refers to tyrosine receptor kinases involved in promoting angiogenesis. Hilberg F et al. Cancer Res 2008; 68: (12). June 15, 2008] 25 VEGF: vascular endothelial growth factor FGF: fibroblast growth factor PDGF: platelet -derived growth factor

26 LUME-Lung 1: study design Stage IIIB/IV or recurrent NSCLC patients after first-line chemotherapy (all histologies) R A N D O M IZ E 1:1 BIBF mg BID p.o., Day Docetaxel 75 mg/m 2 IV, Day 1, 21-day cycles (n=655) Placebo BID p.o., Day Docetaxel 75 mg/m 2 IV, Day 1, 21-day cycles (n=659) PD PD n=1314 Number of docetaxel cycles not restricted Monotherapy allowed after 4 cycles of combination therapy Stratification: ECOG PS (0 vs. 1) Prior bevacizumab (yes vs. no) Histology (squamous vs. non-squamous) Brain metastases (yes vs. no) Regions: Europe/Asia/South Africa Accrual: 23 Dec 2008 to 09 Feb 2011 Reck M, et al. Lancet Oncol 2014; 15:

27 Probability of PFS (%) LUME-Lung 1: primary endpoint met significantly longer PFS with the addition of nintedanib to docetaxel Nintedanib + docetaxel Placebo + docetaxel Median PFS (months) HR = 0.79 (95% CI: ); p= Time (months) No. at risk Nintedanib Placebo Reck M, et al. Lancet Oncol 2014;15: Independent central review in all patients

28 Probability of survival (%) OS: Key secondary endpoint All patients Nintedanib + docetaxel Placebo + docetaxel Median, mo HR (95% CI) 0.94 ( ) p value Number at risk Nintedanib Placebo Time (months) OS = overall survival; mo = months; HR = hazard ratio; CI = confidence interval. Reck M, et al. Lancet Oncol. 2014;15:

29 Probability of survival (%) OS: Key secondary endpoint met Patients with adenocarcinoma histology % Nintedanib + docetaxel Placebo + docetaxel Median, mo HR (95% CI) 0.83 ( ) p value % 25.7% Number at risk Nintedanib Placebo % Time (months) OS = overall survival; mo = months; HR = hazard ratio; CI = confidence interval. Reck M, et al. Lancet Oncol. 2014;15:

30 Best tumor response Independent Central Review in Major Histologies Adenocarcinoma Squamous Cell Carcinoma Best response, n (%) Nintedanib + docetaxel (n=322) Placebo + docetaxel (n=336) Nintedanib + docetaxel (n=276) Placebo + docetaxel (n=279) Complete response (CR) (0.4) Partial response (PR) 15 (4.7) 12 (3.6) 13 (4.7) 6 (2.2) Stable disease (SD) 179 (55.6) 136 (40.5) 123 (44.6) 92 (33.0) Disease control rate* (CR + PR + SD) 194 (60.2) 148 (44.0) 136 (49.3) 99 (35.5) Progressive disease 87 (27.0) 147 (43.8) 90 (32.6) 134 (48.0) *Statistically significant improvement in disease control rate with nintedanib + docetaxel (Odds ratio 1.93; p< for adenocarcinoma and Odds ratio 1.78, p< for squamous cell carcinoma)

31 Key secondary endpoint Primary endpoint LUME-Lung 1: hierarchical analysis used to reduce error rate and maintain power for the important OS endpoint Independently assessed PFS All histologies Previously analysed trial, LUME-Lung 2, showed enhanced benefit in early progressing adenocarcinoma tumours, so stepwise testing was used to preserve power and reduce error* Significant finding for PFS at time of OS OS Adenocarcinoma Time since start of first-line therapy <9 months Significant finding OS All adenocarcinoma Significant finding OS All histologies *Hanna N, et al. ASCO Abstract #8034; Hanna N, et al. ESMO Abstract #3418; Kaiser R, et al. ESMO Abstract #3479. Reck M, et al. Lancet Oncol 2014;15:

32 Probability of survival (%) OS: Key secondary endpoint met Adenocarcinoma + time since start of first-line therapy <9 months Nintedanib + docetaxel Placebo + docetaxel Median, mo % HR (95% CI) 0.75 (0.60 to 0.92) p value Feb 2013, 345 events % 17.0% Number at risk Nintedanib Placebo 0 8.5% Time (months) OS = overall survival; mo = months; HR = hazard ratio; CI = confidence interval. Reck M, et al. Lancet Oncol. 2014;15:

33 Adverse Events Occurring in 5% of the Patients With Adenocarcinoma Nintedanib + docetaxel (n=320) n (%) Placebo + docetaxel (n=333) n (%) All grades Grade 3 All grades Grade 3 Any AE 308 (96.3) 243 (75.9) 314 (94.3) 228 (68.5) Diarrhoea 139 (43.4) 20 (6.3) 82 (24.6) 12 (3.6) Neutrophil count decreased 131 (40.9) 116 (36.3) 135 (40.5) 116 (34.8) ALT increased 121 (37.8) 37 (11.6) 31 (9.3) 3 (0.9) Fatigue 99 (30.9) 15 (4.7) 98 (29.4) 14 (4.2) AST increased 97 (30.3) 13 (4.1) 24 (7.2) 2 (0.6) Nausea 91 (28.4) 3 (0.9) 59 (17.7) 2 (0.6) White blood cell count decreased 89 (27.8) 63 (19.7) 94 (28.2) 61 (18.3) Decreased appetite 75 (23.4) 4 (1.3) 52 (15.6) 5 (1.5) Vomiting 62 (19.4) 4 (1.3) 41 (12.3) 2 (0.6) Alopecia 56 (17.5) 1 (0.3) 68 (20.4) 0 (0) Dyspnoea 54 (16.9) 15 (4.7) 52 (15.6) 20 (6.0) Neutropenia 44 (13.8) 38 (11.9) 51 (15.3) 45 (13.5) Only 1.2% of the patients in the nintedanib arm discontinued treatment due to diarrhoea Cough 42 (13.1) 3 (0.9) 63 (18.9) 2 (0.6) Pyrexia 39 (12.2) 2 (0.6) 47 (14.1) 1 (0.3) 1.7% of the patients treated with nintedanib discontinued due to liver-related investigations Stomatitis 36 (11.3) 4 (1.3) 26 (7.8) 1 (0.3) Haemoglobin decreased 35 (10.9) 3 (0.9) 46 (13.8) 7 (2.1) Constipation 22 (6.9) 0 (0) 39 (11.7) 1 (0.3) LUME-Lung 1 Adverse events were classified according to Common Terminology Criteria for Adverse Events version 3.0 Reck et al. Lancet Oncol. 2014;15: Suppl.

34 Early vs Late Progressors: Mechanistic Hypothesis Rapidly progressing adenocarcinomas depend more strongly on vascularization for oxygen and nutrient supply than slowly growing tumors High intrinsic rate of tumor cell proliferation (oncogenome-dependent) Rapid disease progression High-level production of angiogenic growth factors by tumor cells High-level angiogenesis nintedanib

35 Probability of survival (%) Consistent Trend Towards Survival Benefit Regardless of Prior Treatment in Patients With Adenocarcinoma Overall Survival by Prior First-line Chemotherapy Prior taxane treatment Nintedanib + docetaxel Placebo + docetaxel Median OS (months) HR = 0.75 (95% CI: ) Prior pemetrexed treatment Nintedanib + docetaxel Placebo + docetaxel Median OS (months) HR = 0.79 (95% CI: ) Prior bevacizumab treatment Nintedanib + docetaxel Placebo + docetaxel Median OS (months) HR = 0.61 (95% CI: ) Time (months) Time (months) Time (months) No. at risk Nintedanib Placebo CI = confidence interval; HR = hazard ratio; OS = overall survival. Krzakowski M, et al. Ann Oncol (2014);25(Suppl 4): iv158. Abstract 471P and poster; Mellemgaard A, et al. Ann Oncol (2014);25(Suppl 4): iv157. Abstract 473P and poster; Boehringer Ingelheim data on file.

36 OS (%) OS (%) OS by PD-L1 Expression 100 1% PD-L1 expression level 100 5% PD-L1 expression level % PD-L1 expression level mos (mo) Nivo 17.2 Doc Niv o mos (mo) 18.2 Doc Niv o mos (mo) 19.4 Doc Nivo Doc HR (95% CI) = 0.59 (0.43, 0.82) 10 HR (95% CI) = 0.43 (0.30, 0.63) 10 HR (95% CI) = 0.40 (0.26, 0.59) Time (months) Time (months) Time (months) <1% PD-L1 expression level 90 <5% PD-L1 expression level 90 <10% PD-L1 expression level mos (mo) Nivo mos (mo) Nivo mos (mo) Nivo Nivo Doc Doc Doc Doc HR (95% CI) = 0.90 (0.66, 1.24) 10 HR (95% CI) = 1.01 (0.77, 1.34) 10 HR (95% CI) = 1.00 (0.76, 1.31) Time (months) Time (months) Time (months) Symbols represent censored observations.

37 SELECCIÓN DE PACIENTES CUESTIONES PENDIENTES DESARROLLO DE RESISTENCIA INMUNOTERAPIA

38 PFS Estimate OS Estimate AVALON: bevacizumab long survivals Progression Free Survival Overall Survival Median PFS: 15 m (95% CI:14-16) Median OS: 31 m (95% CI: 22-39) 1-yr survival: 97% (95% CI: ) 2-yr survival: 62% (95% CI: 51-73) Months Months Most frequent toxicities Response Rate AE (% of patients) Grade 1 Grade 2 Grade 3 Grade 4 Epistaxis Hypertension Asthenia Proteinuria n % 95% CI Objective Response Rate 86 83% (74-89) Complete Response (CR) 9 9% Partial Response (PR) 77 74% Stable disease (SD) 18 17% De Castro et al, Clin Transl Oncol 2016

39 AvaALL Beyond the horizon... beyond progression Stage IIIB/IV non-squamous NSCLC treated with platinumdoublet (4 6 cycles) + bevacizumab PLUS >2 cycles of bevacizumab Maintenance (n=600) Enroll Phase IIIb study of bevacizumab continued beyond progression Primary endpoint: OS PD 1 Secondary endpoints include PFS, safety, QoL and biomarker analysis Actively recruiting patients R A N D O M I S E 1:1 Primary endpoint: OS SOC2 * + bevacizumab PD 2 SOC3 + bevacizumab PD 3 SOC4 ± bevacizumab SOC2* SOC3 SOC4 *SOC2: labelled agents for second-line treatment of NSCLC SOC3 and beyond: choice of labelled agents is the investigator s choice Gridelli, et al. Clin Lung Cancer 2011

40 Jinushi M et al, Clin Cancer Res 2007

41 Limitations of Anti-Angiogenic Therapies Moserle, Jiménez-Valerio & Casanovas Cancer Discovery, 2014

42 Anti-T antigen H&E Tumor Adaptation to Antiangiogenics: more Invasion and Metastasis Control (end-stage) Anti-VEGFR2 1 week Anti-VEGFR2 4 weeks 150 µm 150 µm 150 µm Ac Ac Ac T 50 µm T 50 µm 50 µm T Pàez-Ribes et al. Cancer Cell 2009

43 How to Block Alternative Proangiogenic Resistance? Biological base of combining anti-vegfr and Immunotherapy? Inhibition of VEGF-VEGFR exerts some Immune Activation! Vanneman & Dranoff Nat.Rev.Cancer 2012

44 Factors controlling infiltration of T cells into solid tumors CY Slaney Cancer Res; 74(24);

45 CÁNCER DE PULMÓN DE CÉLULAS NO PEQUEÑAS (CPCNP) ESTADIO IV NO ESCAMOSO ESCAMOSO DETERMINAR EGFR Y ALK + - INHIBIDORES EGFR o ALK QUIMIOTERAPIA +/- bevacizumab QUIMIOTERAPIA

46 Erlotinib + Bevacizumab JO25567 phase II study of 1L erlotinib ± bevacizumab in Japanese patients with EGFR Mut+ NSCLC Stage IIIB/IV or recurrent NSCLC Non-squamous histology EGFR Mut+ exon 19 deletion / L858R* No prior treatment ECOG PS 0 1 (n=152) R Bevacizumab 15mg/kg i.v. q3w + erlotinib 150mg/day 1:1 Stratified by: gender, stage, smoking status, EGFR Mut type Erlotinib 150mg/day PD PD Primary endpoint PFS by independent review Secondary endpoints QoL OS Safety ORR DCR Response duration *T790M excluded; EGFR mutation assays performed at investigational site using: PNA LNA PCR Clamp PCR-Invader, Cycleave or Other methods ECOG PS = Eastern Cooperative Oncology Group performance status; DCR = disease control rate i.v. = intravenous; ORR = overall response rate; PD = progressive disease QoL = quality of life; q3w = every 3 weeks Exploratory endpoints Biomarkers JapicCTI Seto, et al. Lancet Oncol 2014

47 Tumour volume change from baseline (%) Tumour volume change from baseline (%) JO25567: tumour response Bevacizumab + erlotinib Responder (CR or PR) Non-responder (SD, PD or NE) Erlotinib CR = complete response; NE = non-evaluable; PR = partial response; SD = stable disease Seto, et al. Lancet Oncol 2014

48 PFS probability JO25567: PFS by independent review in all patients (primary endpoint) Bevacizumab + erlotinib (n=75) Erlotinib (n=77) HR=0.54 ( ) Log-rank p= months Time (months) Seto, et al. Lancet Oncol 2014

49 PFS estimate PFS estimate Kato, et al. ASCO 2014 JO25567 (1L erlotinib + bevacizumab vs 1L erlotinib): PFS by EGFR mutation type Exon 19 deletion Erlotinib + bevacizumab: 18.0 months Erlotinib: 10.3 months HR=0.41 ( ) Exon 21 L858R Erlotinib + bevacizumab: 13.9 months Erlotinib: 7.1 months HR=0.67 ( ) Time (months) Time (months)

50 Other phase II studies of an EGFR TKI + bevacizumab in 1L treatment of EGFR Mut+ NSCLC RC ACCRU [USA] Primary endpoint: PFS Stage IV NSCLC Non-squamous histology ECOG PS 0 1 (n=150) R Erlotinib 150mg/day Erlotinib 150mg/day + bevacizumab 15mg/kg i.v. q3w BELIEF 2 ETOP [EU] Primary endpoint: PFS Stage IIIB/IV NSCLC Non-squamous histology ECOG PS 0 2 (n=102) Erlotinib 150mg/day + bevacizumab 15mg/kg i.v. q3w Sub-study 1: T790M+ (n=35) Sub-study 2: T790M (n=67) OLCSG OLCSG [JAPAN ] Stage IV NSCLC Non-squamous histology ECOG PS 0 2 (n=42) Primary endpoint: 1-yr PFS rate Gefitinib 250mg/day + bevacizumab 15mg/kg i.v. q3w 1. NCT ; 2. NCT ; 3. Nogami, et al. ESMO 2014

51 ETOP 2-11 BELIEF: PFS by T790M mutation (N=109) Events/N Median PFS (95%CI) 12m PFS (95%CI) All 57/ m ( ) 56.7% ( ) T790M+ 15/ m (13.1-NE) 72.4% ( ) T790M- 42/ m ( ) 49.4% ( ) ETOP 2-11 BELIEF 18 th ECCO 40 th ESMO European Cancer Congress, September 2015

52 ETOP 2-11 BELIEF 18 th ECCO 40 th ESMO European Cancer Congress, September 2015 ETOP 2-11 BELIEF: PFS by Exon19/21 (N=109) Events/N Median PFS (95%CI) All 57/ m ( ) Exon19+ 35/ m ( ) Exon21+ 22/ m ( ) Med PFS T790M m T790M m Exon19+ pts Med PFS T790M m T790M- 9.4 m Exon21+ pts

53 Potential to prevent or delay resistance: T790M Preclinical data Data suggest erlotinib + bevacizumab is active against T790M+ tumours EGFR L858R T790M Bev = 68% inhibition Bev + erlotinib = 75% inhibition Naumov, et al. Clin Cancer Res 2009

54 TRATAMIENTO EFICAZ COMPLEMENTARIO Y NO EXCLUYENTE Antiangiogénicos en Ca de Pulmón BÚSQUEDA DE PACIENTES CANDIDATOS NO RESISTENCIA CRUZADA ENTRE ANTIANGIOGÉNICOS