Antiangiogénicos de segunda generación

Dra. Marga Majem

Hospital de la Santa Creu i Sant Pau Barcelona

AGENDA

• Introduction

• Tumor angiogenesis

• Antiangiogenic agents

– Bevacizumab

– New antiangiogenics

• Ramucirumab

• Nintedanib

• Who benefits most from the antiangiogenic strategies?

• Lung cancer is the leading cause of cancer-related mortality worldwide, with about 85% patients diagnosed NSCLC.

• Locally advanced or metastatic NSCLC accounts for 80% patients. 5-year survival rates for patients with stage IV NSCLC is < 5%.

• The standard care for advanced NSCLC is CT, which prolongs survival, controls symptoms and improves quality of life. Regardless of the emergence of new agents, CT provides only marginal benefit in overall survival.

• Another treatment option is to inhibit tumor angiogenesis (tumor-associated vasculature).

INTRODUCTION

• Essential for the development and

progression of malignant tumours.

• Tumor-associated vessels provide

oxygen and nutrients that favor tumor

growth and favor tumor metastasis.

• VEGF pathway: one of the best

characterized proangiogenic pathways

stimulate downstream signaling

cascades that coordinate endothelial cell

proliferation, differentiation,

permeability and migration to

generate new blood vessels

TUMOR ANGIOGENESIS

• The fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) signaling pathways might be involved in adaptive resistance to VEGF therapy

ANTIANGIOGENIC AGENTS

Nintedanib

Inhibition of VEGF ligand • Blocks VEGF binding • Inhibits signaling due to

VEGF(s) Antibody to VEGFR-2 •Blocks ligand binding •Blocks receptor activation and signaling

Tyrosine kinase inhibitor to VEGFR. •Blocks receptor kinase activity and signaling

Inhibition of VEGF ligand

• Bevacizumab: humanized monoclonal antibody that binds to VEGF.

• Aflibercept: recombinant human fusion protein (VEGF-trap) that binds to VEGF and

PlGF.

Antibody to VEGFR-2

• Ramucirumab, a fully human monoclonal antibody that specifically binds VEGFR2.

Tyrosine kinase inhibitor to VEGFR-2

• Simultaneous inhibition of other pathways concerning angiogenesis and tumor

proliferation: PDGF, FGF, EGF,...

• Multi-targeted antiangiogenic tyrosine kinase inhibitors:

– Sunitinib: inhibits VEGF1–3, PDGFR-a and b, and RET.

– Sorafenib: inhibits VEGFR2–3, PDGFR-b, c-kit, Raf and flt-3.

– Cediranib: inhibits VEGFR1–3, PDGFR-a/b, FGFR1 and c-kit.

– Vandetanib: inhibits VEGFR2 and 3, RET and EGFR.

– Motesanib: inhibits VEGFR1–3, PDGFR, c-kit and RET.

– Nintedanib: inhibits VEGF1–3, PDGF-a/b, and FGFR1–3

– Axitinib: inhibits VEGFR1–3, PDGFR-b and c-kit.

– Pazopanib: inhibits VEGFR1–3, PDGFR-a/b and c-kit.

– Linifanib: inhibits VEGFR1–3, PDGFR-b, c-Kit and FLT-3.

ANTIANGIOGENIC AGENTS

Inhibition of VEGF ligand

• Bevacizumab: humanized monoclonal antibody that binds to VEGF.

• Aflibercept: recombinant human fusion protein (VEGF-trap) that binds to VEGF and PlGF.

Antibody to VEGFR-2

• Ramucirumab, a fully human monoclonal antibody that specifically binds VEGFR2.

Tyrosine kinase inhibitor to VEGFR-2

• Simultaneous inhibition of other pathways concerning angiogenesis and tumor

proliferation: PDGF, FGF, EGF,...

• Multi-targeted antiangiogenic tyrosine kinase inhibitors:

– Sunitinib: inhibits VEGF1–3, PDGFR-a and b, and RET.

– Sorafenib: inhibits VEGFR2–3, PDGFR-b, c-kit, Raf and flt-3.

– Cediranib: inhibits VEGFR1–3, PDGFR-a/b, FGFR1 and c-kit.

– Vandetanib: inhibits VEGFR2 and 3, RET and EGFR.

– Motesanib: inhibits VEGFR1–3, PDGFR, c-kit and RET.

– Nintedanib: inhibits VEGF1–3, PDGF-a/b, and FGFR1–3

– Axitinib: inhibits VEGFR1–3, PDGFR-b and c-kit.

– Pazopanib: inhibits VEGFR1–3, PDGFR-a/b and c-kit.

– Linifanib: inhibits VEGFR1–3, PDGFR-b, c-Kit and FLT-3.

ANTIANGIOGENIC AGENTS

Bevacizumab

• Humanized monoclonal antibody that binds to VEGF.

• The only antiangiogenic agent approved for the first-line treatment of

NSCLC.

• Restricted to patients with non-squamous NSCLC (70% of patients)

Bevacizumab in first-line + CT

BEVACIZUMAB. New roles

Maintenance beyond progression:

• AvaALL trial: phase III, patients with advanced non-squamous NSCLC who

have progressed following bevacizumab plus platinum-based CT to

standard second-line therapy with or without bevacizumab.

• Primary end-point: overall survival.

Adjuvant setting:

• ECOG E1505: impact of adding bevacizumab to adjuvant chemotherapy in

patients with completely resected stage IB–IIIA NSCLC.

EGFR mutation:

• Bevacizumab + Erlotinib fase II trial. JO 25567 trial

• Ramucirumab

• Nintedanib

NEW ANTIANGIOGENICS IN NSCLC.

NEW ANTIANGIOGENICS IN NSCLC. Ramucirumab

• RAMUCIRUMAB (LY3009806):

– Fully human IgG1 monoclonal Ab.

– Selectively blocks VEGFR-2.

• VEGFR-2 signaling:

– Involved in proliferation, migration, and survival of endothelial cells

– Mediating the increased endothelial permeability associated with cancer

angiogenesis.

• Ramucirumab inhibit VEGF ligand binding and subsequent activation and

downstream signaling of pathways (permeability, migration, and proliferation)

RAMUCIRUMAB in second-line + CT

Med OS: 10.5m (R) vs 9.1m (P)

RESPONSE RATE

PFS

Med PFS: 4,5 m (R) vs 3,0 m (P)

Med PFS: 4,5 m (R) vs 3,0 m (P)

Med OS: 10.5m (R) vs 9.1m (P)

RESPONSE RATE

PFS OVERALL SURVIVAL

Med OS: 10,5 m (R) vs 9.1 m (P)

Med OS: 11.1 m (R) vs 9.7 m (P) Med OS: 9.5 m (R) vs 8.2 m (P)

Comments to the REVEL trial

• REVEL met its primary endpoint of OS improvement in the total population (including ADK and SCC). Also RAM+DOC showed significant improvement in PFS and ORR compared to PL+DOC.

• Better outcome of the control group: Only PS 0-1.

• Exclusion criteria excluded patients at increased risk from anti-angiogenic therapy (major blood vessel encasement or invasion and intratumour cavitation) able for docetaxel.

• The addition of RAM to DOC did not result in an increase of SAEs and AEs leading to death.

• Safety profile was as expected for an anti-VEGFR agent.

• Ramucirumab

• Nintedanib

SECOND GENERATION ANTIANGIOGENICS.

1. Hilberg F, et al. Cancer Res 2008;68:4774–8; 2. Boehringer Ingelheim Data on file; 3. Stopfer P, et al. Xenobiotica. 2011;41:297–311; 4. Bousquet G, et al. Br

J Cancer 2011;105:1640–5; 5. Ellis PM, et al. Clin Cancer Res 2010;16:2881–9; 6. Doebele RC, et al. Ann Oncol 2012;23:2094–102.

IC50

(nmol/L)

VEGFR

1 / 2 / 3

34/ 21/ 13

PDGFR

α / β

59/ 65

FGFR

1 / 2 / 3

69/ 37/ 108

NINTEDANIB in LUNG CANCER

• Nintedanib inhibits VEGFR, PDGFR y FGFR, all participating in angiogenesis.

• Inhinition of VEGFR and FGFR new vessels

• Inhibition of FGFR y PDGFR former vessels

NINTEDANIB in second-line + CT

Nintedanib 200mg BID PO, D2–21, + Docetaxel 75mg/m2 IV, D1,

21-day cycles (n=655)

Placebo BID PO, D2–21, + Docetaxel 75mg/m2 IV, D1,

21-day cycles (n=659)

N=1314

RANDOMISE

•Stage IIIB/IV* or recurrent NSCLC

•Failed 1st-line chemotherapy

•Any histology

•ECOG PS 0 or 1

•No prior docetaxel or VEGF/VEGFR inhibitors**

•No active brain metastases

1:1

PD

PD

Number of docetaxel cycles not restricted Monotherapy allowed after ≥4 cycles of combination therapy

** Other than bevacizumab

EXCLUSION CRITERIA: • Active Brain Mets • Cavitary/ necrotic tumours, centrally located tumours with radiographic

evidence of invasion of major blood vessels

• Recent history of clinically signifi cant haemoptysis or a major thrombotic. • Clinically relevant major bleeding event

Primary endpoint:

PFS by independent central

review

Key secondary endpoint: OS

pre-planned analyses of

adenocarcinoma and ITT

LUME-Lung 1: hierarchical analysis used to reduce error rate and maintain power for the

important OS endpoint

*Hanna N, et al. ASCO 2013. Abstract #8034; Hanna N, et al. ESMO 2013. Abstract #3418;

Kaiser R, et al. ESMO 2013. Abstract #3479.

Reck M, et al. Lancet Oncol 2014;15:143–155.

Prim

ary

en

dp

oin

t K

ey s

eco

nd

ary

en

dp

oin

t

Independently

assessed PFS All histologies

OS

Adenocarcinoma

Time since start of first-

line therapy <9 months

OS

All adenocarcinoma

OS

All histologies

Significant

finding for

PFS at time

of OS

Significant

finding

Significant

finding

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*

PATIENT CHARACTERISTICS

RESPONSE RATE

PFS total population: 3.4 months vs 2.7 months;

HR 0·79 (95% CI 0.68–0.92), p=0.0019).

PFS Adenocarcinoma: 4,0 months vs 2.8 months;

HR 0.77, (95%CI 0.62–0.96), p=0.0193

PFS Squamous: 2,9 months vs 2.6 months;

HR 0.77, (95% CI 0.62–0.96), p=0.0200

Progression Free Survival

ADK PD<9m: 10.9 months vs 7.9 months; HR 0.75 (95% CI 0.60–0.92), p=0.0073.

(PFS 4.2 months vs 1.5 months;

HR 0·68 [95% CI 0·54–0·84], p=0.0005).

All ADK: 12.6 months vs 10.3 months; HR 0·83 (95% CI 0.70–0.99), p=0.0359.

Total: 10.1 months vs 9.1 months; HR 0.94 (95% CI 0.83–1.05), p=0.2720.

Overall Survival

33

45

40

35

30

25

20

15

10

5

0

Pa

tie

nts

(%

)

All CTCAE grades ≥15% incidence

CTCAE grades ≥3 ≥1% incidence

Nintedanib + docetaxel

Placebo + docetaxel

50

45

40

35

30

25

20

15

10

5

0

50

Patients with AE, %

Nintedanib +

docetaxel (n=652)

Placebo +

docetaxel (n=655)

Any AE leading to discontinuation 22.7 21.7

Any serious AE 34.4 31.5

VEGF/VEGFR inhibitor-associated adverse events P

ati

en

ts (

%)

20

15

10

5

0

20

15

10

5

0

Nintedanib + docetaxel

Placebo + docetaxel

CTCAE Grade ≥3 (%)

All CTCAE grades (%)

Nintedanib + docetaxel

Placebo + docetaxel

EJC; 17 December 2014

No differences in cough, dyspnoea, pain

between the two arms

No differences in function scores

between the two arms

The significant improvement in PFS and

the significant OS benefit in

adenocarcinoma with nintedanib +

docetaxel had no detrimental effect on

patient-reported QoL.

• Docetaxel plus Nintedanib significantly improved PFS independently of histology in second line NSCLC patients.

• There is evidence of improved OS in patients with adenocarcinoma including those patients with a poor prognosis (refractory to first-line CT or had a very short response).

• This may reflect the biologic mechanism behind tumor progression fast-progressing tumors are more dependent on new vasculature that are driven by growth factors where Nintedanib works on.

• The significant improvement in PFS and the significant OS benefit in adenocarcinoma with Nintedanib + docetaxel had no detrimental effect on patient-reported QoL.

Comments to the LUME-Lung 1 trial

Who benefits most from the antiangiogenic strategies?

• ECOG PS 0-1.

• < 65 years (65% REVEL, LUME-Lung 1)

• Adenocarcinoma histology. – Bevacizumab

– Ramucirumab (subgroup analysis)

– Nintedanib

• No/stable BRAIN Mets.

• Patients that not meet Key exclusion criteria for antiangiogenics: – Cavitary/ necrotic tumours, radiographic evidence of invasion of major blood vessels.

– Recent significant haemoptysis / bleeding.

– Therapeutic anticoagulation.

• Patients with a poor prognosis (refractory or very short response) – Nintedanib.

• Second line: Previous Bevacizumab is allowed.

Who benefit most from the antiangiogenic strategies?

Predictive factors for antiangiogenic therapy

• To date, no validated biomarker has been identified for any angiogenesis inhibitor. Several studies in various cancer types have failed to identify a relevant biomarker for antiangiogenic drugs.

• A major challenge is to develop robust biomarkers that can guide selection of patients for whom antiangiogenic therapy is most beneficial.

• In the absence of a predictive biomarker, which patients will benefit from antiangiogenics is not known.

CONCLUSIONS

• To identify a useful biomarker that allow us to determine specific patients who might benefit from antiangiogenics is crucial to do a step forward in the antiangiogenic strategies.

Antiangiogénicos de segunda generación

Dra. Marga Majem

Hospital de la Santa Creu i Sant Pau Barcelona