Targeting Angiogenesis in NSCLC

David Heigener

30.09.2016 1

...where is THAT???

30.09.2016 3

30.09.2016 4

Mexico 1986

We met before!

Brazil 2014

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30.09.2016 6

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Non-small-cell Lung Cancer

Worldwide, lung cancer is the leading cause of cancer mortality in males

and the second-leading cause in females1

~85% of lung cancers are of NSCLC histology2

Most NSCLC cases (>75%) are diagnosed in late stages of disease (stage III

or IV)3

5-year survival rates are <15% across all stages of disease4

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ANGIOGENESIS: A HALLMARK OF CANCER

Hanahan & Weinberg. Cell 2011

Anti-angiogenic 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

Evading

growth

suppressors

Avoiding

immune

destruction

Enabling

replicative

immortality

Tumour-

promoting

inflammation

Activating

invasion &

metastasis

Genome

instability

mutation

Resisting

cell

death

Degrading

cellular

energetics

Sustaining

proliferative

signalling

Inducing

angiogenesis

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Angiogenesis and Tumor Growth

Journal of experimental Medicine 1972; 133: 275-88

10Modified from Scappaticci, F. A. J Clin Oncol; 20:3906-3927 2002

VEGF

Receptor

TKI

VEGF

Antibodies

Targets of Antiangiogenic Treatment

VEGF

Receptor

Antibodies

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Agenda

• Bevacizumab in First-Line Treatment of Lung Cancer

– Combination with Chemotherapy

– Combination with Erlotinib

• The Value of Maintenance

• Biomarkers for Angiogenesis

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Overall Survival: 12.3 Versus 10.3 Months

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Progression-free Survival 6.2 Versus 4.5 Months

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ECOG 4599 + AVAIL: Response

40

30

20

10

0

Bevacizumab7.5mg/kg

+ CG (n=323)

Bevacizumab

15mg/kg+ CG

(n=332)

Placebo+ CG

(n=324)

An

sp

rec

hra

te (

%)

Bevacizumab 15mg/kg

+ CP (n=381)

CP (n=392)

E4599

AVAiL

p<0.001

p=0.0023

p<0.0001

40

30

20

10

0

15%

35%

20%

30%34%

Sandler, et al. N Engl J Med 2006; Reck, et al. J Clin Oncol 2009

The Value of Response

Pre Bevacizumab Under Bevacizumab

18Zhou et al.; J Clin Oncol 2015

Beyond-Trial: Design

CP + bevacizumab

15mg/kg q3w

(up to 6 cycles)

CP + placebo q3w

(up to 6 cycles)

Locally advanced,

metastatic or

recurrent NSCLC

(stage IIIB, IV)

first-line

n=270

Primary endpoint

– PFS

R1:1

Secondary endpoints

– ORR

– OS

– DoR and safety

– PFS with bev to 3rd PD

Phase III (double-blinded, multi-centre) study

PDBevacizumab*

15 mg/kg q3w

PDPlacebo

Zhou et al.; J Clin Oncol 2015

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Beyond: PFS

Zhou et al.; J Clin Oncol 2015

30.09.201621Zhou et al.; J Clin Oncol 2015

Overall Survival

30.09.201622Zhou et al.; J Clin Oncol 2015

30.09.201623Zhou et al.; J Clin Oncol 2015

HR HR (95% CI)

0.76 (0.39–1.47)

0.52 (0.27–1.02)

0.66 (0.57–0.77)

0.75 (0.63–0.90)

0.85 (0.71–1.02)

0.55 (0.38–0.79)

0.72 (0.66–0.79)

P<0.001

Efficacy of Bevacizumab in First-line Treatment 0f Non-squamous NSCLC :

Meta-Analysis of Data from RCTs

Soria, et al. Ann Oncol 2013

OS PFS

Trial HR HR (95% CI)

AVF-0757g 7.5 1.13 (0.52–2.42)*

AVF-0757g 15 1.18 (0.54–2.59)*

ECOG 4599 0.80 (0.69–0.93)

AVAiL 7.5 0.92 (0.75–1.13)

AVAiL 15 1.02 (0.83–1.26)

JO19907 0.99 (0.65–1.50)

Total0.90 (0.81–0.99)

P=0.03

0.0 0.5 1.0 1.5 2.0 2.5

Favours bevacizumab Favours control

Test for heterogeneity p=0.44

0.0 0.5 1.0 1.5

Test for heterogeneity p=0.17

For AVF0757g trial, direction of OS HR

unknown; worst scenario chosen

Favours bevacizumab Favours control

25

Tolerability of Bevacizumab in first-line treatment of non-squamous NSCLC :

Meta-Analysis of data from RCTs

Soria, et al. Ann Oncol 2013

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Agenda

• Bevacizumab in First-Line Treatment of Lung Cancer

– Combination with Chemotherapy

– Combination with Erlotinib

• The Value of Maintenance

• Biomarkers for Angiogenesis

Preclinical Effect of Bevacizumab and Erlotinib

– Mouse Model with EGFR-mut Xenograft

* p < 0,01; ** p < 0,05; *** p < 0,001.

1. Li et al. Cancer Chemo Pharmacol 2014

Seto et al.; Lancet Oncol, 2014 28

29

Progression-free survival

Seto et al.; Lancet Oncol, 2014

30

Overall survival (immature, no stats!)

Seto et al.; Lancet Oncol, 2014

Jo25567-Study: Safety

Bevacizumab +

Erlotinib

(n = 75)

Erlotinib

(n = 77)

Grade-3/4-AEs, n (%) 68 (91)** 41 (53)

Erlotinib-Duration of Tx

(median), Days431 (21–837) 254 (18–829)

Bevacizumab-Duration

of Tx

(median), Days325 (1–815) –

Bevacizumab-

Discontinuation due to

AE, %41 –

Erlotinib-

Discontinuation due to

AE, %16 18

Seto et al.; Lancet Oncol, 2014

32

putting in to perspective: afatinib vs erlotinib/bevacizumab in japanese pts w/o

brain mets *

1. Seto T et al., Lancet Oncol 2014, 15(11):1236-1244. / 2. Kato T et al., Cancer Sci 106 (2015) 1202–1211. / 3. Data on file.

JO25567 PFS (Months) ORR [%]

Frequent

Mutations

Del19 L858R Frequent

Mutations

Erlotinib +

Bevacizumab (n=75)

16,01

HR 0,54

signifikant

18,01

HR 0,41

signifikant

13,91

HR 0,67

nicht signifikant

69%1

Afatinib,

Subpopulation

Japanese pts*

(n=61)

16,42

HR 0,26

significant

19,22

HR 0,14

significant

13,82

HR 0,56

not significant

62%3

LUX-Lung 3 PFS (Months) ORR [%]

* Post-hoc-Subgruppenanalyse der LUX-Lung 3-Studie

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Agenda

• Bevacizumab in First-Line Treatment of Lung Cancer

– Combination with Chemotherapy

– Combination with Erlotinib

• The Value of Maintenance

• Biomarkers for Angiogenesis

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Progression-free Survival

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Overall Survival

E4599: retrospective analyses of non-progressors

on study 21 days after cycle 6

OS

esti

mate

1.0

0.8

0.6

0.4

0.2

0

4.5 8 12 18 24 30 36 42 48

Time since treatment initiation (months)

Bev/CP non-progressors

CP non-progressors

Sandler, et al. WCLC 2011

Median OS, months

CP non-

progressors

(n=134)

Bev + CP non-

progressors

(n=217)

Postinduction* 11.4 12.8

HR (adjusted)=0.75

p=0.03

Overall‡ 15.8 17.0

*Calculated from the landmark date +21 days‡Calculated from start of induction treatment

AvaALL: phase IIIb study of bevacizumab

continued beyond progression in NSCLC

• Primary endpoint: OS

• Secondary endpoints: PFS, safety, QoL and biomarker analysis

• Actively recruiting patients

Enroll

Primary endpoint: OS

PD1

SOC2*

+

bevacizumab

SOC3‡

+

bevacizumab

SOC4

±

bevacizumab

SOC2* SOC3‡ SOC4

PD3

Ran

do

mis

e 1

:1

PD2

Stage IIIB/IV

non-squamous NSCLC

treated with platinum-

doublet (4–6 cycles)

+ bevacizumab PLUS

> 2 cycles of

bevacizumab

maintenance

n=600

Gridelli, et al. Clin Lung Cancer 2011

*SOC2: labelled agents for second-line treatment of NSCLC ‡SOC3 and beyond: choice of labelled agents is the investigator’s choice

30.09.2016 39

Agenda

• Bevacizumab in First-Line Treatment of Lung Cancer

– Combination with Chemotherapy

– Combination with Erlotinib

• The Value of Maintenance

• Biomarkers for Angiogenesis

40

Poor Man´s Biomarker

41

OS in Lung Cancer: High Blood Pressure (HBP (+))

versus Normotensive (HBP (-))

Mok et al.; J Thorac Oncol 2014 42

43

Serum-Biomarkers Evaluated:

Mok et al.; J Thorac Oncol 2014

44

Survival as a Function of

Serum-VEGF-A Level

Mok et al.; J Thorac Oncol 2014

45

Hypertension and VEGF A are prognostic but

presumably not predictive (but control Arm is

lacking in both trials).

Other possible Candidate:

TSFT

(see in next Presentation)

Translational research: Optimising treatment in patients

without oncogenic alteration

Reck M, Reinmuth N, Kugler C, Olchers T, Sonnek J, Watermann I, Ammerpohl O,

Goldmann T, Thomas M, Huber RM, Klingmüller U, Stiewe H, Golpon H

Retrospective

identification of

patients with

available tissue

Completely resected

adenocarcinoma

Stage I, II

Relapse

(local/distant)

within 1 year

Without

relapse

≥1 year

Clinical validation in clinical cohort with

available biomaterials receiving nintedanib

plus docetaxel Specific profile of vessels addicted to

fast-progressing tumours

I

II

Deep

phenotyping

Transcriptome

Methylation profile

Infiltration of immune cells

Morphological markers

Vessel density, patterns of vessel

growth, types of vascularisation

Tissue-based markers

VEGFR 1–3, FGF, PDGF,

ICAM-1, CD34, C 105, FAP, KI67

Oncogenic alterations

EGFR, ALK, KRAS, BRAF, RET

...to find the one who makes the

difference...

30.09.2016 47

like him.

Thank you for the Attention!

May 2015: Barcelona – Munich 3:0