targeting angiogenesis in nsclc david heigener · 30.09.2016 7 non-small-cell lung cancer...
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Targeting Angiogenesis in NSCLC
David Heigener
30.09.2016 1
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...where is THAT???
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30.09.2016 4
Mexico 1986
We met before!
Brazil 2014
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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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30.09.2016 8
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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30.09.2016 9
Angiogenesis and Tumor Growth
Journal of experimental Medicine 1972; 133: 275-88
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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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30.09.2016 13
Overall Survival: 12.3 Versus 10.3 Months
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30.09.2016 14
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
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The Value of Response
Pre Bevacizumab Under Bevacizumab
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18Zhou et al.; J Clin Oncol 2015
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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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30.09.201620
Beyond: PFS
Zhou et al.; J Clin Oncol 2015
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30.09.201621Zhou et al.; J Clin Oncol 2015
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Overall Survival
30.09.201622Zhou et al.; J Clin Oncol 2015
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30.09.201623Zhou et al.; J Clin Oncol 2015
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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
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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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30.09.2016 26
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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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
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Seto et al.; Lancet Oncol, 2014 28
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29
Progression-free survival
Seto et al.; Lancet Oncol, 2014
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30
Overall survival (immature, no stats!)
Seto et al.; Lancet Oncol, 2014
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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
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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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30.09.2016 33
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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30.09.201634
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30.09.201635
Progression-free Survival
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30.09.201636
Overall Survival
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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
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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
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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
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40
Poor Man´s Biomarker
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41
OS in Lung Cancer: High Blood Pressure (HBP (+))
versus Normotensive (HBP (-))
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Mok et al.; J Thorac Oncol 2014 42
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43
Serum-Biomarkers Evaluated:
Mok et al.; J Thorac Oncol 2014
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44
Survival as a Function of
Serum-VEGF-A Level
Mok et al.; J Thorac Oncol 2014
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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)
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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...
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30.09.2016 47
like him.
Thank you for the Attention!
May 2015: Barcelona – Munich 3:0