Riccardo Giampieri, MD, PhD Università Politecnica delle ... · Riccardo Giampieri, MD, PhD...
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Riccardo Giampieri, MD, PhD
Università Politecnica delle Marche
Ospedali Riuniti di Ancona
Antiangiogenic therapy in
GI cancer: current status
and future directions
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Before starting…
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Summary
- Antiangiogenesis in colorectal cancer: a
“continuous history”
- Antiangiogenesis in gastric cancer: a
“promising benchmark”
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Colon Cancer
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Why continuous?
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Continuous angiogenesis inhibition?
Maintenance trials
CAIRO-3 AIO-0207
SAKKMACRO
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Maintenance trials: combined results
Arnold et Al, ASCO 2014
PFS
OS
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Perhaps prolonged VEGF-A
inhibition is not enough…RAS/BRAF WT
RAS/BRAF MUT
Hegewisch et Al, Lancet Oncology 2015 Giampieri & Cascinu, Lancet Oncology 2015
In an unselected population the “gain” of
maintenance treatment is somehow
counteracted by other factors but in a
population of patients with “poor” prognostic
features (RAS/RAF mutants) maintenance
treatment might have
greater activity.
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Angiogenesis inhibition after 1°line?
- Bevacizumab again!
- Aflibercept (only FOLFOX-based 1° line pts)
- Ramucirumab (only FOLFOX-based 1° line pts)
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BEV + standard
first-line CT (either
oxaliplatin or
irinotecan-based)
(n=820)
Randomise 1:1
Standard second-line CT
(oxaliplatin or irinotecan-
based) until PD
BEV (2.5 mg/kg/wk) +
standard second-line CT
(oxaliplatin or irinotecan-
based) until PD
PD
Study conducted in 220 centres in Europe and Saudi Arabia
Primary endpoint • Overall survival (OS) from randomisation
Secondary endpoints
included
• Progression-free survival (PFS)
• Best overall response rate
• Safety
Stratification factors • First-line CT (oxaliplatin-based, irinotecan-based)
• First-line PFS (≤9 months, >9 months)
• Time from last BEV dose (≤42 days, >42 days)
• ECOG PS at baseline (0/1, 2)
Bevacizumab maintenance after
PD: TML trial
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TML (ML18147) : OS
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Bevacizumab maintenance after
PD: BEBYP trial
B. Second-line CT+ BV
RANDOM
I-line CT * + BVStratification
‐ Center
‐ PS 0/1-2
‐ CT-free interval
(> vs ≤ 3 mos)
‐ II-line CT
• FOLFIRI• FOLFOX• FOLFOXIRI• Fluoropyrimidine mono-tx
• FOLFIRI (34% in both arms)
• mFOLFOX-6 (66% in both arms)
A. Second-line CT
N=184 pts
Masi GL et al, Ann Oncol 2015
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BEBYP : RESULTS
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• Fusion protein of key domains
from human VEGF receptors
1 and 2 with human IgG Fc¹
• Blocks all human VEGF-A
isoforms, VEGF-B, and
placental growth factor
(PlGF)²
• High affinity – binds VEGF-A
and PlGF more tightly than
native receptors
1. Holash J et al. Proc Natl Acad Sci USA. 2002;99:11393-11398.
2. Tew WP et al. Clin Cancer Res. 2010;16:358-366.
Aflibercept: Structure
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Primary endpoint: overall survival
Sample size: HR=0.8, 90% power, 2-sided type I error 0.05
Final analysis of OS: analyzed at 863rd death event using a 2-sided
nominal significance level of 0.0466 (α spending function)
Metastatic
Colorectal Cancer
R
A
N
D
O
M
I
Z
E
Aflibercept 4 mg/kg IV, day 1
+ FOLFIRI
q2 weeks
Placebo IV, day 1
+ FOLFIRI
q2 weeks
1:1 Disease Progression
Death
600
600
Stratification factors:
•ECOG PS (0 vs 1 vs 2)
•Prior bevacizumab (Y/N)
VELOUR study design
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16
VELOUR: OS
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17
VELOUR: RR
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18
OS by prior Bevacizumab
Prior Bevacizumab No Prior Bevacizumab
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19
PFS by prior Bevacizumab
Prior Bevacizumab No Prior Bevacizumab
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Ramucirumab: RAISE
Tabernero J et Al, Lancet Oncology 2015
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RAISE: OS & PFS
Tabernero J et Al, Lancet Oncology 2015
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SUMMARY of 2° lines
Trial OS (HR) PFS (HR) RR (%) Toxicity
ML18147(BEV)
HR=0.81
p=0.0062
HR=0.68
p<0.0001
5.4 vs. 3.9
p=ns
No
unexpected
AEs
BEBYP
(BEV)
HR=0.77
p=0.04
HR=0.70
p=0.001
20 vs. 15
p=ns
No
unexpected
AEs
VELOUR(AFL)
HR=0.81 HR=0.7519.8 vs. 11.1
< 0.001
Increased CT-
related AEs
RAISE(RAM)
HR=0.84
p=0.0005
HR=0.79
p=0.0005
13 vs. 12.5
p=ns
Increased CT-
related AEs
Giampieri R et Al, CROH 2016
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•KIT
•PDGFR
–RET1. Wilhelm SM et al. Int J Cancer 2011.
2. Mross K et al. Clin Cancer Research 2012.
3. Strumberg D et al. Expert Opin Invest Drugs 2012.
PDGFR-β
FGFR
VEGFR1-3
TIE2
Regorafenib
Inhibition of neoangiogenesis
Inhibition of tumor microenvironment
signaling
Inhibition of proliferation
Biochemic
activity
Regorafenib
IC50
mean ± SD
nmol/l (n)
VEGFR1 13 ± 0.4 (2)
Murine
VEGFR24.2 ± 1.6 (10)
Murine
VEGFR346 ± 10 (4)
TIE2 311 ± 46 (4)
PDGFR-β 22 ± 3 (2)
FGFR1 202 ± 18 (6)
KIT 7 ± 2 (4)
RET 1.5 ± 0.7 (2)
RAF-1 2.5 ± 0.6 (4)
B-RAF 28 ± 10 (6)
B-RAFV600E 19 ± 6 (6)
Regorafenib: not just antiangiogenic…
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Regorafenib in CRC: CORRECT
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Regorafenib in Asia: CONCUR
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Regorafenib to “many”: CONSIGN
Primary endpoint: Safety
Efficacy endpoint: PFS (investigator-
assessed)
Prospective, single-arm
Conducted at 188 sites across 25 countries; planned enrollment approximately 3,000 patients
Treatment with regorafenib until one of the following:
PD by radiological assessment or clinical progression
Death
Unacceptable toxicity
Withdrawal of consent
Determination by the treating physician that discontinuation is in the best interest of the patient
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Tossicità CONSIGN
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CONSIGN PFS
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CONSIGN PFS x KRAS
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Gastric Cancer
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Angiogenesis inhibition in gastric
adenocarcinoma: unsteady start
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Different countries = surrogate for
efficacy?
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Angiogenesis inhibition in gastric
cancer 2.0
Wilke et Al, Lancet Oncology 2014Fuchs et Al, Lancet Oncology 2014
REGARD RAINBOW
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Ramucirumab II line: Results
Wilke et Al, Lancet Oncology 2014Fuchs et Al, Lancet Oncology 2014
REGARD RAINBOW
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•Wilke H et al. Lancet 2014
RAINBOW:
Stratification by geographical area
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•Wilke H et al. Lancet 2014
RAINBOW:
Effectiveness by geographical area
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Angiogenesis inhibition 2.0 –
Asian Bootleg
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Angiogenesis Inhibition 3.0
Primary endpoint: PFS
Secondary endpoints:
OS,ORR,CBR, Safety
Prior CT lines
1: 42%
2: 58%
Pavlakis N ASCO 2015
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INTEGRATE: results
Pavlakis N ASCO 2015
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Pavlakis N ASCO 2015
INTEGRATE: toxicity
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Future developments?
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Ramucirumab + Oxaliplatin 1° line?
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Maybe not
Yoon et al WGIC 2014
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… and yet still…
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… perhaps it is a matter of ORIGIN
Yoon et al WGIC 2014
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ORIGIN that is surrogate for biology
8%
22%
20%
50%GEJ
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Switch-maintenance in gastric cancer?
ARMANI trial
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Switch-maintenance in gastric cancer?
MANTRA trial
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Switch-maintenance in colorectal
cancer? RAVELLO trial
Martinelli et al. ASCO 2015
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Conclusions
- Colorectal cancer: 4 different drugs (Bevacizumab 1°-2° line,
Aflibercept 2° line FOLFOX 1° only, Ramucirumab 2° line
FOLFOX 1° only, Regorafenib 2 or + line) with no molecularly
driven selection
- Gastric cancer: 1 drug currently available (Ramucirumab 2°
line alone or + Paclitaxel) + many to come! (Apatinib 2-3°
line, Regorafenib 3° line) with a hint towards a histology/site
of involvement selection