Jared Weiss MD Assistant Professor of Medicine Division of Hematology and Oncology University of North Carolina School of Medicine Attending Physician UNC Lineberger Comprehensive Cancer ID: 631179
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Slide1
Antiangiogenic Agents in Advanced NSCLC
Jared Weiss, MD Assistant Professor of Medicine Division of Hematology and Oncology University of North Carolina School of Medicine Attending PhysicianUNC Lineberger Comprehensive Cancer CenterChapel Hill, North Carolina
Corey Langer, MDDirector of Thoracic Oncology Abramson Cancer Center and Professor of Internal Medicine Hospital of the University of Pennsylvania Philadelphia, Pennsylvania
Expanding HorizonsSlide2
Program GoalsCritically analyze clinical trial data for use of existing and emerging
antiangiogenic agents in the treatment of advanced NSCLCOutline which patients with advanced NSCLC may potentially benefit from the use of an antiangiogenic agentSlide3
Rationale for Anti-VEGF Therapy
Solid stresses and vascular leakiness result in decreased flow to some areas of tumor and increased pressure in tumorsDecrease access of drugs, immune cellsResult in hypoxia, which induces tumor progression and decreases efficacy of drugs that require oxygen, and low pH Antiangiogenic therapy targeting VEGF or VEGFR may restore a more normal vasculature, generating an environment less favorable to cancer cell growthWeinmann M, et al. Onkologie. 2004;27:83-90[2]; Goel S, et al. Physiol Rev. 2011;91:1071-1121.
[26]Slide4
Targeted Approaches to
Anti-VEGF
Therapy
Anti-receptor-blocking
antibodies
Anti-ligand
-
blocking
antibodies
Tyrosine kinase inhibitors
Bevacizumab
Nintedanib
Ramucirumab
VEGF
VEGFR
Image courtesy of C. Langer, MD.Slide5
BevacizumabRecombinant humanized IgG1 monoclonal antibody
Binds VEGF and prevents interaction of VEGF to its receptorsHalf-life is approximately 20 days (range, 11-50 days)Avastin (bevacizumab) [package insert]; 2014.[3] Slide6
Bevacizumab + Paclitaxel/Carboplatin in Advanced NSCLC Phase 2 Study Design
Excluded:CNS metastasisTherapeutic anticoagulation
Primary efficacy end points = TTP and tumor response rate.
*Patients received up to 6 cycles.
†
Crossover to single agent
bevacizumab
(15 mg/kg) was allowed at disease progression.
Johnson DH, et al.
J
Clin
Oncol
.
2004;22:2184-2191.[4]
Paclitaxel 200 mg/m2 carboplatin AUC 63 times weekly*; N = 32
PC* +
B
evacizumab
15 mg/kg every 3 wk
; N = 35
PC* +
Bevacizumab
7.5 mg/kg every 3 wk;
N = 32
Bevacizumab
7.5 mg/kg
every 3 wk to PD or unacceptable toxicity
Progression of
disease
†
Bevacizumab
15 mg/kg
every 3
wk
to PD or unacceptable toxicity
Patients with previously
untreated
advanced NSCLC
ECOG PS≤2(N = 98)
RandomizedSlide7
6 cases of severe (n = 2) or fatal (n = 4) pulmonary hemorrhage
4 (31%) of 13 bevacizumab-treated patients with squamous cell histology2 (4%) of 53 bevacizumab-treated patients with histology other than squamous cellPatients receiving chemotherapy alone (n = 32) had no pulmonary hemorrhagesBased on this analysis, squamous cell histology was identified as a risk factor for pulmonary hemorrhage for treatment with bevacizumabThese phase 2 data were used to design the phase 3 trial exclusion criteriaBevacizumab + PC in Advanced NSCLC Pulmonary Bleeding in Phase 2 Study
Johnson DH, et al. J Clin Oncol. 2004;22:2184-2191.[4]Slide8
Bevacizumab + PC in Advanced NSCLCPhase 2 Study Efficacy Results: Nonsquamous Patients Only
Control(n = 25)Bev (7.5 mg/kg)(n = 22)Bev (15 mg/kg)(n = 32)ORR, %20
31.850Median TTP, mo4.06.37.1Median survival time, mo12.214.017.8
Johnson DH, et al.
J
Clin
Oncol
.
2004;22:2184-2191.
[4]Slide9
ECOG 4599: PC ± Bevacizumab
in Nonsquamous Advanced NSCLCPhase 3 Study DesignSandler A, et al.
N Engl J Med. 2006;355:2542-2550.[5]
*
N
o
crossover to
bevacizumab
permitted.
Excluded:
CNS metastasis
History of hemoptysis
Primary
end point: OS
Paclitaxel 200 mg/m2 carboplatin AUC 6 every 3 wk up to 6 cycles*N = 444
PC
+
b
evacizumab
(15 mg/kg every 3 wk) up to 6 cyclesN = 434Single-agent
bev
every 3 wk
until PD or unaccept-able toxicity
Randomized
Patients with previously untreated
nonsquamous
advanced NSCLC
ECOG PS=0/1
N = 878Slide10
E4599Efficacy Results
PCPCB P ValueRR
16%35%< .001PFS4.5 mo6.2 mo
< .001
Median OS
10.3
mo
12.3
mo
.003
1-y survival
44%
51%
2-y survival
15%23%
Sandler A, et al. N Engl J Med. 2006;355:2542-2550.[5]Slide11
Patients
Event (Grade 3-5)
PC(n = 440)PCB(
n = 427
)
Clinically significant bleeding
event
a
0.7%
4.4%
(
P
< .001)
Hypertension (grade
3/4)
b0.7%7
%
(
P < .001)
Neutropenia
16.8%
25.5%
(
P = .002)
Treatment-related deaths
(
actual numbers)
a,b2
15
E4599
Selected Safety Issues
a. Sandler A,
et al.
N Engl J Med. 2006;355:2542-2550.[5]
b. Avastin
(bevacizumab) [package insert]; 2014.[3]
*Pulmonary hemorrhagic events are included with the clinically significant bleeding events. Slide12
AVAiLCisplatin + Gemcitabine ± Bevacizumab in Nonsquamous Disease
Phase 3 trial1043 patients in a 1:1:1 ratio to chemotherapy + placebo; chemotherapy + bevacizumab (7.5 mg/kg); chemotherapy + bevacizumab (15 mg/kg)End points included:PFS – primaryOS – secondaryEfficacy results:PFSBev (7.5 mg/kg) arm vs placebo: HR = 0.75 (0.64-.0.87); P = .0003Bev (15 mg/kg) arm vs placebo: HR = 0.85 (0.73-1.00); P = .0456
OSBev (7.5 mg/kg) arm vs placebo: HR = 0.93 (0.78-1.11); P = .420Bev (15 mg/kg) arm vs placebo: HR = 1.03 (0.86-1.23); P = .761Reck, M, et al. Ann Oncol
.
2010;21:1804-1809.
[6]Slide13
POINTBREAK: Pemetrexed/Carboplatin + Bevacizumab vs PCBPhase 3 Study Design
Patel J, et al. J Clin Oncol. 2013;34:4349-4357.[10] Primary end point: OS*Stable treated brain metastases allowed; patients were excluded if they had a coagulopathy or were taking full-dose anticoagulation at the time of randomization.
Pemetrexed (500 mg/m2)/carboplatin (AUC 6)/bevacizumb (15 mg/m2) every 3 wk up to 4 cycles; N = 472
Paclitaxel (200 mg/m
2
)/carboplatin (AUC 6)/
b
evacizumab
(15 mg/m
2
) every 3
wk
up to 4 cycles;
N = 467Patients with advanced nonsquamous NSCLC*
No prior systemic treatment for lung cancer ECOG PS = 0/1N = 939Single-agent Bev every 3 wk until PD or treatment d/c
Bev + pemetrexed every 3 wk until PD or
treatment d/c
RandomizedSlide14
Patel J, et al. J Clin
Oncol. 2013;34:4349-4357.[10] POINTBREAKEfficacy and Safety ResultsEfficacy for pemetrexed/carboplatin/bevacizumab vs PCBOS: HR = 1.00; median OS = 12.6 vs 13.4 mo; P = .949PFS: HR = 0.83; median PFS = 6.0 vs 5.6 mo; P = .012ORR: 34.1% vs 33.0%
DCR: 65.9% vs 69.8%SafetySignificantly more grade 3/4 neutropenia, febrile neutropenia, sensory neuropathy, and alopecia with PCBSignificantly more grade 3/4 anemia, thrombocytopenia, and fatigue with pemetrexed/carboplatin/bevacizumab Slide15
ECOG 5508
Phase 3 Study DesignExcluded:Untreated CNS metastasesPrimary end point: OSClinicalTrials.gov NCT01107626.[15]
PC + bevacizumab every 3 wk x 4 cyclesPatients with advanced nonsquamous NSCLCNo prior systemic treatment for advanced lung
cancer
ECOG PS=0/1
Single-agent
B
ev every 3
wk
B
ev +
p
emetrexed
every 3 wkSingle-agent pemetrexed every 3
wkRandomizedSlide16
E4599Subgroup Analyses of Median Survival Time According to Sex and Age
< 45 y< 60 y≥ 60 y
P Value (< 60 y vs ≥ 60 y)Women (PC)5.8 mo11.0 mo
13.8
mo
.11
Women
(PCB)
16.8
mo
(
P
= .07
± Bev)15.5 mo(P
= .12 ± Bev)12.8 mo(P = .2 ± Bev).18Men (PC)9.3 mo
8.5 mo.85Men (PCB)12.4 mo11.0 mo
.59
P
Value: sex/treatment.0006
< .0001
Wakelee
H, et al. Lung Cancer. 2012;76:410-415.[18]Slide17
E4599Landmark Analyses of Effect of Maintenance Bevacizumab
Analyses conducted in patients in both the PC and PCB groups alive and progression free through the completion of 6 cycles + 21 d217 patients in PCB group; 134 patients in PC groupPostinduction PFS, 4.4 vs 2.8 mo (HR = 0.64; P < .001) for PCB and PC groups, respectively
Median OS (PCB vs PC), 12.8 vs 11.4 mo (HR = 0.75; P = .03)In the maintenance setting, Bev was associated with < 1% grade 3 or 4 hematologic toxicities; no grade 3 or 4 nausea, vomiting or diarrhea; no grade 5 toxicities Lopez-Chavez J, et al. J Thorac
Oncol
.
2012;7:1707-1712.
[19]Slide18
Compound
Mechanism of ActionN trials
NEnd Point
Thalidomide
Antiangiogenic
2
1267
OS
Cediranib
VEGFR TKI
1
296
OS
Vandetanib
Multikinase
TKI
3
2698
PFS/OS
AE-941
Antiangiogenic
1
379
OS
Sorafenib
Multikinase
TKI
2
1830
OS
Sunitinib
Multikinase
TKI
1
960
OS
Aflibercept
VEGF/
PlGF
1
913
OS
Total
11
8343
Clinically
Negative
P
hase 3
T
rials
in NSCLC
With Antiangiogenic
A
gents
(2000-2011)
Image courtesy of C. Langer, MD.Slide19
Predicting Response to Bevacizumab
Patient selection for antiangiogenic therapy is now primarily based on exclusion for toxicityCirculating VEGF-A seems prognostic, but not predictiveaRetrospective analysis suggests improved outcomes associated with bevacizumab in patients developing hypertension on therapybAvailable evidence does not suggest hypertension as a surrogate for the efficacy of antiangiogenic therapy in advanced NSCLCa. Hegde PS, et al.
Clin Cancer Res. 2013;19:929-937.[21]b. Koyama N. Cancer Biomark. 2014;14:259-265.[22] Slide20
LUME-Lung 1: Second-line Docetaxel + Nintedinib vs Docetaxel + Placebo
Phase 3 Study DesignPrimary end point: PFSSecondary end points: OS, ORR, safety
*555 patients had advanced squamous NSCLC.Reck M, et al. Lancet Oncol. 2014;15:143-155.[23]
Patients with advanced
NSCLC (all
histologies
)
*
and disease progression on first-line chemotherapy
ECOG PS=0/1
Docetaxel (75 mg/m
2
; d1) every 3
wk + nintedanib (200 mg twice daily) (d2-21)N =655Docetaxel (75 mg/m
2;d1) every 3 wk + placebo (twice daily) (d2-21)N = 659RandomizedSlide21
LUME-Lung 1Efficacy and Safety Outcomes
Reck M, et al. Lancet Oncol. 2014;15:143-155.[23] Arm
NomPFS (all)mOS(all)
mOS
(ad)
1
yr
OS (ad)
2
yr
OS (ad)
NTB
6553.4 mo10.1mo12.6
mo52.7%25.7%PBO
659
2.7
mo9.1 mo10.3
mo
44.7%
19.1%HR0.790.94
0.83
P
Value0.0019
0.272
0.0359
Arm
Diarrhea
(all)
Diarrhea Grade 3-5
ALT
Grade 3-4 ALT
NTB, %
42.3
6.7
28.5
7.8
PBO, %
21.8
2.6
8.4
0.9Slide22
REVEL: Second-line Docetaxel + Ramucirumab vs Docetaxel + Placebo
Phase 3 Study DesignPrimary end point: OSSecondary end points: PFS, ORR
*25% in the ramucirumab arm and 27% in the placebo arm had advanced squamous NSCLC.; †Patients who discontinued combination therapy due to toxicity of ramucirumab or docetaxel were allowed to continue with monotherapy.
Garon
EB, et al.
Lancet
. 2014;665-673.
[25]
Patients* with squamous or
nonsquamous
advanced
NSCLC
and
disease progression on first-line platinum-based chemotherapy
ECOG PS=0/1N= 1253 Docetaxel (75 mg/m2) + ramucirumab (10 mg/kg) d1 every 21 d†
N = 628Docetaxel (75 mg/m2) + placebo d1 every 21 dN = 625
RandomizedSlide23
Efficacy
(Arm)NORRmPFS
mOS*RAM23%
4.5
mo
10.5
mo
PBO
14%
3.0
mo
9.1
mo
HR
0.76
0.86P Value
< .0001
.0001
.023
Safety: ≥ Grade 3 AEs
RAM (
N =627), %
PBO (
N
=618), %Neutropenia
49
39
Febrile neutropenia
16
10
Hypertension
6
2
Pulmonary hemorrhage†
1
1
Any Gr pulmonary hemorrhage8
7
Garon
EB, et al.
Lancet
. 2014;665-673.
[25]REVELEfficacy and Safety Outcomes*Median OS was longer for RAM + DOC for most patient
subgroups, including patients with disease characterized by squamous or
nonsquamous histology. †
Rates of pulmonary hemorrhage did not differ by histologic group.Slide24
SummaryAntiangiogenic Agents in Advanced NSCLC
Bevacizumab, the first targeted agent to receive FDA approval for first-line use in advanced NSCLC, is approved:In combination with PCFor patients with nonsquamous histologyNot approved in those with antecedent hemoptysis or untreated brain metastasesRamucirumab is the first monoclonal antibody to show a survival benefit in the second-line setting (in combination with docetaxel) and the first to benefit patients with disease characterized by squamous histologyNintedanib
is the only TKI to show a potential OS benefit in the second-line settingSlide25
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