Bevacizumab-based therapy is the standard of care for frontline
non-squamous NSCLC
Bryan J. Schneider, M.D.Assistant Professor of Medicine
Anbinder Clinical Scholar in OncologyWeill Cornell Medical College
Initial Presentation
• Woman, 65 years of age with persistent cough and shortness of breath
• Former smoker– One pack per day at 20-60 years of age– No smoking in the last 5 years
• ECOG PS 1
MedicalHistory
• No prior thrombotic or hemorrhagic disorders• No history of gross hemoptysis
Imaging
• Chest CT confirms 4-cm noncentrally located mass • Large pleural effusion• Lymph node involvement• MRI rules out CNS metastases
Histology • Thoracoscopic thoracentesis and pleural biopsy performed• Histology markers indicate adenocarcinoma
Diagnosis • T2a/N2/M1A stage IV (with malignant pleural effusion) nonsquamous
Patient Profile
2
1. Paclitaxel + Carboplatin
2. Pac + Carbo + Bevacizumab
3. Pemetrexed + Carboplatin
4. Pem + Carbo + Bevacizumab
5. Pemetrexed + Cisplatin
Question
How would you treat this patient if test results indicated EGFR wild-type and ALK negative?
3
What matters to clinicians?
1. Is the treatment effective?– E4599– POINTBREAK
2. Is the treatment safe?– SAiL– ARIES
3. Are there better alternatives?– PARAMOUNT– S130
Vascular Endothelial Growth Factor (VEGF) Signaling
Armand JP, Sledge G. 2001
Is the addition of bevacizumab to chemotherapy superior to chemotherapy alone in ns-NSCLC?
NSCLC – Advanced Disease
Approach Median Survival
1-Year Survival
Best Supportive Care 6 mo 10-20%
Older Platinum Regimens 7-8 mo 20-40%
Newer Platinum Regimens 8-10 mo 30-40%
E4599 Phase III Trial Design: Bevacizumab + PC
Stratification:– Disease stage– Degree of weight loss– Prior RT– Measurable disease
Bevacizumab 15 mg/kg IV q3w until
PD or unacceptable toxicity1
Bevacizumab + PC q3w × 6bevacizumab 15 mg/kg
carboplatin AUC 6 paclitaxel 200 mg/m2
PC q3w × 6 carboplatin AUC 6
paclitaxel 200 mg/m2
(no crossover permitted)
First-line treatment of patients with stage IIIB with malignant pleural effusion, stage IV,
or recurrent nsNSCLC(N=878)
Endpoints:– Primary: OS– Secondary: response rate,
PFS, toxicity
1. Sandler A, et al. N Engl J Med. 2006;355:2542-2550.
Bevacizumab + PC significantly increased median OS by 19%(12.3 vs 10.3 months with PC alone) in Study E4599
In Study E4599, Bevacizumab + PC Demonstrated Clinically Meaningful 1- and 2-Year OS Rates
0.0
0.2
0.4
0.6
0.8
1.0
Prop
ortio
nSu
rviv
ing
0 6 42 4818 3012 24 36Time, Months
HR=0.80; P=0.013(repeated 95% CI, 0.68-0.94)
Bev + PC 12.3 monthsPC 10.3 months
Median Survival
1-year survival51% vs 44%
2-year survival23% vs 15%
1. Sandler A, et al. N Engl J Med. 2006;355:2542-2550.
PointBreak (JMHD): Study Design
Superiority TrialPrimary endpoint: OSSecondary endpoint: PFS
RANDOMIZE
PD1:1
Eligibility:• Stage III/IV NSCLC • Nonsquamous• No prior systemic
therapy• PS 0/1• Treated brain
metastases (N=900)
Pac + Carbo + Bev 15 mg/kg
q3w × up to 4 cycles
Pem + Carbo + Bev 15 mg/kg
q3w × up to 4 cycles
Pem +Bev
Bev
Stratified for: • PS (0 vs 1)• Sex (M vs F)• Disease stage (IIIB vs IV)• Measurable vs nonmeasurable disease
Patel, et al. Presented at: IASLC. 2012 (abstr LBPL1).
0 3 6 9 12 15 18 21 24 27 30 33 36 39
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time from Induction (Months)
Surv
ival
Pro
babi
lity
Pem + Carbo + Bev
Pac + Carbo + Bev
OS median, months 12.6 13.4HR (95% CI); P value 1.0 (0.86-1.16); P=0.949
Survival rate, % 1-year 52.7 54.12-year 24.4 21.2
PointBreak: OS From Randomization (ITT)
Patel, et al. Presented at: IASLC. 2012 (abstr LBPL1).
SAiL: OS consistent across chemotherapy regimens
Crino, et al. Lancet Oncol 2010;11:733-40
Med
ian
OS
(mon
ths)
20
15
10
5
0 OverallSAiL
population
14.3 14.7 7.8 9.4
Bev +single-
agent CT
Bev +non-platinum
doublets
Bev +carboplatin
doublets
Bev +cisplatin doublets
SAiL: efficacy by chemotherapy regimen
14.6
n=1,067 n=815 n=13 n=42n=2,166
Summary
• Addition of bevacizumab consistently improves survival when added to platinum-doublet chemotherapy in ns-NSCLC– Platinum/taxane– Platinum/pemetrexed
• Median OS 13-15 month range– 8-10 months with chemotherapy alone
• One-year survival surpasses 50%
Will the addition of bevacizumab to chemotherapy lead to more complications than it is worth?
Bevacizumab + chemotherapy
ARIES (Bevacizumab Registry: Investigation of Effectiveness and Safety)
First-line, advanced non-squamous NSCLC
(n=2,212)
Bevacizumab (7.5mg/kg or 15mg/kg) every 3 weeks
+ standard of care chemotherapy(up to 6 cycles)
SAiL (Safety of Bevacizumab in Lung)
PDBevacizumab
to progression
First-line, advancednon-squamous NSCLC
(n≈2,000)PD
Bevacizumab to
progression
SAiL and ARIES: Bevacizumab safety and efficacy confirmed in real-life clinical practice(>4,000 patients)
SAiL: safety profile
• In this real-life clinical population (over 2000 patients)– incidence of grade ≥3 pulmonary hemorrhage and HTN was very
low
Adverse event Grade ≥3 (%) Grade 5 (%)Bleeding
EpistaxisPulmonary hemorrhageCNS bleed
3.61.20.6
2 pts
0.70
0.3 (8 pts)1 pt
HTN 6.0 0
Proteinuria 3.0 0
Thromboembolism 7.7 1.1
Crino, et al. Lancet Oncol 2010;11:733-40
ARIES: safety profile• In this real-life clinical population
– incidence of grade ≥3 bleeding was low, despite inclusion ofpatients with CNS metastases, history of hemoptysis andpatients on therapeutic anticoagulants
Fischbach, et al. ASCO 2009
Adverse event (%)All patients(n=1,758)
Age ≥70 years
(n=584)
ECOGPS ≥2
(n=168)
CNS mets
(n=126)
History of hemoptysis*
(n=124)
Therapeutic anticoagulants
(n=85)
Grade ≥3 bleedingEpistaxisPulmonaryhemorrhageCNS bleeding
3.20.3
0.70.1
2.90.2
0.30.0
4.20.0
0.60.6
–––
0.0
6.50.8
3.20.0
1.20.0
0.01.2
Arterial thromboembolic events 1.6 2.6 3.0 – 2.4 2.4
*No recent significant hemoptysis (≥½ teaspoon)
Bevacizumab in patients with full-dose anticoagulation therapy
SAiL (n=1,699)1
Grade 3–5 events (%)
Therapeutic anticoagulation
(n=152)
No therapeutic anticoagulation
(n=1,547)Epistaxis 1.6 2.6Hemoptysis 1.6 0.6Other hemorrhage 4.9 3.4
1. Griesinger, et al. ASCO 2008; 2. Fischbach, et al. ASCO 2009
In the SAiL and ARIES trials, there was no increase in bleeding in patients receiving concurrent Bevacizumab and FDAC
ARIES (n=1,758)2
Grade 3–5 events (%)Therapeutic
anticoagulation (n=85)
No therapeutic anticoagulation
(n=1,653)Epistaxis 0 0.4Hemoptysis 0 0.7Other hemorrhage 1.2 1.1
PointBreak: CTCAEs (Version 3) Possibly Related to a Study Drug (Safety Population)
Pem arm, %(n=442)
Pac arm, %(n=443)
Grade 3/4 (5) Grade 3/4 (5) Anemia* 14.5 2.7
Thrombocytopenia* 23.3 5.6
Neutropenia* 25.8 40.6
Febrile neutropenia* 1.4 4.1
Fatigue* 10.9 5.0
Hemorrhage GI/pulmonary 1.8 (0.5) 0.5 (0.7)
Thromboembolic event 3.2 2.0
Neuropathy sensory* 0.0 4.1
Alopecia† – –
Other grade 5 events (Pem arm/Pac arm, %)
Includes CNS ischemia (0.2/0.7); cardiac events (0.2/0.7); ARDS (0.5/0); infection (0.2/0); other
hemorrhage (0.2/0.2)
*Significant difference between arms for grade 3/4 toxicities. †Maximum grade is grade 2. Patel, et al. Presented at: IASLC. 2012 (abstr LBPL1).
S130: Grade 3/4 CTCAEs Possibly Related to a Study Drug (Safety Population)
EventPem + Carbo,
%(n=171)
Pac + Carbo + Bev, % (n=166)
P Value
Anemia* 19 5 <0.001Thrombocytopenia* 24 10 <0.001Neutropenia* 25 49 <0.001Febrile neutropenia 0 2 0.118Hypertension 0 2 0.058Thrombosis/embolism 0 2 0.058Any hemorrhagic events 1 0 0.499
*Significant difference between arms.Zinner, et al. Presented at: ASCO. 2013 (abstr LBA8003).
Summary
• Bevacizumab is safe and well tolerated– Grade 3-5 toxicity:
• bleeding and thromboembolic events 3%• HTN 6%• Proteinuria 3%
• Bevacizumab it safe in “special” patient populations– Full-dose anticoagulation– Treated brain metastases (no evidence of increased risk of
ICH)
• Pick your toxicity– Alopecia and neuropathy with paclitaxel– Anemia and thrombocytopenia with pemetrexed
Isn’t platinum/pemetrexed without bevacizumab better and easier on the patient?
PARAMOUNT: Cisplatin/Pemetrexed followed by maintenance pem vs. placebo
PD
Pem q3w
Placebo q3wInduction therapy
(n=939)Maintenance
therapy(n=539)*
(57%)
2:1
Criteria: CR/PR/SD (RECIST)
• Previously untreated stage IIIB/IV nonsquamous NSCLC
• ECOG PS 0-1
Pem + Cis q3w ×4
RANDOMIZE
Primary endpoint: PFSSecondary endpoints: OS, safety
Placebo-controlled, randomized, multicenter phase III study
Paz-Ares et al: J Clin Oncol 2013, 10:31(23):2895-902
Kaplan-Meier plots of overall survival (OS) from randomly assigned patients.
Paz-Ares L G et al. JCO 2013;31:2895-2902
E4599: OS in patients with adenocarcinoma histology• Bevacizumab-based therapy extends OS to 14.2 months
– increase of 3.9 months vs CP
– 31% reduction in the risk of death
Duration of survival (months)
Pro
babi
lity
of O
S
0 6 12 18 24 30 36 42 4810.3
Note: preplanned subgroupanalysis in E4599
1.00.90.80.70.60.50.40.30.20.1
0
CP(n=302)
Bevacizumab15mg/kg
+ CP(n=300)
HR(95% CI)
0.69(0.67–0.92)
Median OS (months) 10.3 14.2
14.2
Sandler, et al. JTO 2008;3(Suppl. 4):S283 (Abs. 133)
PointBreak Maintenance Analysis: OS From Randomization (Maintenance Group)
0 3 6 9 12 15 18 21 24 27 30 33 36 39
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time from Induction (Months)
Surv
ival
Pro
babi
lity
Pem + Carbo + Bev
(n=292)
Pac + Carbo + Bev
(n=298)
OS median (95% CI), months
17.74(16.59-20.47)
15.74(14.91-17.67)
Patel, et al. Presented at: ASCO. 2013 (abstr 8012).
S130: Phase III Pemetrexed vs Bevacizumab – Study Design
Primary endpoint: PFS without grade 4 AE (G4PFS)Secondary endpoints:PFS (all), OS, ORR, DCR, safety
PD
Eligibility:• Stage IV NSCLC • Nonsquamous• No prior
chemotherapy• PS 0/1• Stable treated CNS
metastases• No FDAC
(N=361)
RANDOMIZE
Pem 500 mg/m2 + Carbo AUC 6 q3w × 4 cycles
Pac 200 mg/m2 + Carbo AUC 6 + Bev 15 mg/kg
q3w × 4 cyclesBev
Pem
Stratified for: • PS (0 vs 1)• Gender (M vs F)• Disease stage (M1a vs M1b)
Zinner, et al. Presented at: ASCO. 2013 (abstr LBA8003).
S130: Primary Endpoint, Median G4PFS (ITT)
Pem + Carbo Pac + Carbo + Bev
G4PFS median, months 3.9 2.9
HR (90% CI); P value 0.85 (0.70-1.04); P=0.176
Zinner, et al. Presented at: ASCO. 2013 (abstr LBA8003).
100
80
60
40
20
0 3 6 9 12 15 18 21 24 270
Prop
ortio
n
Time From Induction, Months
8775
4433
2617
149
73
50
30
10
00
182179
Patients at risk:Pem + Carbo
Pac + Carbo + Bev
Pem + Carbo Pac + Carbo + Bev
OS median, months 10.5 11.7
HR (95% CI); P value 1.07 (0.83-1.36); P=0.615
1-year OS, % 43.7 48.8
2-year OS, % 18.0 17.6
S130: Secondary Endpoint, OS (ITT)
Zinner, et al. Presented at: ASCO. 2013 (abstr LBA8003).
100
80
60
40
20
0
Prop
ortio
n
Time From Induction, Months0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
182179
156151
125121
10296
7273
4859
3338
2028
1110
113
51
51
50
50
50
Patients at risk:Pem + Carbo
Pac + Carbo + Bev
AVAPERL: Bevacizumab ± Pemetrexed Treatment to Progression – Study Design
PD
Bev 7.5 mg/kg q3w
Bev 7.5 mg/kg + Pem q3wInduction therapy
(n=374)Maintenance
therapy(n=253)*
(68%)
1:1
Criteria: CR/PR/SD (RECIST)
• Previously untreated stage IIIB/IV nonsquamous NSCLC
• ECOG PS 0-2
Bev + Pem + Cis q3w ×4
RANDOMIZE
Primary endpoint: PFSSecondary endpoints: OS, safety
Open-label, randomized, multicenter phase III study
*Rittmeyer, et al. Presented at: ASCO. 2013 (abstr 8014).
AVAPERL: PFS From RandomizationMedian PFS,
MonthsBev 3.7
Bev + Pem 7.4
HR=0.57 (95% CI, 0.44-0.75);
P<0.0001
Rittmeyer, et al. Presented at: ASCO. 2013 (abstr 8014).
0 3 6 9 12 15 18 21 24
PFS,
%
Time, Months
1.0
0.8
0.6
0.4
0.2
0.0
AVAPERL: OS* From Induction
*Study was not powered for OS.A total of 73 (58.4%) and 74 (57.8%) patients died in the Bev alone and Bev + Pem arms, respectively.Rittmeyer, et al. Presented at: ASCO. 2013 (abstr 8014).
HR=0.88 (95% CI, 0.64-1.22);
P=0.32
1.0
0.8
0.6
0.4
0.2
0.0
Cum
ulat
ive
Surv
ival
Time, Months
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Maintenance Median OS, Months
Bev 15.9
Bev + Pem 19.8
+ = censored
Summary of Trials
Induction Therapy
MaintenanceTherapy
Time of Random
N OS (mo)
HR(95% CI)
ECOG 4599Adenocarcinoma
Carbo/Pac
Carbo/PacBev
Placebo
Bev
Before induction
302
300
10.3
14.2
0.69(0.67-0.92)
PARAMOUNT Cis/PemPlacebo
PemAfter induction
180
359
14.0
16.9
0.78(0.64-0.96)
PointBreak
Carbo/PacBev
Carbo/PemBev
Bev
Bev/Pem
After induction
298
292
15.7
17.7
NR
NR
AVAPERL Cis/PemBev
Bev
Bev/PemAfter induction
120
125
15.9
19.8
0.88(0.64-1.22)
Summary
• Platinum/pem pem has not been shown to be superior to bevacizumab-containing regimens
– Maintenance trials enhance for patients likely to benefit• Skews the survival data
– S130• Not better tolerated• Cannot conclude regimens are equal
– When using platinum/pem/bev, continue pem/bev as tolerated.
E5508: Study Design
Eligibility:• Advanced NSCLC,
nonsquamous• No prior treatment
(N=1288*)
Paclitaxel + carboplatin +bevacizumab
q3w× 4 cycles
Bevacizumabq3w
Pemetrexedq3w
Pemetrexed +bevacizumab
q3w
Response or SD
Primary endpoint: OSSecondary endpoints: PFS, ORR, toxicity
818 patients enrolled as of November 2013Sponsor: ECOGPI: S. Ramalingam.
RANDOMIZE
Conclusions
• The addition of bevacizumab to platinum-based chemotherapy is safe and effective with results superior to chemotherapy alone
• No platinum doublet has proven superiority (or equivalence)
– Efficacy– Toxicity
• Should be included in frontline, ns-NSCLC therapy– Carboplatin/paclitaxel – Carboplatin/pemetrexed– Cisplatin/pemetrexed
Thanks!
