Antiangiogenic Agents in Advanced NSCLCAntiangiogenic 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 Horizons

Program GoalsProgram Goals

• Critically analyze clinical trial data for use of existing and emerging antiangiogenic agents in the treatment of advanced NSCLC

• Outline which patients with advanced NSCLC may potentially benefit from the use of an antiangiogenic agent

Rationale for Anti-VEGF TherapyRationale for Anti-VEGF Therapy

• Solid stresses and vascular leakiness result in decreased flow to some areas of tumor and increased pressure in tumors

– Decrease access of drugs, immune cells

– Result 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 growth

Weinmann M, et al. Onkologie. 2004;27:83-90[2]; Goel S, et al. Physiol Rev. 2011;91:1071-1121.[26]

Targeted Approaches to Anti-VEGF TherapyTargeted Approaches to Anti-VEGF Therapy

Anti-receptor-blocking

antibodies

Anti-ligand-blockingantibodies

Tyrosine kinase

inhibitors

Bevacizumab Nintedanib Ramucirumab

VEGF

VEGFR

Image courtesy of C. Langer, MD.

BevacizumabBevacizumab

• Recombinant humanized IgG1 monoclonal antibody

• Binds VEGF and prevents interaction of VEGF to its receptors

• Half-life is approximately 20 days (range, 11-50 days)

Avastin (bevacizumab) [package insert]; 2014.[3]

Bevacizumab + Paclitaxel/Carboplatin in Advanced NSCLC Phase 2 Study Design

Bevacizumab + Paclitaxel/Carboplatin in Advanced NSCLC Phase 2 Study Design

• Excluded:– CNS metastasis– Therapeutic 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* + Bevacizumab 15 mg/kg every 3 wk; N = 35

PC* + Bevacizumab7.5 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 NSCLCECOG PS≤2(N = 98)

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• 6 cases of severe (n = 2) or fatal (n = 4) pulmonary hemorrhage� 4 (31%) of 13 bevacizumab-treated patients with squamous

cell histology� 2 (4%) of 53 bevacizumab-treated patients with histology

other than squamous cell

• Patients receiving chemotherapy alone (n = 32) had no pulmonary hemorrhages

• Based on this analysis, squamous cell histology was identified as a risk factor for pulmonary hemorrhage for treatment with bevacizumab

• These phase 2 data were used to design the phase 3 trial exclusion criteria

Bevacizumab + PC in Advanced NSCLC

Pulmonary Bleeding in Phase 2 Study

Bevacizumab + PC in Advanced NSCLC

Pulmonary Bleeding in Phase 2 Study

Johnson DH, et al. J Clin Oncol. 2004;22:2184-2191.[4]

Bevacizumab + PC in Advanced NSCLCPhase 2 Study Efficacy Results: Nonsquamous Patients Only

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 31.8 50

Median TTP, mo 4.0 6.3 7.1

Median survival time, mo

12.2 14.0 17.8

Johnson DH, et al. J Clin Oncol. 2004;22:2184-2191.[4]

ECOG 4599: PC ± Bevacizumab in Nonsquamous Advanced NSCLCPhase 3 Study Design

ECOG 4599: PC ± Bevacizumab in Nonsquamous Advanced NSCLCPhase 3 Study Design

Sandler A, et al. N Engl J Med. 2006;355:2542-2550.[5]

*No 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 + bevacizumab (15 mg/kg every 3 wk) up to 6 cycles

N = 434

Single-agent bev every 3 wk until PD or unaccept-

able toxicity

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nonsquamous advanced NSCLC

ECOG PS=0/1N = 878

E4599Efficacy ResultsE4599Efficacy Results

PC PCB P Value

RR 16% 35% < .001

PFS 4.5 mo 6.2 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]

Patients

Event (Grade 3-5)PC

(n = 440)PCB

(n = 427)

Clinically significant bleeding eventa 0.7%4.4%

(P < .001)

Hypertension (grade 3/4)b 0.7%7%

(P < .001)

Neutropenia 16.8%25.5%

(P = .002)

Treatment-related deaths (actual numbers)a,b 2 15

E4599Selected Safety IssuesE4599Selected 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.

AVAiLCisplatin + Gemcitabine ± Bevacizumab in Nonsquamous Disease

AVAiLCisplatin + Gemcitabine ± Bevacizumab in Nonsquamous Disease

• Phase 3 trial• 1043 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 – primary� OS – secondary

• Efficacy results:� PFS

• Bev (7.5 mg/kg) arm vs placebo: HR = 0.75 (0.64-.0.87); P = .0003• Bev (15 mg/kg) arm vs placebo: HR = 0.85 (0.73-1.00); P = .0456

� OS• Bev (7.5 mg/kg) arm vs placebo: HR = 0.93 (0.78-1.11); P = .420• Bev (15 mg/kg) arm vs placebo: HR = 1.03 (0.86-1.23); P = .761

Reck, M, et al. Ann Oncol. 2010;21:1804-1809.[6]

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/m2)/carboplatin (AUC 6)/bevacizumab (15 mg/m2) every 3 wk up to 4 cycles; N = 467

• Patients with advanced nonsquamous NSCLC*

• No prior systemic treatment for lung cancer

• ECOG PS = 0/1• N = 939

Single-agent Bev every 3 wk until PD or treatment d/c

Bev + pemetrexed every 3 wk until PD or treatment d/c

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Patel J, et al. J Clin Oncol. 2013;34:4349-4357.[10]

POINTBREAKEfficacy and Safety ResultsPOINTBREAKEfficacy and Safety Results

• Efficacy for pemetrexed/carboplatin/bevacizumab vs PCB

− OS: HR = 1.00; median OS = 12.6 vs 13.4 mo; P = .949

− PFS: HR = 0.83; median PFS = 6.0 vs 5.6 mo; P = .012

− ORR: 34.1% vs 33.0%

− DCR: 65.9% vs 69.8%

• Safety

− Significantly more grade 3/4 neutropenia, febrile neutropenia, sensory neuropathy, and alopecia with PCB

− Significantly more grade 3/4 anemia, thrombocytopenia, and fatigue with pemetrexed/carboplatin/bevacizumab

ECOG 5508Phase 3 Study DesignECOG 5508Phase 3 Study Design

• Excluded:

– Untreated CNS metastases

• Primary end point: OS

ClinicalTrials.gov NCT01107626.[15]

PC + bevacizumab every 3 wk x 4 cycles

• Patients with advanced nonsquamous NSCLC

• No prior systemic treatment for advanced lung cancer

• ECOG PS=0/1

Single-agent Bev every 3 wk

Bev + pemetrexed every 3 wk

Single-agent pemetrexed every 3 wk

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E4599Subgroup Analyses of Median Survival Time According to Sex and Age

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 mo 11.0 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)

.18

Men (PC) 9.3 mo 8.5 mo .85

Men (PCB)

12.4 mo 11.0 mo .59

P Value: sex/treatment

.0006 < .0001

Wakelee H, et al. Lung Cancer. 2012;76:410-415.[18]

E4599Landmark Analyses of Effect of Maintenance Bevacizumab

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 d

• 217 patients in PCB group; 134 patients in PC group

• Postinduction 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]

Compound Mechanism of Action N trials N End 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 Phase 3 Trials in NSCLC With Antiangiogenic Agents (2000-2011)

Image courtesy of C. Langer, MD.

Predicting Response to BevacizumabPredicting Response to Bevacizumab

• Patient selection for antiangiogenic therapy is now primarily based on exclusion for toxicity

• Circulating VEGF-A seems prognostic, but not predictivea

• Retrospective analysis suggests improved outcomes associated with bevacizumab in patients developing hypertension on therapyb

� Available evidence does not suggest hypertension as a surrogate for the efficacy of antiangiogenic therapy in advanced NSCLC

a. Hegde PS, et al. Clin Cancer Res. 2013;19:929-937.[21]

b. Koyama N. Cancer Biomark. 2014;14:259-265.[22]

LUME-Lung 1: Second-line Docetaxel + Nintedinib vs Docetaxel + Placebo Phase 3 Study Design

LUME-Lung 1: Second-line Docetaxel + Nintedinib vs Docetaxel + Placebo Phase 3 Study Design

• Primary end point: PFS• Secondary 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/m2; d1) every 3 wk + nintedanib (200 mg twice daily) (d2-21)N =655

Docetaxel (75 mg/m2;d1) every 3 wk + placebo (twice daily) (d2-21)N = 659

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LUME-Lung 1Efficacy and Safety OutcomesLUME-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 655 3.4 mo10.1mo

12.6 mo

52.7% 25.7%

PBO 659 2.7 mo9.1 mo

10.3 mo

44.7% 19.1%

HR 0.79 0.94 0.83

P Value 0.0019 0.272 0.0359

ArmDiarrhea

(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 0.9

REVEL: Second-line Docetaxel + Ramucirumab vs Docetaxel + Placebo

Phase 3 Study Design

REVEL: Second-line Docetaxel + Ramucirumab vs Docetaxel + Placebo

Phase 3 Study Design

• Primary end point: OS

• Secondary 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=0/1• N= 1253

Docetaxel (75 mg/m2) + ramucirumab (10 mg/kg) d1 every 21 d†

N = 628

Docetaxel (75 mg/m2) + placebo d1 every 21 dN = 625

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Efficacy (Arm) N ORR mPFS mOS*

RAM 23% 4.5 mo 10.5 mo

PBO 14% 3.0 mo 9.1 mo

HR 0.76 0.86

P 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 hemorrhage

8 7

Garon EB, et al. Lancet. 2014;665-673.[25]

REVELEfficacy and Safety OutcomesREVELEfficacy 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.

SummaryAntiangiogenic Agents in Advanced NSCLC

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 PC

� For patients with nonsquamous histology

� Not approved in those with antecedent hemoptysis or untreated brain metastases

• Ramucirumab 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 histology

• Nintedanib is the only TKI to show a potential OS benefit in the second-line setting

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