Targeting angiogenesis in Lung cancer

Lucio Crinò, MDMedical Oncology Department

University Hospital Perugia, Italy

VEGF: Targeted Approaches

Antireceptorblockingantibodies

AntiligandblockingAntibodies and VEGF-TRAP

Tyrosine kinase inhibitors

BevacizumabAflibercept

Adapted from Noonberg SB, et al. Drugs. 2000;59:753-767.

VandetanibSorafenibNindetanib

Ramucirumab

Outline•Antiangiogenic agents in the first-line setting

•Bevacizumab•Recently completed randomised trials

•Multi-targeted antiangiogenic orally administered TKIs•Vascular disrupting agents

•Antiangiogenic agents in a relapsed/refractory setting• Recently completed randomised trials

• Multi-targeted antiangiogenic orally administered TKIs- Nindetanib

• Monoclonal antibodies and decoy receptors•Vascular disrupting agents

•Other investigational agents• Ramucirumab

Phase III Trials of Bevacizumab combined with P-based CT in NSCLC

Previously untreated stage

IIIB/IV non-squamous NSCLC (n=878)

CP (n=444)

Bevacizumab 15mg/kg† + CP

(n=434)

PD*

PD

PD

PD

PD*

Bevacizumab

Bevacizumab

Placebo + CG (n=347)

Bevacizumab15mg/kg† + CG

(n=351)

Bevacizumab7.5mg/kg† + CG

(n=345)Previously

untreated, stage IIIB, IV or recurrent non-

squamous NSCLC (n=1.043)

*No cross over permitted; †Dose of Avastin every 3 weeksNSCLC = non-small cell lung cancerCP = carboplatin/paclitaxel; PD = progressive disease CG = cisplatin/gemcitabine

Bevacizumab

E4599 (US)

AVAiL (Ex-US)

E4599: Improvement in OS

Sandler A et al. New Engl J Med 2006;355:2542–2550

HR=0.79 (0.67–0.92); P = 0.003

Months

Survival (%)

12 months 24 months

CP + bevacizumab

51 23

CP 44 15

1.0

0.8

0.6

0.4

0.2

0

0 6 12 18 24 30 36 42 48

Pro

bab

ilit

y

10.3 12.3

Bev 7.5mg/kg + CG

AVAiL: Bevacizumab significantly prolongs PFS (primary endpoint)

Placebo + CG 347 178 34 12 30

345 214 63 18 50

351 200 57 12 00

Bev 15mg/kg + CG

Placebo+ CG

Bev 7.5mg/kg

+ CG

Bev15mg/kg

+ CG

HR(95% CI)

0.75 (0.64–0.87)

0.85(0.73–1.00)

p value 0.0003 0.0456

Median PFS (months) 6.2 6.8 6.6

0 6 12 18 24 30

1.0

0.8

0.6

0.4

0.2

0

Time (months)

Pro

bab

ility

of

PF

S

No. at risk

Reck M JCO 2009;27.1227-1234

AVAiL: no significant benefit in OS* (secondary endpoint)

1.0

0.8

0.6

0.4

0.2

0

Pro

bab

ility

of

OS

0 6 12 18 24 30 36Time (months)

347 272 182 100 36 30

345 286 182 107 34 30

351 264 177 92 33 20

Placebo + CG

Bev 7.5mg/kg + CG

No. at risk

Bev 15mg/kg + CG

Reck M, Ann Oncol 2010;21:1804-1809

Placebo+ CG

Bev 7.5mg/kg

+ CG

Bev15mg/kg

+ CG

HR(95% CI)

0.93 (0.78–1.11)

1.03(0.86–1.23)

p value 0.42 0.76

Median OS (months) 13.1 13.6 13.4

Meta-analysis of PFS

Meta-analysis of OS

Soriat JC et al. Ann Oncol. 2013 Jan;24(1):20-30.

Two phase IV studies investigated the safety of the combination of bevacizumab and chemotherapy as first-line

Crino L, et al. Lancet Oncol.11(8),733–740 (2010). Wozniak AJ, et al .J. Clin. Oncol.28(7s), (2010)

…roughly 4000 “real life” pts !!

Main grade ≥3 AE of Phase III and IV trials of bevacizumab + platinum-based first-line CHT for stage IV non-squamous NSCLC

Comparison of the results of Phase III and IV trials of bevacizumab + platinum-based first-

line CHT for stage IV non-squamous NSCLC : OS

Comparison of the results of Phase III and IV trials of bevacizumab + platinum-based first-line CHT for stage IV non-squamous NSCLC : PFS

Outline•Antiangiogenic agents in the first-line setting

•Bevacizumab

•Recently completed randomised trials•Multi-targeted antiangiogenic orally administered TKIs•Vascular disrupting agents

•Antiangiogenic agents in a relapsed/refractory setting• Recently completed randomised trials

• Multi-targeted antiangiogenic orally administered TKIs- Nindetanib

• Monoclonal antibodies and decoy receptors•Vascular disrupting agents

•Other investigational agents• Ramucirumab

VEGFR-TKIs in Development in NSCLC

ClinicalTrials.gov.

Vandetanib EGFR/VEGFR/RET-TKI Phase III First line/refractory

Sorafenib VEGFR-TKI Phase III First line/refractory

Sunitinib VEGFR-TKI Phase III Refractory

Cediranib VEGFR-TKI Phase III First line

Motesanib VEGFR-TKI Phase III First line

Nindetanib VEGFR-TKI Phase III Refractory

Pazopanib VEGFR-TKI Phase III Maintenance/refractory

Linifanib VEGFR-TKI Phase II First line/refractory

Axitinib VEGFR-TKI Phase II First line/refractory

Tivozanib VEGFR-TKI Phase II Refractory

Vandetanib(ZD6474)

1,000

Motesanib(AMG-706)

VEGFR-1VEGFR-2VEGFR-3

Sunitinib ABT-869 Sorafenib Vatalanib(PTK787)

Axitinib(AG13736)

PazopanibCediranib

(AZD-2171)

100

10

1

0.1 Tivozanib(AV-951)

More potent

Less potent

Reported Potencies of Selected Molecules Targeting VEGFRs

Chow, JCO 2007 Eskens, Proceedings of the 99th Annual Meeting of the AACR 2008

ESCAPE: Phase III Trial of Carboplatin and Paclitaxel ± Sorafenib

CPSCarboplatin AUC 6 Day 1 +

Paclitaxel 200 mg/m2 Day 1 + Sorafenib 400 mg BID Days 2-19

q3w

Sorafenib400 mg BID

CPPCarboplatin AUC 6 Day 1 +

Paclitaxel 200 mg/m2 Day 1 + Placebo Days 2-19 q3w

Placebo

Scagliotti G, et al. J Clin Oncol. 2010;28:1835-1842.

Stratified by region, ECOG PS (0 vs 1), squamous vs nonsquamous, stage (IIIB wet vs IV)

Patients with stage IIIb/IV NSCLC

and no previous CHT

(N = 926)

There was no significant improvement in PFS (4.6 vs 5.4 mos; p=0.43) or OS (10.7 vs 10.6 mos; p=0.13)

Outline•Antiangiogenic agents in the first-line setting

•Bevacizumab•Recently completed randomised trials

•Multi-targeted antiangiogenic orally administered TKIs

•Vascular disrupting agents

•Antiangiogenic agents in a relapsed/refractory setting• Recently completed randomised trials

• Multi-targeted antiangiogenic orally administered TKIs

- Nindetanib- Vandetanib

• Monoclonal antibodies and decoy receptors•Vascular disrupting agents

•Other investigational agents• Ramucirumab

Nintedanib is a triple angiokinase inhibitor which targets three classes of receptors critical for the formation and maintenance of tumour blood vessels: VEGFR, PDGFR and FGFR*

Nintedanib: mechanism of action

*Hilberg F, et al. Cancer Res, June 15, 2008; 68: (12) :4774–4782

VEGFR1 / 2 / 3

PDGFR / a b

FGFR1 / 2 / 3

IC50 [nM] 34 / 21 / 13

59 / 65 69 / 37 / 108

IGF1R, InsR

EGFR, HER2, CDK1, CDK2, CDK4

IC50 [nM] >1000, <10000

>50000

NN

NH

NH

O

NCH3

O

O

O

CH3

CH3

CH3 S

O

O

OH

Nintedanib è sottoposto a sperimentazione clinica

LUME-Lung 1

M. Reck et al, the Lancet Oncology 2014;15:143-55

1:1 Randomization

Oral nintedanib* 200 mg twice daily+

Docetaxel x n cycles

Oral Placebo twice daily+

Docetaxel x n cycles

Patients with stage IIIB/IV or recurrent NSCLC (all histologies) after failure of first-line chemotherapy N=1,300

NINDETANIB MAINTENANCE**

Primary endpoint: PFSSecondary endpoints: OS; RR according to modified RECIST criteria; clinical improvement; AEs (according to

CTCAE version 3.0); changes in safety laboratory parameters; QoL

Primary Endpoint: PFS Independent Central Review in All Patients

100

80

60

40

20

0

Prob

abili

ty o

f pro

gres

sion

free

su

rviv

al (%

)

0 2 4 6 8 10 12 14 16 18Time (months)

Nintedanib + docetaxel

Placebo + docetaxel

Median, mo 3.4 2.7

HR (95% CI) 0.79 (0.68 to 0.92)

p-value 0.0019

No. at riskNintedanib 565 295 155 57 19 4 3 1 0

Placebo 569 250 116 43 21 2 1 0 0

Nintedanib + docetaxel

Placebo + docetaxel

Median, mo 4.0 2.8

HR (95% CI) 0.77 (0.62 to 0.96)

p-value 0.0193

PFSIndependent Central Review in Major Histologies

Adenocarcinoma Squamous Cell Carcinoma

100

80

60

40

20

00 2 4 6 8 10 12 14 16

Time (months)

Prob

abili

ty o

f pro

gres

sion

free

sur

viva

l (%

)

Nintedanib + docetaxel

Placebo + docetaxel

Median, mo 2.9 2.6

HR (95% CI) 0.77 (0.62 to 0.96)

p-value 0.0200

100

80

60

40

20

00 2 4 6 8 10 12 14 16

Time (months)

Prob

abili

ty o

f pro

gres

sion

free

sur

viva

l (%

)

No. at risk

Nintedanib 277 150 86 32 13 1 1 0

Placebo 285 129 70 288 12 1 1 0

No. at risk

Nintedanib 240 122 59 22 5 3 2 1 0

Placebo 247 101 36 13 8 1 0 0 0

Overall Survival Patients with Adenocarcinoma Histology

100

80

60

40

20

0

Prob

abili

ty o

f sur

viva

l (%

)

52.7%

44.7% 25.7%

19.1%

0 4 8 12 16 20 24 28 32 36Time (months)

Feb 2013, 535 events

OS AdenoT<9mo

OSAdeno

OSAll pts

Nintedanib 322 263 203 163 131 96 72 46 25 10 Placebo 336 269 184 139 101 73 55 33 15 7

No. at risk

Nintedanib + docetaxel

Placebo + docetaxel

Median, mo 12.6 10.3

HR (95% CI) 0.83 (0.70 to 0.99)

p-value 0.0359

OS: Patients with Adenocarcinoma and Time Since Start of 1st Line Therapy <9mo

100

80

60

40

20

0

Prob

abili

ty o

f sur

viva

l (%

)

0 2 4 6 8 10 12 14 16 18Time (months)

44.7%

31.2%

17.0%

8.5%

OS AdenoT<9mo

OSAdeno

OSAll pts

Feb 2013, 345 events

Nintedanib 206 167 119 92 73 51 35 16 9 3 Placebo 199 154 91 62 42 25 17 12 5 1

No. at risk

Nintedanib + docetaxel

Placebo + docetaxel

Median, mo 10.9 7.9

HR (95% CI) 0.75 (0.60 to 0.92)

p-value 0.0073

Safety in All Treated PatientsSummary of Adverse Events (AEs)

Patients with AE, n (%)Nintedanib +

docetaxel (n=652)Placebo +

docetaxel (n=655)

Any AE, all grades 610 (93.6) 609 (93.0)

Drug-related AE, all grades 498 (76.4) 446 (68.1)

Any AE, grades ≥3 465 (71.3) 421 (64.3)

Drug-related AE, grades ≥3 331 (50.8) 275 (42.0)

Any AE leading to discontinuation

148 (22.7) 142 (21.7)

Any serious AE 224 (34.4) 206 (31.5)Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used

The most common adverse events were diarrhoea (42.3% versus 21.8%) and reversible ALT and AST elevations (28.5% versus 8.4%).

Safety in All Treated PatientsMost Frequent AEs, All Grades and Grades ≥3

45

40

35

30

25

20

15

105

0

Patie

nts

(%)

Diarrhea

Fatigue

ALT incre

ased

Nausea

AST in

crease

d

Appetite decrease

d

Dyspnea

Vomiting

AlopeciaCough

Pyrexia

ALT incre

ased

Diarrhea

Fatigue

Dyspnea

AST in

crease

d

Pneumonia

Asthenia

Chest pain

Appetite decrease

d

All CTCAE grades (%)≥15% incidence

CTCAE grades ≥3 (%)≥1% incidence

Nintedanib + docetaxelPlacebo + docetaxel

Constipation

Decrease

d neutrophils

Decrease

d neutrophils

50

45

40

35

30

25

20

15

105

0

50

Safety in All Treated Patients AEs Frequently Observed with VEGF/VEGFR Inhibitors

Nintedanib + docetaxelPlacebo + docetaxel

Patie

nts

(%)

Bleeding

GI perfo

ration

Thromboembolis

m VTEATE

Hyperte

nsion

VTE, venous thromboembolism; ATE, arterial thromboembolism

All CTCAE grades (%) CTCAE grades ≥3 (%)

14.1

11.6

0.5 0.5

4.65.1

1.52.81.4

0.6 0.9

3.5

Bleeding

GI perfo

ration

Thromboembolis

m VTEATE

Hyperte

nsion

2.31.8

0.2 0.5 2.1 3.1

1.2 1.10.5 0.6

0.20.6

25

20

15

10

5

0

25

20

15

10

5

0

LUME-Lung 2•(planned n 1111 non-squamous NSCLC) nintedanib (200 mg twice daily; day 2–21) plus pemetrexed (500 mg/m2 every 21 days) vs pemetrexed alone • Recruitment was halted early (n 713 pts) based on a pre-planned futility analysis of investigator-assessed PFS by an independent data monitoring committee although no safety concerns were raised.• Subsequent analysis showed that the primary end-point of centrally reviewed PFS was met . •Nintedanib plus pemetrexed significantly improved PFS (HR 0.83, 95% CI 0.70–99; 4.4 vs 3.6 mos; p=0.04), but not OS, vs pemetrexed alone.•T he incidence of G3 hypertension, bleeding and thromboembolism was similar between treatment arms.

Hanna et al. J Clin Oncol 2013; 31: 8034.

Outline•Antiangiogenic agents in the first-line setting

•Bevacizumab•Recently completed randomised trials

•Multi-targeted antiangiogenic orally administered TKIs

•Vascular disrupting agents

•Antiangiogenic agents in a relapsed/refractory setting• Recently completed randomised trials

• Multi-targeted antiangiogenic orally administered TKIs- Nindetanib

• Monoclonal antibodies and decoy receptors•Vascular disrupting agents

•Other investigational agents• Ramucirumab

Ramucirumab (IMC-1121B)

• Ramucirumab is a fully human IgG1 monoclonal antibody that binds with high affinity to human VEGFR-2 (Kd ~ 50 pM)1

• Ramucirumab is specific for the human VEGFR-2 receptor2

• Ramucirumab potently blocks binding of VEGF-A to VEGFR-2 (IC50 = 0.8 nM)1

• Ramucirumab blocks binding of VEGF-C and VEGF-D to VEGFR-23

1. Lu et al. J Biol Chem 2003;278(44):43496-507.2. Data on file, ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company.3. Data on file, ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company.

REVEL: Study Design

Abbreviations: Bev=bevacizumab; ECOG PS=Eastern Cooperative Oncology Group performance status; ORR=objective response rate; PFS=progression-free survival; ROW=rest of the world; q3wks=every 3 weeks.

- Stage IV NSCLC after one platinum- based chemo +/- maintenance

- Prior Bev allowed- All histologies - PS 0 or 1

Treatment until disease

progression or unacceptable

toxicity

Ramucirumab 10 mg/kg +Docetaxel 75 mg/m2 q3wks

N=628

Placebo +

Docetaxel 75 mg/m2 q3wksN=625

RANDOMIZE

1:1

Stratification factors:• ECOG PS 0 vs 1• Gender • Prior maintenance• East-Asia vs. ROW

Primary endpoint: Overall Survival

Secondary endpoints:PFS, ORR, safety, patient-reported outcomes

Tumor Response by RECIST v1.1ITT Population, Investigator Assessment

RAM+DOC N=628

PL+DOC N=625

P-value

Response, n (%)

CR 3 (0.5) 2 (0.3)PR 141 (22.5) 83 (13.3)SD 258 (41.1) 244 (39.0)PD 128 (20.4) 206 (33.0)Unknown/not assessed 98 (15.6) 90 (14.4)

ORR (CR+PR), % (95% CI) 22.9 (19.7-26.4) 13.6 (11.0-16.5) <.001

DCR (CR+PR+SD), % (95% CI) 64.0 (60.1-67.8) 52.6 (48.6-56.6 ) <.001

Abbreviations: CI=confidence interval; CR=complete response; DCR=disease control rate; ITT=intention-to-treat; ORR=objective response rate; PD=progressive disease; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors; SD=stable disease.

Progression-Free SurvivalITT Population, Investigator Assessment

Median (95% CI) Censoring Rate

RAM+DOC vs PL+DOC:

4.5 (4.2-5.4) 11.1%3.0 (2.8-3.9) 6.7%

Stratified HR (95% CI) = 0.762 (0.677-0.859)Stratified log-rank P < .0001

RAM+DOCPL+DOC

Pro

gre

ssio

n-F

ree

Su

rviv

al (

%)

RAM+DOCPL+DOC

Number at risk

RAM+DOCPL+DOC

Censored

0 3 6 9 12 15 18 21 24 27 30 33

383301

204172

12095

5937

3817

119

74

33

32

00

00

36

Survival Time (months)

628625

00

0

20

40

60

80

100

Forest Plot of PFS by SubgroupsUnstratified Analysis

Favors RAM+DOC

0.3 0.6 1.0 1.6 2.7 4.5

SubgroupCategory Unstratified HRRAM+DOC, n PL+DOC, n

Geographic region ROW 585 579 0.78

Sex Male 419 415 0.79Female 209 210 0.74

<70 501 500 0.73 ECOG PS 1 420 425 0.79

0 207 199 0.74Smoking history Never 109 141 0.81

Ever 518 483 0.76Best response to platinum PD 178 182 0.71

CR/PR/SD 420 417 0.80No 475 476 0.74Prior taxaneYes 153 149 0.90No 540 533 0.77Prior bevacizumabYes 88 92 0.83No 493 482 0.79Prior maintenanceYes 135 143 0.74

Histology Squamous 157 171 0.76Nonsquamous 465 447 0.77

East Asia 43 46 0.68

Age, years 127 125 0.94 ≥70

Favors PL+DOC

Overall SurvivalITT Population

Median (95% CI) Censoring RateRAM+DOC

RAM+DOC vs PL+DOC:

10.5 (9.5-11.2) 31.8%PL+DOC 9.1 (8.4-10.0) 27.0%

Stratified HR (95% CI) = 0.857 (0.751-0.979)Stratified log-rank P = .0235

0

20

40

60

80

100

Ove

rall

Su

rviv

al (

%)

RAM+DOCPL+DOC

Number at risk

0 3 6 9 12 15 18 21 24 27 30 33

527501

415386

329306

231197

156129

10386

7056

4536

2323

119

20

36

Survival Time (months)

628625

00

RAM+DOCPL+DOC

Censored

REVEL: Conclusions

• REVEL met its primary endpoint of OS improvement.

• RAM+DOC showed statistically significant improvement in PFS and ORR compared to PL+DOC.

• OS and PFS improvement were consistent in most major subgroups, including squamous and nonsquamous histology.

• The addition of RAM to DOC did not result in an increase of SAEs and AEs leading to death. Safety profile was as expected for an anti-VEGFR agent in combination with DOC.

• REVEL is the first study showing that addition of a novel agent to standard chemotherapy improves survival in stage IV NSCLC patients with progression after platinum-based chemotherapy.

Predictive markers antiangiogenic agents

• Imaging• PET• Dynamic Contrast enhanced (DCE) MRI• Alternative RECIST criteria

• Physiologic: hypertension• Circulating endothelial cells• VEGF polymorphisms• Circulating vascular Marker

Take home messages• Why there has been such an high failure rate of

trials of antiangiogenic agents in NSCLC? - agents may not effectively combat the redundancy of angiogenic pathways. - highly heterogeneous nature of NSCLC

• Confirmed efficacy of bevacizumab in eligible patients in first-line (non-squamous, no invasion of central blood vessels, no history of gross hemoptysis, no major cardiovascular disease)

• Nindetanib and Ramucirumab might be important news in the NSCLC scenario in the second line setting

• Currently no predictive biomarkers available