1. Medical Oncology Department University Hospital Perugia, Italy
Targeting angiogenesis in Lung cancer
Lucio Crinò, MD
Medical Oncology Department
University Hospital Perugia, Italy

2. VEGF: Targeted Approaches
Vandetanib
Sorafenib
Nindetanib
Ramucirumab
Bevacizumab
Aflibercept
Antireceptor
blocking
antibodies
Tyrosine kinase inhibitors
Antiligand
blocking
Antibodies
and VEGF-TRAP
Adapted from Noonberg SB, et al. Drugs. 2000;59:

3. 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

4. Phase III Trials of Bevacizumab combined with P-based CT in NSCLC
E4599 (US)
CP (n=444)
PD*
Previously untreated stage IIIB/IV
non-squamous NSCLC (n=878)
Bevacizumab 15mg/kg† + CP (n=434)
Bevacizumab PD
Bevacizumab
7.5mg/kg† + CG (n=345)
Bevacizumab
AVAiL (Ex-US) PD
Previously untreated, stage IIIB, IV or recurrent non-squamous NSCLC (n=1.043)
Placebo + CG (n=347)
PD*
Bevacizumab
15mg/kg† + CG (n=351)
Bevacizumab PD
*No cross over permitted; †Dose of Avastin every 3 weeks NSCLC = non-small cell lung cancer
CP = carboplatin/paclitaxel; PD = progressive disease CG = cisplatin/gemcitabine

5. E4599: Improvement in OS HR=0.79 (0.67–0.92); P = 0.003 10.3 12.3 1.0
Months
Survival (%)
12 months
24 months
CP + bevacizumab 51 23 CP 44 15
1.0
0.8
0.6
0.4
0.2
Probability
10.3
12.3
Sandler A et al. New Engl J Med 2006;355:2542–2550 5 5

6. AVAiL: Bevacizumab significantly prolongs PFS (primary endpoint)
1.0
0.8
0.6
0.4
0.2
Placebo + CG
Bev 7.5mg/kg + CG
Bev 15mg/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
Probability of PFS
No. at risk
Time (months)
Placebo + CG
Bev 7.5mg/kg + CG
Bev 15mg/kg + CG
Reck M JCO 2009; 6 6

7. AVAiL: no significant benefit in OS* (secondary endpoint)
Placebo + CG
Bev 7.5mg/kg + CG
Bev 15mg/kg + CG
1.0
0.8
0.6
0.4
0.2
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
Probability of OS
Time (months)
Placebo + CG
Bev 7.5mg/kg + CG
No. at risk
Bev 15mg/kg + CG
Reck M, Ann Oncol 2010;21: 7

8. Meta-analysis of OS Meta-analysis of PFS
Soriat JC et al. Ann Oncol Jan;24(1):20-30.

9. …roughly 4000 “real life” pts !!
Two phase IV studies investigated the safety of the combination of bevacizumab and chemotherapy as first-line
…roughly 4000 “real life” pts !!
Crino L, et al. Lancet Oncol.11(8),733–740 (2010).
Wozniak AJ, et al .J. Clin. Oncol.28(7s), (2010)

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

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

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

13. Outline Other investigational agents
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

14. VEGFR-TKIs in Development in NSCLC
Vandetanib
EGFR/VEGFR/RET-TKI
Phase III
First line/refractory
Sorafenib
VEGFR-TKI
Sunitinib
Refractory
Cediranib
First line
Motesanib
Nindetanib
Pazopanib
Maintenance/refractory
Linifanib
Phase II
Axitinib
Tivozanib
ClinicalTrials.gov.

15. Reported Potencies of Selected Molecules Targeting VEGFRs
1,000
VEGFR-1
Less potent
VEGFR-2
VEGFR-3
100 10
More
potent 1
Motesanib (AMG-706)
Sunitinib
ABT-869
Pazopanib
Sorafenib
Vatalanib (PTK787)
Vandetanib (ZD6474)
Cediranib
(AZD-2171)
Axitinib (AG13736)
0.1
Tivozanib
(AV-951)
Chow, JCO 2007
Eskens, Proceedings of the 99th Annual Meeting of the AACR 2008

16. ESCAPE: Phase III Trial of Carboplatin and Paclitaxel ± Sorafenib
Stratified by region, ECOG PS (0 vs 1), squamous vs nonsquamous, stage (IIIB wet vs IV)
CPS Carboplatin AUC 6 Day 1 + Paclitaxel 200 mg/m2 Day 1 + Sorafenib 400 mg BID Days 2-19 q3w
Sorafenib 400 mg BID
Patients with stage IIIb/IV NSCLC and no previous CHT
(N = 926)
CPP Carboplatin AUC 6 Day 1 + Paclitaxel 200 mg/m2 Day 1 + Placebo Days 2-19 q3w
Placebo
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)
Scagliotti G, et al. J Clin Oncol. 2010;28:

17. Outline Other investigational agents
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

18. Nintedanib: mechanism of action
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*
VEGFR
1 / 2 / 3
PDGFR
a / b
FGFR
IC50 [nM]
34 / 21 / 13
59 / 65
69 / 37 / 108
IGF1R, InsR
EGFR, HER2, CDK1, CDK2, CDK4
IC50 [nM]
>1000, <10000
>50000
Nintedanib è sottoposto a sperimentazione clinica
*Hilberg F, et al. Cancer Res, June 15, 2008; 68: (12) :4774–4782

19. Oral nintedanib* 200 mg twice daily Oral Placebo twice daily
LUME-Lung 1
Patients with stage IIIB/IV or recurrent NSCLC (all histologies) after failure of first-line chemotherapy
N=1,300
1:1 Randomization
Oral nintedanib* 200 mg twice daily +
Docetaxel x n cycles
Oral Placebo twice daily +
Docetaxel x n cycles
NINDETANIB MAINTENANCE**
Primary endpoint: PFS
Secondary endpoints: OS; RR according to modified RECIST criteria; clinical improvement; AEs (according to CTCAE version 3.0); changes in safety laboratory parameters; QoL
M. Reck et al, the Lancet Oncology 2014;15:143-55

20. Primary Endpoint: PFS Independent Central Review in All Patients
100
Nintedanib + docetaxel
Placebo + docetaxel
Median, mo
3.4
2.7
HR (95% CI)
0.79 (0.68 to 0.92)
p-value
0.0019 80 60
Probability of progression free survival (%) 40 20
Time (months)
No. at risk
Nintedanib
Placebo

21. PFS Independent Central Review in Major Histologies
Adenocarcinoma
Squamous Cell Carcinoma
100
100
Nintedanib + docetaxel
Placebo + docetaxel
Median, mo
4.0
2.8
HR (95% CI)
0.77 (0.62 to 0.96)
p-value
0.0193
Nintedanib + docetaxel
Placebo + docetaxel
Median, mo
2.9
2.6
HR (95% CI)
0.77 (0.62 to 0.96)
p-value
0.0200 80 80 60 60
Probability of progression free survival (%)
Probability of progression free survival (%) 40 40 20 20
Time (months)
Time (months)
No. at risk
Nintedanib
Placebo
No. at risk
Nintedanib
Placebo

22. Overall Survival Patients with Adenocarcinoma Histology
100
Nintedanib + docetaxel
Placebo + docetaxel
Median, mo
12.6
10.3
HR (95% CI)
0.83 (0.70 to 0.99)
p-value
0.0359 80 60
52.7%
Feb 2013, 535 events
Probability of survival (%) 40
25.7%
44.7% 20
19.1%
Time (months)
No. at risk
Nintedanib
322
263
203
163
131 96 72 46 25 10
Placebo
336
269
184
139
101 73 55 33 15 7
OS Adeno T<9mo
OS Adeno
OS All pts

23. Nintedanib + docetaxel Probability of survival (%)
OS: Patients with Adenocarcinoma and Time Since Start of 1st Line Therapy <9mo
100
Nintedanib + docetaxel
Placebo + docetaxel
Median, mo
10.9
7.9
HR (95% CI)
0.75 (0.60 to 0.92)
p-value
0.0073 80 60
Feb 2013, 345 events
Probability of survival (%)
44.7% 40
17.0% 20
31.2%
8.5%
Time (months)
No. at risk
Nintedanib
206
167
119 92 73 51 35 16 9 3
Placebo
199
154 91 62 42 25 17 12 5 1
OS Adeno T<9mo
OS Adeno
OS All pts

24. Safety in All Treated Patients Summary 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%).

25. All CTCAE grades (%) ≥15% incidence CTCAE grades ≥3 (%) ≥1% incidence
Safety in All Treated Patients Most Frequent AEs, All Grades and Grades ≥3
All CTCAE grades (%) ≥15% incidence
CTCAE grades ≥3 (%) ≥1% incidence 50 50 45 45
Nintedanib + docetaxel
Placebo + docetaxel 40 40 35 35 30 30
Patients (%) 25 25 20 20 15 15 10 10 5 5
Diarrhea
Fatigue
Nausea
Dyspnea
Cough
Vomiting
Alopecia
Pyrexia
Diarrhea
Fatigue
Dyspnea
Asthenia
Constipation
Pneumonia
Chest pain
ALT increased
AST increased
ALT increased
AST increased
Appetite decreased
Appetite decreased
Decreased neutrophils
Decreased neutrophils

26. Safety in All Treated Patients AEs Frequently Observed with VEGF/VEGFR Inhibitors
All CTCAE grades (%)
CTCAE grades ≥3 (%) 25 25
Nintedanib + docetaxel
Placebo + docetaxel 20 20 15
14.1 15
11.6
Patients (%) 10 10
5.1 5
4.6
3.5 5
2.8
3.1
2.3
2.1
1.5
1.4
1.8
0.5
0.5
0.6
0.9
0.5
1.2
1.1
0.2
0.5
0.6
0.6
0.2
VTE
ATE
VTE
ATE
Bleeding
Bleeding
GI perforation
Hypertension
GI perforation
Hypertension
Thromboembolism
Thromboembolism
VTE, venous thromboembolism; ATE, arterial thromboembolism

27. 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.

28. Outline Other investigational agents Ramucirumab
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

29. Ramucirumab (IMC-1121B)
Ramucirumab is a fully human IgG1 monoclonal antibody that binds with high affinity to human VEGFR (Kd ~ 50 pM)1
Ramucirumab is specific for the human VEGFR-2 receptor2
Ramucirumab potently blocks binding of VEGF-A to VEGFR (IC50 = nM)1
Ramucirumab blocks binding of VEGF-C and VEGF-D to VEGFR-23
Lu et al. J Biol Chem 2003;278(44):
Data on file, ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company.

30. Treatment until disease progression or unacceptable toxicity
REVEL: Study Design
1:1 R A N D O M I Z E
Ramucirumab 10 mg/kg +
Docetaxel 75 mg/m2 q3wks
N=628
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
Placebo +
Docetaxel 75 mg/m2 q3wks
N=625
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
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.

31. Tumor Response by RECIST v1.1 ITT 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 ( )
13.6 ( )
<.001
DCR (CR+PR+SD), % (95% CI)
64.0 ( )
52.6 ( )
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.

32. Progression-Free Survival ITT Population, Investigator Assessment
RAM+DOC
PL+DOC
Number at risk
Censored 3 6 9 12 15 18 21 24 27 30 33
383
301
204
172
120 95 59 37 38 17 11 7 4 2 36
Survival Time (months)
628
625 20 40 60 80
100
Median (95% CI)
Censoring Rate
RAM+DOC vs PL+DOC:
4.5 ( )
11.1%
3.0 ( )
6.7%
Stratified HR (95% CI) = ( )
Stratified log-rank P < .0001
RAM+DOC
PL+DOC

33. Forest Plot of PFS by Subgroups Unstratified Analysis
Category
Subgroup
RAM+DOC, n
PL+DOC, n
Unstratified HR
Geographic region
ROW
585
579
0.78
East Asia 43 46
0.68
Sex
Male
419
415
0.79
Female
209
210
0.74
Age, years
127
125
0.94
≥70
<70
501
500
0.73
ECOG PS 1
420
425
0.79
207
199
0.74
Smoking history
Never
109
141
0.81
Ever
518
483
0.76
Best response to platinum PD
178
182
0.71
CR/PR/SD
420
417
0.80 No
475
476
0.74
Prior taxane
Yes
153
149
0.90 No
540
533
0.77
Prior bevacizumab
Yes 88 92
0.83 No
493
482
0.79
Prior maintenance
Yes
135
143
0.74
Histology
Squamous
157
171
0.76
Nonsquamous
465
447
0.77
0.3
0.6
1.0
1.6
2.7
4.5
Favors RAM+DOC
Favors PL+DOC

34. Overall Survival ITT Population20 40 60 80
100
Overall Survival (%)
RAM+DOC
PL+DOC
Number at risk 3 6 9 12 15 18 21 24 27 30 33
527
501
415
386
329
306
231
197
156
129
103 86 70 56 45 36 23 11 2
Survival Time (months)
628
625
Censored
Median (95% CI)
Censoring Rate
RAM+DOC
RAM+DOC vs PL+DOC:
10.5 ( )
31.8%
PL+DOC
9.1 ( )
27.0%
Stratified HR (95% CI) = ( )
Stratified log-rank P = .0235

35. 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.

36. Predictive markers antiangiogenic agents
Imaging
PET
Dynamic Contrast enhanced (DCE) MRI
Alternative RECIST criteria
Physiologic: hypertension
Circulating endothelial cells
VEGF polymorphisms
Circulating vascular Marker

37. 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