1. Vecchi e nuovi antiangiogenetici
Cesare Gridelli
Division of Medical Oncology “S.G. Moscati” Hospital – Avellino (Italy)

2. Proangiogenic Ligands and their Receptors
Jubb AM & Harris AL. Lancet Oncol 2010;11:1172–83.

3. First-Line Treatment of A-NSCLC
EGFR-mutation
ALK analysis
Non-squamous cell carcinoma
Metastatic NSCLC, PS 0-2
Squamous cell carcinoma
EGFR mutation (del 19 or L858R in exon 21)
EGFR wild type (or not done)
EGFR-TKI
Radiotherapy
CNS
Central airways
Bone
Soft tissue
Platinum plus
Pemetrexed or gemcitabine or taxanes or vinorelbine OR
Platinum combination plus
Bevacizumab* (PS 0,1)
Elderly/PS 2
Platinum combination (preferred in fit elderly) or
Monotherapy (preferred in unfit elderly)
Gemcitabine or taxane or vinorelbine 3
ALK positive 2
Crizotinib 1 2

4. First-Line Treatment of Advanced NSCLC
Adenocarcinoma
Large cells
NSCLC NOS
Squamous cell carcinoma
EGFR mutation and ALK negative
EGFR mutation positive
ALK positive
PS 0-1
PS 2
PS 3-4
Gefitinib Erlotinib
Afatinib
Crizotinib
Doublet chemotherapy (category 1) OR
Cetuximab/vinorelbine/ cisplatin (category 2B)
Chemotherapy
Best supportive care
Bevacizumab + chemotherapy (if criteria met)
Cisplatin/pemetrexed (category 1) (if criteria met)
Cetuximab/vinorelbine/cisplatin (category 2B)
Best supportive care only

5. Proangiogenic Ligands and their Receptors
Bevacizumab
Bevacizumab
Jubb AM & Harris AL. Lancet Oncol 2010;11:1172–83.

6. Overall Survival, % Month
100
Hazard ratio, 0.79; P=0.003 80
BPC group (305 events in 417 patients) 60
Overall Survival, % 40
PC group (344 events in 433 patients) 20 6 12 18 24 30 36 42
Month
BPC, bevacizumab-paclitaxel-carboplatin; PC, paclitaxel-carboplatin. The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab versus 10.3 months in the chemotherapy-alone group. Sandler A, et al. N Engl J Med. 2006;355(24):

7. Duration of OS (months)
0.8
0.6
0.4
0.2
Avastin-based therapy (n=602)
extends OS to 14.2 months
31% reduction in the risk of death (HR=0.69)
Avastin + CP (n=300)
CP (n=302)
Probability of OS
10.3
14.2
Duration of OS (months) 7

8. Antiangiogenic Drugs as Chemosensitizing Agents
Recently, in Cancer Cell an artcile suggest that a subset of chemotherapeutic agents (such as paclitaxel) induce CEP mobilisation and act like VDA agent whereas other agent such as gemcitabine do not present this effect. This VDA propertie of chemotherapy could explain the clinical benefit to adding anti-VEGF-VEGFR therapies with chemotherapy.
Paclitaxel induces rapid chemotherapy-induced acute endothelial progenitor cell mobilization (CEP), indicating synergy with bevacizumab.
Gemcitabine does not induce CEP.
Shaked Y et al, Cancer Cell 14, , 2008

9. Does the Chemo Partner Make a Difference
Does the Chemo Partner Make a Difference?: Taxane Versus Non-Taxane Regimens
N=29 studies
N=5890 pts.
Median OS:
14.4 vs m,
P=0.5
Behera et al,
J Thorac Oncol, 2015

10. First-Line Treatment of Advanced NSCLC
Adenocarcinoma
Large cells
NSCLC NOS
Squamous cell carcinoma
EGFR mutation and ALK negative
EGFR mutation positive
ALK positive
PS 0-1
PS 2
PS 3-4
Gefitinib Erlotinib
Afatinib
Crizotinib
Doublet chemotherapy (category 1) OR
Cetuximab/vinorelbine/ cisplatin (category 2B)
Chemotherapy
Best supportive care
Bevacizumab + chemotherapy (if criteria met)
Cisplatin/pemetrexed (category 1) (if criteria met)
Cetuximab/vinorelbine/cisplatin (category 2B)
Best supportive care only

11. Presented By Terufumi Kato at 2014 ASCO Annual Meeting
Study design
Presented By Terufumi Kato at 2014 ASCO Annual Meeting

12. Primary endpoint: PFS by independent review
Presented By Terufumi Kato at 2014 ASCO Annual Meeting

13. BEVERLY : STUDY DESIGN R Control arm
Erlotinib 150 mg orally once daily
Experimental arm
Bevacizumab 15 mg/kg iv every 21 days
NSCLC
Non-squamous Activating EGFR mutation Stadio IIIB o IV
PS 0-2 R
1:1
Treatment in both arms will be given until disease progression or unacceptable toxicity or patient’s or physician’s motivated decision to stop
Strata:
PS (0-1 vs 2)
Type of mutation (exon19 del vs 21 L858R mut vs others)
Primary endpoints: investigator-assessed and blinded, indipendent centrally-reviewed PFS
Sample size: 200 pts
Centres involved: about 60
PI: C. GRIDELLI

14. treated with platinum-
AvaALL: Trial design
Global trial conducted in ~20 countries
Enroll
Primary endpoint: OS
PD1
SOC2* + bevacizumab
SOC3† + bevacizumab
SOC4 ± bevacizumab
SOC2*
SOC3†
SOC4
PD3
Randomize 1:1
PD2
Stage IIIB/IV
non-squamous NSCLC
treated with platinum-
doublet (4-6 cycles)
+ bevacizumab PLUS
> 2 cycles of
bevacizumab
maintenance
N=500
* SOC2: Labelled agents for 2nd-line treatment of NSCLC (erlotinib, pemetrexed and docetaxel)
† SOC3 and beyond: Choice of labelled agents in 3rd-line and beyond is the Investigator’s choice
PI: C. Gridelli

15. Proangiogenic Ligands and their Receptors
Ramucirumab
Bevacizumab
VEGFR TKI
Bevacizumab
Jubb AM & Harris AL. Lancet Oncol 2010;11:1172–83.

16. 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
No major blood vessel invasion, or cavitation
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
Pérol, ASCO 2014; Garon, Lancet 2014

17. 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
Pérol, ASCO 2014; Garon, Lancet 2014

18. Survival Time (months) Survival Time (months)
OS by Histology
Nonsquamous OS
Squamous OS
Stratified HR (95% CI) = 0.84 ( )
RAM+DOC
PL+DOC
11.1 ( )
9.7 ( )
35.5%
29.3%
Median (95% CI)
Censoring
Rate
vs PL+DOC
Stratified HR (95% CI) = 0.89 ( )
RAM+DOC
PL+DOC
9.5 ( )
8.2 ( )
21.7%
19.9%
Median (95% CI)
Censoring
Rate
vs PL+DOC 3 6 9 12 15 18 21 24 27 30 33 36
100 80 60
Overall Survival (%) 40 20
Survival Time (months)
465
447
RAM+DOC
PL+DOC
Number at risk
401
362
311
282
251
226
182
144
125 94 64 54 39 10 5 1
Censored
RAM+DOC
PL+DOC
Censored
100 80 60
Overall Survival (%) 40 20 3 6 9 12 15
Survival Time (months) 18 21 24 27 30 33 36
157
171
Number at risk
124
132
103 99 78 75 49 48 31 23 16 14 8 2 5 1 4
Pérol, ASCO 2014; Garon, Lancet 2014

19. Presented By Maurice Perol at 2014 ASCO Annual Meeting
Selected Treatment-Emergent Adverse Events Occurring in ≥20% of Patients or ≥5% Higher in the RAM+DOC Arm
Presented By Maurice Perol at 2014 ASCO Annual Meeting

21. Proangiogenic Ligands and their Receptors
Ramucirumab
Bevacizumab
Nindetanib
PDGFR TKI
FGFR TKI
VEGFR TKI
Nindetanib
Bevacizumab
Nindetanib
Jubb AM & Harris AL. Lancet Oncol 2010;11:1172–83.

22. LUME-Lung 1: Randomised Phase III Study
Nintedanib 200 mg BID po, Days 2–21 + docetaxel 75 mg/m2 IV, Day 1, 21-day cycles (n=655)
Placebo BID po, Days 2–21, + docetaxel 75 mg/m2 IV, Day 1, 21-day cycles (n=659)
N=1314
RANDOMISE
1:1 PD
Number of docetaxel cycles not restricted
Monotherapy allowed after ≥4 cycles of combination therapy
Stage IIIB/IV*
or recurrent NSCLC patients after first-line chemotherapy
(all histologies)
The LUME-Lung 1 trial was a global randomised controlled Phase III trial
Patients with Stage IIIB/IV or recurrent NSCLC (all histologies) who had failed prior first-line chemotherapy were recruited to the study
In total, 1773 patients were recruited and 1314 patients were subsequently randomised to treatment:
Nintedanib + docetaxel: nintedanib 200 mg twice daily orally + docetaxel 75 mg/m2 by intravenous infusion on Day 1
Placebo + docetaxel: oral placebo + docetaxel 75 mg/m2 by intravenous infusion on Day 1. Oral placebo tablet was given in order to maintain blinding of the trial patients and the treating physicians to treatment
The number of docetaxel cycles was not restricted, and patients were able to continue monotherapy with either nintedanib/placebo or docetaxel after they had received 4 cycles of combination therapy; patients could receive any treatment until progression (combination therapy or either of the agents as monotherapy)
The primary endpoint and key secondary endpoints are shown
Additional notes:
Docetaxel was administered every 3 weeks until unacceptable AEs or disease progression
Nintedanib 100 mg or placebo capsules (×2) were taken each morning and evening after a meal (Boehringer Ingelheim, data on file)
Prior to randomisation, patients were stratified by ECOG PS (0 vs 1), previous bevacizumab treatment (yes vs no), histology (squamous vs non-squamous), and presence of brain metastases (yes vs no)
The study was conducted at 211 centres in 27 countries (23 European countries, plus China, South Korea, India and South Africa)
Patients were enrolled into the study between 23 December 2008 and 9 February 2011
Primary Endpoint: PFS by independent central review
Key Secondary Endpoint: OS, prespecified hierarchical analyses of patients with adenocarcinoma who progressed in <9 months after start of first-line therapy, all patients with adenocarcinoma, and ITT population
Stratification: ECOG PS (0 vs. 1) Prior bevacizumab (yes vs. no) Histology (squamous vs. non-squamous) Brain metastases (yes vs. no)
Regions: Europe/Asia/South Africa
Accrual: 23 Dec 2008 to 09 Feb 2011
Reck M, et al. Lancet Oncol. 2014;15:

23. All histology

25. Grade ≥3 AEs in Patients with Adenocarcinoma*
Lume Lung 1: Grade ≥3 AEs
Grade ≥3 AEs in Patients with Adenocarcinoma*
In patients with adenocarcinoma histology, the most frequently observed AEs of grade ≥3 that occurred in more than twice as many patients in the nintedanib + docetaxel arm than the placebo + docetaxel arm were liver enzyme elevations (ALT and AST increase) and asthenia; grade ≥3 diarrhoea was also more common with nintedanib + docetaxel than with placebo + docetaxel
The rate of haematological grade ≥3 AEs was not increased by the addition of nintedanib to docetaxel
Boehringer Ingelheim data on file:
Rate of asthenia
Reck M, et al. Lancet Oncol. 2014;15:

26. Approved by EMA on November 21, 2014
VARGATEF® (nintedanib) is indicated
in combination with docetaxel
for the treatment of adult patients with
locally advanced, metastatic or locally recurrent non small cell lung cancer (NSCLC) of adenocarcinoma tumour histology
after first-line chemotherapy
On November 21, 2014, the European Commission granted approval to Vargatef® (nintedanib) in combination with docetaxel for use in adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy.
This approval was based on the data from LUME-Lung 1 Phase III trial.

27. LUME-Columbus Phase III Study: 2-line NSCLC
Key inclusion criteria
Stage IIIB/IV NSCLC of adenocarcinoma histology
1 prior treatment line
≥1 measurable target lesion
ECOG PS 0 or 1
EGFR-mutation negative
Alk translocation negative
Key exclusion criteria
Prior VEGFR inhibitors (except bevacizumab) or docetaxel
Active brain metastases
RANDOM
I ZE
Nintedanib: 200 mg BID + Docetaxel * PD 1
* 75 mg/m2 IV, on Day 1 of every 3-week cycle - No restriction of number of courses 1
Placebo: 200 mg BID + Docetaxel * PD
N = 800
Stratification
Time since start 1st line (<9mo vs. ≥9mo)
ECOG PS (0 vs. 1)
Co- Primary Endpoints: OS and PFS (by independent review; 6 weeks CT-schedule)
Secondary Endpoints: OR, DC, HRQOL
Study Start Date:
September 2014
Accrual
Completed
Estimated Primary Completion Date:
July 2015 (Final data collection date for primary outcome measure)

28. Chairmen
F. de Marinis
C. Gridelli
Panelists
F. Ciardiello
L. Crinò
J.Y. Douillard
F. Griesinger
D. Lambrechts
M. Perol
S. Ramalingam
E. Smit

29. Which selection criteria for antiangiogenetic treatment?
Non-squamous
PS 0-1
No serious cardio-vascular comorbidities
No cavitation
No major vessel invasion
No previous hemoptysis
No recent thromboembolic disease or hemorrhage
No severe or uncontrolled hypertension
No recent major surgery (< 4 weeks)
No recent thoracic radiation, including the mediastinum

30. Any predictive biomarker for antiangiogenetic treatment ?
So far, no biomarker for NSCLC patient selection (as well as other cancers) has been validated for clinical practice.

31. Advanced NSCLC: Old Algorythm (just yesterday) for Second- and Third-line therapy
1 ° Progression of disease
Squamous
NOS
Nonsquamous
EGFR WT/UNK
EGFR mutated
EGFR mutated
EGFR WT/UNK
ALK Negative/UKN
ALK
positive
Gefitinib or Erlotinib
Crizotinib
Docetaxel or
Erlotinib
Pemetrexed or Docetaxel or
Erlotinib
2° Progression of disease
Erlotinib (if not previously administered)

32. NEW TREATMENT ALGORITHM IN ADVANCED SQUAMOUS NSCLC
Platin +
GEM/TXT/TAX/VNR
Squamous
1st Line
Nivolumab
2nd Line
Pembrolizumab
(PD-L1 > 50%)
Docetaxel ±
Ramucirumab
3rd Line
Afatinib > Erlotinib
4rd Line

33. NEW TREATMENT ALGORITHM IN ADVANCED NON SQUAMOUS NSCLC
Non Sq WT
P/Pem
P-based CTx + BEVA
1st Line
Pem Maintenance
BEVA until PD
Nivolumab
Pembrolizumab
PD-L1 >50%
2nd Line
Docetaxel ± Nindetanib
Docetaxel ± Ramucirumab
3rd Line
Erlotinib
Pemetrexed
4rd Line
Erlotinib
5rd Line

34. Consensus for clinical research
Issue
Priority
Identification, validation and clinical performance of biomarkers
High
How incorporate immunotherapy and antiangiogenic treatment in the overall strategy
Efficacy of the combination of antiangiogenic drugs and TKI for EGFR and other mutation NSCLC
Efficacy of Ramucirumab for 1° line squamous NSCLC (including maintainance)
Efficacy of Bevacizumab beyond progression
Medium
Efficacy of new antiangiogenic drugs plus Docetaxel after immunotherapy
Develop rationale combinations among antiangiogenic drugs
Optimize dose, schedule and timing of antiangiogenic drugs