1) Bevacizumab is an anti-angiogenic drug that has shown efficacy in improving progression-free survival and overall survival when added to chemotherapy for first-line treatment of non-squamous non-small cell lung cancer based on results from phase 3 trials. 2) The IMpower150 trial found that adding atezolizumab, an immune checkpoint inhibitor, to bevacizumab and chemotherapy further improved progression-free and overall survival compared to bevacizumab and chemotherapy alone in previously untreated non-squamous non-small cell lung cancer. 3) The NEJ026 trial found that adding bevacizumab to erlotinib, an EGFR tyrosine kinase inhibitor, significantly improved

1. Roleof Bevacizumabin Lung
Cancer

2. Estimated Incidence, Mortality and Prevalence in
2018
Incidence Deaths 5 year prevalence
World 20 93 876 17 61 007 21 29 964
India 67 795 63 475 65 805

3. No. 1 cancer across the world in
terms of incidence and death.
4th most common cancer in India in
terms of incidence.
3rd most common cancer causing death in
India.

4. Lung
cancer
Non Small
cell (85-
90%)
Squamous
cell
carcinoma
Non Squamous
cell
carcinoma
Large
cell
carcino
ma
Adenocarcino
ma
Small Cell (10-
15%)
Lung Cancer Types

5. NSCLC Histologies: Distribution by Percentages
50
%
10
%
30
%
10
% Adenocarcinoma
Large Cell Carcinoma
Squamous Cell Carcinoma
Other

6. RISK FACTORS FOR LUNG CANCER

7. ACTIVE SMOKING & PASSIVE SMOKING
BOTH ARE RISK FOR LUNG CANCER

8. GENETICS
OF
NSCLC

12. Diagnosi
s
• Physical Examination
• Chest Exam/X-Ray
• CT, PET Scan, MRI
• Sputum Cytology
• Bronchoscopy
• Biopsy

13. T R E A T M E N T

14. Chem
o-
therap
y
Targete
d
therapy
Radiatio
n
Therap
y
Surge
ry
Immun
o-
therap
y
TREATMENT

15. Chemotherapy
Common drugs for NSCLC:
• Cisplatin
• Carboplatin
• Paclitaxel
• Abraxane
• Docetaxel
• Gemcetabine
• Irinotecan
• Etopside
• Vinblastine
• Pemetrexed
 Combination of 2 drugs – preferred
 3 drugs- more side effects- not too much
benefit

16. Therapeutic plateau reached with chemotherapyin
NS
CLC
Platinum doublets:
8–10 months2
Best supportive care:
2–5 months4
Cisplatin/pemetrexed:
11 months1
6 8 10 12 14
Median OS (months)
1. Scagliotti Oncologist 2009; 2. Schiller NEJM 2002
3. Bunn Clin Cancer Res 1998; 4. Ganz Cancer 1989
0 2 4
1970
s
1990
s
2000
s
1980
s
Single-agent platinum:
6–8 months3

17. Bevacizumabin treatment oflung cancer
• Two positive phase III trials in the first-line setting
• E4599: Significant ORR, PFS and OS benefits: Bevacizumab combined with
paclitaxel
+ carboplatin vs chemotherapy alone1
• AVAiL: Significant ORR and PFS benefits:
Bevacizumab combined with cisplatin + gemcitabine vs chemotherapy alone2
• Efficacy findings substantiated in:
• SAiL, a large non-randomised observational study3
• ARIES, a registry study4

18. • Primary endpoint: OS
• Secondary endpoints: ORR,
PFS
Previous
ly
untreate
d
stage IIIB/IV
non-
squamous
NSCLC
(n=878)
Bevacizuma
b
15 mg/kg
q3w
+ carboplatin
+ paclitaxel
(n=434)
Carboplatin
+
paclitaxela
(n=444)
R
E4599:first line bevacizumabinNSCLC
6 cycles
Sandler NEJM 2006
Bevacizuma
b 15 mg/kg
q3w
Treat
to
PD
aNo crossover to bevacizumab permitted

19. E4599: S
ignificantlyimproved OS (primary
endpoint)
0 6 12 18 30 36 42 48
10.3 12.
3
O
S
Carboplatin
+
paclitaxel
(n=433)
Bevacizuma
b +
carboplatin
+ paclitaxel
(n=417)
10.
3
Median
(months) HR
(95% CI)
1-year rate,
%
4
4
12.3
0.79 (0.67–
0.92)
p=0.003
5
1
24
OS
(months)
Estimated
probability 1.0
0.8
0.6
0.4
0.2
0.0
Sandler NEJM 2006

20. E4599:Significantly improvedPFS
12
PFS (months)
0 6 18 24 30
PFS
Carboplatin +
paclitaxel
(n=433)
Bevacizumab
+ carboplatin +
paclitaxel
(n=417)
Median, months
HR (95% CI)
4.5 6.2
0.66 (0.57–0.77)
p<0.001
4.5 6.
2
Estimated
probability
1.0
0.8
0.6
0.4
0.2
0
Sandler NEJM 2006

21. E4599:Significantly improvedORRa
aPatients with measurable disease at baseline
Carboplatin +
paclitaxel (n=392)
Bevacizumab
+ carboplatin +
paclitaxel (n=381)
Patients
(%)
15%
35%
0
10
20
30
40 p<0.001
Sandler NEJM 2006

22. 10.3 14.
2
Sandler J Thorac Oncol
O
S
Carboplatin
+
paclitaxel
(n=302)
carboplatin
+
paclitaxel
(n=300)
10.
3
Median,
months HR
(95% CI)
14.
2
0.69 (0.58–0.83)
0 6 12 18 24
OS
(months)
1.0
Bevacizumab +
30 36 42 48
Estimated
probability
0.8
0.6
0.4
0.2
0
E4599:Pronounced OSbenefit in patientswith
adenocarcinoma (Subgroup analysis)

23. Median OS-13
months

24. SAiL(MO19390): Bevacizumabin NSCLCin routine
oncology practice
• Primary endpoint: Safety
• Secondary endpoints: TTP, OS, safety in patients developing CNS
metastases
Previously
untreated
stage IIIB/IV
or recurrent
non-
squamous
NSCLC
(n=2212)
Bevacizuma
b
7.5 or 15
mg/kg q3w +
standard
chemotherap
y
Treat to
PD
Bevacizumab
7.5 or 15
mg/kg
q3w
a
6 cycles
aPatients with CR, PR or SD Crinó Lancet Oncol 2010

25. SAiL:OSin routine oncology practiceconsistent
with phaseIIIdata
14.6
(95% CI 13.8–
15.3)
15 20
OS (months)
0 5 10 25 30 35
Estimated
probability
1.0
0.8
0.6
0.4
0.2
0
Crinó Lancet Oncol 2010

27. SAiL:consistent efficacy benefit in Asianpatients
(n=314) and overall population(n=2,212)
1.00
0.75
0.50
0.25
0
TTP
estimate
0 6 12 18 24 30 36
Time (months)
Asian
1
Overall
2
Median
TTP
(months)
95% CI
8.3
7.7–8.8
7.8
7.5–8.1
Censored patients:
23.2%
1. Tsai, et al. JTO 2011; 2. Crinò, et al. Lancet
Asian
1
Overall
2
Median
OS
(months)
95% CI
18.9
17.4–
20.7
14.6
13.8–
15.3
1.00
0.75
0.50
0.25
0
OS
estimate
Censored patients:
48.4%
SAiL Asian
population Overall
SAiL population
0 6 12 18 24 30 36
Time (months)

28. • Primary endpoint: PFS
• Secondary endpoints: ORR, OS, duration of
response
Previous
ly
untreate
d
stage IIIB/IV
non-
squamous
NSCLC
(n=276)
Bevacizuma
b
15 mg/kg
q3w
+ carboplatin
+ paclitaxel
(n=138)
Carboplatin
+
paclitaxel
(n=138)
R
6 cycles
Zhou C, et al. JCO 2015
Bevacizuma
b 15 mg/kg
q3w
Treat
to
PD
BEYOND:First line bevacizumabin NSCLCin
Chinesepatients

29. Zhou C, et al. JCO 2015
BEYOND:ConsistentPFS
Median PFS: 9.2 vs
6.5 months, HR-
0.40, p<0.001

30. Zhou C, et al. JCO 2015
BEYOND:Longer than previously reported OS
Median OS: 24.3 vs 17.7
months, HR-0.68,
p=0.0154

32. PhaseIII NEJ026:Erlotinib ± Bevacizumabin EGFR-
Mutated AdvancedNSCLC
• Primary endpoint: PFS
• Secondary endpoints: OS, tumor response,
DoR, QoL, safety
Furuya N, et al. ASCO 2018. Abstract
9006.
Erlotinib 150 mg QD +
Bevacizumab 15 mg/kg
Q3W (n = 112)
Erlotinib 150 mg
QD (n = 112)

33. NEJ026:PFSby Investigator Assessment
10
0
8
0
6
0
4
0
2
0
PFS
Probability Erlotinib +
bevacizumab
Erlotinib
The interim analysis: 128
events
Median PFS,
Mos
16.
6
12.
4
HR: 0.563 (95% CI: 0.394-
0.804; P* =
.00057)
*log-rank test 2
sided
Median follow up: 12.5
mos
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Mos

34. A post-hoc subgroup analysis based on
patient characteristics suggested that
progression-free survival HRs favored the
erlotinib plus bevacizumab group over the
erlotinib alone group in most subgroups,
although these differences were not
statistically significant

35. Safety
• 98 (88%) of 112 patients in the erlotinib plus bevacizumab
group and 53 (46%) of 114 patients in the erlotinib alone group
had grade 3 or worse adverse events.
• The most common grade 3–4 adverse event was rash.
• The adverse events were manageable .

36. Conclusion
promisin
g
strateg
y
to improve PFS
in
patients with EGF
R-
positive NSCLC.
• Interim analysis showed that the median progression-free
survival of patients in the erlotinib plus bevacizumab group
was significantly improved compared with that of
patients in the erlotinib alone
group.
• The additionof bevacizumab to erlotinib therefore
seems to be a
• Multivariate analyses of PFS indicated that
erlotinib and bevacizumab combination therapy
was broadly effective.

37. IMpower150: Addition of Atezolizumab to
Carbo/Pac +Bevacizumab in Advanced NSCLC
• Randomized phase III
study
Stratified by sex, PD-L1 expression, liver
mets
Patients with stage IV or
recurrent,
chemotherapy- naive
nonsquamous NSCLC
(PD on or intolerance to
targeted agents
allowed); available
tumor tissue
(N = 1202)
Atezolizumab 1200 mg IV Q3W +
Carboplatin/Paclitaxel
(n = 510)
Carboplatin/Paclitaxel Q3W
+ Bevacizumab 15 mg/kg
IV Q3W (n = 336; control
arm)
Atezolizumab 1200 mg IV
Q3W +
Carboplatin/Paclitaxel Q3W
+ Bevacizumab 15 mg/kg IV
Q3W (n = 356)
Atezolizumab
until PD or
loss of benefit
and/or
bevacizumab
until PD
Atezolizumab
Bevacizumab
Atezolizumab
+
Bevacizumab
4-6
cycles
Reck. ESMO I-O Congress 2017. Abstr LBA1_PR. Kowanetz. AACR 2018. Abstr CT076. Socinski. NEJM.
2018;378:2288.
Slide credit:
clinicaloptions.com
Maintenance
therapy
(no crossover
allowed)
 Primary endpoints: PFS, OS
 Secondary endpoints: PFS (IRF), ORR, OS at Yrs 1 and 2, QoL,
safety, PK

38. IMpower150: Updated PFSin ITTWT
Population* (Coprimary Endpoint)
Socinski. ASCO 2018. Abstr
9002.
Data cutoff: January 22, 2018. *ITT WT: patients
without
EGFR or ALK alterations; 87% of randomized
patients.
Atezolizumab
+
Carbo/Pac +
Bev (n =
359)
Carbo/Pac +
Bev (n =
337)
HR: 0.59 (95% CI: 0.50-0.70; P <
.0001)
Median follow-up: ~ 20
mos
Patients at
Risk, n
Atezolizumab
+ Carbo/Pac +
Bev
Carbo/Pac +
Bev
PFS
(%)
100
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
34
Mos
359336315301293267234213190168154 146125112 85 80 69 68 53 50 37 33 24 20 12 11 6 3
1 1 1
337 323 294 263 244 215 180 148 127 103 89 78 61 50 35 29 21 18 14 13 6 6 5 5 1
1
+
+
+ ++++
+
+ +
+++ ++++ +++
+++
+
+++
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+++++++
+
+
+
+
+
+

39. IMpower150: Landmark OSin ITTPopulation (Including
Patients With EGFR and ALKAberrations)
Mos
• Clinically meaningful OS benefit with atezolizumab + bevacizumab + chemotherapy vs
bevacizumab
+ chemotherapy was observed in all patients
Socinski. ASCO 2018. Abstr
9002.
HR: 0.76
(95% CI: 0.63-0.93)
Median follow-up: ~ 20
mos
10
0
90
80
70
60
50
40
30
20
10
0
OS
(%)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
34
Atezolizumab
+ Carbo/Pac
+ Bev (n =
400)
Carbo/Pa
c
+ Bev
(n =
400)

40. IMpower150: OSbySubgroup
Socinski. ASCO 2018. Abstr
9002.
Carbo/Pac +
Bev
*For prevalence, ITT WT (n = 696) used for
PD-L1, liver metastases groups; ITT (n =
800) for rest.
Median OS,
Mos
20.
3
17.
1
13.
2
19.
8
19.
8
NE
19.
2
16.
4
14.
1
9.1
16.
7
14.
9
17.
5
14.
7
Subgro
up
PD-L1 high (TC3 or IC3)
WT
PD-L1 low (TC1/2 or IC1/2)
WT
PD-L1 negative (TC0 and
IC0)
W
T
Liver metastases
WT
No liver metastases
WT
ITT (including
EGFR/ALK+)
EGFR/ALK+
only ITT WT
n
(%)*
136
(20)
226
(32)
339
(49)
94 (14)
602
(86)
800
(100)
104 (13)
696
(87)
0.
2
2.
0
1.0
HR
Favors
Favor
s Atezolizumab + Carbo/Pac + Bev
H
R
0.7
0
0.8
0
0.8
2
0.5
4
0.8
3
0.7
6
0.5
4
0.7
8
ABC
P
25.2
BC
P
15.
0

41. IMpower150: Safety
Socinski MA, et al. ASCO 2018. Abstract
9002.
Safety Outcome Atezolizuma
b +
Carbo/Pac
(n = 400)
Atezolizumab
+ Bev +
Carbo/Pac (n
= 393)
Bev +
Carbo/Pac
(n = 394)
Median doses received, n (range)
 Atezolizumab
 Bevacizumab
10 (1-43)
NA
12 (1-44)
10 (1-44)
NA
8 (1-38)
Treatment-related AE, n (%)
 Grade 3/4
 Grade 5
• Fatal hemorrhagic
377 (94)
172 (43)
4 (1)
2 (< 1)
370 (94)
223 (57)
11 (3)
6 (2)
377 (96)
191 (49)
9 (2)
3 (< 1)
Serious AE, n (%) 157 (39) 174 (44) 135 (34)
AE leading to d/c of any treatment, n
(%)
53 (13) 133 (34) 98 (25)

42. IMpower150: Immune-RelatedAEs
*Grade 5 acute hepatitis, n = 1. †Grade 5 interstitial lung disease,
n = 1.
Socinski MA, et al. ASCO 2018. Abstract 9002.
Immune-Related AEs
Occurring in > 5% of
Patients in Any Arm, n
(%)
Atezolizumab + Atezolizumab + Bev + Bev +
Carbo/Pac Carbo/Pac Carbo/Pac
(n = 394)
(n = 400) (n = 393)
Any
Grade
Grade
3/4
Any
Grade
Grade
3/4
Any
Grade
Grade
3/4
Rash
Hepatitis
 Laboratory
abnormalitie
s
Hypothyroidism
Pneumonitis
Hyperthyroidism
Colitis

43. IMpower150: Conclusions
• In patients with untreated advanced nonsquamous NSCLC, addition of atezolizumab to
carboplatin/paclitaxel
+ bevacizumab significantly prolonged survival vs carboplatin/paclitaxel + bevacizumab alone
• Median PFS: 8.3 vs 6.8 mos (HR: 0.59; 95% CI: 0.50-0.70; P < .0001)
• Median OS: 19.2 vs 14.7 mos (HR: 0.78; 95% CI: 0.64-0.96; P = .0164)
• Benefit associated with atezolizumab observed in patients with liver metastases or EGFR/ALK
genomic aberrations, across PD-L1 subgroups, and regardless of Teff gene signature
expression
• Combination of anti–PD-L1 and anti-VEGF therapies does not appear to increase the risk of irAEs
• OS data for comparison of atezolizumab + CT vs bevacizumab + CT not yet mature
• Median OS for atezolizumab + carbo/pac vs bev + carbo/pac: 19.4 vs 14.7 mos (HR: 0.88; P = .2041)
• Investigators conclude that atezolizumab + carboplatin/paclitaxel + bevacizumab is a new SoC
option for first-line management of patients with advanced nonsquamous NSCLC
Socinski MA, et al. ASCO 2018. Abstract
9002.

44. CNSmetastases–Lungcancer
Objectio
n
Patients with CNS metastases cannot
receive bevacizumab due to an
unacceptably high bleeding risk

45. CNSmetastases–response
In 2009, the European Medicines Agency removed a prior contraindication, allowing patients with
untreated CNS metastases to receive bevacizumab
Meta-analysis of safety data across multiple tumour types demonstrated that CNS haemorrhage in
Bevacizumab-treated patients with CNS metastases is rare; these data led to a label update1,2
Since the initial case of CNS haemorrhage, over 1,000,000 patients have been treated with
Bevacizumab, providing a large safety database3
1. Avastin SmPC
2. Besse, et al. Clin Cancer Res 2010
3. Avastin PSUR 2011 [RDR 1041900] submitted to EMA on April

46. CNSmetastases–EUlabel update
Total of
>13,000 patients
across multiple
tumour types
Patients with CNS metastases
can receive bevacizumab-based therapy
 Cerebral haemorrhage in bevacizumab-treated patients with CNS metastases is
rare (based on safety data from >13,000 patients across multiple tumour types)
543 patients
had CNS
metastases
Only 7 of the 543
patients (1.3%)
experienced
CNS bleeding;
no grade 5 events
Besse, et al. Clin Cancer Res 2010
25 March 2009:
EMA removed
label restriction
to allow patients
with untreated
CNS metastases
to receive
bevacizumab
EMA = European Medicines Agency
• In 2009, the EMA removed the label restriction to
allow patients with untreated CNS metastases to
receive bevacizumab1
• Decision was based on a meta-analysis of safety
data from 17 studies across multiple tumour
types, which concluded that there was no
increased risk of CNS bleeding in Bevacizumab-
treated patients2
1. Avastin SmPC
2. Besse, et al. Clin Cancer Res

47. Treatment of Advanced Non–Small Cell Lung
Cancer in 2018
Abbreviations: PD-L1, programmed cell death 1 ligand 1; EGFRmt, EGFR mutated.
aIf crizotinib treatment was started prior to FDA approval of alectinib for 1st-line
treatment.
bCarboplatin/pemetrexed/pembrolizumab is also FDA approved in this
setting.
cPembrolizumab use requires PD-L1 >1%.

48. Bevacizumab place in therapy in NSCLC in
2018
Mutation
Yes N
o
EGFR
Erlo, Gefi,
Afa
Osirmatinib
If T790M-
Osirmatinib
Platinum
doublet
±
Bevacizumab
Platinum doublet
± Bevacizumab
Docetaxel ±
ramucirumab/Gemitabin
e
ALK ROS1
Alectinib Crizotinib
Ceritinib or
Platinum doublet ±
Bevacizumab
Alectinib
or
Ceritinib
Platinum doublet ±
Bevacizumab (if not
in 2nd line)
Platinum doublet ±
Bevacizumab (if
not in 2nd
Crizotinib
Platinum doublet
± Bevacizumab
Ramucirumab/Ge
m citabine

49. Bevacizumab place in therapy in NSCLC in
2018
Mutation
Yes No
PD-L1≥50%
Pembrolizuma
b
Platinum doublet
± Bevacizumab
Docetaxel ±
Ramucirumab
or gemcitabine
Platinum doublet with
Pemetrexed
±
Bevacizuma
b
Nivolumab
or
atezolizuma
b
PD-L1≤50%
Carboplatin/pemetrexe
d/pembrolizumab
Docetaxel ±
Ramucirumab
or gemcitabine
Docetaxel ±
Ramucirumab
or gemcitabine

50. Category 1Arecommendation from ESMO
guidelines

51. Thankyou