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
carcinoma
Adenocarcinoma
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
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 chemotherapy in
NSCLC
Platinum doublets:
8–10 months2
Best supportive care:
2–5 months4
Cisplatin/pemetrexed:
11 months1
Median OS (months)
0 2 4 6 8 10 12 14
1. Scagliotti Oncologist 2009; 2. Schiller NEJM 2002
3. Bunn Clin Cancer Res 1998; 4. Ganz Cancer 1989
1970s
1990s
2000s
1980s
Single-agent platinum:
6–8 months3
17. Bevacizumab in treatment of lung 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
Previously
untreated
stage IIIB/IV non-
squamous NSCLC
(n=878)
Bevacizumab
15 mg/kg q3w
+ carboplatin +
paclitaxel
(n=434)
Carboplatin +
paclitaxela
(n=444)
R
6 cycles
Sandler NEJM 2006
Bevacizumab
15 mg/kg q3w
Treat to
PD
aNo crossover to bevacizumab permitted
E4599: first line bevacizumab in NSCLC
24. SAiL (MO19390): Bevacizumab in NSCLC in 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)
Bevacizumab
7.5 or 15 mg/kg
q3w + standard
chemotherapy
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: OS in routine oncology practice consistent
with phase III data
OS (months)
0 5 10 15 20 25 30 35
14.6
(95% CI 13.8–15.3)
Estimated
probability 1.0
0.8
0.6
0.4
0.2
0
Crinó Lancet Oncol 2010
26.
27. SAiL: consistent efficacy benefit in Asian patients
(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
Asian1 Overall2
Median TTP
(months) 8.3 7.8
95% CI 7.7–8.8 7.5–8.1
Censored patients: 23.2%
1. Tsai, et al. JTO 2011; 2. Crinò, et al. Lancet Oncol 2010
Time (months)
Asian1 Overall2
Median OS
(months) 18.9 14.6
95% CI 17.4–20.7 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
Time (months)
0 6 12 18 24 30 36
28. • Primary endpoint: PFS
• Secondary endpoints: ORR, OS, duration of response
Previously
untreated
stage IIIB/IV non-
squamous NSCLC
(n=276)
Bevacizumab
15 mg/kg q3w
+ carboplatin +
paclitaxel
(n=138)
Carboplatin +
paclitaxel
(n=138)
R
6 cycles
Zhou C, et al. JCO 2015
Bevacizumab
15 mg/kg q3w
Treat to
PD
BEYOND: First line bevacizumab in NSCLC in
Chinese patients
29. Zhou C, et al. JCO 2015
BEYOND: Consistent PFS
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
31.
32. Phase III NEJ026: Erlotinib ± Bevacizumab in EGFR-
Mutated Advanced NSCLC
• 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)
Stratified by sex, stage, EGFR mutation, and smoking history
Chemotherapy-naive patients
with stage IIIB/IV or recurrent
nonsquamous NSCLC, EGFR
mutation–positive (exon 19 deletion
or L858R, no T790M), ECOG PS ≤ 2,
asymptomatic CNS mets allowed
(N = 224)
Treatment
continued
until PD
33. NEJ026: PFS by Investigator Assessment
100
80
60
40
20
0
PFS
Probability
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Mos
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
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
• 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 addition of bevacizumab to erlotinib therefore seems to be a
promising strategy to improve PFS in patients with EGFR-
positive NSCLC.
• 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
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
Stratified by sex, PD-L1 expression, liver mets
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
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. CNS metastases –Lung cancer
Objection
Patients with CNS metastases cannot receive
bevacizumab due to an unacceptably high
bleeding risk
45. CNS metastases –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 27, 2011
46. CNS metastases –EU label update
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)
Besse, et al. Clin Cancer Res 2010
Total of
>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
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 2010
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 No
EGFR
Erlo, Gefi, Afa Osirmatinib
If T790M-
Osirmatinib
Platinum doublet
± Bevacizumab
Platinum doublet
± Bevacizumab
Docetaxel ±
ramucirumab/Gemitabine
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 line)
Crizotinib
Platinum doublet
± Bevacizumab
Ramucirumab/Gem
citabine
49. Bevacizumab place in therapy in NSCLC in
2018
Mutation
Yes No
PD-L1≥50%
Pembrolizumab
Platinum doublet
± Bevacizumab
Docetaxel ±
Ramucirumab or
gemcitabine
Platinum doublet with
Pemetrexed ±
Bevacizumab
Nivolumab or
atezolizumab
PD-L1≤50%
Carboplatin/pemetrexe
d/pembrolizumab
Docetaxel ±
Ramucirumab or
gemcitabine
Docetaxel ±
Ramucirumab or
gemcitabine
