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Conversationsin OncologySunday, 13 November 2016Kerry HotelPudong, Shanghai, China
2
Antiangiogenic Therapy: Clinical Benefit for Second-Line NSCLC Professor Myung-Ju Ahn
3
• Consultant or advisory role: Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Novartis
• Honoraria: Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Novartis
• Research funding: AstraZeneca
Disclosures
4
• Review the role of angiogenesis in NSCLC
• Discuss current approaches in the development of antiangiogenic agents for the treatment of NSCLC
• Discuss future perspectives on the use of antiangiogenic agents in NSCLC
Outline
5
Angiogenesis: A Hallmark of Cancer
Hanahan D and Weinberg RA. Cell. 2011;144:646.
Resistingcell death
Degradingcellular
energetics
Sustainingproliferativesignalling
Inducingangiogenesis
Evadinggrowth
suppressors
Avoidingimmune
destruction
Enablingreplicativeimmortality
Tumour-promoting
inflammation
Activatinginvasion andmetastasis
Genomeinstabilitymutation Antiangiogenic therapy
Regression of existing tumour vasculature
Inhibition of new vessel growth No bone marrow suppression No cumulative toxicities
Improved efficacy in combination with a
well-established safety profile
6
How does anti-angiogenic therapy work?
Jain RK. J Clin Oncol. 2013;31:2205-18.
7
FGFR = fibroblast growth factor receptor; PDGFR = platelet-derived growth factor receptor; VEGFR = vascular endothelial growth factor receptor.1. Bergers G and Hanahan D. Nat Rev Cancer. 2008;8:592; 2. Bottsford-Miller et al. J Clin Oncol. 2012;30:4026; 3. Cooper et al. Onco Targets Ther. 2016;9:1953; 4. Hilberg et al. Cancer Res.2008;68:4774.
VEGFR Inhibition1–3 Triple Angiokinase Inhibition4
VEGFR2
Ramucirumab
Inhibition of Tumour Angiogenesis
1. Effective inhibition of tumour angiogenesis
2. Normalisation of brittle and permeable blood vessels
3. Suppression of tumour escape mechanisms
8
Historical Development of Antiangiogenic Agents
Ang = angiopoietin; FGFR = fibroblast growth factor receptor; mAb = monoclonal antibody; MMPIs = matrix metalloproteinase inhibitors; PDGFR = platelet-derived growth factor receptor; TKI = tyrosine kinase inhibitor; VEGFR = vascular endothelial growth factor receptor.
First generation
1990s
• Thalidomide• Interferon-α• Tecogalan• Minocycline• Suramin• TNP-470• MMPIs
FAILED
Second generation
2000s
• Bevacizumab (now integrated in standard care)
• Endogenous antiangiogenics: endostatin, angiostatin
• TKIs (VEGFR ± PDGFR)
LARGELY DISAPPOINTING
IN NSCLC
Third generation
2010s
• Angiokinase inhibitors that target multiple pathways (eg, VEGFR, FGFR, PDGFR)
- Nintedanib efficacy confirmed in phase III trial
• New targets (eg, Ang1/2 inhibitors)
• VEGFR2 mAb: ramucirumab
PROMISING or ESTABLISHED IN
NSCLC
9
• Monotherapy
• Combination (usually based on synergistic interaction in preclinical models) – Chemotherapy– Targeted agent– Immunotherapy (eg, PD1 blockade)
Current Antiangiogenic Approaches in NSCLCSynergistic Interaction Between Bevacizumab and Chemo1
1. Ferrara N. Oncology. 2005;69(suppl 3);11; 2. Martinelli E et al. Clin Cancer Res. 2010;16:4990.
Synergistic Interaction Between Sorafenib and Erlotinib2
CI values between 0.02 and 0.5 suggest a significant synergistic interaction
10
First-Line TreatmentBevacizumab (+ Erlotinib in EGFR+)
11
1st-line
First-Line Treatment of Metastatic NSCLC:ESMO Guidelines
EGFR-mutation negative/unknown
EGFR-mutation positive
Nonsquamous cell carcinoma
ALK-rearranged
Squamous cell carcinoma
ALK TKICisplatin + 3rd-gen CT
+/-Bevacizumab
EGFR TKI+/ Bevacizumab
Cisplatin + 3rd-gen CT
ESMO = European Society for Medical Oncology; CT = chemotherapy; ALK = anaplastic lymphoma kinase. Modified from Reck et al. Ann Oncol. 2014;25(suppl 3):iii27 and Besse et al. Ann Oncol. 2014;25:1475.Modified from Novello et al Ann Oncol 2016;27(supple 5)
12
Treatment of Advanced NSCLC After First-Line Chemotherapy
Median OS <1 year No significant improvement in survival reported in this setting in nearly a decade!
NSCLC = non–small cell lung cancer. 1. Shepherd et al. J Clin Oncol. 2000;18:2095; 2. Hanna et al. J Clin Oncol. 2004;22:1589; 3. Shepherd et al. N Engl J Med. 2005;353:123; 4. Reck M et al. Lancet Oncol. 2014;15:143; 5. Garon EB et al. Lancet. 2014;384:665. Nintedanib is approved in the European Union (EU) under the brand name VARGATEF® for use in combination with docetaxel in adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. Registration conditions differ internationally, please refer to locally approved prescribing information. Nintedanib is not approved in other indications.
Docetaxel approved by
EMA1
Pemetrexed approved by
EMA2
Erlotinib approved by
EMA3
Nintedanib plus docetaxel
approved by EMA
(LUME-Lung 1)4
Ramucirumab plus docetaxel approved by
FDA(REVEL)5
20152004 2006 2008 2010 2012 20141998 2000 2002 2016
Pembrolizumab
Nivolumab
13
Phase 3 Studies With Antiangiogenic Agents in Second-Line Treatment of Advanced NSCLC
Nintedanib is approved in the European Union (EU) under the brand name VARGATEF® for use in combination with docetaxel in adult patients with locally advanced, metastatic, or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. Registration conditions differ internationally. Please refer to locally approved prescribing information. Nintedanib is not approved in other indications.FGFR = fibroblast growth factor receptor; FLT3 = Fms-like tyrosine kinase 3; IV = intravenous; NSCLC = non–small cell lung cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free survival.1. Garon EB et al. Lancet. 2014;384:665; 2. Reck M et al. Lancet Oncol. 2014;15:143; 3. Hanna NH et al. J Clin Oncol. 2013;31(suppl). Abstract 8034 and poster.
Trial Mechanism of action Patients Regimens Primaryendpoint(s)
Secondaryendpoint(s)
REVEL1 IV monoclonal antibody targeting VEGFR-2
Stage IV NSCLC; any histology
(squamous 26%)
Ramucirumab + docetaxel
OS PFSORRPlacebo +
docetaxel
Trial Mechanism of action Patients Regimens Primaryendpoint(s)
Secondaryendpoint(s)
LUME-Lung 12Oral triple angiokinase
inhibitor targetingVEGFR 1–3, FGFR 1–
3, PDGFR α/β, RET and FLT3
Stage IIIB/IVNSCLC; any histology
(squamous 42%)
Nintedanib + docetaxel PFS
(central review)
OSPFS
(investigator)ORR
Placebo + docetaxel
LUME-Lung 23 Stage IIIB/IV NSCLC; nonsquamous histology
Nintedanib + pemetrexedPFS
(central review)
OSPFS
(investigator)ORRPlacebo + pemetrexed
14
• Ramucirumab is a fully human IgG1, high-affinity (50 pM) neutralising monoclonal antibody specific for the human VEGFR-2 receptor
Ramicirumab: Fully Human IgG With High Affinity to VEGFR-2
15
REVEL: Study Design
Bev = bevacizumab; ECOG PS = Eastern Cooperative Oncology Group performance status; ORR = objective response rate; PFS = progression-free survival; ROW = rest of world.
• 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 q3wN=628
Placebo +
Docetaxel 75 mg/m2 q3wN=625
RANDOMISE
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
16
REVEL: Overall Survival (ITT Analysis)
Median OSRAM+DOC 10.5 (9.5-11.2)PL+DOC 9.1 (8.4-10.0)HR: 0.857 (0.75-0.98); p = 0.023
Garon EB et al. Lancet. 2014;384:655.
All patients (primary endpoint)1.00.90.80.70.60.50.40.30.20.1
00 3 6 9 12 15 18 21 24 27 30 33 36
Ove
rall
Surv
ival
Months
628 527 415 329 231 156 103 70 45 23 11 2 0Ramucirumab625 501 386 306 197 129 86 56 36 23 9 0 0Placebo
Number at risk
Non-squamous histology (73%)1.0
0.9
0.8
0.70.6
0.5
0.4
0.30.2
0.1
00 3 6 9 12 15 18 21 24 27 30 33 36
Ove
rall
Surv
ival
Months
465 401 311 251 182 125 80 54 39 21 10 1 0Ramucirumab447 362 282 226 144 94 64 40 27 18 5 0 0Placebo
Number at risk
Squamous histology (26%)
Ove
rall
Surv
ival
1.0
0.9
0.8
0.70.6
0.5
0.4
0.30.2
0.1
00 3 6 9 12 15 18 21 24 27 30 33 36
Months
157 124 103 78 49 31 23 16 6 2 1 1 0Ramucirumab171 132 99 75 48 31 20 14 8 5 4 0 0Placebo
Number at risk
Median OSRAM+DOC 11.1 (9.9-12.3)PL+DOC 9.7 (8.5-10.0)HR: 0.83 (0.71-0.97); p = 0.020
Median OSRAM+DOC 9.5 (8.0-10.8)PL+DOC 8.2 (6.3-9.4)HR: 0.883 (0.69-1.13); p = 0.319
17
REVEL: 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<0.0001
RAM+DOCPL+DOC
Prog
ress
ion-
Free
Sur
viva
l (%
)
RAM+DOCPL+DOCCensored
0 3 6 9 12 15 18 21 24 27 30 33 36
Survival Time (months)RAM+DOCPL+DOC
Number at risk383301
204172
12095
5937
3817
119
74
33
32
00
00
628625
00
0
20
40
60
80
100
18
REVEL: OS by Subgroups
OS = overall survival.Garon EB et al. Lancet. 2014;384:655.
19
Selected Treatment-Emergent Adverse Events Occurring in ≥20% of Patients or ≥5% Higher in the RAM+DOC Arm
Difference between arms for term was ≥5% higher in the RAM+DOC arm.Presented by Maurice Perol at 2014 ASCO Annual Meeting.
Preferred and Consolidateda TermRAM+DOC
(N=627)PL+DOC(N=618)
Grade 1-2, % Grade 3-4, % Grade 1-2, % Grade 3-4, %Neutropaeniaa 6.2 48.8 6.1 39.8Febrile neutropaenia 0 15.9 0 10.0Thrombocytopaenia 10.5 2.9 4.5 0.6Fatiguea 40.7 14.0 39.5 10.5Decreased appetite 26.8 2.2 23.6 1.3Nausea 25.8 1.1 26.1 1.5Stomatitis 19.0 4.3 11.3 1.6Mucosal inflammation 13.2 2.9 6.5 0.5Diarrhoea 27.1 4.6 24.6 3.1Neuropathya 20.4 2.7 18.8 1.6Oedema peripheral 16.3 0 8.3 0.3Lacrimation increased 13.2 0.2 4.5 0
• No grade 5 toxicity was observed for the events presented on this slide
20
Nintedanib: A Triple-Angiokinase Inhibitor
• Oral angiokinase inhibitor targeting:– VEGFR 1–3– FGFR 1–3– PDGFR α/β
21
Nintedanib Clinical Development in Lung Cancer
NSCLC = non–small cell lung cancer.
Advanced NSCLC After First-Line Chemotherapy
LUME-Lung 1Phase III
NSCLC (all histologies)
LUME-Lung 2Phase III
Nonsquamous NSCLC
22
LUME-Lung 1: Randomised Controlled Phase III Study
*UICC/AJCC = Union Internationale Contre le Cancer/American Joint Committee on Cancers (6th or 7th edition). BID = twice daily; po = by mouth; IV = intravenous; NSCLC = non–small cell lung cancer; PD = progressive disease; PFS = progression-free survival; OS = overall survival; ITT = intent-to-treat; ECOG PS = Eastern Cooperative Oncology Group performance status.Reck M et al. Lancet Oncol. 2014;15:143.
Stratification: ECOG PS (0 vs 1)Prior bevacizumab (yes vs no)Histology (squamous vs nonsquamous)Brain metastases (yes vs no)
Regions: Europe/Asia/South AfricaAccrual: 23 Dec 2008 to 9 Feb 2011
Primary Endpoint: PFS by independent central reviewKey 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
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
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)
23
• Key inclusion criteria– Histologically or cytologically confirmed, locally advanced and/or metastatic, stage IIIB–IV* or
recurrent NSCLC – All NSCLC histologies– ECOG PS 0 or 1– Failure after first-line chemotherapy
• Key exclusion criteria– Prior docetaxel or VEGF/VEGFR inhibitors (other than bevacizumab)– Active brain metastases or leptomeningeal disease– Cavitary or necrotic tumours
Major Eligibility Criteria
*UICC/AJCC = Union Internationale Contre le Cancer/American Joint Committee on Cancers (6th or 7th edition). ECOG PS = Eastern Cooperative Oncology Group performance status; NSCLC = non–small cell lung cancer; VEGFR = vascular endothelial growth factor receptor.Reck M et al. Lancet Oncol. 2014;15:143.
24
LUME-Lung 1 Statistical Methodology
Primary endpoint
Key Secondary Endpoint
Independently assessed PFS ITT/all histologies
OSAdenocarcinoma
Time since start of first-line therapy <9 months
OSAll adenocarcinoma
OSITT/all histologies
Significant finding
Significant finding
• An exploratory analysis of LUME-Lung 2 data showed evidence for enhanced survival benefit in early progressing adenocarcinoma tumours1,2
• To confirm this finding in LUME-Lung 1, prespecified stepwise testing was incorporated in the secondary endpoint OS analysis. This stepwise approach was applied to control the type I error rate3
Significant finding
OS = overall survival; PFS = progression-free survival; ITT = intention-to-treat.1. Hanna N et al. J Clin Oncol. 2013;31(suppl). Abstract 8034; 2. Kaiser R et al. Eur J Cancer. 2013;49(suppl 2). Abstract 3479, Poster P388; 3. Reck M et al. Lancet Oncol. 2014;15:143.
25
Primary Endpoint PFS by Independent Central Review, All Patients
LUME-Lung 1 Met Its Primary Endpoint With Significant Improvement in Progression-Free Survival in All Patients
565 295 155 57 19 4 3 1 0569 250 116 43 21 2 1 0 0
NintedanibPlacebo
No. at risk
100
80
60
40
20Prob
abili
ty o
f PFS
(%)
0Time (months)
02 4 6 8 10 12 14 16 18
CI = confidence interval; HR = hazard ratio; PFS = progression-free survival.Reck M et al. Lancet Oncol. 2014;15:143.
Nintedanib + Docetaxel
Placebo + Docetaxel
Median PFS (months) 3.4 2.7
HR = 0.79 (95% CI: 0.68–0.92); P=0.0019
26
Asian vs Non-Asian Patients: PFS (LUME-Lung 1)
Reck M et al. Lancet Oncol. 2014;15:143.
27
Significant Improvement in Median Overall Survival in Patients With Adenocarcinoma
Key Secondary Endpoint, Prespecified Hierarchical Analysis
322 263 203 163 131 96 72 46 25336 269 184 139 101 73 55 33 15
NintedanibPlacebo
No. at risk107
Nintedanib + Docetaxel
Placebo + Docetaxel
Median OS (months) 12.6 10.3
HR 0.83 (95% CI: 0.70–0.99); P=0.0359
100
80
60
40
20
Prob
abili
ty o
f Sur
viva
l (%
)
0Time (months)
04 8 12 16 20 24 28 32 36
52.7%
44.7%25.7%
1-YEAR SURVIVAL
2-YEAR SURVIVAL
19.1%
CI = confidence interval; HR = hazard ratio; PFS = progression-free survival.Reck M et al. Lancet Oncol. 2014;15:143.
28
Asian vs Non-Asian Patients: OS (LUME-Lung 1)
Reck M et al. Lancet Oncol. 2014;15:143.
29
206 167 119 92 73 51 35 16 9199 154 91 62 42 25 17 12 5
NintedanibPlacebo
No. at risk31
100
80
60
40
20
Prob
abili
ty o
f sur
viva
l (%
)
0Time (months)
04 8 12 16 20 24 28 32 36
Overall Survival in Patients With Adenocarcinoma Who Progressed in <9 Months After Start of First-Line Therapy
Key Secondary Endpoint, Prespecified Hierarchical Analysis
Nintedanib + Docetaxel
Placebo + Docetaxel
Median OS (months) 10.9 7.9
HR = 0.75 (95% CI: 0.60–0.92); P=0.0073
46.8%
34.3% 20.7%
1-YEAR SURVIVAL
2-YEAR SURVIVAL
10.4%
CI = confidence interval; HR = hazard ratio; PFS = progression-free survival.Reck M et al. Lancet Oncol. 2014;15:143.
30
100
80
60
40
20
Prob
abili
ty o
f Sur
viva
l(%
)
0Time (months)
04 8 12 16 20 24 28 32 36
Overall Survival in Patients With Adenocarcinoma and No Response to First-Line Chemotherapy
CI = confidence interval; HR = hazard ratio; OS = overall survival; PD = progressive disease.Mellemgaard A et al. Eur J Cancer. 2013;49(suppl 2). Abstract 3409 and oral presentation.
53 44 27 22 18 13 10 7 464 51 24 14 11 7 3 2 2
NintedanibPlacebo
No. at risk21
Adenocarcinoma and PD as Best Response to First-Line Chemotherapy
Nintedanib + Docetaxel
Placebo + Docetaxel
Median OS (months) 9.8 6.3
HR = 0.62 (95% CI: 0.41–0.94); P=0.0246
43.0%
24.6%21.5%
1-YEAR SURVIVAL
2-YEAR SURVIVAL
5.3%
31
Nintedanib + Docetaxel Safety Profile: All Grades Adverse Events
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. *Group term. Highlighted events are AEs for which the frequency for nintedanib was >20% greater than with placebo.AEs = adverse events; ALT = alanine aminotransferase; AST = aspartate aminotransferase; WBC = white blood cell.Reck M et al. Lancet Oncol. 2014;15:143; Boehringer Ingelheim data on file.
All Grade AEs in ≥10% of Patients With Adenocarcinoma
4341
38
31 3028 28
2319 19 18 17 17
14 13 12 11 117
25
41
9
29
7
18
28
1612
1720
1611
1519
14
8
1412
0
10
20
30
40
50
Patie
nts
(%)
Nintedanib + docetaxel
Placebo + docetaxel
32
The Majority of Grade ≥3 AEs Occurred at Similar Rates Between Treatment Arms
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. *Reported as AEs of ‘all grades’ occurring in at least 10% of the patients in either treatment arm. Highlighted events are AEs for which the frequency for nintedanib was greater than twice the frequency with placebo.AEs = adverse events; ALT = alanine aminotransferase; AST = aspartate aminotransferase; WBC = white blood cell.Reck M et al. Lancet Oncol. 2014;15:143; Boehringer Ingelheim data on file.
36
20
12 12
6 5 5 4 3 1 1 1 1 1 1 1 0.3 0
35
18
14
14
6 41 1 2 1 0.3 2 1 1 0.3 0 0.3
0
10
20
30
40
50
Patie
nts
(%)
Nintedanib + docetaxelPlacebo + docetaxel
Grade ≥3 AEs in Patients With Adenocarcinoma*
33
Adverse Events Commonly Associated With VEGF/VEGFR Inhibitors
ATE = arterial thromboembolism; GI = gastrointestinal; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor; VTE = venous thromboembolism.Reck M et al. J Clin Oncol. 2014;32(5 suppl). Abstract 8100 and poster; Boehringer Ingelheim data on file.
11
0.3
5
3
1
3
11
0.3
5
12
1
0
5
10
15
Patie
nts
(%)
Nintedanib + docetaxelPlacebo + docetaxel
Adverse Events of Special Interest in Patients With Adenocarcinoma
10.3
3
1 1 0.32
0.3
3
1 1 0.30
5
10
15
Patie
nts
(%)
Nintedanib + docetaxelPlacebo + docetaxel
All grades (%) Grade ≥3 (%)
34
Addition of Nintedanib to Docetaxel Did Not Further Compromise Patients’ Self-Reported Quality of Life
EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire-core 30; EORTC QLQ-LC13; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire and Lung Cancer-13; NS = non-significant; QoL = Quality-of-life.Novello S et al. Eur J Cancer. 2015;51:317.
EORTC QLQ-C30 and QLQ-LC13 Prespecified Symptoms of Interest
Difference in mean score
P ValueCough (QLQ-LC13) NSDyspnoea (QLQ-LC13) NS
Dyspnoea at rest NSDyspnoea after walking NSDyspnoea after climbing stairs NS
Short of breath (QLQ-C30) NSPain (QLQ-C30) NS
Have pain 0.0332Pain affecting daily activities NS
Pain in chest (QLQ-LC13) 0.0196Pain in arm and shoulder (QLQ-LC13) 0.0004Pain in other parts (QLQ-LC13) NS
Global health status/QOL NS
Favours nintedanib
-10 -5 0 5Favours placebo
35
Treatment of Advanced Adenocarcinoma in Second Line
4.6**
9.2*9.0*
7.8*
12.6*
10.5
0
2
4
6
8
10
12
14Su
rviv
al T
ime,
mo
No significant OS benefit
2000 2004 2004 2005 2014
Nintedanib14
● ● ● ●
*NSCLC–adenocarcinoma; ** NSCLC–all histologies; BSC = best supportive care.1. Shepherd FA et al. J Clin Oncol. 2000;18:2095; 2. Hanna N et al. J Clin Oncol. 2004;22:1589; 3. Scagliotti G et al. Oncologist. 2009;14:253; 4. Shepherd FA et al. N Engl J Med. 2005;353:123; 5. Wojtowicz-Praga S und Leon L. Ann Oncol. 2012;23(suppl 9):abstr 1277P; 6. Scagliotti GV et al. J Clin Oncol. 2012;30:2070; 7. Herbst RS et al. Lancet Oncol. 2011;11:619; 8. de Boer RH et al. J Clin Oncol. 2011;29:1067; 9. Natale RB et al. J Clin Oncol. 2011;29:1059; 10. Ramlau R et al. J Clin Oncol. 2012;303640; 11. Lara PN et al. J Clin Oncol. 2011;29:2965; 12. Scagliotti GV et al. J Clin Oncol. 2012;30:2829; 13. Belani CP et al. BMC Cancer. 2014;14:290; 14. Reck M et al. Lancet Oncol. 2014;15:143; 15. Garon EB et al. Lancet. 2014;384:665.
●
Survival Advantages Since 2000
BSC1
Docetaxel2,3Pemetrexed2,3
Erlotinib4,5
Sunitinib6
Vandetanib7–9
Aflibercept10
Vadimezan11
Motesanib12
Axitinib13
NS NS NS NS NS
Ramucirumab15
36
Cisplatin + 3rd-gen CT1st-Line
Second-Line Treatment of Metastatic NSCLC:ESMO Guidelines
EGFR-mutation negative/unknown
EGFR-mutation positive
Nonsquamous cell carcinoma
ALK-rearranged
Squamous cell carcinoma
ALK TKIEGFR TKI
+/-bevacizumab
NivolumabPembrolizumab
(PDL1 >1%)Ramucirumab-
DocetaxelDocetaxel or
EGFR TKI
EGFR TKI
Platinum doublet
Priorchemotherapy
Prior platinum-based treatment
Crizotinib
Platinum doublet
Prior crizotinib
Docetaxel or pemetrexed or
erlotinibNivolumab
PembrolizumabRamuc+ docNintedanib+
doc
Cisplatin + 3rd-gen CT
+/- bevacizumab
Modified from Reck et al. Ann Oncol. 2014;25(suppl 3):iii27 and Besse et al. Ann Oncol. 2014;25:1475.Modified from Novello et al Ann Oncol 2016;27(supple 5)
2nd-LinePrior
EGFR TKI
37
• Numerous phase III studies with PD1/PDL1 inhibitors in first- and second-line setting
• Patients selected (PD-L1+) or not; various methodologies – predictive role awaiting more analyses by PDL1+
• Checkmate 057 study: 2L nivolumab vs docetaxel in non-SCC, EGFR, ALK wild-type NSCLC (N=582)2
– Nivolumab demonstrated superior OS (HR=0.73; 96% CI: 0.59, 0.89; P=0.00155), higher ORR (19.2% vs 12.4%; P=0.0235). PD-L1 expression associated with benefit from NIVO (OS HR 0.59 with PDL1 ≥1% vs 0.40 PDL1 ≥10%). Grade 3–5 drug-related AEs occurred in 10.5% of NIVO and 53.7% of DOC pts
• Checkmate 017: 2L Nivolumab vs docetaxel in SCC patients who failed 1L chemotherapy3
– Nivolumab demonstrated significantly improved OS (HR= 0.59; 95% CI, 0.44 to 0.79; P<0.001), response rate (20% vs 9%, p=0.008) and PFS (HR= 0.62; 95% CI, 0.47 to 0.81; P<0.001) regardless of PD-L1 expression level
• KEYNOTE 010, second-line pembrolizumab vs docetaxel in NSCLC4
– Pembrolizumab demonstrated superior OS (HR= 0.71, 0.61 for 2 mg/kg vs 10 mg/kg) and PFS in patients with TPS ≥50% of PD-L1 expression (Herbst et al. ESMO 2016. LBA48)
• OAK: 2L Atezolizumab vs docetaxel in NSCLC who failed 1,2L chemotherapy5
– Atezolizumab improved OS in all patients (HR=0.73, 13.8m vs 9.6m)
Evolving Evidence With Immunotherapy
1. www.clinicaltrials.gov. Accessed October 20, 2016; 2. Paz-Ares L et al. J Clin Oncol. 2015;33:(suppl; abstr LBA109); 3. Brahmer J et al. N Engl J Med. 2015;373:123-35 4.Garon EB. Lancet Oncol. 2016;17:259. 5 Barlesi et al. ESMO 2016
38
Evolving Evidence With Immunotherapy
Docetaxel Overall survival
0
2
4
6
8
10
12
14
16
18
Checkmate
057
Nivolulmab
Checkmate
017
Nivolulmab
OAK
Atezolizumab
Keymate010
PDL1>50% vs.
1~49%
LUME-lung-1
Nitedanib
+Docetaxel
REVEL
Ramucirumab
+Dacetaxel
12.2 months
9.2 months
13.8months
15.8months
10.5months
12.6months
10.5months
0
2
4
6
8
10
12
39
Treatment related adverse events in Checkmate 057
Brahmer J et al. N Engl J Med. 2015;373:123-35
• Given the survival improvement regardless of PD-L1 expression and less side effects related to immune-check point inhibitors, the positioning of nintedanib or ramucirumab combined with docetaxel as second line therapy might be challenge
40
Cisplatin + 3rd-gen CT1st-Line
Second-Line Treatment of Metastatic NSCLC:ESMO Guidelines
EGFR-mutation negative/unknown
EGFR-mutation positive
Nonsquamous cell carcinoma
ALK-rearranged
Squamous cell carcinoma
ALK TKIEGFR TKI
+/-bevacizumab
NivolumabPembrolizumab
(PDL1 >1%)Ramucirumab-
DocetaxelDocetaxel or
EGFR TKI
EGFR TKI
Platinum doublet
Priorchemotherapy
Prior platinum-based treatment
Crizotinib
Platinum doublet
Prior crizotinib
Docetaxel or pemetrexed or
erlotinibNivolumab
Pembrolizumab(PDL1>1%)
Ramuc+ docNintedanib+
doc
Cisplatin + 3rd-gen CT
+/- bevacizumab
Modified from Reck et al. Ann Oncol. 2014;25(suppl 3):iii27 and Besse et al. Ann Oncol. 2014;25:1475.Modified from Novello et al Ann Oncol 2016;27(supple 5)
2nd-LinePrior
EGFR TKI
Atezolizumab
Atezolizumab
41
• Lack of direct comparison between immune-checkpoint inhibitors and antiangiogenic inhibitors
• To off all the treatment options available would be important to extend patient survival and outcomes
• Considerations for choice of best option for second line therapyPatient characteristics Drugs– Performance status - Efficacy and safety profile of drugs– Comorbidities– Disease burden– Cancer-related symptoms– Response and tolerability to first-line therapy
Positioning of antiangiogenic agents as second-line therapy in the era of immune checkpoint inhibitors
42
Positioning of antiangiogenic agents as second-line therapy in the era of immune checkpoint inhibitors
Checkmate 057 (non-squamous cell )
OAK
• Given that more patients progress within 4 months with I-O drug compared to docetaxel, those patients might benefit from chemotherapy +/- antiangiogenic drug
43
Positioning of antiangiogenic agents as second-line therapy in the era of immune checkpoint inhibitors(adenocarcinoma)
1st-LinePlatinum-based
treatment
2nd-Line
3rd-Line
Modified from Bronte et al Ther Adv Med Oncol 2016(3), 1880197
NSCLC-adenocarcinomaNon-oncogene addicted
Chemotherapy fit
Docetaxel+ nintedanib
Docetaxel+ramucirumab
Immunotherapy
Immunotherapy
Yes No
Others (EGFR TKI)
Non-elderlyPS 0-1Tolerable to first line therapyNo comorbiditiesProgress within 9 months
44
• VEGF not only promotes angiogenesis but acts as a key mediator of the immunosuppressive microenvironment
– Affects lymphocyte trafficking across endothelium to tumor
– Has systemic effect on immune-regulatory cell functionvia Treg, MDSCs, DC, etc
Synergistic Combination of Antiangiogenesis and Immunotherapy
Inhibition of Tumour Angiogenesis and Immune Checkpoints
iDC = immature dendritic cell; IDO = indoleamine 2, 3-dioxygenase; IL-10 = interleukin-10; iNOS = inducible nitric oxide synthase; MDSC = myeloid-derived suppressor cell; NK = natural killer; PD1 = programmed death 1; PD-L1 = programmed death ligand 1; PGE2 = prostaglandin E2; RNOS = reactive nitrogen oxide species; TAM = tumour-associated macrophage; TGFβ = transforming growth factor-β; Treg = regulatory T cell; VEGF = vascular endothelial growth factor.
Nintedanib
Vessel normalisation
N
T
CD4
Treg
CD8NK
TAM
MDSC
iDCAnti-PD1
Dendritic cell maturation
VEGFPromotion of Tregs
- Discourages T-cell infiltration- Inhibits T-cell function
45
• Simultaneous treatment with anti-PD-1 and anti-VEGFR2 mAbs inhibited tumour growth synergistically in vivo
Synergistic Combination of Antiangiogenesis and Immunotherapy
Yasuda S et al. Clin Exp Immunol. 2013;172:500.
46
Ongoing Phase I Trials of Combination of Antiangiogenic Agents and Immune Checkpoint Inhibitors in NSCLC
Manegold C et al. J Thorac Oncol. 2016. [Epub ahead of print]
Compounds ClinicalTrials gov Pt No Relevant regimens
BevacizumabNivolumabipilimumab
NCT01454102(Checkmate 012)
412 Cohort D: nivolumab + bevacizumab maintenance
Bevacizumabpembrolizumab
NCT02039674 308 Part I Cohort B: pembrolizumab + paclitaxel+ carboplatin + bevacizumab
Bevacizumabatezolizumab
NCT01633970 225 Cohort A: atezolizumab + bevacizumabCohort B: atezolizumab + bevacizumab + FOLFOX
Ramucirumabpembrolizumab
NCT02443324 92 Cohort 3: ramucirumab + pembrolizumab in NSCLC
Nintedanibpembrolizumab
NCT02856425 258 Nintedanib + pembrolizumab
Nintedanibnivolumab
In preparation 50 Nintedanib + nivolumab
47
• Currently available antiangiogenic therapies target VEGF/VEGFR and PDGFR signalling and therefore do not neutralise all relevant mechanisms involved in angiogenesis1,2
• Acquired resistance to VEGF-targeted therapy is a major challenge for treatment of advanced or metastatic tumours2,3
• Activation or upregulation of FGF/FGFR and PDGF/PDGFR signalling serves as a mechanism of resistance to VEGF/VEGFR-targeted therapy4-6
• The PDGF/PDGFR and FGF/FGFR pathways have been implicated in the development of resistance to antiangiogenesis through induction of epithelial-mesenchymal transition (EMT)7-9
Current Challenges: The Need for Greater/More Complete Blockade of the Angiogenesis Pathway?
1. Rogosin S et al. Clin Lung Cancer. 2012;13:326; 2. Clarke JM and Hurwitz HI. J Gastrointest Oncol. 2013;4:253; 3. Ellis LM and Hicklin DJ. Clin Cancer Res. 2008;14:6371; 4. Batchelor TT et al. Cancer Cell. 2007;11:83; 5. Casanovas O et al. Cancer Cell. 2005;8:299; 6. Erber R et al. FASEB J. 2004;18:338; 7. Eckert MA et al. Cancer Cell. 2011;19:372; 8. Jechlinger M et al. J Clin Invest. 206;116;1561; 9. Wu Q et al. Cancer Treat Rev. 2013;39:640.
Crosstalk Among Key Regulators of Angiogenesis
48
• There are no well-validated biomarkers that can help monitor efficacy, toxicity, or resistance to current antiangiogenic therapies1,2
Lack of Biomarkers
1. Ellis LM and Hicklin DJ. Clin Cancer Res. 2008;14:6371; 2. Jain RK et al. Nat Rev Clin Oncol. 2009;6:327.
49
• Currently in unselected NSCLC adenocarcinoma (non-SCC) populations– Bevacizumab improves OS when added to chemo first line– Antiangiogenic agents improve OS and PFS added to chemo second line; benefit greatest with
docetaxel in adenocarcinoma Nintedanib added to docetaxel chemotherapya is an effective option for second-line treatment of
NSCLC patients with adenocarcinoma (median OS, 12.6 vs 10.3 months; HR=0.83; P=0.0359) OS benefit with nintedanib in patients who progressed within the first 9 months since the start of 1st
line therapy and those who had PD as their best response. The earlier the progression on 1st line chemotherapy, the larger the benefits seen (lower HR).
• The role of immunotherapy as second-line therapy in PD-L1 “unselected” NSCLC population should be further explored
• In the future, rationale and opportunity exist to explore novel immunotherapy and antiangiogenic agent combinations without chemotherapy
Summary
aCurrently is not approved for the treatment of patients with NSCLC in South Korea.PD-L1 = programmed cell death ligand 1.