SECOND LINE TREATMENT NSCLC
Martin Reck
Airway Research Center North (ARCN)
LungenClinic
Grosshansdorf, Germany
DISCLOSURE SLIDE
Honoraria for lectures and consultancy from:
Abbvie, Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche
Institutional support for clinical research from:
BMS
I declare no conflict of interest with the discussed content
THE PRINCIPAL PROBLEM
• Rising incidence and high mortality of lung cancer
• Low frequency of specific early symptoms (> 60% of patientsdiagnosed with advanced stage of disease)
• Low frequency of targetable oncogenic alterations in caucasianpatients
• Ultimate progression following each systemic treatment (nearly eachpatient will be in need of an efficacious second-line treatment)
311.03.2019
CHALLENGES IN SECOND-LINE TREATMENT I
• Pretreated Patients
• Reduced performance status: Tolerability becomes moreimportant.
• Low response rates: Tumor control becomes important.
• More symptomatic patients: Symptom control and symptomimprovement become important .
• It is hard to show any improvement in efficacy...
0 10 20 30 40 50 60 70 80
SECOND-LINE TREATMENT – CHALLENGES II
1J Clin Oncol 2002;20:1335–43; 2J Clin Oncol 2003;21:2933–39; 3Lung Cancer 2006;52:155–63; 4Br J Cancer 2006;95:966–73; 5J Thoracic Oncol 2007;2(Suppl. 4):S666 Abs. P2-235; 6J Clin Oncol 2007;25:5233–39; 7J Clin Oncol 2008;26(Suppl. 15S):426s Abs. 8011; 8J Clin Oncol 2008;26(Suppl. 15S):6s Abs. 3; 9J Clin
Oncol 2008;26:3543–51; 10J Clin Oncol 2009;27:591–98
In recent studies, approximately 50% of patients did not receive second-line therapy
Fidias et al. 200910
Scagliotti et al. 20089
Pirker et al. 20088
Ciuleanu et al. 20087
Park et al. 20076
Barata et al. 20075
von Plessen et al. 20064
Brodowicz et al. 20063
Belani et al. 20032
Socinski et al. 20021
Patients receiving 2nd-line therapy (%)
1. Before Immunotherapy
THE THREE PERIODS OF SECOND-LINE TREATMENT
SECOND LINE TREATMENT NSCLC – FIRST RESULTS
Docetaxel Pemetrexed Erlotinib
RR, % 5.0–12.0 7.1–11.8 7.9–9.0
Median PFS, m 2.0–3.1 2.6–2.9 2.2–3.6
Median OS, m 5.7–8.0 6.7–8.9 6.7–7.9
1-year OS,% 28.7–37.0 29.7–38.5 31.0–35.7
Shepherd, et al. JCO 2000; Fossella, et al. JCO 2000; Ramlau, et al. JCO 2006; Paz-Ares, et al. BJC 2008 Kim, et al. Lancet 2008; Krzakowski, et al. JCO 2010; Hanna, et al. JCO 2004, Cullen, et al. Ann Oncol 2008
Shepherd, et al. NEJM 2005; Vamvakas, et al. ASCO 2010; Ciuleanu, et al. IASLC Chicago 2010; Reck M , et al, Lancet Oncology 2014; Garon E et al, Lancet 2014; Soria JC, Lancet Oncology 2015
THE NON INSPIRING TRUTH IN SECOND LINE TREATMENTStudy Treatment HR for PFS Median PFS (mo) HR for OS Median OS (mo)
Tax 320 (n=373) Docetaxel (D75/100) vs ifofosfamide or vinorelbine TTP: 2.0 (D75) vs 1.8 (p=0.093) NR (p=ns) 5.7 (D75) vs 5.6
Tax 317 (n=104) Docetaxel (D75/100) vs BSC TTP: 2.4 (D75) vs 1.5 (p=0.001) NR (p=0.01) 7.5 (D75) vs 4.6
JMEI (n=571) Pemetrexed vs docetaxel
Adenocarcinoma (n=302)
Squamous (n=172)
0.97
0.83
1.4 (p=0.046)
2.9 vs 2.9
3.5 vs 3.5
2.3 vs 2.7
0.99
0.92
1.56 (p=0.018)
8.3 vs 7.9
9.0 vs 9.2
6.2 vs 7.4
BR.21 (n=727) Erlotinib vs placebo
Adenocarcinoma (n=365)
Squamous (n=222)
0.61 (p<0.001) 2.2 vs 1.8 0.70 (p<0.001)
0.70 (p=0.008)
0.67
6.7 vs 4.7
ISEL (n=1692) Gefitinib vs placebo
Adenocarcinoma (n=767)
TTP: 0.82 TTP: 3.0 vs 2.6 0.89
0.84
5.6 vs 5.1
ZODIAC (n=1391) Vandetanib + docetaxel vs docetaxel
Adenocarcinoma (n=829)
Squamous (n=344)
0.79 (p<0.0001)
0.80 (p<0.05)
0.79
4.0 vs 3.2 0.91
0.89
0.98
10.6 vs 10.0
ZEAL (n=534) Vandetanib + pemetrexed vs pemetrexed
Adenocarcinoma (n=336)
Squamous (n=114)
0.86
0.80
1.04
4.1 vs 2.8 0.86
0.82
1.08
10.5 vs 9.2
ZEST (n=1240) Vandetanib vs erlotinib
Adenocarcinoma (n=741)
Squamous (n=272)
0.98
1.00
1.09
2.6 vs 2.0 1.01
0.99
1.25
6.9 vs 7.8
VITAL (n=913) Aflibercept + docetaxel vs docetaxel 0.82 (p<0.05) 5.2 vs 4.1 1.01 10.1 vs 10.4
BETA (n=636) Bevacizumab + erlotinib vs erlotinib
Adenocarcinoma (n=477)
Squamous (n=28)
0.62 (p<0.0001) 3.4 vs 1.7 0.97
1.07
0.91
9.3 vs 9.2
TAILOR (n=222) Docetaxel vs erlotinib, non-EGFR mutations 0.69 (p=0.014) 3.4 vs 2.4
TITAN (n=304) Docetaxel/pemetrexed vs erlotinib, fast progressors
Adenocarcinoma (n=210)
Squamous (n=154)
1.19 2.2 vs 1.6 0.96
0.95
0.86
5.5 vs 5.3
Vinflunine (n=551) Vinflunine vs docetaxel 1.004 2.3 vs 2.3 0.973 6.7 vs 7.2
Topotecan (n=829) Oral topotecan vs docetaxel 1.20 (p=0.02) TTP: 11 vs 13 wk 1.23 (p=0.0568) 6.4 vs 7.1
SUN1087 (n=960) Sunitinib + erlotinib vs erlotinib
Non-squamous (n=568)
Squamous (n=270)
0.807 (p=0.023)
0.859
0.797
3.6 vs 2.0 0.922
0.943
0.935
9.0 vs 8.5
NEW PRINCIPLES OF ANTIANGIOGENIC
TREATMENT
Ramucirumab:• Humanised, monoclonal IgG1 AB• Specific Binding of VEGFR2 Nintedanib (Vargatef)
• orale Angiokinaseinhibitor• Binding to VEGF 1-3, PDGF α,β; FGF 1-3
REVEL-Trial: Docetaxel + Ramucirumab vs Docetaxel + Placebo in 2nd line
treatment of NSCLC
• Study objective
– To compare the efficacy and safety of ramucirumab+docetaxel with placebo+docetaxel in
pretreated patients with stage IV non-squamous and squamous NSCLC
Lancet 2014; 384: 665-73
Primary endpoint
• OS
Secondary endpoints
• PFS, objective response rate, safety and PROs
R
1:1
PD
PDKey patient inclusion criteria
• Stage IV NSCLC
• Non-squamous or squamous
• Previous platinum-based CT
• ECOG PS 0/1
(n=1253)
Placebo + docetaxel 75 mg/m2 q3w
(n=625)
Ramucirumab 10 mg/kg + docetaxel 75 mg/m2 q3w
(n=628)
Stratification
• Gender, region (East Asia vs ROW),
ECOG PS (0 vs 1), prior maintenance
therapy
• Key results
– Ramucirumab+docetaxel significantly improved survival over placebo + docetaxel
Median (95% CI) Censoring rateRAM+DOC
RAM+DOC vs PL+DOC:
10.5 (9.5, 11.2) 31.8%PL+DOC 9.1 (8.4, 10.0) 27.0%
Stratified HR (95% CI) 0.857 (0.751, 0.979)Stratified log-rank p=0.0235
0
20
40
60
80
100
Overa
ll s
urv
ival
(%)
RAM+DOCPL+DOC
Number at risk
0 3 6 9 12 15 18 21 24 27 30 33
527501
415386
329306
231197
156129
10386
7056
4536
2323
119
20
36
Survival time (months)
628625
00
RAM+DOCPL+DOCCensored
OS PFS
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
Pro
gre
ssio
n-F
ree
Su
rviv
al
(%)
RAM+DOCPL+DOC
Number at risk
RAM+DOCPL+DOCCensored
0 3 6 9 12 15 18 21 24 27 30 33
383301
204172
12095
5937
3817
119
74
33
32
00
00
36Survival Time (months)
628625
00
0
20
40
60
80
100
RAM, ramucirumab; DOC, docetaxel
REVEL-Trial: Docetaxel + Ramucirumab vs Docetaxel + Placebo in 2nd line
treatment of NSCLC
RAM+DOC PL+DOC P-value
Response 22.9% 13.6% <0.01
DCR 64.0% 52.6% <0.001 Lancet 2014; 384: 665-73
NINTEDANIB IN NSCLC
DESIGN: LUME 1
12
Nintedanib 200mg BID p.o., D2–21,+ Docetaxel 75mg/m2 IV, D1,
21-day cycles (n=655)
Nintedanib 200mg BID p.o., D2–21,+ Docetaxel 75mg/m2 IV, D1,
21-day cycles (n=655)
Placebo BID p.o., D2–21,+ Docetaxel 75mg/m2 IV, D1,
21-day cycles (n=659)
Placebo BID p.o., D2–21,+ Docetaxel 75mg/m2 IV, D1,
21-day cycles (n=659)
N=1314
R
A
N
D
O
M
I
Z
E
R
A
N
D
O
M
I
Z
E
Stratification: ECOG PS (0 vs 1)Prior bevacizumab (yes vs no)Histology (squamous vs non-squamous)Brain metastases (yes vs no)
Stage IIIB/IVor recurrent
NSCLC patients after 1st line
chemotherapy
(all histologies)
1:1
PD
PD
Number of docetaxel cycles not restricted Monotherapy allowed after ≥4 cycles of combination therapy
Regions: Europe / Asia / South AfricaAccrual: Dec 23, 2008 to Feb 9, 2011
Reck et al., Lancet Oncology 2014, published online Jan 09
LUME 1 TRIAL: DOCETAXEL + NINTEDANIB VS DOCETAXEL +
PLACEBO IN 2ND LINE TREATMENT OF NSCLC
PFS in ITT (Primary Endpoint) OS in ADCA (Secondary Endpoint)
Reck M, et al. Lancet Oncol. 2014;15(2):143-55
LUME 1: EFFICACY IN UNFAVORABLE POPULATIONS
OS in patients with PD as best response to FL(exploratory analysis)
OS in patients with early progressing tumor(key secondary endpoint)
Mellemgaard et al. Eur J Cancer 2013;49(suppl 2):Abstract 3409; Reck et al. Lancet Oncol 2014;15:143–155
Docetaxel Pemetrexed ErlotinibAfatinib(SCC)
Docetaxel+ Ramucirumab
(NSCLC)
Docetaxel+ Nintedanib
(NSCLC)
RR, % 5.0–12.0 7.1–11.8 7.9–9.0 6 234.4
Central Review
Median PFS, m 2.0–3.1 2.6–2.9 2.2–3.6 2.4 4.5 3.4
Median OS, m 5.7–8.0 6.7–8.9 6.7–7.9 7.9 10.5 10.1
1-year OS,% 28.7–37.0 29.7–38.5 31.0–35.7 nr nr nr
Shepherd, et al. JCO 2000; Fossella, et al. JCO 2000; Ramlau, et al. JCO 2006; Paz-Ares, et al. BJC 2008
Kim, et al. Lancet 2008; Krzakowski, et al. JCO 2010; Hanna, et al. JCO 2004, Cullen, et al. Ann Oncol 2008
Shepherd, et al. NEJM 2005; Vamvakas, et al. ASCO 2010; Ciuleanu, et al. IASLC Chicago 2010; Reck M , et al, Lancet Oncology
2014; Garon E et al, Lancet 2014; Soria JC, Lancet Oncology 2015
*Second- and third-line therapy
SECOND LINE TREATMENT NSCLC – UPDATED RESULTS
1. Before Immunotherapy
2. During Immunotherapy
THE THREE PERIODS OF SECOND-LINE TREATMENT
INHIBITION OF PD-1 /PD-L1:
A NEW CONCEPT TO OVERCOME AVOIDANCE OF IMMUNE
DESTRUCTION
Hanahan D, Weinberg RA. Cell. 2011;144:646–674; Wolchok J: ASCO 2013 17
Inhibition of PD-1 /PD-L1
ANTI – PD-1 MONOTHERAPY IN PRETREATED PATIENTSPRIMARY ENDPOINT: OS!
Nivolumab – CheckMate 017 (PIII)1
2nd Line, squamous, PD-L1 All-ComerNivolumab – CheckMate 057 (PIII)2
2nd Line, non-squamous, PD-L1 All-Comer
Pembrolizumab - Keynote 010 (PII/III)3
2nd+ Line, PD-L1 TPS ≥1%Atezolizumab – OAK (PIII)4
2nd+ Line, PD-L1 All-Comer
1. Borghaei H et al. Poster presentation at ASCO 2016. 9025. 2. Brahmer JR et al. Oral presentation at AACR 2017. CT077. 3. Herbst RS et al. Poster presentation at ASCO 2017. 9090. 4. Rittmeyer A et al. Lancet. 2017;389(10066):255-265.
CONSISTENT BENEFIT IN OS
Borghaei et al., 2016, ASCO.1Time (Months)
100
80
60
40
20
00 6 30
OS
(%
)
1812 24 36
NivolumabDocetaxel
Checkmate 017 (SQ)1
Time (Months)
2-yr OS = 23%2-yr OS = 8%
NivolumabDocetaxel
100
80
60
40
20
00 6 30
OS
(%
)
1812 24 36
Checkmate 057 (NSQ)1
2-yr OS = 29%2-yr OS = 16%
Herbst et al., 2017, ASCO.3
OS
(%
)
Rittmeyer et al., 2017, Lancet.4Time (Months)
100
80
60
40
20
00 3 6 9 12 15 18 21 24 27
Atezolizumab
Docetaxel
+++++++++++++++++++++++++++++++
+++++++++++++++++++++++++++
++
++++++++++
++
+++++++++
++
OAK4
18-mo OS = 40%18-mo OS = 27%
Time (Months)
100
80
60
40
20
00 5 10 15 20 25 30 35
OS
(%
)
Pembro 2 mg/kgPembro 10 mg/kgDocetaxel
KEYNOTE-010 (≥1% PD-L1)3
30-mo OS = 29.5%30-mo OS = 22.1%30-mo OS = 12.3%
Borghaei H et al. Poster presentation at ASCO 2016. 9025. 2. Brahmer JR et al. Oral presentation at AACR 2017. CT077. 3. Herbst RS et al. Poster presentation at ASCO 2017. 9090. 4. Rittmeyer A et al. Lancet. 2017;389(10066):255-265.
LONG TERM OS IN KN 010
OVERALL SURVIVAL (PRIMÄRER ENDPUNKT)
KN010_Herbst et al. #LBA63_ESMO_2018
PD-L1 =/> 50%Med OS: 16.9 vs 8.2 m3 y OS: 35% vs 13%HR 0.53, p<0.00001
PD-L1 =/> 1%Med OS: 11.8 vs 8.4 m3 y OS: 23% vs 11%HR 0.69, p<0.00001
CONSISTENT BENEFIT IN TOLERABILITYCheckmate 017 (SQ)1
N=272Checkmate 057 (NSQ)1
(N=582)
Nivo Doc Nivo Doc
TRAEs (%) 61 87 71 88
Grade 3–5 8 56 11 54
DC Rate (%) 6 10 6 15
Minimum follow-up: 24.2 mos
Cross-study comparisons are not intended.
2L=second line; atezo=atezolizumab; DC=discontinuation; doc=docetaxel; I-O=immuno-oncology; IQR=interquartile range; nivo=nivolumab; NSCLC=non-small cell lung cancer;PD-L1=programmed death ligand 1; pembro=pembrolizumab; TRAE=treatment-related adverse event.
1. Borghaei H et al. Presented at ASCO 2016. 9025. 2. Herbst RS et al. Lancet. 2016;387(10027):1540-1550. 3. Rittmeyer A et al. Lancet. 2017;389(10066):255-265.
Table extracted from: Rittmeyer et al., 2017, Lancet.3
Pembro(2 mg/kg)
Pembro(10 mg/kg)
Doc
TRAEs (%) 63 66 81
Grade 3–5 13 16 35
DC Rate (%) 4 5 10
Median follow-up: 13.1 mos (IQR 8.6–17.7)
Atezo Doc
TRAEs (%) 64 86
Grade 3–5 15 43
DC Rate (%) 8 19
Median follow-up: 21 mos
KEYNOTE-010 (≥1% PD-L1)2
N=1034OAK3
N=850Table extracted from: Borghaei et al., 2016, ASCO.1
Table extracted from: Herbst et al., 2016, Lancet.2
IMPACT ON SYMPTOM CONTROL / QUALITY OF LIFE
EXAMPLE: CHECKMATE 17
Improvement of Health Status Time to Deterioration of Health Status
Reck M et al, J Thorac Oncol 2018
SECOND LINE IMMUNOTHERAPY: OPEN QUESTIONS
• Importance of PD-L1 Expression
CORRELATION OF PD-L1 EXPRESSION AND EFFICACY
Borghaei H, ASCO 2016; Rittmeyer A, Lancet 2016; Herbst R, Lancet 2015
EFFICACY OF IMMUNOTHERAPIES IN PDL-1 NEGATIVE PATIENTS
Brahmer J et al, ESMO Asia 2015; Rittmeyer A et al, Lancet 2016, Barlesi ESMO 2016
RR: 9%DOR: 18.3 months RR: 8% (Atezo) vs 11% (Doce)
OS: 12.6 vs 8.9 months (HR 0.75)
Nivolumab – CM 57 Atezolizumab - Oak
SECOND LINE IMMUNOTHERAPY: OPEN QUESTIONS
• Importance of PD-L1 Expression
• Duration of treatment
Exploratory Analysis• Improvement in PFS (HR 0.42), 1 year PFS:
65% vs 40%• Improvement in PFS independent from RR• Trend in OS (HR 0.63)• Some stabilizations by reexposure
A Signal – CheckMate 153
Spigel D et al, ESMO 2017; abstract 1297O
SOMETIMES TREATMENT DURATION DOES MATTER
28
64 year old female patients, ADCA stage IV, EGFR -, ALK -, PDL-1 >50%PD after Cisplatin/Pemetrexed and Docetaxel / Nintedanib
Third Line Treatment with Pembrolizumab
04.01.17 18.05.17 02.11.17 07.01.19
A quality of clinical and radiological response that we could not achieve by chemotherapy
SECOND LINE IMMUNOTHERAPY: OPEN QUESTIONS
• Importance of PD-L1 Expression
• Duration of treatment
• Treatment beyond progression?
Atezo Post-PD Other Post PDNo Treatment
Post PD
Number 168 (51%) 94 (28%) 70 (21%)
Median OS12.7 m
(9.3 ; 14.9)8.8 m
(6.0 ; 12.1)2.2 m
(1.9 ; 3.4)
18 m OS 37% 20% 9%
Treatment beyond ProgressionExample Atezolizumab
Gandara D et al, ASCO 2017; abstract 9001
SECOND LINE IMMUNOTHERAPY: OPEN QUESTIONS
• Importance of PD-L1 Expression
• Duration of treatment
• Treatment beyond progression?
• The Question of Hyperprogression
Courtesy of S. Champiat, ESMO IO Course 2018
PATTERNS OF PROGRESSION
(DETERMINATION OF HYPERPROGRESSION IS COMPLEX)
Champiat et al.
Clin. Cancer Research
2016
Kato et al.
Clin. Cancer Research
2017
Saada-Bouzid et al.
Annals of Oncology 2017
Ferrara et al.
WLC presentation
Oct. 2017
Population
N = 131
Metastatic cancersphase 1 trials
PD1 or PD-L1 inhibitors monotherapy
N = 155
Metastatic cancerswith molecular profiling
CTLA-4, PD-1/PD-L1 inhibitors or other investigational agents
N= 34
recurrent and/or Metastatic
head and neck squamous
cell carcinoma
PD-1/PD-L1 inhibitors
N= 406
Advanced NSCLC
PD-1/PD-L1 inhibitors + IO combo
HPD rate ?9%
(12/131)
6%
(6/102)
29%
(10/34)
14%
(56/406)
Associated factors
Age(66 vs 55, p = 0.007)
All analysis were performedfor TTF < 2months only,
no correlation was evaluated for hyperprogression
Regional recurrence (TGKR≥2: 90% vs TGKR<2 : 37%, p=0.008)
Metastatic sites > 2(9% vs 19%, p = 0.005)
Reported studies integrating tumor kinetics
No association with tumor PD-L1 status, baseline tumor burden, number or type of previous
therapeutic lines, baseline corticosteroid use, presence of inflammatory markers at baseline
Courtesy of S. Champiat, ESMO IO Course 2018
• Before Immunotherapy
• During Immunotherapy
• After Immunotherapy
THE THREE PERIODS OF SECOND-LINE TREATMENT
OPPORTUNITIES OF POST PROGRESSION TREATMENT WILL CHANGE
TODAY
1. NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer, V.6.2015
2. Reck M et al. Ann Oncol 2014;25(Suppl 3):27-39
3. Sanofi Aventis. Taxotere® (docetaxel) prescribing information. Nov 2014
4. Eli Lilly and Company. Alimta® (pemetrexed) prescribing information. Sep 20135. Astellas Pharma and Genentech. Tarceva® (erlotinib) prescribing information. June 2015
Progression during or after platinum therapyProgression during or after platinum therapy
ChemotherapyChemotherapy AntiangiogenicsAntiangiogenics Immune checkpoint
inhibitors
Immune checkpoint
inhibitors
Nintedanib6,a
(+ docetaxel)
Nintedanib6,a
(+ docetaxel)Docetaxel3Docetaxel3 Pemetrexed4Pemetrexed4 Ramucirumab7
(+ docetaxel)
Ramucirumab7
(+ docetaxel)
Nivolumab8
Atezolizumab10
Nivolumab8
Atezolizumab10
Not suitable for
squamous NSCLC
Not suitable for
squamous NSCLC
US and EU approved
for squamous and
nonsquamous NSCLC
US and EU approved
for squamous and
nonsquamous NSCLC
Not suitable
for SqCLC
Not suitable
for SqCLC
If not given previouslyIf not given previously
If docetaxel
not given
previously
If docetaxel
not given
previously
EGFR TKIEGFR TKI
Erlotinib5Erlotinib5
May be
inferior to
chemotherapy in WT
patients
May be
inferior to
chemotherapy in WT
patients
6. Boehringer Ingleheim. Vargatef® (nintedanib) summary of product characteristics. March 2015
7. Eli Lilly and Company. Cyramza® (ramucirumab) prescribing information. April 2015
8. Bristol-Myers Squibb. Opdivo® (nivolumab) prescribing information. April 2016
9. Merck & Co., Inc. Keytruda® (pembrolizumab) prescribing information. October 2015
10. Chugai Pharmaceutical. Tecentriq® (atezolizumab) prescribing information in Japan. April 2018
Pembrolizumab9,bPembrolizumab9,b
Only approved for
patients whose tumors
express PD-L1
Only approved for
patients whose tumors
express PD-L1
aApproved in EU only; bApproved in US only
1. NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer, V.6.2015
2. Reck M et al. Ann Oncol 2014;25(Suppl 3):27-39
3. Sanofi Aventis. Taxotere® (docetaxel) prescribing information. Nov 2014
4. Eli Lilly and Company. Alimta® (pemetrexed) prescribing information. Sep 20135. Astellas Pharma and Genentech. Tarceva® (erlotinib) prescribing information. June 2015
6. Boehringer Ingleheim. Vargatef® (nintedanib) summary of product characteristics. March 2015
7. Eli Lilly and Company. Cyramza® (ramucirumab) prescribing information. April 2015
8. Bristol-Myers Squibb. Opdivo® (nivolumab) prescribing information. April 2016
9. Merck & Co., Inc. Keytruda® (pembrolizumab) prescribing information. October 2015
10. Chugai Pharmaceutical. Tecentriq® (atezolizumab) prescribing information in Japan. April 2018
EGFR TKIEGFR TKI
May be
inferior to
chemotherapy in WT
patients
May be
inferior to
chemotherapy in WT
patients
OPPORTUNITIES OF POST PROGRESSION TREATMENT WILL CHANGE
TOMORROW?
Progression during or after platinum therapyProgression during or after platinum therapy
ChemotherapyChemotherapy AntiangiogenicsAntiangiogenics Immune checkpoint
inhibitors
Immune checkpoint
inhibitors
Nintedanib6,a
(+ docetaxel)
Nintedanib6,a
(+ docetaxel)Docetaxel3Docetaxel3 Pemetrexed4Pemetrexed4 Ramucirumab7
(+ docetaxel)
Ramucirumab7
(+ docetaxel)
Nivolumab8
AtezolizumabNivolumab8
Atezolizumab
Not suitable for
squamous NSCLC
Not suitable for
squamous NSCLC
US and EU approved
for squamous and
nonsquamous NSCLC
US and EU approved
for squamous and
nonsquamous NSCLC
Not suitable
for SqCLC
Not suitable
for SqCLC
If not given previouslyIf not given previously
If docetaxel
not given
previously
If docetaxel
not given
previously
Erlotinib5Erlotinib5 Pembrolizumab9,bPembrolizumab9,b
Only approved for
patients whose tumors
express PD-L1
Only approved for
patients whose tumors
express PD-L1
aApproved in EU only; bApproved in US only
Pemetrexed FLin most patients
VEGF: A KEY MEDIATOR OF THE IMMUNESUPPRESSIVE
MICROENVIRONMENT OF THE TUMOR
Adapted from Monjazeb AM et al. 1. Monjazeb AM et al. Front Oncol. 2013 Jul 26;3:197. 2. Fukumura D et al. Nat Rev Clin Oncol. 2018;15(5):325-340.
VEGF creates an immunosuppressive microenvironment2
• Upregulation of immunosuppressive cells:• Regulatory T-cells (T-regs)• Myeloid-Derived Suppressor Cells (MDSCs)
• Impaired antigen presentation: • Suppression of dendritic cell (DC) maturation, macrophages
(TAMs)• Impaired T-cell function (CTLs)
N
T
CD4
Treg
CD8
NK
TAM
MDSC
iDC
VEGF
EFFICACY OF DOCETAXEL + NINTEDANIB 3L TREATMENT AFTER
CHEMOTHERAPY AND IMMUNOTHERAPY
VARGADO (Cohort B) Interim Analysis 2018
Spanish NPU
Corral et al WCLC 2017
Population N
Median PFS
(Months)
Invest*
NMedian PFS (Months)
Invest*
3L Nintedanib + docetaxel
Prior IO 21 5.5 11 3.2
VARGADO (Cohort B) Interim Analysis 2018
Spanish NPU
Corral et al WCLC 2017
Population NORR
(%)
DCR
(%)N
ORR
(%)
DCR
(%)
3L Nintedanib + docetaxel
Prior IO 12 58 83 11 36.5 82.0
PFS
ORR & DCR
Interim Data Cut-Off 01 August 2018
1. Grohé et al. Ann Oncol. 2018;29 (suppl 10):55P. 2. Corral J et al. J Thorac Oncol. 2017;12(11 suppl 2):abstr P2.01-022.
OS data were not yet mature at the time of the analysis
VARGADO COHORT B (PRIOR IO):
TREATMENT DURATION BY TREATMENT
*Single-agent nintedanib treatment ongoing.§Previous therapies not documented.1. Grohé et al. Ann Oncol. 2018;29 (suppl 10):55P
Interim Data Cut-Off 01 August 2018
ENHANCING IMMUNOGENICITYBY COMBINATION
• Enhancement of T-Cell priming
• Removal of coinhibitory signals
• Supply of costimulatory signals
• Conditioning the tumor microenvironment
Whiteside TL, Clin Cancer Res (2016); 22(8): 1845–55
THE LANDSCAPE OF COMBINATION TRIALS(IT WILL BECOME DIFFICULT TO KEEP THE OVERVIEW...)
Combination trials with a
anti-PD-1/anti-PDL1
backbone
Tang J et al., Ann Oncol 2018, e-published
CONCLUSIONS
• Second Line Treatment represents an effective and important
part of lung cancer treatment
• Second Line Treatment should be offered to all eligible patients
(we should be able to beat the 50%)
• Second Line Treatment has undergone signficant changes with
the implementation of immunotherapies
• Second Line Treatment will have to undergo significant changes
with the introduction of immunotherapies in first-line treatment