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Treating second-line and beyond in non-mutated, non-squamous NSCLC:
now and tomorrow
Sanjay Popat, BSc, MBBS, FRCP, PhD
Royal Marsden Hospital
London, United Kingdom
ESMO 2018 Congress, Munich, Germany, 19-23 October 2018
2
• Personal financial interests:
– Honoraria: BMS, Roche, Takeda, AstraZeneca, Chugai, Novartis, Pfizer, MSD, EMD Serono,
Guardant Health, AbbVie, Boehringer Ingelheim, Medscape, Tesaro, OncLive
– Leadership: none
– Stock: none
– Licensing: none
– Direct funding: Elsevier
• Institutional financial interests:
– Institutional research funding: BMS, Clovis Oncology, Roche, Eli Lilly, Takeda, Pfizer, Epizyne,
Ariad, Bayer, Boehringer Ingelheim, Celgene, EMD Serono, MSD, Synta
• Non-financial interests: none
Disclosures
ESMO 2018 Congress, Munich, Germany, 19-23 October 2018
3
Nonsquamous NSCLC
• NSCLC accounts for 85%-90% of lung cancers1
– ADC accounts for 40% of all lung cancers, and is the most common NSCLC subtype
• Driver mutations have been identified in NSCLC and are used to guide therapy2
– EGFR mutations: 10%-12% of whites1
– ALK rearrangement: 5% of patients1
• First-line immunotherapy trial outcomes have led to a rapid shift in treatment paradigms
for patients with NSCLC with no EGFR or ALK mutations3–5
– In the EU, pembrolizumab is approved as a first-line monotherapy for patients with metastatic
NSCLC and PD-L1 ≥50% and in combination with chemotherapy for patients with metastatic
nonsquamous NSCLC regardless of PD-L1 tumour expression status4,5
• Despite recent advancements, treatment of refractory or progressive disease after first-
line chemotherapy remains a challenge6
1. ESMO Web site. www.esmo.org/content/download/7252/143219/file/EN-Non-Small-Cell-Lung-Cancer-Guide-for-Patients.pdf. Accessed 2 October 2018; 2. Planchard et al. Ann Oncol. 2018; 29 (suppl 4):
iv192–iv237.; 3. Pabani and Butts. Curr Oncol. 2018;25:S944: 4. Keytruda SmPC. Merck Sharp & Dohme B.V. 2018; 5. Merck press release. https://investors.merck.com/news/press-release-
details/2018/European-Commission-Approves-Mercks-KEYTRUDA-pembrolizumab-in-Combination-with-Pemetrexed-and-Platinum-Chemotherapy-for-the-First-Line-Treatment-of-Patients-with-Metastatic-
Nonsquamous-NSCLC-with-No-EGFR-or-ALK-Genomic-Tumor-Aberrations/default.aspx. Accessed 2 October 2018; 6. Corrales et al. Front Med (Lausanne). 2017;4:13. doi: 10.3389/fmed.2017.00013.
ESMO 2018 Congress, Munich, Germany, 19-23 October 2018
4
Current Treatment Landscape for Stage IV
Nonsquamous NSCLC: ESMO Guidelines
a In the absence of contraindications and conditioned by the registration and accessibility of anti-PD-(L)1 combinations with platinum-based ChT, this strategy will be preferred to platinum-based ChT in patients with PS 0-1 and PD-L1 < 50%. Alternatively, if TMB can accurately be evaluated, and conditioned by the registration and accessibility, nivolumab plus ipilimumab should be preferred to platinum-based standard ChT in patients with NSCLC with a high TMB. bNot EMA-approved. ESMO = European Society for Medical Oncology; PD-L1 = programmed death-ligand 1; PS = performance status; Mb = megabases; MCBS = Magnitude of Clinical Benefit Scale; ChT = chemotherapy; nab-PC, albumin-bound paclitaxel and carboplatin; BSC = best supportive care; IO = immuno-oncology; EMA = European Medicines Agency.
Maintenance treatment:
Pemetrexed (continuation) [I,A]
Gemcitabine (continuation) [I,B]
Pemetrexed (switch) [I,B]
± bevacizumab (if given before)
Nivolumab [I,A; MCBS 5]
Atezolizumab [I,A; MCBS 5]
Pembrolizumab if PD-L1 >1% [I,A; MCBS 5]
Docetaxel [I,B]
Pemetrexed [I,B]
Ramucirumab/docetaxel [I,B; MCBS 1]
Nintedanib/docetaxel [II,B]
Erlotinib [II,C]
PD-L1 ≥50%
4-6 cycles:
Carboplatin-based doublets:
<70 years and PS 2 [II, A]
≥70 years and PS 0-2 [I,A]
Single-agent ChT:
Gemcitabine, vinorelbine,
docetaxel [I,B]
or pemetrexed [III,B]
BSC [II,B]
Any expression of PD-L1a
PS 0-1
Pembrolizumab
[I,A; MCBS 5]
PS 0-1
High TMB
≥10 mutations/Mb
Nivolumab/
ipilimumab
[I,A]b
Pembrolizumab/pe
metrexed and
platinum-based
ChT (4 cycles),
followed by
pembrolizumab
[I,A; MCBS 4]
Atezolizumab/
pemetrexed/
platinum-based
ChT (4-6 cycles),
followed by
atezolizumab
[I,B]b
Atezolizumab/
bevacizumab with
carboplatin and
paclitaxel
(4-6 cycles),
followed by
atezolizumab/
bevacizumab [I,A]b
4-6 cycles
Cisplatin/gemcitabine [I,A]
Cisplatin/docetaxel [I,A]
Cisplatin/paclitaxel [I,A]
Cisplatin/vinorelbine [I,A]
Carboplatin/gemcitabine [I,A]
Carboplatin/docetaxel [I,A]
Carboplatin/paclitaxel [I,A]
Carboplatin/vinorelbine [I,A]
Cisplatin/pemetrexed [II,A]
Carboplatin/pemetrexed [II,B]
nab-PC [I,B]
+/- bevacizumab [I,A with
carboplatin/paclitaxel, otherwise III,B]
PS 0-1
Platinum-based ChT
(see first-line treatment without IO)
Disease progression Partial response
or stable disease
Disease progression
BSC
Stage IV NSCC: Molecular tests negative (ALK/BRAF/EGFR/ROS1)
<70 years and PS 2 or
Selected ≥70 years and PS 0-2 PS 3-4
PS 3-4 PS 0-2
ESMO 2018 Congress, Munich, Germany, 19-23 October 2018
Planchard et al. Ann Oncol. 2018; 29 (suppl 4): iv192–iv237.
5
First-Line Immunotherapy for Patients With NSCLCa
Trial Treatment Median PFS (mo) HR for PFS Median OS (mo) HR for OS ORR (%)
KEYNOTE-0241,2,e ≥50% PD-L1: Pembrolizumab (n=154) vs chemo (n=151)
Mixed: nonsquamous (pembrolizumab, n=125; chemo, n=124)
10.3 vs 6.0
–
0.50b
0.55
30.0 vs 14.2
–
0.63c
–
45.5 vs 29.8
–
KEYNOTE-0423
≥1% PD-L1: Pembrolizumab (n=637) vs chemo (n=637)
Mixed: nonsquamous (pembrolizumab, n=394; chemo, n=388)
TPS ≥50%: 7.1 vs 6.4 0.81d 20.0 vs 12.2 0.69b 39.5 vs 32.0
TPS ≥20%: 6.2 vs 6.6 0.94 17.7 vs 13.0 0.77c 33.4 vs 28.9
TPS ≥1%: 5.4 vs 6.5
–
1.07
–
16.7 vs 12.1
–
0.81c
0.86
27.3 vs 26.5
–
KEYNOTE-1894,e Pembrolizumab + chemo (n=410) vs placebo + chemo (n=206)
All nonsquamous
8.8 vs 4.9 0.52b
NR vs 11.3
0.49b 47.6 vs 18.9
IMpower1505,6
Arm A: atezolizumab + chemo (n=402)
Arm B: atezolizumab + bevacizumab + chemo (n=400)
Arm C: bevacizumab + chemo (n=400)
All nonsquamous
B vs C 8.3 vs 6.8 0.59b 19.2 vs 14.7 0.78d 56 vs 41
A vs C – – 19.4 vs 14.7 0.88 40 vs 41
IMpower1327 Atezolizumab + chemo (n=292) vs chemo (n=286)
All nonsquamous 7.6 vs 5.2 0.60b 18.1 vs 13.6 0.81 47 vs 32
Checkmate 227
Part I8,9
≥1% PD-L1: nivo + ipi (n=396); chemo (n=397); or
nivo (n=396)
<1% PD-L1: nivo + ipi (n=187); chemo (n=186); or
nivo + chemo (n=177)
Mixed: nonsquamous (n=1252)
Nivo + ipi vs
chemo
TMB ≥10
mut/Mb):
7.2 vs 5.5
9.5 vs 5.6
0.58b
0.55
23.0 vs 16.4
–
0.79
–
45.3 vs 26.9
–
IMpower130 (N=724), an ongoing phase 3 clinical trial comparing atezolizumab + chemo with chemo alone, met its coprimary end points of OS and PFS10,11
a These are not head-to-head trials and study designs are different; direct cross-trial comparisons cannot be made; P<0.001; cP=0.002; dP<0.05; eUsed as basis for regulatory approval in the United States and EU. PFS = progression-free survival; HR = hazard ratio; OS = overall survival; ORR = objective response rate; chemo = chemotherapy; nivo = nivolumab; ipi = ipilimumab. 1. Reck et al. N Engl J Med. 2016;375:1823; 2. Brahmer et al. WCLC 2017. Abstract OA 17.06. 3. Lopes et al. ASCO 2018. Abstract LBA4; 4. Gandhi et al. N Engl J Med. 2018;378:2078; 5. Socinski et al. N Engl J Med. 2018;378:2288; 6. Socinski et al. ASCO 2018. Abstract 9002; 7. Papadimitrakopoulou et al. WCLC 2018. Abstract OA05.07. 8. Hellmann et al. N Engl J Med. 2018;378:2093; 9. Hellmann et al. AACR 2018. Abstract CT077; 10. Roche. Media release. May 2018. www.roche.com/media/releases/med-cor-2018-05-29.htm. Accessed 2 October 2018; 11. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02367781. Accessed 3 August 2018.
ESMO 2018 Congress, Munich, Germany, 19-23 October 2018
6
a These are not head-to-head trials and study designs are different; direct cross-trial comparisons cannot be made; b P<0.01; c P<0.05; d P<0.001; e Pooled pembrolizumab doses; f Used as basis for regulatory approval; g By independent central review.
1. Borghaei et al. N Engl J Med. 2015;373:1627; 2. Herbst et al. Lancet. 2016;387:1540; 3. Herbst et al. ASCO 2017. Abstract 9090; 4. Rittmeyer et al. Lancet. 2017;389:255;
5. Fehrenbacher et al. J Thorac Oncol. 2018;13:1156; 6. Garon et al. Lancet. 2014;384:665; 7. Reck et al. Lancet Oncol. 2014;15:143; 8. Nintedanib SmPC 2018.
Second-Line Trials in Patients With NSCLCa
Trial Treatment Median PFS (mo) HR for PFS Median OS
(mo) HR for OS ORR (%)
Checkmate 0571f Nivolumab (n=292) vs docetaxel (n=290)
All nonsquamous
2.3 vs 4.2
0.92
12.2 vs 9.4
0.73b
19 vs 12c
KEYNOTE-0102,3,f
≥1% PD-L1: Pembrolizumab (2 mg/kg n=344; 10 mg/kg, n=346) vs
docetaxel (n=343)
Mixed: nonsquamous (pembrolizumab 2 mg/kg, n=240; 10 mg/kg,
n=244; docetaxel, n=240)
2 mg: 3.9 vs 4.0
10 mg: 4.0 vs 4.0
–
2 mg: 0.88
10 mg:
0.79b
0.86e
10.5 vs 8.6
13.4 vs 8.6
–
0.73d
0.59d
0.63e
18.0 vs 9.0d
18.0 vs 9.0d
–
OAK4,5,f Atezolizumab (n=425) vs docetaxel (n=425)
Mixed: nonsquamous (atezolizumab, n=313; docetaxel, n=315)
2.8 vs 4.0
–
0.93
–
13.8 vs 9.6
15.6 vs 11.2
0.75d
0.74b
14.6 vs 13.4
–
REVEL6,f
Ramucirumab + docetaxel (n=628) vs placebo + docetaxel (n=625)
Mixed: nonsquamous (ramucirumab + docetaxel, n=465; docetaxel,
n=447)
4.5 vs 3
4.6 vs 3.7
0.76d
0.77d
10.5 vs 9.1
11.1 vs 9.7
0.86c
0.83c
22.9 vs 13.6d
21.9 vs 14.5b
LUME-Lung 17,8,f
Nintedanib + docetaxel (n=655) vs placebo + docetaxel (n=659)
Mixed:nonsquamous ADC (nintedanib + docetaxel, n=322 vs placebo +
docetaxel, n=336)
3.4 vs 2.7
4.0 vs 2.8
0.79b
0.77c
10.1 vs 9.1
12.6 vs 10.3
0.94
0.83c
4.4 vs 3.3g
4.7 vs 3.6g
Use of first-line immunotherapy will affect which treatments,
including immunotherapy, will be available for use in second-line therapy and beyond
ESMO 2018 Congress, Munich, Germany, 19-23 October 2018
7
• Currently available antiangiogenic therapies
target different signalling pathways
• Many patients are intrinsically refractory or develop
resistance to existing antiangiogenic agents that
principally target VEGF-A or -B and VEGFR-2
• A multitargeted approach to treatment may limit
the development of resistance and maximise
antitumour efficacy
• Nintedanib is an oral triple angiokinase inhibitor
targeting VEGFR 1-3, FGFR 1-3, PDGFR α/β
Multiple Targets of Angiogenesis Inhibitors
VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor; FGFR = fibroblast growth factor receptor; PDGFR = platelet-derived growth factor receptor;
FLT-3 = fms-like tyrosine kinase 3.
Zhao and Adjei. Oncologist. 2015;20:660. ESMO 2018 Congress, Munich, Germany, 19-23 October 2018
8
Nintedanib for NSCLC: Phase 3 LUME-Lung 1 Study
Stratification: ECOG PS (0 vs. 1) Prior bevacizumab (yes vs no) Histology (squamous vs nonsquamous) Brain metastases (yes vs no)
Regions: Europe/Asia/South Africa
Accrual: 23 Dec 2008 to 09 Feb 2011
Primary Endpoint: PFS by independent central review
Key Secondary Endpoint: OS, prespecified hierarchical analyses of patients with ADC who progressed in <9 months after start of first-line therapy, all patients with ADC, 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=1,314
R
A
N
D
O
M
I
S
E
1:1
PD
PD
Monotherapy allowed after ≥4 cycles of combination therapy
Stage IIIB/IVa
or recurrent
NSCLC patients after
first-line chemotherapy
(all histologies)
PO = orally; IV = intravenously; PD = disease progression; ITT = intent-to-treat.
Reck et al. Lancet Oncol. 2014;15:143. ESMO 2018 Congress, Munich, Germany, 19-23 October 2018
9
LUME-Lung 1:
Consistent PFS Benefit Regardless of Histology
• For patients with adenocarcinoma histology, median PFS was 4 vs 2.8 months (HR [95% CI], 0.77 [0.62-0.96];
P=0.0193) for nintedanib + docetaxel vs placebo + docetaxel
• For patients with SqCC histology, median PFS was 2.9 vs 2.6 months (HR [95% CI], 0.77 [0.62-0.96]; P=0.02)
for nintedanib + docetaxel vs placebo + docetaxel
PFS (Total Population)
Docetaxel plus nintedanib
Docetaxel plus placebo
2 4 6 12 16
PF
S (
%)
100
80
60
40
0
20
0 10 8 14
HR 0.79, 95% CI 0.68-0.92, P=0.0019
CI = confidence interval; SqCC = squamous cell carcinoma.
1. Reck et al. Lancet Oncol 2014;15:143; Reck M et al. J Clin Oncol 2013;31(Suppl.):Abstract LBA8011.
Time (mo)
ESMO 2018 Congress, Munich, Germany, 19-23 October 2018
10
LUME-Lung 1: Significant Improvement
in Median OS in Patients With Adenocarcinoma
Reck et al. Lancet Oncol. 2014;15:143.
Key Secondary Endpoint, Prespecified Hierarchical Analysis
No. at Risk
Nintedanib 322 263 203 163 131 96 72 46 25 10
Placebo 336 269 184 139 101 73 55 33 15 7
4 8 12 24 36
Pro
ba
bilit
y o
f S
urv
iva
l (%
)
100
80
60
40
20
0 20 16 28 32
Time (mo)
52.7%
44.7% 25.7%
1-YEAR SURVIVAL
2-YEAR SURVIVAL
19.1%
Nintedanib
+
Docetaxel
Placebo
+
Docetaxel
Median OS (mo) 12.6 10.3
HR = 0.83 (95% CI: 0.70-0.99); P=0.0359
0
ESMO 2018 Congress, Munich, Germany, 19-23 October 2018
11
LUME-Lung 1: OS in Patients With ADC Who
Progressed <9 Months After Start of First-Line Therapy
Reck et al. Lancet Oncol. 2014;15:143; Reck and Mellemgaard. Biologics. 2015;9:47.
Key Secondary Endpoint, Prespecified Hierarchical Analysis
No. at Risk
Nintedanib 206 167 119 92 73 51 35 16 9 3
Placebo 199 154 91 62 42 25 17 12 5 1
4 8 12 24 36
Pro
ba
bilit
y o
f S
urv
iva
l (%
)
100
80
60
40
20
0 20 16 28 32
Time (mo)
Nintedanib
+
Docetaxel
Placebo
+
Docetaxel
Median OS (mo) 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%
0
ESMO 2018 Congress, Munich, Germany, 19-23 October 2018
12
LUME-Lung 1:
OS in the European ADC Populationa,b
a Exploratory analysis. b Patients without documented death were censored at the date of last contact when the patient was known to be alive.
Gottfried et al. Target Oncol. 2017;12:475; Heigener et al. 1276P, ESMO 2016.
No. at Risk
Nintedanib 229 215 188 168 151 132 116 107 92 80 68 60 50 42 34 26 19 17 8
Placebo 234 218 183 146 122 101 91 79 67 58 50 43 39 31 22 20 11 10 6
4 8 12 24 36
Es
tim
ate
d P
erc
en
tag
e A
live
100
80
60
40
0
20
0 20 16 28 32
Time From Randomization (mo)
2 6 10 14 18 22 26 30 34
Nintedanib
+
Docetaxel
Placebo
+
Docetaxel
Median (mo) 13.4 8.7
HR (95% CI) 0.79 (0.65-0.97);
P=0.0254 53.3%
41.8%
18.8%
25.3%
1-YEAR SURVIVAL
2-YEAR SURVIVAL
ESMO 2018 Congress, Munich, Germany, 19-23 October 2018
13
No. at Risk
Nintedanib 237 225 193 162 141 123 109 96 86 72 60 55 44 34 24 17 11 8 3 2 2 1 0
Placebo 230 210 178 138 111 89 77 64 53 44 34 28 24 21 15 13 5 2 0
4 8 12
Es
tim
ate
d P
erc
en
tag
e A
live
100
80
60
40
0
20
0 20 16
Time From Randomization (mo)
2 6 10 14 18 22 44 42 40 38 36 34 32 30 28 26 24
No. at Risk
Nintedanib 53 50 44 35 27 25 22 20 18 14 13 12 10 9 7 5 4 4 2
Placebo 64 57 51 31 24 16 14 12 11 10 7 4 3 3 2 2 2 2 1
4 8 12
Es
tim
ate
d P
erc
en
tag
e A
live
100
80
60
40
0
20
0 20 16
Time From Randomization (mo)
2 6 10 14 18 22 36 34 32 30 28 26 24
LUME-Lung 1:
OS in European Patients With Faster-Progressing ADCa
a Exploratory analysis.
Gottfried et al. Target Oncol. 2017;12:475; Heigener et al. 1276P, ESMO 2016.
ADC and Time From End of
First-Line Therapy ≤6 Months
ADC and Progressive Disease as Best
Response to First-Line Therapy
Nintedanib Placebo
Median (mo) 11.3 8.2
HR (95% CI) 0.75 (0.61-0.92);
P=0.0047
48.2%
36.5%
12.5%
22.4%
43.0%
24.6%
5.3%
21.5%
Nintedanib Placebo
Median (mo) 9.8 6.3
HR (95% CI) 0.62 (0.41-0.94);
P=0.0246
1-YEAR SURVIVAL
2-YEAR SURVIVAL
1-YEAR SURVIVAL
2-YEAR SURVIVAL
ESMO 2018 Congress, Munich, Germany, 19-23 October 2018
14
Summary of AEs in Patients With ADC
Patients With AEs, n (%)
Nintedanib +
Docetaxel
(n=320)
Placebo +
Docetaxel
(n=333)
Any AE, all grades 308 (96.3) 314 (94.3)
Drug-related AEs, all grades 260 (81.3) 241 (72.4)
Any AE, grades ≥3 243 (75.9) 228 (68.5)
Drug-related AEs, grades ≥3 176 (55.0) 152 (45.6)
Any AE leading to
discontinuation 67 (20.9) 59 (17.7)
Any serious AE 111 (34.7) 107 (32.1)
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common
Terminology Criteria for Adverse Events (aversion 3.0 was used)
1. Reck et al. Lancet Oncol. 2014;15(suppl):143; 2. Boehringer Ingelheim. Data on file.
Gastrointestinal events
• Diarrhea, nausea, and vomiting
• Manageable with supportive treatment
and dose modification
Liver enzyme elevations
(ALT/AST) • Reversible upon dose modification in
the majority of patients
Main AEs (Any Grade) That Were
More Common With Nintedanib1 AEs in Patients With ADC1,2,a
Median duration of treatment in ADC population:
• Overall treatment: nintedanib (4.3 mo) vs placebo (3.0 mo)
• Nintedanib/placebo treatment: nintedanib (4.2 mo) vs placebo (3.0 mo)
ESMO 2018 Congress, Munich, Germany, 19-23 October 2018
15
• Pembrolizumab, as a monotherapy or in combination with chemotherapy, has become
the first-line standard of care in patients with NSCLC without driver mutations1–3
• First-line use of immunotherapies is increasing, which will affect treatment options
for second-line use2–3
• LUME-Lung 1 trial of nintedanib + docetaxel in advanced NSCLC demonstrated4
– Significant prolongation of PFS regardless of histology
– Significant improvement in OS in patients with adenocarcinoma histology
– Manageable safety profile
• An exploratory analysis demonstrated a nearly 5-month median OS improvement
for European patients treated with nintedanib + docetaxel vs placebo + docetaxel5
• Nintedanib in combination with docetaxel is a viable second-line option
for the treatment of refractory or progressive adenocarcinoma NSCLC4,5
Conclusions
1. Pabani and Butts. Curr Oncol. 2018;25:S944: 2. Keytruda SmPC. Merck Sharp & Dohme B.V. 2018; 3. Merck press release. https://investors.merck.com/news/press-release-details/2018/European-
Commission-Approves-Mercks-KEYTRUDA-pembrolizumab-in-Combination-with-Pemetrexed-and-Platinum-Chemotherapy-for-the-First-Line-Treatment-of-Patients-with-Metastatic-Nonsquamous-
NSCLC-with-No-EGFR-or-ALK-Genomic-Tumor-Aberrations/default.aspx. Accessed 2 October 2018; 4. Reck et al. Lancet Oncol. 2014;15:143; 5. Gottfried et al. Target Oncol. 2017;12:475.
ESMO 2018 Congress, Munich, Germany, 19-23 October 2018