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Opportunities for
new treatment
options in
squamous NSCLC
Module 3
Last updated: December 2016
Contents
•
•
•
•
Targeted therapies
Immunotherapy targets
Oncogenic drivers
Ongoing trials in squamous NSCLC
NSCLC, non-small cell lung cancer
1
Targeted
therapies
Potential molecular targets in
squamous NSCLC: EGFR expression1
• EGFR activation plays a significant role in tumorigenesis1
C
EGFR
activation
C
Ligand
EGFR
dimer
Metastatic
spread
Cell survival
Angiogenesis
Tumor
Proliferation
Reprinted by permission from Macmillan Publishers Ltd
Blood
vessel
EGFR, epidermal growth factor receptor;
NSCLC, non-small cell lung cancer
Figure reproduced from ref 1
1. Jakobovits A et al. Nat Biotechnol 2007;25:1134–43
3
EGFR activation is a relevant target
for squamous NSCLC1-2
mAbs bind to the extracellular portion of
EGFR and have shown clinical benefit
when combined with 1st-line
chemotherapy treatment of squamous
NSCLC1,3,4
Most
squamous
NSCLC
express
EGFR2
EGFR
Proliferation
Metastasis
TKIs bind to the intracellular tyrosine
kinase domain of EGFR and should be
limited to EGFR M+ NSCLC in the 1stline treatment setting5
<5% of
squamous
NSCLC are
EGFR M+6
EGFRvIII mutant
Invasion
Apoptosis
EGFR, epidermal growth factor receptor; mAb, monoclonal antibody;
NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor
1. Pirker R et al. Lancet 2009;373:1525–31; 2. Lopez-Malpartida AV et al. Lung Cancer 2009;65:25–33; 3. Erbitux [package insert].
Princeton, NJ: Bristol-Myers Squibb Company 2013; 4. Thatcher N et al. Lancet Oncol 2015;16:763–74;
5. Laurie SA, Goss GD. J Clin Oncol 2013;31:1061–9; 6. Pan Y et al. Chest 2014;145:473–9
4
Advances in 1st-line therapy for advanced
squamous NSCLC: EGFR ‒ necitumumab
Necitumumab treatment setting: Approved as 1st-line therapy in combination with gemcitabinecisplatin for metastatic squamous NSCLC (US)1 or locally advanced / metastatic EGFR-expressing
squamous NSCLC (EU)2
Results from a randomized Phase III clinical trial:3
HR (95% CI)
Median OS
Median PFS
11.5
a
9.9
5.7
b
or bsecondary endpoint
4
Gem / cis (n=548)
0.85 (0.74, 0.98)
p=0.02
5.5
0
aPrimary
0.84 (0.74, 0.96)
p=0.01
Necitumumab
+ gem / cis (n=545)
8
12
Time (months)
Necitumumab + gemcitabine-cisplatin is FDA / EMA approved for metastatic squamous NSCLC;1,2 the NCCN does not include
necitumumab + gemcitabine-cisplatin as a treatment option4
CI, confidence interval; cis, cisplatin; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency;
FDA, Food and Drug Administration; gem, gemcitabine; HR, hazard ratio; NCCN, National Comprehensive Cancer Network;
NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival
1. FDA. Necitumumab. Highlights of prescribing information. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125547s000lbl.pdf (accessed June 20, 2016);
2. EMA. Necitumumab summary of product characteristics. 2016. Available at: http://www.ema.europa.eu/docs/en_GB/
document_library/EPAR_-_Product_Information/human/003886/WC500202694.pdf (accessed June 20, 2016);
3. Thatcher N et al. Lancet Oncol 2015;16:763–74; 4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology
(NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2017. © National Comprehensive Cancer Network, Inc. 2016.
All rights reserved (accessed December 12, 2016. To view the most recent and complete version of the guideline, go online to NCCN.org.
NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®,
and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
5
Immunotherapy
targets
Immunotherapy targets in NSCLC:
CTLA-4 and PD-1 pathways (1 of 2)
CTLA-4 and PD-1 pathways are immune checkpoint pathways
that play critical roles in controlling T-cell immune responses1
CTLA-4 pathway
Tumor
antigen
presentation
TCR
MHC
PD-1 pathway
Tumor
antigen
presentation
Deactivated
CD8+ T-cell
MHC
B7
CTLA-4
Deactivated
CD8+ T-cell
TCR
CD28
PD-L1
PD-1
PD1: PD-L1
binding
CTLA-4: B7 binding
Tumor cell
Tumor cell growth
and proliferation
Reprinted with permission from Dove Medical Press Ltd
T-cells can become unresponsive after CTLA-4 binds B7 molecules on APC,
or when PD-1 binds PD-L1 or PDL-2 on target cells
APC, antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte-associated antigen-4;
MHC, major histocompatibility complex; NSCLC, non-small cell lung cancer;
PD-1, programmed cell death protein-1; PD-L1, programmed cell death ligand-1; TCR, T cell receptor
1. Davies M. Cancer Manag Res 2014;6:63–75
7
Immunotherapy targets in NSCLC:
CTLA-4 and PD-1 pathways (2 of 2)
Anti-CTLA-4, PD-1, or PD-L1 antibodies can restore
T-cell activation and killing of tumor cells1
Activated
CD8+ T-cell
Activated
CD8+ T-cell
Cytolytic molecules
CD28
B7
PD-1
CTLA-4
PD-L1
Anti-CTLA-4 antibody
Tumor cell
Tumor cell
Anti-PD-1 antibody
Tumor cell death
Reprinted with permission from Dove Medical Press Ltd
•
Anti-CTLA and -PD-1 antibodies are associated with unconventional response
patterns and immune-related adverse events1
APC, antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte-associated antigen-4;
NSCLC, non-small cell lung cancer; PD-1, programmed cell death protein-1;
PD-L1, programmed cell death ligand-1
1. Davies M. Cancer Manag Res 2014;6:63–75
8
Advances in other treatment settings in
advanced NSCLC: nivolumab immunotherapy
Nivolumab treatment setting: Approved for metastatic NSCLC on progression or after platinum-based
chemotherapy1,2
Results from a randomized Phase III clinical trial:3
Nivolumab (n=135)
Docetaxel (n=137)
HR (95% CI)
Median OS
9.2
a
0.59 (0.44, 0.79)
p<0.001
6.0
3.5
Median PFS b
0.62 (0.47, 0.81)
p<0.001
2.8
0
4
8
12
Time (months)
aPrimary
or bsecondary endpoint
CI, confidence interval; HR, hazard ratio; NSCLC, non-small cell lung cancer;
OS, overall survival; PFS, progression-free survival
1. FDA. Nivolumab. Highlights of prescribing information. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125527s000lbl.pdf
(accessed June 20, 2016); 2. EMA. Nivolumab BMS summary of product characteristics. 2015.
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003840/WC500190648.pdf (accessed
June 20, 2016); 3. Brahmer J et al. N Engl J Med 2015;373:123–35
9
Advances in other treatment settings in
advanced NSCLC: pembrolizumab
immunotherapy
Pembrolizumab treatment setting: Indicated for first-line treatment for patients with metastatic NSCLC
whose tumors express PD-L1 in ≥50% of cells and who do not have EGFR- or ALK-positive tumor
mutations. Also indicated for patients with locally advanced or metastatic NSCLC progressing after ≥1
prior chemotherapy regimen and whose tumors express PD-L1 with ≥1% of cells. Patients with EGFRor ALK-positive tumor mutations should also have received targeted therapy prior to treatment with
pembrolizumab1,2
Results from a randomized Phase III clinical trial:3,4
Pembrolizumab 10 mg/kg (n=346)
Median OS
TPS ≥50%
Median OS
Pembrolizumab 2 mg/kg (n=345)
3,a
18.8
15.8
0.54 (0.39, 0.73)
8.2
12.7
4,a
10.4
8.5
4.0
3.9
4.0
4,a
Median PFS
0
aPrimary
endpoint
Docetaxel (n=343)
HR (95% CI)
4
8
12
Time (months)
16
0.48 (0.35, 0.66)
0.71 (0.58, 0.88)
p=0.0008
0.61 (0.49, 0.75)
p<0.0001
0.88 (0.74, 1.05)
p=0.07
0.79 (0.66, 0.94)
p=0.004
20
ALK, anaplastic lymphoma kinase; CI, confidence interval; EGFR, epidermal growth factor receptor;
HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival;
PD-L1, programmed cell death ligand-1; TPS, tumor proportion score
1. FDA. Pembrolizumab. Highlights of prescribing information. Available at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf (accessed
December 12, 2016); 2. EMA Summary of opinion (post authorization). Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/003820/WC500218016.pdf
(accessed February 22 2017); 3. Herbst R et al. ESMO Congress 2016. Abstract LBA48; 4. Herbst RS et al. Lancet 2016;387:1540–50
10
Advances in other treatment settings in
advanced NSCLC: atezolizumab immunotherapy
Atezolizumab treatment setting: Approved for metastatic NSCLC with progression on or after
platinum-based chemotherapy; patients with EGFR- or ALK-positive tumor mutations should have
progressed on approved therapy for these mutations1
OS results from a randomized Phase III clinical trial:2
Atezolizumab (n=425)
Docetaxel (n=425)
HR (95% CI)
15.6
*Nonsquamous
NSCLC
0.73 (0.60, 0.89)
p=0.0015
11.2
8.9
Squamous
NSCLC
0.73 (0.54, 0.98)
p=0.0383
7.7
0
4
8
Time (months)
12
16
ǂThere are 4 main pathological types of lung cancer (adeno-, squamous cell, small cell and large cell carcinoma). For reasons of clinical consequences,
different pathological types of lung cancer are sometimes grouped into a category (non-small cell carcinoma or nonsquamous non-small cell carcinoma)
when it is necessary or useful to consider them in the same way, even if the tumors are pathologically different
CI, confidence interval; HR, hazard ratio; NSCLC, non-small cell lung cancer;
OS, overall survival; PFS, progression-free survival
1. FDA. Atezolizumab. Highlights of prescribing information. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761041lbl.pdf (accessed December 12, 2016);
2. Barlesi F et al. ESMO Congress 2016;Abstract LBA44.
11
Oncogenic drivers
Squamous cell carcinomas frequently have
genetic mutations in multiple pathways
132
Synonymous
Nonsynonymous
Overall no.
mutations per
megabase
Significantly mutated genes in squamous NSCLC1
100
80
60
40
20
0
81%
15%
8%
16%
12%
20%
3%
15%
8%
7%
70
50
30
Frame shift
Inframe indel
Other nonsynonymous
TP53
CDKN2A
PTEN
PIK3CA
KEAP1
MLL2
HLA-A
NFE2L2
NOTCH1
RB1
10
Samples with
mutations, %
Synonymous
Missense
Splice site
Nonsense
Statistically significant recurrent mutations found in 10 genes,
including mutation of TP53 in nearly all specimens
0.5 2.0 3.5
–log10
(Q value)
Reprinted by permission from Macmillan Publishers Ltd
CDKN2A, cyclin-dependent kinase inhibitor 2A; HLA-A, human leukocyte antigen A; KEAP1, kelch-like ECH-associated protein 1;
MLL2, mixed lineage leukemia 2; NFE2L2, nuclear factor (erythroid derived 2)-like 2; NOTCH1, neurogenic locus notch
homolog protein 1; NSCLC, non-small cell lung cancer; PIK3CA, phosphatidylinositol 3-kinase catalytic subunit;
PTEN, phosphatase and tensin homolog; RB1, retinoblastoma 1; TP53, tumor protein 53
1. Cancer Genome Atlas Research Network. Nature 2012;489:519–25
13
Oncogenic drivers with effective treatments are
rare in nonsquamous vs squamous NSCLC1-3
Nonsquamous* NSCLC1
EGFR M+
15–20%
Unknown oncogenic
drivers or oncogenic
drivers without
proven treatments
Squamous NSCLC2,3
EGFR M+ or
EML4-ALK+
<5%
EML4-ALK+
3–7%
Unknown oncogenic
drivers or oncogenic
drivers without
proven treatments
*There are 4 main pathological types of lung cancer (adeno-, squamous cell, small cell, and large cell carcinoma). For reasons of clinical consequences,
different pathological types of lung cancer are sometimes grouped together into a category (non-small cell carcinoma or nonsquamous non-small cell
carcinoma) when it is necessary, or useful, to considered them in the same way, even although the tumors may be different
ALK, anaplastic lymphoma kinase;
EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer
1. Gerber DE et al. Am Soc Clin Oncol Educ Book 2014:e353–65;
2. Pao W, Girard N. Lancet Oncol 2011;12:175–80;
3. Perez-Moreno P et al. Clin Cancer Res 2012;18:2443–51
14
Understanding of oncogenic drivers specific
to squamous NSCLC is limited1-3
• Molecular characterization of squamous NSCLC has only
recently begun in earnest2
• A genomic and epigenetic analysis of squamous NSCLC
suggests that squamous NSCLC tumors are genetically
complex, identifying:3
•
•
•
•
TP53 mutations in almost all samples
HLA-A loss-of-function mutations
Alterations in the FGFR kinase family
Frequent alterations in pathways involved in cell cycle control,
response to oxidative stress, apoptotic signaling, and / or
squamous cell differentiation
• The potential of these mutations as molecular targets in the
treatment of squamous NSCLC is currently unknown3
FGFR, fibroblast growth factor receptor; HLA-A, human leukocyte antigen A;
NSCLC, non-small cell lung cancer; TP53, tumor protein 53
1. Gerber DE et al. Am Soc Clin Oncol Educ Book 2014;e353–65;
2. Liao RG et al. Lung Cancer Manag 2012;1:293–300;
3. Cancer Genome Atlas Research Network. Nature 2012;489:519–25
15
Potential oncogenic drivers for guiding
treatment in squamous NSCLC1
Data from recent genomic studies of squamous cell lung cancers1
Approximate frequency, %
45
41%
40
35
30
25
20
15
12%
10
5%
5
10%
10%
4%
10%
4%
4%
BRAF
mutation
EGFR
ErbB2
Unknown
amplification amplification
0
FGFR1
amplification
FGFR2 /
FGFR3
mutation
PIK3CA
mutation
DDR2
mutation
PDGFRA
amplification
Most agents under evaluation for squamous NSCLC are directed
against normal components of upregulated pathways or against mutated proteins
and will likely provide modest, incremental survival benefits2
DDR2, discoidin domain receptor 2; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor
receptor; NSCLC, non-small cell lung cancer; PDGFR, platelet-derived growth factor receptor;
PIK3CA, phosphatidylinositol 3-kinase catalytic subunit
1. Liao RG et al. Lung Cancer Manag 2012;1:293–300; 2. Vincent MD. Front Oncol 2014;4:320
16
Selected potential target pathways
in squamous NSCLC1,2
RTK
PI3K
Developmental
SOX2
amplification /
SOX2
overexpression
EGFR
amplification
PIK3CA
mutations
FGFR1
amplification
PTEN deletion
DDR2 mutations
AKT1/2/3
overactivation
DNA repair
PARP
RB
CDK4/6
AKT, alpha serine/threonine-protein kinase; CDK4/6, cyclin-dependent kinase 4/6;
DDR2, discoidin domain receptor tyrosine kinase 2; EGFR, epidermal growth factor receptor;
FGFR, fibroblast growth factor receptor; NSCLC, non-small cell lung cancer;
PARP, polyadenosine diphosphate (ADP)–ribose polymerase;
PIK3CA, phosphatidylinositol 3-kinase catalytic subunit; PI3K, phosphoinositide-3-kinase;
PTEN, phosphatase and tensin homolog; RB, retinoblastoma;
RTK, receptor tyrosine kinase; SOX, SRY-related HMG box
1. Shtivelman E et al. Oncotarget 2014;5:1392–433; 2. Stead LF et al. PLoS One 2013;8:e78823
17
EGFR mutations and amplification
in squamous cell lung cancer
Canonical exon 19 deletions and exon 21 L858R mutations are
rare in squamous cell lung cancers except in never-smokers1,2
EGFR amplification occurs in ~7% of squamous cell lung cancers1
Rare EGFR L861Q mutations have been reported1
EGFR, epidermal growth factor receptor
1. Cancer Genome Atlas Research Network. Nature 2012;489:519–25;
2. Rekhtman N et al. Mod Pathol 2012;26:511–22
18
Potential molecular targets in squamous
NSCLC: FGFR1 amplifications
•
•
•
•
FGFR1 amplification has been identified in >12% of squamous NSCLC, predominantly in
current / former smokers1-3
Correlation has been observed between lymph node metastases and tumor FGFR1
amplification status in patients with squamous NSCLC4
Focal FGFR1 amplification is associated with tumor growth and survival in lung cancer cell lines1
FGFR inhibition resulted in tumor stasis / regression in preclinical squamous NSCLC models3
Target
FGFR1–3
Product
AZD4547
Phase in squamous NSCLC5
II/III (Lung-MAP study NCT02154490)
FGFR1–3
AZD4547
II (NCT02664935)
FGFR1–3
AZD4547
II (NCT02117167)
Maintenance
Pan-FGFR
Ponatinib
II (NCT01935336)
All lines
Lucitanib (TKI)
II (NCT02109016)
≥2nd-line
II (NCT01948141);
I/II LUME-Lung3 (NCT01346540)
II (NCT01861197)
2nd- / 3rd-line
1st-line
2nd-line
VEGFR-FGFR
VEGFR-FGFR-PDGFR
Nintedanib / BIBF 1120
VEGFR-FGFR-PDGFR
Dovitinib (TKI)
Treatment setting
≥2nd-line
After completion of
all appropriate
SOC therapy
FGFR, fibroblast growth factor receptor; Lung-MAP, The Lung Cancer Master Protocol;
NSCLC, non-small cell lung cancer; PDGFR, platelet-derived growth factor receptor;
SOC, standard of care; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor
1. Weiss J et al. Sci Transl Med 2010;2:62ra93; 2. Heist RS et al. J Thorac Oncol 2012;7:1775–80;
3. Zhang J et al. Clin Cancer Res 2012;18:6658–67; 4. Göke F et al. Chest 2012;142:1020–6; 5. ClinicalTrials.gov
19
Potential molecular targets in squamous
NSCLC: DDR2 mutations
• DDR2 mutations have been identified in ~4% of squamous NSCLC
tumors and cell lines1
• Preclinical data suggest DDR2 mutations may promote squamous
NSCLC cell proliferation, migration, and invasion2
Product
Dasatinib
(multitargeted TKI)
Development phase
in squamous
NSCLC
Comments
No ongoing studies
Phase II studies terminated for safety reasons
(NCT01491633)3 and lack of efficacy / slow
accrual (NCT01514864)4
Preclinical: inhibited proliferation of DDR2-mutated
squamous NSCLC cell lines in vitro and in vivo1
DDR2, discoidin domain receptor 2; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor
1. Hammerman PS et al. Cancer Discov 2011;1:78–89; 2. Miao L et al. BMC Cancer 2014;14:369;
3. Brunner AM et al. J Thorac Oncol 2013;8:1434–7; 4. ClinicalTrials.gov. NCT01514864
20
Oncogenic PI3K pathway changes are
common in squamous cell lung cancer
16%
8%
•
•
•
PIK3CA mutation1
PTEN mutation2
Alterations in the PIK3 pathway affect cell survival and proliferation1
PI3K / AKT alterations (including PIK3CA and PTEN deletions) occur in ~59% of
squamous cell lung cancers1
PIK3CA amplification occurs in ~33% of squamous cell tumors1
AKT, alpha serine/threonine-protein kinase; PI3K, phosphoinositide-3-kinase;
PIK3CA, phosphatidylinositol 3-kinase catalytic subunit; PTEN, phosphatase and tensin homolog
1. Shtivelman E et al. Oncotarget 2014;5:1392–433;
2. Cancer Genome Atlas Research Network. Nature 2012;489:519–25
21
Potential molecular targets in squamous
NSCLC: PI3K pathway changes
• The pan-PI3K inhibitor buparlisib was assessed for 1st-line or
2nd-line therapy in patients with squamous NSCLC1,2
•
Clinical trials with buparlisib in squamous NSCLC have been terminated
due to failure meet primary endpoints1 and safety profile2
Development phase
in squamous NSCLC
Line
Primary endpoint
Clinical trial
registry
BASALT-11
II
≥2nd
PFS
NCT01297491
BASALT-22,3
Ib
1st
MTD / DLT
NCT01820325
BASALT-32,3
II
2nd
DLT / PFS
NCT01911325
Study
DLT, dose-limiting toxicity; MTD, maximum tolerated dose;
NSCLC, non-small cell lung cancer; PI3K, PI3K, phosphoinositide-3-kinase
PFS, progression-free survival
1. Vansteenkiste JF et al. J Thorac Oncol 2015;10:1319–27;
2. Adjei AA et al. J Clin Oncol 2016;34(suppl):abstr e20522; 3. ClinicalTrials.gov
22
Targeting developmental pathways:
SOX2
SOX2 is a lineage-survival oncogene that is expressed
during initiation of branching morphogenesis in the lung1
SOX2 amplification has been identified in 21% of
squamous NSCLC tumors2 and is needed for proliferation,
growth, and survival of squamous NSCLC cell lines3
Direct targeting of SOX2 is difficult due to its role
in transcriptional cellular function3
SOX2 gene amplification and increased protein expression have been
associated with a favorable prognosis in squamous NSCLC4
NSCLC, non-small cell lung cancer; SOX, SRY-related HMG box
1. Shtivelman E et al. Oncotarget 2014;5:1392–433;
2. Cancer Genome Atlas Research Network. Nature 2012;489:519–25;
3. Bass AJ et al. Nat Genet 2009;41:1238–42;
4. Wilbertz T et al. Mod Pathol 2011;24:944–53
23
Potential molecular targets in squamous
NSCLC: PARP
•
•
•
PARPs are key components
of several DNA repair pathways1
PARP1 has been identified
as a platinum-DNA damage
response protein1
In cell lines, PARP inhibition
could enhance the effectiveness
of platinum chemotherapy when
administered as combination
therapy1 and this approach is being
studied in patients with squamous
NSCLC2
PARP1 expression in
paraffin-embedded NSCLC1
Haiying Cheng H, et al. PARP inhibition selectively
increases sensitivity to cisplatin in ERCC1-low non-small cell
lung cancer cells Carcinogenesis (2013) 34 (4): 739-749,
by permission of Oxford University Press
NSCLC, non-small cell lung cancer; PARP, polyadenosine diphosphate (ADP)-ribose polymerase
1. Cheng H et al. Carcinogenesis 2013;34:739–49;
2. Ramalingam S et al. Int J Radiat Oncol Biol Phys 2014;90(Suppl 5):S4, abs 8
24
Potential molecular targets in squamous
NSCLC: CDK4/6
•
RB1 is phosphorylated by the cyclin D/CDK4 complex; RB1
mutations are found in 7% of squamous NSCLC tumors1
Line
Planned
N
Primary
endpoint
Clinical trial
registry
Y
2nd
42
ORR
NCT02785939
N
No standard
curative /
palliative
measures
139
Safety
NCT02022982
Abemaciclib + BSC vs erlotinib + BSC
N
3rd
550
PFS / OS
NCT02152631
Abemaciclib vs docetaxel
Y
2nd
150
PFS
NCT02450539
Abemaciclib + pembrolizumab
N
≥2nd
75
Safety
NCT02779751
Abemaciclib (brain metastasis)
N
NR
247
CR / PR
NCT02308020
Drug
Squamous
NSCLC only
Palbociclib2
Palbociclib (CDK4/6+)
Palbociclib + PD-0325901
(KRAS mutant)
Abemaciclib2
BSC, best standard-of-care; CDK 4/6, cyclin-dependent kinase; CR, complete response;
KRAS, kirsten rat sarcoma; NR, not reported; NSCLC, non-small cell lung cancer; ORR, objective response
rate; OS, overall survival; PFS, progression-free survival; PR, partial response
1. Shtivelman E et al. Oncotarget 2014;51:1392-1433; 2. ClinicalTrials.gov
25
Ongoing Phase III trials
in squamous NSCLC
Biomarker-driven investigation of previously
treated squamous NSCLC: Lung-MAP (S1400)
study design
•
The Lung Cancer Master Protocol (Lung-MAP) study is a Phase II/III study using a
multidrug, targeted screening approach to match patients with substudies testing
investigational new treatments based on their unique tumor profiles
(NCT02154490)1,2
Common biomarker profiling (PS must be 0-1 to be eligible for any of the substudies)
Non-matched substudiesa
Eligible for biomarker-driven substudies
(patients are not eligible if they have previously received nivolumab)
Checkpoint naive
Nivolumab/
ipilimumab
Nivolumab
PIK3
mutation
CCGA
Taselisib
Palbociclib
Primary endpoints:
Phase II: PFS
Phase III: <33%
improvement in
median PFS; OS
FGFR amplification,
mutation, or fusion
AZD4547
aPatients
who enrolled in a previous non-matched substudy and progressed following 12 months of
durvalumab treatment are eligible for retreatment with durvalumab2
FGFR, fibroblast growth factor receptor; NSCLC, non-small cell lung cancer; OS, overall survival;
PFS, progression-free survival; PIK3CA, phosphatidylinositol 3-kinase catalytic subunit; PS, performance status
1. Lung-MAP. Available at: http://www.lung-map.org/about-lung-map. Accessed June, 2016;
2. Clinicaltrials.gov. NCT02154490
27
Cytotoxic and targeted therapies with Phase III
studies recruiting patients with squamous
NSCLC
Squamous
NSCLC only
Line
Planned
N
Primary
endpoint
Clinical trial
registry
Nab-P as maintenance
after nab-P + CP vs BSC
Y
Maintenance
540
PFS
NCT02027428
Nedaplatin + D vs CSP + D
Y
1st
488
PFS
NCT02643407
Custirsen (clusterina) / docetaxel
vs docetaxel
N
2nd
700
OS
NCT01630733
Brigatinib vs crizotinib
N
2nd
270
PFS
NCT02737501
Regimen
Newer cytotoxic agents1
Targeted therapies1
aPhase
IV study
Patients with squamous NSCLC only
BSC, best supportive care; CP, carboplatin; CSP, cisplatin; D, docetaxel;
nab-P, albumin-bound paclitaxel; NSCLC, non-small cell lung cancer; OS, overall survival; P, paclitaxel;
PARP, polyadenosine diphosphate (ADP)–ribose polymerase; PFS, progression-free survival
1. ClinicalTrials.gov
28
Immunotherapies with Phase III studies
recruiting patients with squamous NSCLC (1 of 2)
Squamous
NSCLC only
Line
Planned
N
Primary
endpoint
Clinical trial
registry
Nivolumab or in combination with
ipilimumab or CT vs CT
N
1st
2220
OS / PFS
NCT02477826
Nivolumab + ipilimumab
vs nivolumab
Y
2nd
350
PFS / OS
NCT02785952
Nivolumab Q2W vs Q4W
N
2nda
620
PFS
NCT02713867
Nivolumab vs docetaxel
N
2nd
500
OS
NCT02613507
Nivolumab + ipilimumab or nivolumab
+ CT vs CT
N
2nd
465
PFS
NCT02864251
Pembrolizumab vs CT
N
1st
1240
OS
NCT02220894
Pembrolizumab + CT vs CT
Y
1st
560
PFS / OS
NCT02775435
Regimen
Anti-PD-11
aAfter
4 months of nivolumab
Patients with squamous NSCLC only
CP, carboplatin; CT, chemotherapy; CTLA-4, cytotoxic T-lymphocyte-associated antigen-4;
NR, not reported; NSCLC, non-small cell lung cancer; OS, overall survival;
PD-1, programmed cell death protein-1; PFS, progression-free survival
1. ClinicalTrials.gov
29
Immunotherapies with Phase III studies
recruiting patients with squamous NSCLC (2 of 2)
Squamous
NSCLC only
Line
Planned
N
Primary
endpoint
Clinical trial
registry
Atezolizumab in combination with CP
+ P or CP + nab-P vs CP + nab-P
Y
1st
1025
PFS
NCT02367794
Atezolizumab vs CT
N
1st
570
PFS / OS
NCT02409342
Durvalumab + tremelimumab
vs CT
N
1st
800
OS
NCT02542293
Avelumab vs CT (PD-L1+)
N
1st
420
PFS
NCT02576574
Regimen
Anti-PD-L11
Patients with squamous NSCLC only
CP, carboplatin; CT, chemotherapy; CTLA-4, cytotoxic T-lymphocyte-associated antigen-4;
nab-P, albumin-bound paclitaxel; NSCLC, non-small cell lung cancer; OS, overall survival; P, paclitaxel;
PD-L1, programmed cell death ligand-1; PFS, progression-free survival; SOC, standard of care
1. ClinicalTrials.gov
30
Vaccines with Phase III studies recruiting
patients with squamous NSCLC
Squamous
NSCLC only
OSE2101 (HLA-A2+)
vs CT
EGF vaccine vs CT
Regimen
Line
Planned
N
Primary
endpoint
Clinical trial
registry
N
2nd / 3rd
500
OS
NCT02654587
N
1st
418
OS
NCT02187367
Vaccine1
BSC, best supportive care; CT, chemotherapy; EGF, epidermal growth factor;
NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival
1. ClinicalTrials.gov
31
Conclusions
• Potential oncogenic drivers for guiding treatment in squamous
NSCLC include:
•
FGFR1 amplifications
•
DDR2 mutations
•
PIK3CA mutations
•
CDK4/6 amplifications
• Potential therapies currently in Phase III development
for squamous NSCLC include new cytotoxic agents (nab-paclitaxel),
agents targeting the EGFR pathway, PARP inhibitors, and
immunotherapies
CDK 4/6, cyclin-dependent kinase 4/6; DDR2, discoidin domain receptor 2;
EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor;
NSCLC, non-small cell lung cancer; PARP, polyadenosine diphosphate (ADP)-ribose polymerase;
PIK3CA, phosphatidylinositol 3-kinase catalytic subunit
32