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

2
Targeted therapies
Potential molecular targets in
squamous NSCLC: EGFR expression1

• EGFR activation plays a significant role in tumorigenesis 1

Ligand Metastatic
C
C
EGFR EGFR spread
activation dimer

Cell survival

Angiogenesis

Blood
Tumor vessel

Proliferation
EGFR, epidermal growth factor receptor;
Reprinted by permission from Macmillan Publishers Ltd NSCLC, non-small cell lung cancer
Figure reproduced from ref 1
1. Jakobovits A et al. Nat Biotechnol 2007;25:1134–43
4
EGFR activation is a relevant target
for squamous NSCLC1-2

mAbs bind to the extracellular portion TKIs bind to the intracellular tyrosine
of EGFR and have shown clinical kinase domain of EGFR and should
benefit when combined with 1st-line be limited to EGFR M+ NSCLC in the
chemotherapy treatment of squamous 1st-line treatment setting5
NSCLC1,3,4 <5% of
Most squamous
squamous NSCLC are
NSCLC EGFR M+6
express
EGFR2 EGFR EGFRvIII mutant

Proliferation Metastasis 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
5
 Advances in 1st-line therapy for advanced
squamous NSCLC: EGFR ‒ necitumumab

Necitumumab treatment setting: Approved as 1st-line therapy in combination with gemcitabine-

cisplatin 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)
Gem / cis (n=548)
11.5 0.84 (0.74, 0.96)
Median OS
a
p=0.01 Necitumumab
9.9 + gem / cis (n=545)

b
5.7 0.85 (0.74, 0.98)
Median PFS p=0.02
5.5

0 4 8 12
a
Primary or bsecondary endpoint 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.
6
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 responses 1

CTLA-4 pathway PD-1 pathway

Tumor Tumor Deactivated
Deactivated
antigen antigen CD8+ T-cell
CD8+ T-cell
presentation presentation
TCR TCR
MHC MHC

B7
CTLA-4 CD28
PD-1
PD-L1
PD1: PD-L1
CTLA-4: B7 binding
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
8
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 Activated
Cytolytic molecules CD8+ T-cell
CD8+ T-cell

CD28
B7 CTLA-4 PD-1
PD-L1
Anti-CTLA-4 antibody
Tumor cell Anti-PD-1 antibody
Tumor cell
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 events 1

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
9
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
Docetaxel (n=137) Nivolumab (n=135)

HR (95% CI)

9.2 0.59 (0.44, 0.79)

Median
a OS
6.0 p<0.001

3.5 0.62 (0.47, 0.81)

Median
b PFS
p<0.001
2.8

0 4 8 12
Time (months)
Primary or bsecondary endpoint
a 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
10
 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
EGFR- or 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
Docetaxel (n=343) Pembrolizumab 2 mg/kg (n=345) Pembrolizumab 10 mg/kg (n=346)
HR (95% CI)
3,a 18.8
Median OS TPS ≥50% 15.8 0.48 (0.35, 0.66)
8.2 0.54 (0.39, 0.73)

12.7
4,a
Median OS 10.4 0.71 (0.58, 0.88) 0.61 (0.49, 0.75)
8.5 p=0.0008 p<0.0001

4.0
4,a
Median PFS 3.9 0.88 (0.74, 1.05) 0.79 (0.66, 0.94)
4.0 p=0.07 p=0.004

0 4 8 12 16 20
a
Primary endpoint Time (months) 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
11
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 mutations 1
OS results from a randomized Phase III clinical trial: 2
Docetaxel (n=425) Atezolizumab (n=425)
HR (95% CI)

15.6 0.73 (0.60, 0.89)

*Nonsquamous NSCLC p=0.0015
11.2

8.9 0.73 (0.54, 0.98)

Squamous NSCLC p=0.0383
7.7

0 4 8 12 16
Time (months)
ǂ
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 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.
12
Oncogenic drivers
 Squamous cell carcinomas frequently have
genetic mutations in multiple pathways
mutations per
Significantly mutated genes in squamous NSCLC1

132
100 Synonymous Frame shift
Overall no.

megabase

Synonymous 80 Missense Inframe indel

Non- 60 Splice site Other non-
synonymous 40 Nonsense
20
synonymous
0
81% TP53
15% CDKN2A
8% PTEN
16% PIK3CA
12% KEAP1
20% MLL2
3% HLA-A
15% NFE2L2
8% NOTCH1
7% RB1
70 50 30 10 0.5 2.0 3.5
Samples with –log10
mutations, % Statistically significant recurrent mutations found in 10 genes, (Q value)
including mutation of TP53 in nearly all specimens
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
14
Oncogenic drivers with effective treatments are

rare in nonsquamous vs squamous NSCLC1-3

Nonsquamous* NSCLC1 Squamous NSCLC2,3

EGFR M+ or
EGFR M+ EML4-ALK+
15–20% <5%

Unknown Unknown
oncogenic drivers oncogenic drivers
or oncogenic or oncogenic
drivers without EML4-ALK+ drivers without
proven treatments 3–7% 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
15
Understanding of oncogenic drivers specific
to squamous NSCLC is limited 1-3

• 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
16
Potential oncogenic drivers for guiding
treatment in squamous NSCLC1
45 Data from recent genomic studies of squamous cell lung cancers 1
41%
40
Approximate frequency, %

35
30
25
20
15
10
12%
5 10% 10% 10%
0 5% 4% 4% 4%

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 benefits 2
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
17
Selected potential target pathways
in squamous NSCLC1,2

RTK PI3K Developmental DNA repair RB

SOX2
EGFR PIK3CA amplification /
amplification PARP CDK4/6
mutations SOX2
overexpression

FGFR1
amplification PTEN deletion

AKT1/2/3
DDR2 mutations
overactivation

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
18
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-smokers 1,2

EGFR amplification occurs in ~7% of squamous cell lung cancers 1

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
19
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 NSCLC 4
• Focal FGFR1 amplification is associated with tumor growth and survival in lung cancer cell lines 1
• FGFR inhibition resulted in tumor stasis / regression in preclinical squamous NSCLC models 3
Target Product Phase in squamous NSCLC5 Treatment setting
FGFR1–3 AZD4547 II/III (Lung-MAP study NCT02154490) ≥2nd-line
After completion of
FGFR1–3 AZD4547 II (NCT02664935) all appropriate
SOC therapy
FGFR1–3 AZD4547 II (NCT02117167) Maintenance
Pan-FGFR Ponatinib II (NCT01935336) All lines
VEGFR-FGFR Lucitanib (TKI) II (NCT02109016) ≥2nd-line
II (NCT01948141); 2nd- / 3rd-line
VEGFR-FGFR-PDGFR Nintedanib / BIBF 1120
I/II LUME-Lung3 (NCT01346540) 1st-line
VEGFR-FGFR-PDGFR Dovitinib (TKI) II (NCT01861197) 2nd-line

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
20
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

Development phase
in squamous
Product NSCLC Comments
Phase II studies terminated for safety reasons (
NCT01491633)3 and lack of efficacy / slow accrual
Dasatinib (NCT01514864)4
No ongoing studies
(multitargeted TKI) 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
21
Oncogenic PI3K pathway changes are
common in squamous cell lung cancer

16% PIK3CA mutation1

8%
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
22
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 Clinical trial

Study in squamous NSCLC Line Primary endpoint registry
BASALT-11 II ≥2nd PFS NCT01297491
BASALT-22,3 Ib 1st MTD / DLT NCT01820325
BASALT-32,3 II 2nd DLT / PFS NCT01911325

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
23
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
24
Potential molecular targets in squamous
NSCLC: PARP

• PARPs are key components

of several DNA repair pathways1 PARP1 expression in
paraffin-embedded NSCLC1
• 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 Haiying Cheng H, et al. PARP inhibition selectively increases
sensitivity to cisplatin in ERCC1-low non-small cell lung

studied in patients with squamous cancer cells Carcinogenesis (2013) 34 (4): 739-749,
by permission of Oxford University Press

NSCLC2

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
25
 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
Squamous Planned Primary Clinical trial
Drug NSCLC only Line N endpoint registry
Palbociclib2
Palbociclib (CDK4/6+) Y 2nd 42 ORR NCT02785939
No standard
Palbociclib + PD-0325901 curative /
N 139 Safety NCT02022982
(KRAS mutant) palliative
measures
Abemaciclib2
Abemaciclib + BSC vs erlotinib +
N 3rd 550 PFS / OS NCT02152631
BSC
Abemaciclib vs docetaxel Y 2nd 150 PFS NCT02450539

Abemaciclib + pembrolizumab N ≥2nd 75 Safety NCT02779751

Abemaciclib (brain metastasis) N NR 247 CR / PR NCT02308020

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
26
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)
Primary endpoints:
Phase II: PFS
Phase III: <33%
improvement in
Non-matched substudiesa median PFS; OS
Eligible for biomarker-driven substudies
(patients are not eligible if they have previously received nivolumab)

PIK3 FGFR amplification,

Checkpoint naive CCGA
mutation mutation, or fusion

Nivolumab/ Taselisib Palbociclib AZD4547

Nivolumab
ipilimumab

a
Patients who enrolled in a previous non-matched substudy and progressed following 12 months of
durvalumab treatment are eligible for retreatment with durvalumab 2

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
28
Cytotoxic and targeted therapies with Phase III
studies recruiting patients with squamous
NSCLC
Clinical
Squamous Planned Primary trial
Regimen NSCLC only Line N endpoint registry
Newer cytotoxic agents1
Nab-P as maintenance
Y Maintenance 540 PFS NCT02027428
after nab-P + CP vs BSC
Nedaplatin + D vs CSP + D Y 1st 488 PFS NCT02643407
Targeted therapies1
Custirsen (clusterina) / docetaxel
N 2nd 700 OS NCT01630733
vs docetaxel
Brigatinib vs crizotinib N 2nd 270 PFS NCT02737501
Phase IV study
a
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
29
Immunotherapies with Phase III studies
recruiting patients with squamous NSCLC (1 of 2)

Squamous Planned Primary Clinical trial

Regimen NSCLC only Line N endpoint registry
Anti-PD-11
Nivolumab or in combination with OS /
N 1st 2220 NCT02477826
ipilimumab or CT vs CT PFS
Nivolumab + ipilimumab PFS /
Y 2nd 350 NCT02785952
vs nivolumab OS
Nivolumab Q2W vs Q4W N 2nda 620 PFS NCT02713867
Nivolumab vs docetaxel N 2nd 500 OS NCT02613507
Nivolumab + ipilimumab or nivolumab
N 2nd 465 PFS NCT02864251
+ CT vs CT
Pembrolizumab vs CT N 1st 1240 OS NCT02220894
PFS /
Pembrolizumab + CT vs CT Y 1st 560 NCT02775435
After 4 months of nivolumab
a OS
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
30
Immunotherapies with Phase III studies
recruiting patients with squamous NSCLC (2 of 2)

Squamous Planned Primary Clinical trial

Regimen NSCLC only Line N endpoint registry
Anti-PD-L11
Atezolizumab in combination with
Y 1st 1025 PFS NCT02367794
CP + P or CP + nab-P vs CP + nab-P
Atezolizumab vs CT N 1st 570 PFS / OS NCT02409342
Durvalumab + tremelimumab
N 1st 800 OS NCT02542293
vs CT
Avelumab vs CT (PD-L1+) N 1st 420 PFS NCT02576574

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
31
Vaccines with Phase III studies recruiting
patients with squamous NSCLC

Squamous Planned Primary Clinical trial

Regimen NSCLC only Line N endpoint registry
Vaccine1

OSE2101 (HLA-A2+)
N 2nd / 3rd 500 OS NCT02654587
vs CT

EGF vaccine vs CT N 1st 418 OS NCT02187367

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
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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
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