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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
2

Targeted therapies

non-small cell lung cancer Figure reproduced from ref 1 1. Jakobovits A et al.25:1134–43 4 . Nat Biotechnol 2007. epidermal growth factor receptor. Reprinted by permission from Macmillan Publishers Ltd NSCLC.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.

3. Laurie SA. Pan Y et al. Lancet Oncol 2015.31:1061–9.4 <5% of Most squamous squamous NSCLC are NSCLC EGFR M+6 express EGFR2 EGFR EGFRvIII mutant Proliferation Metastasis Invasion Apoptosis EGFR. Lopez-Malpartida AV et al.65:25–33.16:763–74. NJ: Bristol-Myers Squibb Company 2013. 5. Goss GD. mAb. Lancet 2009.145:473–9 5 . non-small cell lung cancer. Thatcher N et al. Lung Cancer 2009.373:1525–31. Chest 2014. monoclonal antibody. Pirker R et al. epidermal growth factor receptor. 4. J Clin Oncol 2013.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. Princeton. 3. tyrosine kinase inhibitor 1. NSCLC. 6. 2. TKI. Erbitux [package insert].

PFS. © National Comprehensive Cancer Network.98) Median PFS p=0.2017. National Comprehensive Cancer Network. Highlights of prescribing information. All rights reserved (accessed December 12. cisplatin. 2. FDA. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V. go online to NCCN. Food and Drug Administration. NSCLC.pdf (accessed June 20. European Medicines Agency. NCCN®.accessdata. cis. OS.9 + gem / cis (n=545) b 5. confidence interval.84 (0. gem.1. and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network. 0. 4. 3. Lancet Oncol 2015.pdf (accessed June 20. 6 . NCCN GUIDELINES®. 2016.fda. 2016). epidermal growth factor receptor.16:763–74. Necitumumab summary of product characteristics. Thatcher N et al. non-small cell lung cancer.ema.02 5. NCCN. progression-free survival 1.85 (0.74.3.5 0. Inc.eu/docs/en_GB/document_library/EPAR_-_Product_Information /human/003886/WC500202694. 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. FDA. EGFR. Available at: http://www. 2016. NATIONAL COMPREHENSIVE CANCER NETWORK®. Necitumumab.01 Necitumumab 9. 2016). Inc. overall survival.96) Median OS a p=0. 0.74. hazard ratio.europa. To view the most recent and complete version of the guideline. EMA.gov/drugsatfda_docs/label/2015/125547s000lbl.2 the NCCN does not include necitumumab + gemcitabine-cisplatin as a treatment option4 CI. 2016.5 0 4 8 12 a Primary or bsecondary endpoint Time (months) Necitumumab + gemcitabine-cisplatin is FDA / EMA approved for metastatic squamous NSCLC. HR. gemcitabine.7 0. Available at: http://www. EMA.org.

Immunotherapy targets .

Cancer Manag Res 2014. cytotoxic T-lymphocyte-associated antigen-4. non-small cell lung cancer. CTLA-4. Davies M. PD-1. programmed cell death protein-1. major histocompatibility complex. or when PD-1 binds PD-L1 or PDL-2 on target cells APC. MHC. NSCLC. programmed cell death ligand-1.6:63–75 8 . antigen-presenting cell. T cell receptor 1.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. TCR. PD-L1.

Immunotherapy targets in NSCLC: CTLA-4 and PD-1 pathways (2 of 2) Anti-CTLA-4. PD-1. Cancer Manag Res 2014. NSCLC. programmed cell death protein-1. Davies M. non-small cell lung cancer. programmed cell death ligand-1 1. antigen-presenting cell. 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. cytotoxic T-lymphocyte-associated antigen-4.6:63–75 9 . CTLA-4. PD-L1.

ema. NSCLC.001 3. 0.0 p<0.gov/drugsatfda_docs/label/2015/125527s000lbl.59 (0. Available at: http://www.373:123–35 10 . OS. 2. progression-free survival 1. http://www. N Engl J Med 2015.5 0. Highlights of prescribing information. 2015.accessdata.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003840/WC500190648.pdf (accessed June 20. 2016).8 0 4 8 12 Time (months) Primary or bsecondary endpoint a CI. HR.europa.fda.81) Median b PFS p<0. EMA.2 0. 2016). 0. overall survival. non-small cell lung cancer. Nivolumab BMS summary of product characteristics. Brahmer J et al.79) Median a OS 6.pdf (accessed June 20.001 2.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. Nivolumab. FDA. 3. PFS.44. hazard ratio. confidence interval.62 (0.47.

merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi. 0. 0. Lancet 2016.eu/docs/en_GB/document_library/Summary_of_opinion/human/003820/WC500218016. tumor proportion score 1. 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. 2016). Herbst RS et al.71 (0. progression-free survival. anaplastic lymphoma kinase.0001 4.8 Median OS TPS ≥50% 15.pdf (accessed February 22 2017). hazard ratio.39.2 Results from a randomized Phase III clinical trial:3.or ALK-positive tumor mutations.ema. Abstract LBA48. 0.74. Patients with EGFR.73) 12. 1. NSCLC.05) 0. overall survival. non-small cell lung cancer.0008 p<0.4 0.a 18.a Median PFS 3. EGFR.387:1540–50 11 .79 (0.35. FDA.4 Docetaxel (n=343) Pembrolizumab 2 mg/kg (n=345) Pembrolizumab 10 mg/kg (n=346) HR (95% CI) 3.61 (0.2 0. EMA Summary of opinion (post authorization). Pembrolizumab. 4. 3.88 (0. OS. PFS.004 0 4 8 12 16 20 a Primary endpoint Time (months) ALK.europa. Herbst R et al.5 p=0. 2. confidence interval.66.54 (0. 0. epidermal growth factor receptor. ESMO Congress 2016.94) 4.07 p=0.49.7 4.0 p=0. Highlights of prescribing information.66) 8. HR.75) 8.8 0. Available at: http://www.9 0.a Median OS 10.or ALK-positive tumor mutations should also have received targeted therapy prior to treatment with pembrolizumab1. 0. programmed cell death ligand-1.pdf (accessed December 12. CI.88) 0.48 (0. PD-L1.58.0 4. 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. TPS. Available at http://www.

60. OS.54. overall survival. ESMO Congress 2016. 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. patients with EGFR. 12 . squamous cell.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) 15.73 (0. 0.0015 11. Available at: http://www. 2016).accessdata. NSCLC.98) Squamous NSCLC p=0. confidence interval. For reasons of clinical consequences.Abstract LBA44.gov/drugsatfda_docs/label/2016/761041lbl. hazard ratio. Atezolizumab. PFS.pdf (accessed December 12. 2.2 8.9 0.73 (0. small cell and large cell carcinoma).6 0. FDA. Barlesi F et al. non-small cell lung cancer. 0.fda.7 0 4 8 12 16 Time (months) ǂ There are 4 main pathological types of lung cancer (adeno-.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.0383 7. HR. progression-free survival 1. Highlights of prescribing information. even if the tumors are pathologically different CI.89) *Nonsquamous NSCLC p=0.

Oncogenic drivers .

Nature 2012. KEAP1. phosphatidylinositol 3-kinase catalytic subunit. tumor protein 53 1. nuclear factor (erythroid derived 2)-like 2.5 Samples with –log10 mutations. 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. MLL2. RB1.5 2. human leukocyte antigen A. cyclin-dependent kinase inhibitor 2A. 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. PIK3CA. HLA-A. NSCLC. phosphatase and tensin homolog. (Q value) including mutation of TP53 in nearly all specimens Reprinted by permission from Macmillan Publishers Ltd CDKN2A. PTEN. NFE2L2. non-small cell lung cancer. NOTCH1. megabase Synonymous 80 Missense Inframe indel Non.489:519–25 14 . TP53. % Statistically significant recurrent mutations found in 10 genes.0 3. retinoblastoma 1. neurogenic locus notch homolog protein 1. kelch-like ECH-associated protein 1. Cancer Genome Atlas Research Network. mixed lineage leukemia 2.

and large cell carcinoma). to considered them in the same way. Lancet Oncol 2011. squamous cell. 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. EGFR. Perez-Moreno P et al. NSCLC. 3. anaplastic lymphoma kinase. or useful.12:175–80.18:2443–51 15 . Girard N. Pao W. non-small cell lung cancer 1. Gerber DE et al.Oncogenic drivers with effective treatments are rare in nonsquamous vs squamous NSCLC1-3 Nonsquamous* NSCLC1 Squamous NSCLC2. Clin Cancer Res 2012. Am Soc Clin Oncol Educ Book 2014:e353–65. small cell. 2. For reasons of clinical consequences. even although the tumors may be different ALK. epidermal growth factor receptor.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-.

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. tumor protein 53 1. HLA-A. 3. Lung Cancer Manag 2012. fibroblast growth factor receptor. non-small cell lung cancer. 2. Gerber DE et al.1:293–300.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. TP53. NSCLC.e353–65.489:519–25 16 . Nature 2012. Liao RG et al. Cancer Genome Atlas Research Network. and / or squamous cell differentiation • The potential of these mutations as molecular targets in the treatment of squamous NSCLC is currently unknown3 FGFR. human leukocyte antigen A. Am Soc Clin Oncol Educ Book 2014. apoptotic signaling. response to oxidative stress.

2.1:293–300. epidermal growth factor receptor. phosphatidylinositol 3-kinase catalytic subunit 1. non-small cell lung cancer. FGFR. % 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. EGFR. PIK3CA. Front Oncol 2014. discoidin domain receptor 2. Liao RG et al. NSCLC. fibroblast growth factor receptor. incremental survival benefits 2 DDR2. PDGFR.4:320 17 . Lung Cancer Manag 2012. Vincent MD.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. platelet-derived growth factor receptor.

RTK.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. 2. non-small cell lung cancer. Stead LF et al. polyadenosine diphosphate (ADP)–ribose polymerase. fibroblast growth factor receptor. receptor tyrosine kinase. DDR2. SOX. SRY-related HMG box 1. epidermal growth factor receptor. alpha serine/threonine-protein kinase. PI3K. phosphatase and tensin homolog. RB. CDK4/6. retinoblastoma. PIK3CA.8:e78823 18 . discoidin domain receptor tyrosine kinase 2. cyclin-dependent kinase 4/6.5:1392–433. phosphoinositide-3-kinase. PTEN. Shtivelman E et al. FGFR. Oncotarget 2014. PLoS One 2013. NSCLC. phosphatidylinositol 3-kinase catalytic subunit. EGFR. PARP.Selected potential target pathways in squamous NSCLC1.

Rekhtman N et al. Cancer Genome Atlas Research Network.489:519–25. Mod Pathol 2012.2 EGFR amplification occurs in ~7% of squamous cell lung cancers 1 Rare EGFR L861Q mutations have been reported1 EGFR. 2.26:511–22 19 . epidermal growth factor receptor 1.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. Nature 2012.

2nd. Heist RS et al./ 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. VEGFR.142:1020–6. TKI. 5. tyrosine kinase inhibitor. Weiss J et al. Sci Transl Med 2010. Lung-MAP. 4. J Thorac Oncol 2012. vascular endothelial growth factor receptor 1. standard of care. fibroblast growth factor receptor. 3. non-small cell lung cancer. The Lung Cancer Master Protocol.7:1775–80. SOC. NSCLC. platelet-derived growth factor receptor. Zhang J et al. Chest 2012. Göke F et al. Clin Cancer Res 2012. 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). 2. PDGFR.gov 20 .Potential molecular targets in squamous NSCLC: FGFR1 amplifications • FGFR1 amplification has been identified in >12% of squamous NSCLC.2:62ra93. ClinicalTrials.18:6658–67.

NSCLC.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. ClinicalTrials. discoidin domain receptor 2. Miao L et al. Hammerman PS et al. tyrosine kinase inhibitor 1. TKI. 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.gov. 2. 3. Cancer Discov 2011. 4. Brunner AM et al.14:369. BMC Cancer 2014. non-small cell lung cancer. NCT01514864 21 . migration.1:78–89.8:1434–7. J Thorac Oncol 2013.

alpha serine/threonine-protein kinase. phosphatase and tensin homolog 1. phosphoinositide-3-kinase.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. PIK3CA. PTEN. 2.5:1392–433.489:519–25 22 . PI3K. Cancer Genome Atlas Research Network. Oncotarget 2014. Shtivelman E et al. Nature 2012. phosphatidylinositol 3-kinase catalytic subunit.

MTD.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. non-small cell lung cancer.3 II 2nd DLT / PFS NCT01911325 DLT. dose-limiting toxicity. 3. J Thorac Oncol 2015. Adjei AA et al. 2.34(suppl):abstr e20522.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. PI3K.10:1319–27. progression-free survival 1. maximum tolerated dose. NSCLC. ClinicalTrials.gov 23 . PI3K. Vansteenkiste JF et al. J Clin Oncol 2016. phosphoinositide-3-kinase PFS.

4.24:944–53 24 .5:1392–433. SOX. Oncotarget 2014. 2. 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.489:519–25. Bass AJ et al. growth. Cancer Genome Atlas Research Network. Nature 2012. 3. Mod Pathol 2011. non-small cell lung cancer.41:1238–42. Nat Genet 2009. Wilbertz T et al.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. Shtivelman E et al. SRY-related HMG box 1.

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. non-small cell lung cancer. et al. 2. Ramalingam S et al.34:739–49. by permission of Oxford University Press NSCLC2 NSCLC.90(Suppl 5):S4. PARP inhibition could enhance the effectiveness of platinum chemotherapy when administered as combination therapy1 and this approach is being Haiying Cheng H. 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. Cheng H et al. PARP. Carcinogenesis 2013. Int J Radiat Oncol Biol Phys 2014. polyadenosine diphosphate (ADP)-ribose polymerase 1. abs 8 25 .

Oncotarget 2014. CDK 4/6. not reported. ClinicalTrials. progression-free survival. cyclin-dependent kinase. NR. objective response rate. PFS. CR. ORR. NSCLC. PR. complete response. best standard-of-care. 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. non-small cell lung cancer. overall survival. 2. Shtivelman E et al. OS.51:1392-1433. kirsten rat sarcoma.gov 26 . partial response 1. KRAS. Potential molecular targets in squamous NSCLC: CDK4/6 • RB1 is phosphorylated by the cyclin D/CDK4 complex.

Ongoing Phase III trials in squamous NSCLC .

Available at: http://www. 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.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. 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. NCT02154490 28 . progression-free survival. 2016. Clinicaltrials. non-small cell lung cancer. NSCLC. Lung-MAP. 2. targeted screening approach to match patients with substudies testing investigational new treatments based on their unique tumor profiles (NCT02154490)1. overall survival. PFS. Checkpoint naive CCGA mutation mutation. PS. phosphatidylinositol 3-kinase catalytic subunit. Accessed June. PIK3CA. OS Eligible for biomarker-driven substudies (patients are not eligible if they have previously received nivolumab) PIK3 FGFR amplification. performance status 1. OS.org/about-lung-map. fibroblast growth factor receptor.lung-map.gov.

nab-P. ClinicalTrials. docetaxel. paclitaxel. overall survival. cisplatin. NSCLC. P. progression-free survival 1. carboplatin. best supportive care. D. polyadenosine diphosphate (ADP)–ribose polymerase. PFS.gov 29 . non-small cell lung cancer. CP. PARP. OS. albumin-bound paclitaxel. CSP.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.

CT. programmed cell death protein-1. non-small cell lung cancer. overall survival. PFS. cytotoxic T-lymphocyte-associated antigen-4. NR.gov 30 . chemotherapy. OS. ClinicalTrials.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. progression-free survival 1. NSCLC. PD-1. CTLA-4. carboplatin. not reported.

overall survival. CT. P. SOC.gov 31 . ClinicalTrials. OS. PFS. albumin-bound paclitaxel. programmed cell death ligand-1. PD-L1. non-small cell lung cancer. standard of care 1.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. NSCLC. nab-P. CTLA-4. paclitaxel. progression-free survival. carboplatin. cytotoxic T-lymphocyte-associated antigen-4. chemotherapy.

progression-free survival 1.gov 32 . OS. chemotherapy. epidermal growth factor.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. CT. ClinicalTrials. NSCLC. non-small cell lung cancer. overall survival. best supportive care. EGF. PFS.

PIK3CA. non-small cell lung cancer. fibroblast growth factor receptor. and immunotherapies CDK 4/6. EGFR. DDR2. cyclin-dependent kinase 4/6. discoidin domain receptor 2. phosphatidylinositol 3-kinase catalytic subunit 33 . NSCLC. FGFR. polyadenosine diphosphate (ADP)-ribose polymerase. PARP inhibitors. PARP. epidermal growth factor receptor. agents targeting the EGFR pathway.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).