Selected Emerging Biomarkers in NSCLC

Emerging biomarkers can provide predictive and prognostic value, and treatments currently under clinical investigation offer promise in the future.1

Selected biomarkers for targeted therapy

CAP/IASLC/AMP guidelines recommend testing patients with mNSCLC for MET, RET, HER2, and KRAS mutations as part of a larger testing panel or when EGFR, ROS1, and ALK testing is negative.2

MET amplification or mutations

MET signaling pathway
MET signaling pathway


MET is a receptor tyrosine kinase.3,4 In tumor cells, MET mutations activate multiple signaling pathways, including PI3K and MAPK, to promote cell growth and survival.3,4

 

MET amplification has been associated with a poor prognosis and has been identified as a mechanism of acquired resistance to EGFR-TKIs.3,4

 

Prevalence in lung adenocarcinoma5:

  • ≈1% have high-level MET amplification
  • 3% to 4% have MET exon 14 skipping mutations

HER2 mutations

HER2 signaling pathway
HER2 signaling pathway


HER2 is a receptor tyrosine kinase.3 In tumor cells, HER2 mutations activate multiple signaling pathways, including PI3K and MAPK, to promote cell growth and survival.3

 

Overexpression of HER2 is found in select patients with NSCLC.3

 

Prevalence in NSCLC: ≈2% have HER2 exon 20 insertion mutations3

RET rearrangements

RET signaling pathway
RET signaling pathway


RET is a receptor tyrosine kinase.3 In tumor cells, RET mutations activate multiple signaling pathways, including PI3K and MAPK, to promote cell growth and survival.3,6

 

Prevalence in NSCLC: 1% to 2%5

KRAS mutations

KRAS signaling pathway
KRAS signaling pathway


KRAS is a member of the Ras gene family.7 In tumor cells, activating KRAS mutations may lead to increased signaling through the MAPK pathway to promote cell growth and survival.7

 

KRAS mutations are prognostic of poor survival and are associated with reduced response to EGFR-TKI therapy.1

 

Prevalence in lung adenocarcinoma: ≈25% have KRAS point mutations8

 


Selected biomarkers for immunotherapy

PD-L1 expression is most commonly used to predict response to anti–PD-1/PD-L1 therapy; however, other biomarkers are also being investigated.9

TMB

TMB biomarker
TMB biomarker


TMB is a measure of the number of mutations in a tumor.9

 

A high TMB may increase the number of neoantigens expressed on the tumor, which can9:

 

  • Activate the immune cell response
  • Increase immune cell infiltration
  • Improve response to immunotherapies

 

dMMR and MSI-H

dMMR/MSI-H biomarker
dMMR/MSI-H biomarker


In healthy cells, mismatch repair (MMR) proteins correct certain errors in DNA replication.10 A deficiency in MMR (dMMR) causes mutations to accumulate, which may increase the TMB and thereby enhance response to immunotherapies.10
 

One way to assess dMMR is by measuring microsatellite instability (MSI).10 Microsatellites are short, repetitive DNA sequences that have a high susceptibility to errors typically repaired by MMR proteins.10

dMMR/MSI-H is FDA approved to determine eligibility for treatment with an immunotherapy in solid tumors.11 However, the prevalence of dMMR/MSI-H in NSCLC is less than 1%.12,13

Tumor-infiltrating immune cells

Tumor-infiltrating immune cells
Tumor-infiltrating immune cells


The presence of tumor-infiltrating immune cells within the tumor microenvironment, particularly CD8+ T lymphocytes, is being assessed as a predictive biomarker for immunotherapies alone or in combination with PD-L1 expression. Tumor microenvironments with high immune cell infiltration may be primed for a greater antitumor response.9
 

 

ALK, anaplastic lymphoma kinase; AMP, Association for Molecular Pathology; CAP, College of American Pathologists; dMMR, deficient mismatch repair; EGFR, epidermal growth factor receptor; FDA, Food and Drug Administration; HER2, human epidermal growth factor receptor 2; IASLC, International Association for the Study of Lung Cancer; KRAS, V-Ki-Ras2 Kirsten rat sarcoma viral oncogene homolog; MAPK, mitogen-activated protein kinase; MET, tyrosine-protein kinase Met; mNSCLC, metastatic non–small cell lung cancer; MSI-H, microsatellite instability–high; PD-1, programmed cell death protein 1; PI3K, phosphoinositide 3-kinase; PD-L1, programmed-death ligand 1; RET, RET proto-oncogene; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase; TKI, tyrosine kinase inhibitor; TMB, tumor mutational burden.

 

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non–Small Cell Lung Cancer V3.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed January 31, 2019. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. To view the most recent and complete version of the guideline, go online to NCCN.org. 2. Lindeman NI et al. Arch Pathol Lab Med. 2018;142(3):321-346. 3. Baumgart M et al. Expert Rev Precis Med Drug Dev. 2016;1(1):25-36. 4. Salgia R. Mol Cancer Ther. 2017;16(4):555-565. 5. Soo RA et al. J Thorac Oncol. 2017;12(8):1183-1209. 6. Ferrara R et al. J Thorac Oncol. 2018;13(1):27-45. 7. Tomasini P et al. Oncologist. 2016;21(12):1450-1460. 8. Sholl LM et al. J Thorac Oncol. 2015;10(5):768-777. 9. Voong KR et al. Ann Transl Med. 2017;5(18):376. 10. Viale G et al. Biomed Res Int. 2017;2017:4719194. 11. Keytruda Prescribing Information. Whitehouse Station, NJ: Merck and Co., Inc.; 2018. 12. Le DT et al. Science. 2017;357(6349):409-413. 13. Cortes-Ciriano I et al. Nat Commun. 2017;8:15180.