NSCLC Pathobiology

NSCLC is the most common lung cancer in the US and is a heterogeneous disease consisting of 3 major subtypes

NSCLC percentage graphic
NSCLC Subtypes1,2
Adenocarcinoma
Adenocarcinoma 57%
Adenocarcinoma 57%
Large cell carcinoma 2%
  • Originates in alveolar type II cells
  • Most common subtype
Large Cell Carcinoma
Large cell carcinoma 2%
Large cell carcinoma 2%
Large cell carcinoma 2%
  • Originates in alveolar type II cells, neuroendocrine cells, basal cells, club cells
  • Poorly differentiated
Squamous Cell Carcinoma
Squamous cell carcinoma 28%
Squamous cell carcinoma 28%
Squamous cell carcinoma 28%
  • Originates in alveolar type II cells, basal cells, and club cells
  • Incidence has substantially decreased
Not Otherwise Specified
Not otherwise specified 13%
Not otherwise specified 13%
Not otherwise specified 13%
  • The NSCLC subtype cannot be determined, even after testing
NSCLC=non-small cell lung cancer; SCLC=small cell lung cancer.
NSCLC Biomarkers

The molecular basis of lung cancer is complex and develops through a multistep process. Gene alterations and changes in protein expression contribute to the pathogenesis of NSCLC1

Currently, several testing options, such as NGS panels, are able to detect genetic alterations implicated in NSCLC. IHC testing represents a distinct methodology that captures changes in protein expression.
While there are currently no treatments specifically targeting c-Met overexpression in NSCLC, protein overexpression can be measured via IHC. IHC is also used to test for PD-L1 overexpression3*
Protein
Expression*
Genetic
Alterations*
PD-L1 Overexpression
~30%
c-Met Overexpression†
~25%
Role in Oncogenesis4–6
Associated with immune evasion of cancer cells
Associated with cancer cell growth
Detection Method7,8
IHC
IHC
Approval Status3,9,10
FDA-approved biomarker as a CDx to identify appropriate patients for treatment
Emerging biomarker in research. Non-FDA approved
*This is not an exhaustive list of protein biomarkers and there are currently no FDA-approved tests for c-Met overexpression3
†EGFR wild-type non-squamous NSCLC.
CDx=companion diagnostics; EGFR=epidermal growth factor receptor; FDA=Food and Drug Administration; IHC=immunohistochemistry; MET=mesenchymal-epithelial transition; NGS=next-generation sequencing; NSCLC=non-small cell lung cancer; PD-L1=programmed death ligand 1.

The molecular basis of lung cancer is complex and develops through a multistep process. Gene alterations and changes in protein expression contribute to the pathogenesis of NSCLC1

Currently, several testing options, such as NGS panels, are able to detect genetic alterations implicated in NSCLC. IHC testing represents a distinct methodology that captures changes in protein expression.
While there are currently no treatments specifically targeting c-Met overexpression in NSCLC, protein overexpression can be measured via IHC. IHC is also used to test for PD-L1 overexpression3*
Protein
Expression*
Genetic
Alterations
PD-L1 Overexpression
~30%
c-Met Overexpression†
~25%
Role in Oncogenesis4–6
Associated with immune evasion of cancer cells
Associated with cancer cell growth
Detection Method7,8
IHC
IHC
Approval Status3,9,10
FDA-approved biomarker as a CDx to identify appropriate patients for treatment
Emerging biomarker in research. Non-FDA approved
*This is not an exhaustive list of protein biomarkers and there are currently no FDA-approved tests for c-Met overexpression3
†EGFR wild-type non-squamous NSCLC.
CDx=companion diagnostics; EGFR=epidermal growth factor receptor; FDA=Food and Drug Administration; IHC=immunohistochemistry; MET=mesenchymal-epithelial transition; NGS=next-generation sequencing; NSCLC=non-small cell lung cancer; PD-L1=programmed death ligand 1.

The molecular basis of lung cancer is complex and develops through a multistep process. Gene alterations and changes in protein expression contribute to the pathogenesis of NSCLC1

Currently, several testing options, such as NGS panels, are able to detect genetic alterations implicated in NSCLC. IHC testing represents a distinct methodology that captures changes in protein expression.
While there are currently no treatments specifically targeting c-Met overexpression in NSCLC, protein overexpression can be measured via IHC. IHC is also used to test for PD-L1 overexpression3*
Protein Expression*
PD-L1 Overexpression
~30%
c-Met Overexpression†
~25%
Role in Oncogenesis4–6
Associated with immune evasion of cancer cells
Associated with cancer cell growth
Detection Method7,8
IHC
IHC
Approval Status3,9,10
FDA-approved biomarker as a CDx to identify appropriate patients for treatment
Emerging biomarker in research. Non-FDA approved
*This is not an exhaustive list of protein biomarkers and there are currently no FDA-approved tests for c-Met overexpression3
†EGFR wild-type non-squamous NSCLC.
CDx=companion diagnostics; EGFR=epidermal growth factor receptor; FDA=Food and Drug Administration; IHC=immunohistochemistry; MET=mesenchymal-epithelial transition; NGS=next-generation sequencing; NSCLC=non-small cell lung cancer; PD-L1=programmed death ligand 1.
Genetic Alterations
Oncogenic Mutations in NSCLC
Oncogenic mutations in NSCLC graphic
Role in Oncogenesis1,11
Genetic alterations include activation of growth-promoting proto-oncogenes (eg, KRAS, EGFR) and inactivation of tumor suppressor genes (eg, TP53)
Detection Method12,13
NGS, RT-PCR, FISH, Sanger sequencing
Approval Status3
Several FDA-approved tests available to identify patients with actionable mutations
ALK=anaplastic lymphoma kinase; BRAF=B-Raf; EGFR=epidermal growth factor receptor; FDA=Food and Drug Administration; FISH=fluorescence in situ hybridization; KRAS=K-Ras; MET=mesenchymal-epithelial transition; NGS=next-generation sequencing; NSCLC=non-small cell lung cancer; NTRK=neurotrophic tyrosine receptor kinase; RET=rearranged during transfection; ROS=ROS proto-oncogene; RT-PCR=reverse transcription polymerase chain reaction; TP53=tumor protein 53.
References
  1. Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet. 2021;398(10299):535-554. doi:10.1016/S0140-6736(21)00312-3
  2. Sainz de Aja J, Dost AFM, Kim CF. Alveolar progenitor cells and the origin of lung cancer. J Intern Med. 2021;289:629-635. doi:10.1111/joim.13201
  3. List of cleared or approved companion diagnostic devices. US Food and Drug Administration. Accessed June 27, 2023. https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools
  4. Pawelczyk K, Piotrowska A, Ciesielska U, et al. Role of PD-L1 expression in non-small cell lung cancer and their prognostic significance according to clinicopathological factors and diagnostic markers. Int J Mol Sci. 2019;20(4):824. doi:10.3390/ijms20040824
  5. Liang H, Wang M. MET oncogene in non-small cell lung cancer: mechanism of MET dysregulation and agents targeting the HGF/c-Met axis. Onco Targets Ther. 2020;13:2491-2510. doi:10.2147/OTT.S231257
  6. Fu F, Deng C, Sun W, et al. Distribution and concordance of PD-L1 expression by routine 22C3 assays in East-Asian patients with non-small cell lung cancer. Respir Res. 2022;23(1):302. doi:10.1186/s12931-022-02201-8
  7. Scheel AH, Schäfer SC. Current PD-L1 immunohistochemistry for non-small cell lung cancer. J Thorac Dis. 2018;10(3):1217-1219. doi:10.21037/jtd.2018.02.38
  8. Park S, Choi YL, Sung CO, et al. High MET copy number and MET overexpression: poor outcome in non-small cell lung cancer patients. Histol Histopathol. 2012;27(2):197-207. doi:10.14670/HH-27.197
  9. Motwani M, Panchabhai S, Bar J, et al. P60.12 Prevalence of c-Met overexpression (c-Met+) and impact of prior lines of treatment on c-Met protein expression in NSCLC. JTO. 2021;16(10):S1169-S1170. doi:10.1016/j.jtho.2021.08.633
  10. Sun W, Song L, Ai T, et al. Prognostic value of MET, cyclin D1 and MET gene copy number in non-small cell lung cancer. J Biomed Res. 2013;27(3):220-230. doi:10.7555/JBR.27.20130004
  11. Cooper WA, Lam DC, O’Toole SA, Minna JD. Molecular biology of lung cancer. J Thorac Dis. 2013;5(suppl 5): S479-S490. doi:10.3978/j.issn.2072-1439.2013.08.03
  12. Michaels E, Bestvina CM. Meeting an un-MET need: targeting MET in non-small cell lung cancer. Front Oncol. 2022;12:1004198. doi:10.3389/fonc.2022.1004198
  13. Das R, Jakubowski MA, Spildener J, Cheng YW. Identification of novel MET Exon 14 skipping variants in non-small cell lung cancer patients: a prototype workflow involving in silico prediction and RT-PCR. Cancers (Basel). 2022;14(19):4814. doi:10.3390/cancers14194814
Developed and authored by AbbVie US Medical Affairs.
© 2023 AbbVie Inc. All rights reserved.
ABBV-US-01338-MC, v2.0
Approved: November 2023
Unless otherwise specified, all product names appearing in this internet site are trademarks owned by or licensed to AbbVie Inc., its subsidiaries or affiliates. No use of any AbbVie trademark, trade name, or trade dress in this site may be made without the prior written authorization of AbbVie Inc., except to identify the product or services of the company.
Accessibility Statement
Medical Information
Contact Us
Terms of Use
Privacy Notice
Cookies Settings
Your Privacy Choices
Privacy options