Actionable Biomarkers in NSCLC

Most newly diagnosed patients with mNSCLC have an actionable biomarker1-12



Prevalence of actionable biomarkers*:

Prevalence of actionable biomarkers
Prevalence of actionable biomarkers

 

*A tumor may express multiple biomarkers.

 

NCCN Guidelines recommend molecular testing to identify driver mutations and help guide clinical decisions for all appropriate patients with mNSCLC, if clinically feasible. This includes biomarker testing for EGFR, ALK, ROS1, BRAF V600E, NTRK, and PD-L1.13

 

The NCCN Guidelines for NSCLC provide recommendations for individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays. The NCCN Guidelines Panel for NSCLC strongly advises broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available.


ALK rearrangements

ALK rearrangements
ALK rearrangements

 

ALK is a receptor tyrosine kinase of the insulin receptor family.14 In NSCLC and other tumors, the ALK gene may undergo rearrangement, resulting in a fusion protein.14 The most common ALK rearrangement in NSCLC is the EML4-ALK fusion.15 ALK fusion proteins are oncogenic drivers, which constitutively activate multiple signaling pathways that promote tumor growth and survival.14,15
 

Prevalence in NSCLC: Up to 11%6-8
 

FDA-approved assays to detect ALK rearrangements:

  • Vysis ALK Break Apart FISH Probe Kit (Abbott)16
  • VENTANA ALK (D5F3) CDx Assay17
  • FoundationOne® CDx18

In all appropriate newly diagnosed patients with mNSCLC, testing for ALK rearrangements can identify patients eligible for targeted treatment with ALK-TKIs.13

ROS1 rearrangements

ROS1 rearrangements
ROS1 rearrangements

 

ROS1 is a receptor tyrosine kinase of the insulin receptor family.9 In NSCLC and other tumors, the ROS1 gene can undergo rearrangement, resulting in a fusion protein.9 ROS1 fusion proteins are oncogenic drivers, which constitutively activate multiple signaling pathways that promote tumor growth and survival.9,19
 

Prevalence in NSCLC: 1% to 2% of patients9,10

FDA-approved assay to detect ROS1 rearrangements:

  • Oncomine™ Dx Target Test20

In all appropriate newly diagnosed patients with mNSCLC, testing for ROS1 rearrangements can identify patients eligible for targeted treatment with an ALK-TKI.13

BRAF V600E mutation

BRAF V600E mutation
BRAF V600E mutation

 

BRAF is a serine/threonine kinase that is part of the MAPK signaling pathway.21 BRAF mutations lead to constitutive activation and sustained signaling of the MAPK pathway, which promotes tumor cell growth and survival.11,21,22


Prevalence in mNSCLC:

  • Up to 2% have BRAF V600E mutations11
  • Up to 5% have BRAF mutations (V600E and non-V600E)21,22


FDA-approved assays to detect BRAF V600E mutations:

  • OncomineTM Dx Target Test20
  • FoundationOne® CDx18

In all appropriate newly diagnosed patients with mNSCLC, testing for the BRAF V600E mutation can identify patients eligible for treatment with combination BRAF and MEK inhibitor therapy.13

NTRK rearrangements23,24

NTRK rearrangements
NTRK rearrangements

 

The NTRK genes encode for TRK proteins, which are nerve growth factor receptors.25,26 The NTRK gene may undergo rearrangement, resulting in a fusion protein.24 NTRK fusion proteins are oncogenic drivers, which constitutively activate multiple signaling pathways that promote tumor growth and survival.23-25
 

Prevalence in mNSCLC: ≈3% of patients12

In newly diagnosed patients with mNSCLC, testing for NTRK rearrangements can identify patients eligible for treatment with TRK inhibitor therapy.13

 


 

According to NCCN Guidelines, targeted therapies or immunotherapies offer improved outcomes for patients with mNSCLC whose tumors are positive for sensitizing EGFR mutations, ALK rearrangements, ROS1 rearrangements, BRAF V600E mutations, or PD-L1 expression.13,†

Refer to the NCCN Guidelines for specific treatment recommendations for each setting. Not all agents in a drug class are recommended for each setting.

AKT, protein kinase B; ALK, anaplastic lymphoma kinase; BRAF, v-Raf murine sarcoma viral oncogene homolog B; EGFR, epidermal growth factor receptor; EML4, echinoderm microtubule-associated protein-like 4; ERK, extracellular signal–regulated kinase; FDA, Food and Drug Administration; FISH, fluorescence in situ hybridization; MAPK, mitogen-activated protein kinase; MEK, mitogen activated protein kinase kinase; mNSCLC, metastatic non–small cell lung cancer; mTOR, mammalian target of rapamycin; NCCN, National Comprehensive Cancer Network; NTRK, neurotrophic tyrosine kinase; PD-L1, programmed death-ligand 1; PI3K, phosphoinositide 3-kinase; RAF, v-Raf-1 murine leukemia viral oncogene homolog; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase; TKI, tyrosine kinase inhibitor; TRK, tropomyosin receptor kinase.
 

References: 1. Borghaei H et al. N Engl J Med. 2015;373(17):1627-1639. 2. Garon EB et al. N Engl J Med. 2015;372(21):2018-2028. 3. Herbst RS et al. Nature. 2014;515(7528):563-567. 4. Herbst RS et al. Lancet. 2016;387(10027):1540-1550. 5. Fehrenbacher L et al; POPLAR Study Group. Lancet. 2016;387(10030):1837-1846. 6. Sholl LM et al. J Thorac Oncol. 2015;10(5):768-777. 7. Korpanty GJ et al. Front Oncol. 2014;4:204. 8. Baumgart M et al. Expert Rev Precis Med Drug Dev. 2016;1(1):25-36. 9. Shaw AT et al. N Engl J Med. 2014;371(21):1963-1971. 10. Bergethon K et al. J Clin Oncol. 2012; 30(8):863-870. 11. Baik CS et al. Oncologist. 2017;22(7):786-796. 12. Vaishnavi A et al. Nat Med. 2013;19(11):1469-1472. 13. 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. 14. Shaw AT et al. Clin Cancer Res. 2011;17(8):2081-2086. 15. Shaw AT et al. J Clin Oncol. 2013;31(8):1105-1111. 16. Vysis ALK Break Apart FISH Probe Kit [package insert]. Des Plaines, IL: Abbott Laboratories; 2011. 17. VENTANA ALK (D5F3) CDx Assay [package insert]. Tucson, AZ: Ventana Medical Systems, Inc.; 2017. 18. Foundation Medicine. FoundationOne® CDx technical information. Foundation Medicine website. https://www.foundationmedicine.com/genomic-testing/foundation-one-cdx. Accessed March 27, 2019. 19. Chin LP et al. J Thorac Oncol. 2012;7(11):1625-1630. 20. FDA. Oncomine™ Dx Target Test summary of safety and effectiveness data. FDA website. https://www.accessdata.fda.gov/cdrh_docs/pdf16/p160045b.pdf. June 22, 2017. Accessed November 10, 2018. 21. Nguyen-Ngoc T et al. J Thorac Oncol. 2015;10(10):1396-1403. 22. Oxnard GR et al. J Clin Oncol. 2013;31(8):1097-1104. 23. Amatu A et al. ESMO Open. 2016;1(2):e000023. 24. Vaishnavi A et al. Cancer Discov. 2015;5(1):25-34. 25. Desai A et al. Cancer Biol Med. 2016;13(1):77-86. 26. Bansal P et al. Front Oncol. 2016;6:112.
 

Trademarks are the property of their respective owners.

 

 

MET, RET, HER2, and KRAS: Emerging Biomarkers

 

ALK, anaplastic lymphoma kinase; AMP, Association for Molecular Pathology; CAP, College of American Pathologists; EGFR, epidermal growth factor receptor; IASLC, International Association for the Study of Lung Cancer; HER2, human epidermal growth factor receptor 2; 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; PI3K, phosphoinositide 3-kinase; RET, Ret proto-oncogene; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase; TKI, tyrosine kinase inhibitor.

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.

References: 1. Lindeman NI et al. Arch Pathol Lab Med. 2018.142(3):321-346. doi:10.5858/arpa.2017-0388-CP. 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V6.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed September 27, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org. 3. Baumgart M et al. Expert Rev Precis Med Drug Dev. 2016;1(1):25-36. 4. Soo RA et al. J Thorac Oncol. 2017;12(8):1183-1209. 5. Salgia R. Mol Cancer Ther. 2017;16(4):555-565. 6. Tomasini P et al. Oncologist. 2016;21(12):1450-1460. 7. Sholl LM et al. J Thorac Oncol. 2015;10(5):768-777.