Table 1.

Established and emerging biomarkers for NSCLC in Europe [7, 8]

Predictive biomarkers	Estimated frequency in NSCLC adenocarcinomae	Guideline-recommended testing technologies	EMA-approved targeted therapyh
EGFR mutationsa	15%f	Any appropriate, validated technology, subject to external quality assessment	Afatinib, dacomitinib, erlotinib, gefitinib, osimertinib
KRAS p.G12C mutations	13% 25–33% (all KRAS mutations)	PCR; pyrosequencing; NGS	Sotorasibi
ALK rearrangementsa	5%	FISH (historical standard); IHC (validated against FISH); NGSg	Alectinib, brigatinib, ceritinib, crizotinib, lorlatinib
ROS1 rearrangementsa	2%	FISH (trial-validated standard); IHC to select for confirmatory FISH; NGSg	Crizotinib, entrectinib
NTRK rearrangementsa	< 1%	IHC; FISH; PCR; NGS	Entrectinib, Iarotrectinib
BRAF mutationsb	2%	Any appropriate, validated technology, subject to external quality assessment	Dabrafenib, trametinib
RET rearrangements	2%	Any validated test (e.g. FISH; PCR; NGS)	Selpercatinib
PD-L1 expression levelsc	≥ 50% TPS: 33% 1–49% TPS: 30%  < 1% TPS: 37%	IHC	Immune checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab, cemiplimab) alone or with chemotherapy
Emerging biomarkersd	Estimated frequency in NSCLC adenocarcinoma	Potential testing technology	Targeted therapies under investigation
MET exon skipping mutations	3%	IHC; FISH; NGS	Cabozantinib, capmatinibj,k, crizotinib, MGCD265, tepotinibj,l,m
ERBB2/HER2 mutations and amplifications	2%	NGS	Ado-trastuzumab emtansine, afatinib, dacomitinib, fam-trastuzumab deruxtecan-nxkik,j, trastuzumab, mobocertinib
NRG1 rearrangements	< 1%	NGSg	Afatinib, GSK2849330, AMG 888, seribantumab, zenocutuzumab
FGFR1	Data not available	NGSg	BGJ398, rogaratinib

Table adapted from Kerr et al. [8]. Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved. Reproduced under the terms of Creative Commons Attribution 4.0 International (CC BY 4.0) license

ALK anaplastic lymphoma kinase, BRAF B-Raf proto-oncogene, EGFR epidermal growth factor receptor, EMA European Medicines Agency, ERBB2 Erb-B2 receptor tyrosine kinase 2, FDA Food and Drug Administration, FGFR1 fibroblast growth factor receptor-1, FISH fluorescence in situ hybridisation, HER2 human epidermal growth factor receptor 2, IHC immunohistochemistry, KRAS Kirsten rat sarcoma viral oncogene homolog, MEK mitogen-activated protein kinase, MET hepatocyte growth factor receptor, NGS next-generation sequencing, NRG1 neuregulin-1, NSCLC non-small cell lung cancer, NTRK neurotrophic tyrosine receptor kinase, PD-L1 programmed cell death ligand 1, RET rearranged during transfection, ROS1 ROS proto-oncogene 1, PCR polymerase chain reaction, TPS tumour proportion score

^aPredicts response to targeted therapy with tyrosine kinase inhibitors

^bPredicts response to BRAF with/without MEK inhibitors

^cPredicts response to immunotherapy

^dUnder investigation as predictive biomarkers with the goal of identifying appropriate therapies for patients

^eNo specific driver known in over one-third of cases

^fExon 19 deletions, exon 21 p.L858R mutations, and exon 20 insertions comprise approximately 10%, 6%, and 2.5% of all mutations, respectively

^gEmerging technology

^hAs of January 2022

ⁱOther direct KRAS.^G12C inhibitors are in the pipeline, including adagrasib (MRTX849; FDA Breakthrough Therapy designation), GDC-6036, JNJ-74699157, JDQ443, LY3537982, D-1553

^jFDA approval

^kApproved in Japan

^lUnder review by EMA

^mApproved in the UK under the Early Access to Medicine Scheme