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NSCLC is often diagnosed at a late stage, so it accounts for a large proportion of the mortality burden in lung cancer[1][2]


NSCLC and its three main histological sub-types (adenocarcinoma, squamous cell carcinoma and large cell carcinoma) account for the majority (~85%) of lung cancer cases
(fig. 1).[3][4]

Around 60% of all patients with NSCLC have metastatic disease at the time of diagnosis.[1] Although the exact reasons are unclear, this may in part be due to the late presentation of symptoms, which means the disease is detected too late, delays in patients seeking medical care, or delays in the diagnostic process.[5]

The late presentation of lung cancer ultimately leads to a poor prognosis, where the 5-year survival drops from 68% in stage 1B to 0–10% in stage 4A–4B.[2][6]

Subtypes of lung cancer

Figure 1. Subtypes of lung cancer and NSCLC, including the three main NSCLC histological classifications.[3][4]
The cells of origin and smoking status are indicated for each of the three main histological sub-types of NSCLC.[3]
Adapted from Lemjabbar-Alaoui H et al. 2015.[4]

Many treatment options for locally advanced / metastatic NSCLC rely on early biomarker testing to be effective[7]


The management strategy for locally advanced/metastatic NSCLC should consider several factors such as tumour histology, patient age, performance status, comorbidities, the patient's preference, and, importantly, the tumour’s molecular pathology.[7]

Two testing streams are commonly used to identify patients who may benefit from targeted therapies.[7] These tests are used to detect (fig.2):[7]

  1. Biomarkers that confer sensitivity to immuno-oncology agents
  2. Targetable mutations that drive NSCLC
  • Several targetable NSCLC driver mutations are routinely tested for in Europe, including mutations in ALK, ROS1, BRAF, and EGFR – the most common known actionable biomarker (fig. 2).[7][8]To find out how dysregulation of EGFR can drive NSCLC, visit our page on EGFR
Figure 2. Stage IV NSCLC treatment options.

Figure 2. Stage IV NSCLC treatment options.*[7]
Targeted therapies may be available to patients who have a detectable mutation in EGFR, ALK, BRAF V600, and ROS1.[8]PD-L1 expression should be assessed in those tumours that do not have a detectable biomarker, and these patients should be treated according to clinical practice guidelines.[7]
Adapted from the ESMO clinical practice guidelines, 2020.[7]

The European Guidelines state that EGFR testing should assess all mutations of exons 18 to 21, including at a minimum the most common activating mutations (exon 19 deletion and exon 21 L858R point mutation).[7]

EGFR exon 20 insertion (ex20ins) mutations are generally resistant to currently approved EGFR-TKIs – so if these mutations are detected, platinum-based chemotherapies are often prescribed as a first-line therapy.[9][10][11]

Find out about the harsh realities of EGFR exon 20 insertion mutations.

Driver mutations in locally advanced/metastatic NSCLC are currently used – or are being investigated – as molecular biomarkers[7][12]


These are listed below, along with information on their prevalence in NSCLC sub-populations, and potential treatments:

EGFR

Genomic aberrations: Activating mutations and over-expression[12]
Prevalence of mutations (non-squamous histology): ~15% in Caucasians, ~40% in Asians, and ~75–80% in never-smokers[12]
Prevalence of mutations (squamous histology): ~5%[12]
Prevalence of over-expression: ~39% in adenocarcinoma, ~58% in squamous cell carcinoma, and ~38% in large-cell carcinoma[12]
Treatment: EGFR-TKIs (e.g., gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib)[7]

Please note: Currently approved EGFR-TKI therapies are not effective against all EGFRm NSCLC tumours.[9][10]To learn more about EGFR-TKIs and resistance to these therapies:

ALK

Genomic aberrations: Chromosomal translocation and fusion[12]
Prevalence: ~3–5% in NSCLC, ~10% in never-smokers, and <1% in squamous carcinoma[12]
Treatment: ALK-TKIs (e.g., crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib)[7]

ROS1

Genomic aberrations: Chromosomal translocation and fusion[12]
Prevalence: ~1–2%[12]
Treatment: ROS1-TKI (e.g., crizotinib)[7]

BRAF

Genomic aberrations: Point mutations[7]
Prevalence: 1–3% in adenocarcinoma[13]
Treatment: BRAF inhibitor +/- MEK inhibitor therapy (e.g., dabrafenib and trametinib)[7]

MET

Genomic aberrations: Increased copy number, over-expression, and exon skipping mutations[13][14]
Prevalence of amplification: 2–4% in treatment-naïve tumours, 5–20% in EGFR-TKI-resistant tumours[12]
Prevalence of over-expression: 25–75%[12]
Prevalence of amplification: 2–4% in treatment-naïve tumours, 5–20% in EGFR-TKI-resistant tumours[12]
Prevalence of exon skipping: ~3% in NSCLC[14]
Treatment: Targeting is not routinely recommended according to ESMO guidelines, though a variety of MET-directed TKIs are undergoing development against this target (e.g. capmatinib and tepotinib)[7]

RET

Genomic aberrations: Fusion, rearrangement[13]
Prevalence: 1–2% in adenocarcinoma[13]
Treatment: Targeting is not routinely recommended according to ESMO guidelines[7]

KRAS

Genomic aberrations: Activating mutation[13]
Prevalence: Rare in never-smokers, ~25–30% in adenocarcinoma, and ~5% in squamous cell carcinoma[12]
Treatment: Targeting is not routinely recommended according to ESMO guidelines,[7] though a variety of novel agents targeting downstream effector signaling pathways are under clinical development[12]

HER2

Genomic aberrations: Over-expression, activating mutation[13]
Prevalence of over-expression: 7–34.9%[13]
Prevalence of activating mutations: 1.6–4% in adenocarcinoma[13]
Treatment: Targeting is not routinely recommended according to ESMO guidelines[7]

NTRK1

Genomic aberrations: Fusion[13]
Prevalence: 3% in adenocarcinoma[13]
Treatment: Targeting is not routinely recommended according to ESMO guidelines[7]

Biomarker detection using liquid biopsy and NGS testing is shifting the NSCLC treatment paradigm and is paving the way to precision medicine[15]

With an expanding number of therapeutic targets in advanced NSCLC, the continued uptake of comprehensive detection methods, such as NGS, is essential.[15]

As stated in the ESMO clinician guidelines, to help perform NGS testing, sample collection can be carried out using a minimally invasive liquid biopsy.[7][15]This allows clinically relevant information to be collected both before and after targeted treatment in patients with NSCLC.[7][15]

The ESMO, German Leitlinien Programm Onkologie, Italian Association of Medical Oncology (AIOM) guidelines, and NCCN guidelines all recommend routine testing testing for EGFR exon 20 insertion mutations – detection of these mutations can help to guide treatment[7][16][17][18]

Make EGFR exon 20 insertion mutations unmissable. Test with NGS.

Discover more about EGFR exon 20 insertion mutations here:

What causes EGFR-TKI resistance?
Who do EGFR ex20ins mutations strike?
What impact do EGFR ex20ins mutations have on lives?

* Not all therapies are approved by the European Medicines Agency; please refer to local management guidelines for the recommendations in your area. 

ALK, anaplastic lymphoma kinase; BRAF, v-Raf murine sarcoma viral oncogene homolog B; CD74, Cluster of Differentiation 74; EGFR, epidermal growth factor receptor; FISH, fluorescence in-situ hybridisation; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; KRAS, Kirsten rat sarcoma viral oncogene homologue; MEK, mitogen-activated protein kinase kinase; MPRIP, myosin phosphatase RHO-interacting protein; nab-P, albumin-bound paclitaxel; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; PCR, polymerase chain reaction; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PI3K, phosphoinositide 3-kinase; PS, performance status; RET, rearranged during transfection; ROS1; ROS proto-oncogene 1, receptor tyrosine kinase; RT-PCR, reverse transcription polymerase chain reaction; TMB, tumour mutation burden.

CP-223640

References

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Duma N et al. Mayo Clin Proc 2019; 94(8): 1623–1640.
Zappa C et al. Transl Lung Cancer Res 2016; 5(3): 288–300.
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Ellis P and Vandermeer R. J Thorac Dis 2011; 3: 183–188.
O’Kane G et al. Lung Cancer 2017; 109:137–144.
ESMO clinical practice guidelines. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Updated version published 15 September 2020.
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Crossland V et al. JNCCN 2019; 17(3.5): HSR19-082.
Hirano T et al. Oncotarget 2015; 6(36): 38789–38803.
Dersarkissian M et al. Poster presented at the International Association for the Study of Lung Cancer (IASLC) 2019 World Conference on Lung Cancer. September 7–10 2019. Barcelona, Spain. P2.01–103.
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Vuong H et al. Lung cancer 2018; 123: 76–82.
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NCCN. Clinical Practice Guidelines for Non-Small Cell Lung Cancer V.8.2020. Available at: https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed February 2021.
Passiglia F et al. Crit Rev Oncol Hematol 2020; 146: 102858.
AWMF clinical guidance. S3-Leitlinie Prävention, Diagnostik, Therapie und Nachsorge des Lungenkarzinoms. Langversion 1.0.