Advanced lung cancer treatment and diagnostic solutions

Understanding lung cancer: Diagnosis and treatment options

With an estimated 2.2 million new cancer cases and 1.8 million deaths, lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer death in 2020, representing approximately 11.4% of diagnosed cancers and 18.0% of deaths¹. Lung cancer is the leading cause of cancer morbidity and mortality in men, whereas, in women, it ranks third for incidence, after breast and colorectal cancer, and second for mortality, after breast cancer ¹. Lung cancer mainly affects older people. More than 40% of people diagnosed with lung cancer are aged 75 and older. Although people who have never smoked can develop lung cancer, smoking is the most common cause (accounting for more than 70 % of cases). In many cases, lung cancer goes undetected until it is in advanced stages, or the cancer comes back after initial treatment. Thus, identifying the stage is important for doctors to determine patients’ prognosis and help assess treatment options.

Figure 1: Different types of NSCLC⁴

The two main types of lung cancer are :

– Small Cell Lung Cancer (SCLC), the more aggressive and fast-growing cancer type representing about 15% of patients

– Non-Small Cell Lung Cancer (NSCLC), which represents 80-85% of patients ^2,3.

For decades, NSCLC was considered as a single homogenous disease. Soon after, histological subtyping brought additional information with the identification of adenocarcinoma, squamous cell carcinoma and other subtypes (Figure 1).

Prevalence of drivers in NSCLC in Europe

Today, even more details are available from genotyping characterization, as illustrated by the specific oncogenic driver alterations that are found in NSCLC (Figure 2).

In Europe, KRAS mutations are the most frequently encountered (25%), followed in EGFR (5-15%), MET exon 14 (3%) and BRAF V600E mutations (2-3%).

Gene fusions or rearrangements including ALK, ROS1, RET, NTRK and NRG1 genes represents almost 12% of NSCLC cases.

However, to date, other alterations or unknown drivers still represents most of the NSCLC cases. This underscores the importance of obtaining the most comprehensive molecular profiling to identify the most suitable therapeutic strategy for each patient.

Figure 2: Prevalence of drivers in NSCLC in Europe

The role of biomarker testing in lung cancer treatment

Lung cancer is a diverse disease, characterized by a variety of different genetic and molecular characteristics⁵. These characteristics, known as biomarkers, can serve as indicators of various types of cancer and many promote tumor growth. Biomarker testing (also known as mutation, genomic, or molecular testing) of tumor tissue allows us to look for abnormalities in the DNA and/or RNA and expression levels of specific proteins. Biomarker testing is critical to learning more about each patient’s tumor type and can be used to help determine treatment options. Based on the test results, patients may be matched with targeted therapies aimed at specific biomarkers present in their genetic profile⁶.

Key biomarkers for personalized NSCLC treatment plans

Actionable biomarkers are defined as genetic alterations that are functional in driving malignancy and may be targeted by an approved treatment (Table 2). They can lead to oncogenic activation through several mechanisms, including point mutations, insertions/deletions and rearrangements⁷. Broadly, actionable mutations guiding targeted therapies can be classified according to gene rearrangements (e.g. ALK, ROS1, RET, NTRK, NRG1) or variants including point mutations, insertions/deletions and amplifications (e.g. EGFR, BRAF, KRAS, MET, ERBB2/HER2). These actionable biomarkers help determine whether a targeted therapy might be appropriate. Genomic signatures such as TMB and MSI or PDL-1 expression level can be used to determine whether an immunotherapy drug might be appropriate. Overall, outcomes for patients with actionable oncogenic driver mutations when receiving targeted therapy tend to be improved versus those without actionable mutations⁸. Molecular testing to detect these “actionable targets” therefore plays a key role in the diagnostic work-up for NSCLC patients to guide therapy choices and improve outcomes. The table 1 provides an overview of current and emerging biomarkers in NSCLC, their recommended detection levels and their testing technologies.

Genes	Biomarker types	Atlerations	Recommended detection level	Guidelines recommended testing technologies^9,10
EGFR	Activating mutations	Exon 19 deletions Exon 21 (L858R) Others	DNA	Any appropriate, validated technology (NGS, real time PCR, Sanger sequencing…)
	Resistance mutations	T790M Exon 20 insertion	DNA
	Resistance mutations
ALK	Rearrangements	NA	Protein, DNA and/or RNA	FISH (historical standard) IHC (stand-alone if scoring 3+ or validated against FISH) RT-PCR; NGS
ROS1	Rearrangements	NA	Protein, DNA and/or RNA	FISH trial-validated standard) IHC to select for confirmatory FISH RT-PCR; NGS
NTRK	Rearrangements	Gene fusions	Protein, DNA and/or RNA	IHC, FISH, RT-PCR, NGS
BRAF	Activating mutations	V600E	DNA	Any appropriate, validated technology (NGS, real time PCR, Sanger sequencing…)
RET	Rearrangements	NA	DNA and/or RNA	FISH, RT-PCR, NGS
MET	Activating mutations	Exon14 Skipping	DNA and/or RNA	Any appropriate, validated technology (NGS, real time PCR, Sanger sequencing…)
ERBB2/HER2	Activating mutations	NA	DNA	Any appropriate, validated technology (NGS, real time PCR, Sanger sequencing…)
KRAS	Activating mutations	G12C	DNA
PD-L1	Expression levels	NA	Protein	IHC
MSI	Genomic signatures^b	Unstable	DNA	NGS
TMB	Genomic signatures ^b	High	DNA	NGS
NRG1	Rearrangements^a	NA	DNA and/or RNA	NGS

Table 1. Established and emerging biomarkers for NSCLC
^a Emerging biomarkers
^b Emerging biomarkers in Europe (FDA approved)

Table 2 provides an overview of current biomarkers in NSCLC and associated approved targeted therapies for locally advanced or metastatic NSCLC patients. FDA approval is conditioned by the use of an FDA approved test for the biomarker testing. Table 2: Biomarkers with current FDA or EMA-approved treatment for localy advanced or metastatic NSCLC (As of June, 2023)

Genes	Biomarkers types	Atlerations	FDA-approved therapy (first line)	EMA-approved therapy (first line)
EGFR	Activating mutations	Exon 19 deletions Exon 21 (L858R) Others	Afatinib^a, Dacomitinib^b, Erlotinib ^b, Gefitinib ^b, Osimertinib ^b,^c, Mobocertinib ^d, Amivantamab ^d	Afatinib ^a, Dacomitinib ^a, Erlotinib ^aGefitinib ^a, Osimertinib ^a,^c, Amivantamab ^d
	Resistance mutations	T790M Exon 20 insertion
	Resistance mutations
ALK	Rearrangements	NA	Alectinib, Brigatinib, Ceritinib, Crizotinib, Lorlatinib	Alectinib, Brigatinib, Ceritinib, Crizotinib, Lorlatinib ^e
ROS1	Rearrangements	NA	Crizotinib, Entrectinib	Crizotinib, Entrectinib
NTRK	Rearrangements	Gene fusions	Entrectinib, larotrectinib	Entrectinib, Larotrectinib
BRAF	Activating mutations	V600E	Dabrafenif + Trametinib	Dabrafenif + Trametinib
RET	Rearrangements	NA	Praseltinib, Selpercatinib	Praseltinib, Selpercatinib
MET	Activating mutations	Exon14 Skipping	Capmatinib, Tepotinib	Capmatinib, Tepotinib
ERBB2/HER2	Activating mutations	NA	Fam-trastuzumab	Fam-trastuzumab
KRAS	Activating mutations	G12C	Adagrasib, Sotorasib	Adagrasib, Sotorasib
PD-L1	Expression levels	NA	Immune checkpoint inhibitors	Immune checkpoint inhibitors
MSI	Genomic signatures^b	Unstable	Pembrolizumab	None
TMB	Genomic signatures	High	DNA	NGS
TMB	Genomic signatures	High	Pembrolizumab	None

^a Approved for all activating mutation /^b Approved only for exon 19 deletions and L858R / ^c Approved for T790M mutation-positive (second line) / ^d Approved for Exon 20 insertions / ^e Conditional approval / ^f Specific waiver

In 2020 and 2021, the FDA and EMA approved Osimertinib for adjuvant therapy after complete tumor resection in patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations. This approval was based on findings from the phase 3 ADAURA trial, in which Osimertinib showed a statistically significant and clinically meaningful improvement in disease-free survival (DFS) in the primary analysis of patients with stage II and IIIA EGFR-mutant NSCLC (HR, 0.17), as well as in the overall study population (HR, 0.20)¹⁰. New results have been presented in an oral presentation during the Plenary Session at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. In an updated analysis for the overall population, Osimertinib produced a median DFS of 65.8 months (HR, 0.27) and let to 51% reduction in the risk of death (HR, 0.49)¹¹. Thus, it is essential to test all patients with early-stage lung cancer for EGFR mutations to determine the optimal treatment strategy and to discuss management within a multidisciplinary team. Other Osimertinib studies are also underway to build on the ADAURA results in other EGFR-mutated NSCLC settings. For example, the ongoing ADAURA-2 study (NCT05120349) is evaluating adjuvant Osimertinib in patients with stage IA disease, NeoADAURA (NCT04351555) is assessing neoadjuvant Osimertinib in resectable stage II to IIIB N2 disease, and TARGET (NCT05526755) is investigating a 5-year duration of adjuvant Osimertinib in stage II to IIIB disease.

OncoDEEP® Test: Enhancing NSCLC treatment with precision medicine

Comprehensive biomarker testing is often used for diagnosed lung cancer patients, particularly in NSCLC for the development of patient’s treatment plan; as it looks for large number of genetic alterations and levels of specific proteins. The result of comprehensive biomarker testing helps determine whether any of the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) approved lung cancer targeted therapies, or a particular immunotherapy drug is right as part of the patient’s treatment plan. It is the first step in precision medicine, ensuring that a patient gets matched to the right treatment at the right time, based on the patient’s biomarker status. Furthermore, testing results will also provide information about biomarkers that identify patients who are eligible for current clinical trial recruitment. ASCO, ESMO and NCCN also recommends the routine use of next-generation sequencing (NGS) in advanced non-squamous NSCLC, and that large multi-gene panels could be used if additional costs are considered acceptable compared versus small panels ^12,13,14. Our OncoDEEP^® test is designed to detect all the biomarkers as mentioned in Table 1 and 2 (and more!). We understand the challenges in detecting large array of biomarkers from low quantity and poor-quality tumor genetic material; hence with a team of experts, we have developed, optimized and validated OncoDEEP^® test to be able to detect low level of biomarker in difficult to analyse tumor biopsy. Our test is sensitive enough to detect allelic frequency of 5%, and even down to 1% for FDA and EMA-approved biomarkers! Upon detecting any of the biomarkers that are associated with treatment options or recruiting clinical trials, a report will be generated to help oncologists work out the most suitable cancer treatment plan for their patients.

1. World Health Organization. Globocan 2020 Fact Sheet. Available at: https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf. Accessed September 2021.

2. American Cancer Society. What is Lung Cancer? Available at: http://www.cancer.org/cancer/lung-cancer/about/what-is.html. Accessed September 2021.

3. National Cancer Institute. NCI Dictionary – Small Cell Lung Cancer. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/small-cell-lung-cancer. Accessed September 2021.

4. Wistuba I, Brambilla E, Noguchi M. Chapter 17: Classic Anatomic Pathology and Lung Cancer. In: Pass HI, Ball D, Scagliotti GV, eds. IASLC Thoracic Oncology, Second Edition. Philadelphia, PA: Elsevier; 2018:143-146. Accessed February 10, 2021.

5. KorpantyG, et al. Biomarkers that currently affect clinical practice in lung cancer: EGFR, ALK, MET, ROS-1, and KRAS. Frontiers in Oncology. 2014(4).

6. AwadM and Hammerman P. Durable Responses With PD-1 Inhibition in Lung and Kidney Cancer and the Ongoing Search for Predictive Biomarkers. J Clin Oncol. 2015; 33.

7. E. Smolle, K. Leithner, H. OlschewskiOncogene addiction and tumor mutational burden in non-small-cell lung cancer: clinical significance and limitations Thorac. Cancer, 11 (2) (2020), pp. 205-215

8. L. Tan, M. Alexander, A. Officer, M, et al. Survival difference according to mutation status in a prospective cohort study of Australian patients with metastatic non-small-cell lung carcinoma Int. Med. J., 48 (1) (2018), pp. 37-44

9. European Society for Medical Oncology. Metastatic Non-Small-Cell Lung Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up

10. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB-IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 15):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5

11. Masahiro Tsuboi, Roy S. Herbst, Thomas John, Terufumi Kato, Margarita Majem, Christian Grohé, Jie Wang, Jonathan W. Goldman, Shun Lu, Wu-Chou Su, Filippo de Marinis, Frances A. Shepherd, et al., for the ADAURA Investigators*. Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med. 2023 Jun 4

12. NCCN Non-Small Cell Lung Cancer Version 3.2023 — April 13, 2023

13. Debyani Chakravarty, Amber Johnson, Jeffrey Sklar, Neal I. Lindeman, Kathleen Moore, Shridar Ganesan, Christine M. Lovly, Jane Perlmutter, Stacy W. Gray, Jimmy Hwang, Christopher Lieu, Fabrice André, Nilofer Azad, Mitesh Borad, Laura Tafe, Hans Messersmith, Mark Robson, and Funda Meric-Bernstam. Somatic Genomic Testing in Patients With Metastatic or Advanced Cancer: ASCO Provisional Clinical Opinion. Journal of Clinical Oncology 2022 40:11, 1231-1258

14. F. Mosele, J. Remon, J. Mateo, et al. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group Ann. Oncol., 31 (11) (2020), pp. 1491-1505

You may also be interested in these resources

Press Release

The NHS South East Genomic Medicine Service transitions to the OncoDEEP Kit a Solid Tumour Panel that can transform oncology patients’ lives as a result of timely comprehensive genomic testing.

Oct 15th

The NHS South East Genomic Medicine Service serves approximately 15.4% of the population of England and seeks to improve patient outcomes through care pathway development enabling timely and equitable access to genomic testing and genomically...

Scientific Application Note

LYMPHOMA The FDA have approved the EZH2 inhibitor tazemetostat in folliciular lymphoma, third line for EZH2-mutant disease, or where there are no other treatment options for EZH2 wild-type disease

Jun 22nd

FDA granted accelerated approval to tazemetostat for follicular lymphoma On June 18, 2020, the Food and Drug Administration granted accelerated approval to tazemetostat (TAZVERIK, Epizyme, Inc.), an EZH2 inhibitor, for adult patients with relapsed or...

Scientific Application Note

The evolution of BRCA testing: treatment & prevention opportunities

Dec 20th

Mutation of the BRCA genes (BRCA1 and BRCA2) is associated with response to PARP inhibitors such as olaparib and rucaparib. PARP inhibitors are currently approved in four cancer types: breast (HER2 negative), ovarian, pancreatic and...