Non-small cell lung cancer

Non-small cell lung cancer

Non-small lung cancer treatments

Non-small cell lung cancer (NSCLC) has traditionally been treated using systemic cytotoxic therapies; however, some patients with lung cancer can now benefit from targeted therapies for lung cancer and immune checkpoint inhibitors (ICBs)¹. Targetable mutations indicated in non-small cell lung cancer include RET, ALK, EGFR, ROS1 and BRAF.

Tyrosine kinase inhibitors that target ALK and ROS1 rearrangements have proven to be effective and well tolerated, and are recommended as an option for untreated locally advanced or metastatic EGFR mutated non-small cell lung cancer². There are various tyrosine kinase inhibitors indicated for ALK-rearranged tumours, but the optimal strategy in treatment is under debate, and several studies have demonstrated resistance to targeted therapy in ALK fusion tumors. In ROS1-rearranged non-small cell lung cancer, there is also debate surrounding which tyrosine kinase inhibitor is most efficacious³. Finally, there is growing evidence that tyrosine kinase inhibitors targeting rearranged during transfection (RET) fusion positive non-small cell lung cancers have a favourable response rate and safety profile⁴.

Molecular diagnostics in non-small cell lung cancer

The effectiveness of targeted therapies for non-small cell lung cancer depends on the accuracy of genetic profiling of the tumour; treatment decisions of patients with advanced non-small cell lung cancer has become reliant on blood and/or tissue biomarkers^5,6. Valuable tools such as immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) can detect ALK fusions in metastasised non-small cell lung cancers. While immunohistochemistry is cheaper and easier to implement, fluorescence in situ hybridisation can in some cases more accurately detect genetic variants of non-small cell lung cancers that will respond better to certain tyrosine kinase inhibitors⁷. These findings highlight both the importance and challenges of implementing and interpreting reliable biomarker tests for non-small cell lung cancer in clinics^5,6. The application of next generation sequencing (NGS) assays could become standard of care for identifying targetable genomic alterations in non-small cell lung cancer that would have been undetectable using focussed or single-gene testing, such as RET and ROS1 fusions, with high sensitivity and specificity. RET oncogenes in non-small cell lung cancer can be adequately detected by fluorescence in situ hybridisation, reverse transcriptase polymerase chain reaction (RT-PCR) and next generation sequencing⁴.

New techniques should be combined with traditional techniques for non-small cell lung cancer diagnosis, including chest x-rays, CT scans and sputum cytology or thoracentesis. Where non-small cell lung cancer is detected, techniques such as positive electron tomography- computerised tomography (PET-CT) scans, endobronchial ultrasound scans (EBUS), or biopsies including bronchoscopy, thoracoscopy, mediastinoscopy and percutaneous needle biopsy, are still essential for non-small cell lung tumour classification and staging^8,9.

Measuring response to non-small cell lung cancer treatment

Circulating tumour DNA (ctDNA) could be used as a prognostic pharmacodynamic biomarker for non-small cell lung cancer, both at the stage of diagnosis and to measure response to non-small cell lung cancer treatment. Rapid decreases and clearance of circulating tumour DNA correlates with clinical benefit, whereas increased levels of circulating tumour DNA indicates a progression in non-small cell lung cancer disease. Serial assessment of circulating tumour DNA by next generation sequencing could enable early detection of response to first-line immunotherapy for non-small cell lung cancer¹⁰. In patients with EGFR-mutated non-small cell lung cancer being treated with EGFR tyrosine kinase inhibitors, folate receptor-based assays to count circulating tumour cells (CTCs) can be used for both dynamic monitoring of therapeutic response to first-line EGFR tyrosine kinase inhibitors and prediction of outcome. This could be used as an alternative to traditional computed tomographic scanning¹¹.

References

1. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446–454.
2. National Institute for Health and Care Excellence. Osimertinib for untreated EGFR mutation-positive non-small-cell lung cancer. 2020. https://www.nice.org.uk/guidance/ta654/chapter/1-Recommendation. Accessed 1 July 2021.
3. Sushma Joanna. Molecular Diagnostics and Targeted Therapies in Non-small Cell Lung Cancer (NSCLC): An Update. Discov Med. 2019. https://www.discoverymedicine.com/Sushma-Jonna/2019/03/molecular-diagnostics-and-targeted-therapies-in-non-small-cell-lung-cancer-nsclc-an-update/. Accessed 1 July 2021.
4. Mendoza L. Clinical development of RET inhibitors in RET-rearranged non-small cell lung cancer: Update. Oncology Reviews. 2018;12(2):69–73.
5. Conde E, Rojo F, Gómez J, Enguita AB, Abdulkader I, González A, et al. Molecular diagnosis in non-small-cell lung cancer: Expert opinion on ALK and ROS1 testing. Journal of Clinical Pathology. 2021;0:1–9.
6. Pennell NA, Arcila ME, Gandara DR, West H. Biomarker Testing for Patients With Advanced Non–Small Cell Lung Cancer: Real-World Issues and Tough Choices. Am Soc Clin Oncol Educ B. 2019;39(39):531–542.
7. Thunnissen E, Lissenberg-Witte B, Van Den Heuvel M, Monkhorst K, Skov B, Sorensen J, et al. Crizotinib-Treated ALK Immunopositive Metastasized NSCLC is Associated with an Unfavorable Prognosis when FISH Negative. J Thorac Oncol. 2018;13(10):S452.
8. National Cancer Institute. Non-Small Cell Lung Cancer Treatment (PDQ®)–Patient Version. 2021. https://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq. Accessed 23 June 2021.
9. NHS. Lung cancer. 2019. https://www.nhs.uk/conditions/lung-cancer/. Accessed 23 June 2021.
10. Awad M, Lydon C, Adeni A, Subegdjo S, Jones G, Plagnol V, et al. P3.04-02 Early Plasma ctDNA Response Anticipates Clinical Response to First-Line Immunotherapy in Advanced NSCLC. J Thorac Oncol. 2018;13(10):S922–S923.
11. Jiang T, Zhao J, Zhao C, Li X, Shen J, Zhou J, et al. Dynamic Monitoring and Predictive Value of Circulating Tumor Cells in EGFR-Mutated Advanced Non–Small-Cell Lung Cancer Patients Treated With First-Line EGFR Tyrosine Kinase Inhibitors. Clin Lung Cancer. 2019;20(2):124-133.e2.