NSCLC accounts for 85% of all lung cancers. Compared to small-cell lung cancer, it has a lower doubling rate and growing fraction and more deferred development of metastases, but these favorable, at the first glance, characteristics bring on a considerable disadvantage: NSCLC has low sensitivity to chemotherapy and radiation therapy, so surgery is a treatment of choice. However, only 20% of patients have an early-stage disease at the time of diagnosis1.
The patients with early-stage NSCLC can be managed with a sole surgery with adjuvant chemotherapy considered in cases with high risk of incomplete resection or locoregional recurrence2. For other patients, who have locally advanced or metastatic disease, platinum-based chemotherapy which, as mentioned before, has a limited efficacy, is indicated alone or in combination with surgical and/or radiation treatment.
Targeted therapy for NSCLC which affects a specific abnormality in the neoplastic cells has improved patients’ survival and quality of life. This is why the research regarding the identification of molecular targets for precise treatment and trials of targeted agents are very promising fields in NSCLC research.
Up to date, several targetable genetic alterations are identified, such as EGFR, ALK, KRAS, BRAF, HER2 mutations, ROS1 fusion, RET fusion and other. European Society for Medical Oncology currently recommends for routine assessment only EGFR somatic mutations and ALK rearrangements because there is enough evidence to recommend targeted treatment for NSCLC characterized by one of these abnormalities3.
ALK gene rearrangement occurs in ∼3%–5% of NSCLC and predicts response to ALK-targeted inhibitors, such as crizotinib, ceritinib, and alectinib. Crizotinib which in the early trials demonstrated 90% response in ALK-positive patients was for a long time considered the treatment of choice for ALK-positive NSCLC. Later, the resistance to this agent was shown to be relatively frequent. The results of J-ALEX trial conducted in Japan which compared alectinib with crizotinib were published in the Lancet journal in 2017 and shown alectinib to be superior to crizotinib in the terms of progression-free survival (25.7 months vs. 10.4 months), adverse effects (26% vs. 52%) and CNS progression (9.4% vs. 41.4%)4. It is now approved by the FDA as a first-line treatment for ALK-positive metastatic NSCLC.
Epidermal growth factor receptor (EGFR), is a transmembrane protein with a tyrosine kinase activity responsible for the emergence of several types of cancer including 10-16% of NSCLC3.
The first generation of EGFR tyrosine kinase inhibitors (TKIs) includes ATP-competitive reversible EGFR TKIs gefitinib and erlotinib which target the most frequent EGFR mutation - L858R, Del19. Unfortunately, there is a high rate of acquired tumor resistance developing after ~12 months of treatment with these agents. The most common identified cause is the EGFR T790M resistance mutation7.
To overcome this resistance, second line EGFR were developed. They target not only the EGFR-activating mutations but also T790M and wild-type EGFR. Although showing encouraging results in vitro, in vivo they failed to induce a response in T790M+ NSCLC while demonstrating a significant toxicity7.
Lastly, the third generation EGFR TKIs are developed to possess more specificity in regard to T790M and less effect on EGFR wild type. Currently approved agents include olmutinib nazartinib and osimertinib. The recently published FLAURA trial mentioned in the very beginning of this review compared the first-line osimertinib in advanced NSCLC with L858R or Ex19del EGFR genotypes with the first-generation TKIs (erlotinib or gefitinib)8. The progression-free survival was shown to be 18.9 months in osimertinib group vs. 10.2 months in standard EGFR-TKIs group. Importantly, the median duration of response was also superior in osimertinib group (17.2 months) compared to standard EGFR-TKIs group (8.5 months) with less serious adverse effects in osimertinib group (34% vs. 45%).
Targeted therapy shows encouraging results in NSCLC treatment with more effectiveness and less systemic toxicity compared to standard chemotherapy. Still, resistance to targeted agents and adverse effects are the main challenges needed to be conquered. Currently, there are more than 900 active clinical trials concerning NSCLC listed on ClinicalTrials.gov, so more evidence for the best NSCLC management is pending to be published soon.
Sources
1. W. W. Tan. "Non-Small Cell Lung Cancer", Medscape.com, 17 August 2017. [Online]. Available: https://emedicine.medscape.com/article/279960-overview. [Accessed 21 January 2018].
2. P. E. Postmus, et al. "Early-Stage and Locally Advanced (non-metastatic) Non-Small-Cell Lung Cancer: ESMO Clinical Practice Guidelines," Annals of Oncology, vol. 28, no. suppl.4, p. iv1–iv21, 2017.
3. K.M.. Kerr, et al. "ESMO Consensus Guidelines: Pathology and molecular biomarkers for non-small-cell lung cancer," Annals of Oncology, vol. 25, no. 9, pp. 1681-1690, 2014.
4. Toyoaki H., et al. "Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomized phase 3 trial," The Lancet, vol. 390, no. 10089, p. 29–39, 2017.
5. Kim D.W., et al. "Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non–Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial," Journal of Clinical Oncology, vol. 35, no. 22, pp. 2490-2498, 2017.
6. J. Schieszer, "OncoTherapyNetwork.com", ModernMedicineNetwork, 19 May 2017. [Online]. Available: http://www.oncotherapynetwork.com/lung-cancer-targets/brigatinib-offers-disease-control-crizotinib-refractory-nsclc. [Accessed 21 January 2018].
7. Sullivan I. and Planchard D., "Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line," Frontiers in Medicine, vol. 3, no. 76, 2016.
8. Soria J.Ch., et al. "Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer," The New England Medical Journal vol. 378, pp. 113-125, 2018.