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Abstract
In the last decade, major progress in the treatment of advanced non-small-cell lung cancer has been made through the better understanding of the molecular biology of lung cancer, identification of new oncogene drivers and development of oncogene-directed drugs. Oncogene-directed therapies with EGFR or anaplastic lymphoma kinase tyrosine kinase inhibitors became standard practice in patients with activating EGFR mutations or anaplastic lymphoma kinase rearrangements, improving median survival rates to up to 35 months. Encouragingly, there are still numerous other targeted drugs and treatment strategies under development. In addition, nowadays chemotherapy can be tailored based on histology of the primary tumor and response to induction chemotherapy, raising median survival rates up to 13 months. These major developments, both in oncogene- and non-oncogene-directed therapies is presented in this review, together with a further designation of the most relevant future strategies, such as immunotherapy.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
In the last decade, major advances in the treatment of advanced non-small cell lung cancer (NSCLC) have been made through a better understanding of the molecular biology of lung cancer, the identification of new oncogene drivers and development of oncogene-directed therapies.
Oncogene-directed therapies with EGFR and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors, in conjunction with well-validated methods for the detection of activating EGFR mutations or ALK rearrangements, became the standard practice in patients with biomarker-positive disease. These treatments improved median survival rates to up to 35 months, with improvements in quality of life and symptom control.
Despite high response and progression-free survival rates to EGFR and ALK tyrosine kinase inhibitors, the majority of patients inevitably develop resistance in approximately 1 year’s time; various drugs targeted at the resistance pathways and their combinations are under development.
Nowadays, chemotherapy can be tailored based on the histology of the primary tumor and response to induction chemotherapy, leading to median survivals of 10–13 months compared with 8–10 months achieved by the ‘one-size-fits-all’ chemotherapy.
Targeted therapies with cetuximab, bevacizumab, nintedanib and newer monoclonal antibodies have shown some efficacy when used in combination with chemotherapy in molecularly unselected NSCLC. However, to further improve their outcomes, relevant molecular markers need to be identified.
While recent discoveries are making a difference in mostly non-squamous NSCLC, there is optimism that through the further characterization of the lung cancer genome, biomarker-driven therapies will be developed for squamous NSCLC as well.
Despite all molecular biomarkers and predictive criteria, clinical judgment will remain the sovereign tool for assessing patient’s feasibility for systemic therapy, and palliative therapy endures as an important part in the treatment of patients with advanced NSCLC.