Moving from histological subtyping to molecular characterization: new treatment opportunities in advanced non-small-cell lung cancer

Abstract

Over the last 10 years, the systemic treatment of advanced non-small-cell lung cancer has progressively moved away from the ‘one-size-fits-all’ approach to histological subtyping. Currently, there is a progressive implementation of targeted therapies based on specific molecular characteristics such as the EGF receptor sensitizing mutations and the anaplastic lymphoma kinase rearrangements. Despite the availability of effective agents against these abnormalities, acquired resistance is still a major issue. A new generation of tyrosine kinase inhibitors for EGF receptor and anaplastic lymphoma kinase targeting acquired resistance mechanisms have been recently investigated. Several promising tyrosine kinase inhibitors that hit other targets are also in clinical development, including: rat sarcoma gene/MEK, BRAF1, PIK3A, c-mesenchymal-epithelial transition, c-ros oncogene 1, rearranged during transfection, human EGFR 2, FGFR, VEGFR, PDGFR and discoidin death receptor 2. Furthermore, new advances in immunology have been achieved through the discovery of vaccines and immune checkpoint pathways such as the cytotoxic T-lymphocyte-associated antigen-4, programmed cell death protein 1 and its ligands.

Keywords::

• immunotherapy
• monoclonal antibodies
• non-small-cell lung cancer
• tyrosine kinase inhibitor
• vaccines

Financial & competing interests disclosure

GV Scagliotti has received honoraria from Eli Lilly, Roche, Pfizer and AstraZeneca. The authors have no other 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 apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Molecular profiling of lung cancer is an absolute priority and large molecular screening consortium should be largely encouraged.

• All patients with EGF receptor mutations and anaplastic lymphoma kinase gene rearrangements should get therapy with appropriate agents.

• New generations of EGF receptor-tyrosine kinase inhibitors active also against T790 mutation and a second generation of anaplastic lymphoma kinase-inhibiting agents active also against brain metastases are currently in clinical development.

• Acquired resistance to specific targeted therapies arises within approximately 1 year and it is characterized by multiple mechanisms.

• In adenocarcinoma, multiple new targets have been identified and for some of them specific inhibitors are already in clinical trials (RAS, MEK, BRAF1, PIK3A, c-MET, ROS1, RET, HER2).

• There is a growing interest to further explore the role of immunotherapy because of early significant results with immune checkpoint pathways inhibitors such as the CTLA4, PD1 and its ligand PD1-L1.