Treatment of Lung Cancer

Dear Colleagues,

The treatment of lung cancer, especially non-small cell lung cancer (NSCLC), has changed considerably in the last two decades. At the beginning of this century, standard chemotherapy consisted of various doublets, depending on the type of tumor (squamous, non-squamous), while there are also local differences. However, in general, the doublets consisted of gemcitabine/cisplatin, a taxane/cisplatin, and gemcitabine/pemetrexed. For these doublets, a number of potential predictive biomarkers have been investigated, usually focusing on the properties of the single drugs (e.g., drug metabolism, drug transport, DNA repair mechanism). This sometimes led to some extent of personalized therapy. However, with the recognition that many types of adenocarcinoma are addicted to a specific signaling pathway, new types of therapy, often called targeted therapy, have been introduced. The recognition of activation mutations in the epidermal growth factor receptor (EGFR) led to the registration of the EGFR tyrosine kinase inhibitors (TKI) erlotinib and gefitinib, and later afatinib and dacomitinib. Other resistance mutations led to the development of novel specific TKIs, such as osimertinib targeting, e.g., the T790M mutation. Various resistance mechanisms to osimertinib exist, such as the C797S mutation for which novel TKIs are being developed. Targeting the EML-ALK mutation with crizotinib was a game changer for patients with this mutation; resistance to crizotinib rapidly led to the introduction of novel TKIs, bypassing various resistance mechanisms, such as ceritinib, lorlatinib, and brigatinib. Other aberrations in adenocarcinoma are less frequent, but some specific TKIs are in development, such as exon20 insertions (poziotinib) and RET rearrangement (pralsetinib, selpercatinib). A major breakthrough in the development of novel TKIs are compounds that target RAS mutations. RAS mutations (e.g., G12C) are very common in NSCLC, and these tumors are not sensitive to EGFR TKIs. RAS was considered to be a non-targetable mutation, but with the introduction of various novel TKIs, such as sotorasib and adragrasib, there are now new possibilities. In current development, special emphasis is now also being given to the “non-target” properties of these novel TKIs, such as their metabolism, more efficient gut uptake and brain penetration. The last new developments in the treatment of lung cancer, including small cell lung cancer (SCLC), include the introduction of antibody-based immunotherapy, targeting either PD-1 (nivolumab, pembrolizumab), PD-L1 (atezolizumab, durvalumab), or CTLA4 (ipilimumab) These therapies are either given as neo-adjuvant or after surgery. PD-1 or PD-L1 inhibitors can be given together with CTLA-4 inhibitors, although combinations with conventional chemotherapy are also quite common. Some small molecules targeting metabolic pathways important for the immune response are also being evaluated. There is a rapid increase in the treatment of various lung cancers, which may be new game changers as well. However, insight into which type of therapy should be given to each patient is not always clear.

This Special Issue covers all of these aspects in the treatment of lung cancer.

Prof. Dr. Godefridus J. Peters
Prof. Dr. Rafal Dziadziuszko
Guest Editors

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• lung cancer
• new developments in conventional chemotherapy
• novel tyrosine kinase inhibitors
• non-small cell lung cancer
• immunotherapy