Lung cancer remains one of the leading causes of cancer-related deaths, and non-small cell lung cancer (NSCLC) is the most common form of lung cancer and is typically diagnosed at advanced stages. Extensive genomic studies of NSCLC have been essential to identifying mutations that drive oncogenesis and has been critical to the development of targeted therapies. Here we highlight progress in NSCLC treatment and identify areas of ongoing research.
For decades, chemotherapy was the primary treatment for NSCLC, and platinum-based chemotherapies are still used today in combination with radiotherapy and targeted therapies. Platinum-based chemotherapies have been improved since their initial development in the late 20th century, and “platinum doublets” or “triplets”, which combine two or three different platinum-based cytotoxic compounds, have been shown to better target NSCLC and cause less toxicity. Chemotherapy is still used as a first line treatment for advanced NSCLC, but overall effectiveness is limited when used alone. Advances in targeted therapies and immune checkpoint blockade have greatly enhanced the effectiveness of chemotherapy on overall survival and progression-free survival.
Genetic analysis of NSCLC tumors has led to the use of targeted therapies. Mutations in the epidermal growth factor receptor (EGFR) were identified as the most prevalent defect in NSCLC patients across genders, ethnic groups, and smoking status. Several common mutations have been characterized, but numerous rare mutations have also been identified, and most of these mutations target the tyrosine kinase domain, which results in unchecked cellular proliferation due to engagement of downstream MAKP, PI3K, and STAT signaling pathways. First (gefitinib and erlotinib) and second (afatinib and dacomitinib) generation tyrosine kinase inhibitors (TKIs) have been approved by the FDA to treat EGFR-mutated NSCLC. Unfortunately, treatment resistance and disease recurrence occur at a very high rate, and these TKIs are also associated with significant toxicity and undesirable side effects that result in adjustments of treatment regimens. Third and fourth generation TKIs that target specific EGFR mutations are under development or are being used in ongoing clinical trials, and many of these have been designed to cause fewer adverse events. Mutations in other molecules have also been attributed to smaller subsets of NSCLC, and several clinical trials are now evaluating targeted therapies with inhibitors that target numerous pathways involved in oncogenesis, including, anaplastic lymphoma kinase, c-mesenchymal epithelial transition protein, or the BRAF serine/threonine kinase.
Immunotherapies that target the immune checkpoint molecules like Programmed Death (PD)-1 or its ligand PD-L1 have been shown to have therapeutic effects as second-line treatments in combination with chemotherapy for patients lacking mutations that can be treated with approved targeted therapies. While several of these trials have shown improvements in overall survival, serious adverse events have also been elevated.
Advances in NSCLC have shifted the median overall survival from 2-4 months in the 1960s to more than 2 years since advent chemotherapy combined with immunotherapy or targeted inhibitors in the 2010s. Greater improvements are likely to stem from advances in combination therapies, including the use of bispecific antibodies engineered to target multiple molecules and antibody-drug conjugates. Our deeper understanding of mutations that drive NSCLC and our ever-expanding arsenal of targeted therapies or immune modulators will further improve survival and quality of life for NSCLC patients.
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