Frontiers of ctDNA, Targeted Therapies, and Immunotherapy in Non-Small-Cell Lung Cancer

Chennianci Zhu; Weihao Zhuang; Limin Chen; Wenyu Yang; Wen-Bin Ou


Transl Lung Cancer Res. 2020;9(1):111-138. 

In This Article

Overview of Non-small-cell Lung Cancer (NSCLC)

Lung cancer, the most common type of cancer worldwide, has a morbidity rate of 11.6% and a mortality rate of 18.4%.[1] Approximately 85% of lung cancers are within a group of histological subtypes collectively known as NSCLC. NSCLC is thought to originate in lung epithelial cells and comprises diverse histological subtypes, of which lung adenocarcinoma and lung squamous cell carcinoma are the most common.[2] The most common genetic alterations in NSCLC are mutations in the receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR), Kirsten rat sarcoma (KRAS), tumor suppressor p53 and liver kinase B1 (LKB1); anaplastic lymphoma kinase (ALK) gene fusion; ROS1 gene fusion; and MET amplification.[3,4] Over decades, treatment strategies for lung cancer have changed from chemotherapy to personalized medicine, such as tyrosine kinase inhibitors (TKIs), which specifically target mutations based on individual patients. Immunotherapy, a developing treatment, has already proven effective in treating NSCLC patients. Through controlling the statuses of programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) by antibodies called immune checkpoint inhibitors (ICIs), patients can have a prolonged life with improved quality. Circulating tumor DNA (ctDNA) quantification is often used in TKI-based targeted therapy to facilitate more precise clinical decisions and prognoses. The efficiency of three generations of EGFR- or ALK-TKIs can be evaluated by monitoring the ctDNA level of corresponding EGFR and ALK mutant genes, respectively.

Activating mutations in EGFR, such as exon 19 del and L858R on exon 21, sensitize the majority of NSCLC tumor cells to the first-generation EGFR-TKIs gefitinib and erlotinib and the second-generation EGFR-TKIs afatinib and dacomitinib. Among patients with these tumors, 50% develop acquired resistance due to the EGFR T790M mutation, which was the source of major concern until the development of the third-generation EGFR-TKIs osimertinib and rociletinib.[5–7] With the widespread use of osimertinib, the EGFR C797S resistance mutation appeared as well.[8] In addition to secondary EGFR mutations, bypass mechanisms such as MET or ERBB2 amplification, Hippo pathway inhibition, and insulin-like growth factor 1 receptor (IGF1R) activation also contribute to resistance to EGFR-TKIs.[9–12] EML4-ALK gene fusion is found in 3–7% of NSCLC patients.[13–15] Similar to the resistance to EGFR, resistance to each of the three generations of ALK-TKIs occurs.

KRAS mutations, which are found in approximately 30% of lung adenocarcinomas and 3% of lung squamous cell carcinomas, are not as targetable as EGFR and ALK mutations. KRAS mutations account for 90% of RAS mutations found in lung adenocarcinoma.[16] Among all mutations detected in NSCLC patients, mutations in KRAS and EGFR constitute more than 60% of the mutations found in lung adenocarcinoma.[4,17,18]KRAS and EGFR mutations, however, are usually mutually exclusive, but when these mutations coexist, KRAS mutations may result in tumors that are drug-refractory to EGFR-TKIs and do not respond to anti-EGFR monoclonal antibodies.[19,20] Activated KRAS activates downstream pathways, including the BRAF/MEK/ERK and PI3K/AKT/mTOR pathways. Potential targeted therapies for KRAS-mutant lung cancer have focused on inhibiting the downstream effectors of these signaling pathways instead of mutated KRAS. Unlike EGFR-TKIs, which have evolved into the third generation, the development of clinically effective small molecule drugs for KRAS has met with great obstacles over the past decades. Recently, the association between PD-(L)1 and KRAS has been discussed in several studies, and some have noted that PD-1 expression is significantly associated with the presence of KRAS mutations.[21–24] However, more investigation is needed to increase understanding of immunotherapy so that developments in KRAS treatment no longer remain stagnant.