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

Future Prospects

Decades have passed since researchers first found that mutations in the KRAS, EGFR and ALK genes were related to lung cancer tumorigenesis. Lung cancer treatment has evolved from regular chemotherapy to targeted therapy using RTK inhibitors that diminish only cancer cells with certain gene mutations and to immunotherapy that utilizes our immune system to efficiently and precisely attack tumor cells through regulating PD-(L)1 and CTLA-4 or the genetic engineering of T-cells to perform chimeric antigen receptor T-cell immunotherapy (CAR-T). Each treatment revolution has helped us tackle the world's second largest disease, which causes many deaths. Lots of ongoing studies continue to discuss the potential of TMB as a novel biomarker for immunotherapy, and using ctDNA to calculate bTMB as a more convenient and dynamic approach. Furthermore, ongoing trials on the combination of targeted therapy and immunotherapy might shed light on new strategies for NSCLC treatment.

Genetic profiling is the first step in targeted treatment, and serum or urine ctDNA sampling has greatly simplified the whole biopsy process, making it simpler than tissue biopsy. ctDNA sampling also enables the noninvasive, sensitive and dynamic capture of DNA information from heterogeneous tumors. ctDNA is often used in targeted therapy as a tool to aid in determining treatment efficacy and predicting prognosis.

Although targeted therapy is effective, there are still many cases of developed resistance. Three generations of TKIs have been developed to treat the clinically crucial RTKs in NSCLC EGFR and ALK; however, different TKI resistance mechanisms, such as secondary RTK mutations, gene fusion or signal activation bypass, occur for each drug despite our increasing understanding of the biology and treatment of NSCLC. Figure 2 describes the clinical strategies used to manage resistance in NSCLC. NSCLC patients still face many challenges, such as relatively poor survival rates and frequent metastasis. We hope that the rapid development of targeted therapy and immunotherapy will facilitate the continuous development of new drugs and effective treatment strategies for NSCLC patients.

Figure 2.

Treatment strategies of NSCLC patients. Current refined treatment strategies of NSCLC involve TKI target therapies according to patients' genetic profile after liquid/tissue biopsy, or standard chemotherapy if patients have no targetable mutations, or immunotherapy combined with TKI/chemotherapy. When metastasis occurs, chemotherapy, continued TKI therapy or immunotherapy can be adopted. NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor; ctDNA, circulating tumor DNA; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase.