Lung cancer is the leading cause of cancer mortality globally, with non-small cell lung cancer (NSCLC) accounting for 85% of cases. Despite advancements in first-line treatments such as immunotherapy and targeted therapies, resistance to these treatments is common, creating a significant unmet need for effective second-line therapies. This review evaluates current and emerging second-line therapeutic options for advanced or metastatic NSCLC, focusing on their efficacy and potential to improve patient outcomes. Anti-angiogenic drugs like ramucirumab combined with chemotherapy, particularly docetaxel, have shown moderate success. Antibody-drug conjugates (ADCs) targeting specific tumor antigens offer a promising avenue for targeted therapy, while chimeric antigen receptor (CAR)-T cell therapy and T-cell receptor therapy leverage the patient’s immune system to combat cancer more effectively. mRNA vaccines, although in early stages, show potential for inducing robust immune responses against cancer-specific antigens. Building on this foundation, recent advancements in molecular testing and the exploration of the tumor microenvironment are opening new therapeutic avenues, further enhancing the potential for personalized second-line treatments in NSCLC. While ADCs and bispecific antibodies are gaining traction, more precise biomarkers are needed to optimize treatment response. Regular monitoring through techniques like liquid biopsies allows real-time tracking of mutations such as EGFR T790M, enabling timely therapeutic adjustments. Additionally, the role of neutrophils and macrophages in the tumor microenvironment is increasingly being recognized as a potential therapeutic avenue, with Smad3 emerging as a key target. Further research into drug sequencing, toxicity management, and biomarker development remains crucial to improving NSCLC treatment outcomes.

Fibroblast-activated protein (FAP) expression in glial cells is attributed to FAP-positive foci on tumor vessels and neoplastic cells. Preclinical and pilot studies have shown FAP expression in high-grade gliomas. We aimed at comparing PET imaging with FAP-inhibitor (FAPI-PET) with current standard, i.e., fluoro-ethyl tyrosine (FET) PET in post-treatment setting to differentiate recurrence and post-treatment changes. 6 patients with WHO Grade III and IV glioma who received standard treatment underwent Ga-68-FAPI-04 PET/CT (FAPI-PET/CT). Tracer uptake greater than background was considered positive. FET PET was performed and interpreted as per institutional standards, which formed the basis of treatment decision. There was concordance between FAPI expression and FET uptake in 5 patients suggestive of disease recurrence. There was no FAPI expression seen in 1 patient, in whom FET PET was suggestive of post-treatment changes. FAPI PET uptake correlated with amino acid expression to differentiate post treatment changes from recurrence in high-grade glial tumors; further validation with prospective study and histopathological confirmation is needed.