Lung cancer (LC) is the second most prevalent cancer among men and women in Europe and represents a significant demographic challenge for healthcare systems, contributing to approximately 12.7% of all new cancer diagnoses annually and 18.2% of cancer-related fatalities. Each year, around 1,095,000 new cases and 951,000 cancer-related deaths occur in men, alongside 514,000 new diagnoses and 427,000 deaths in women.1 Despite advancements in treatment, the overall 5-year survival rate for LC remains low at about 10%, largely due to late-stage diagnosis and limited treatment options.2,3 Since the early 20th century, the incidence of LC has risen dramatically, making it the leading cause of cancer-related mortality worldwide in both men and women.3 Non-small cell lung cancer (NSCLC) accounts for 85%-90% of all LC cases and includes squamous-cell carcinoma, adenocarcinoma, and large-cell carcinoma, with the first two subtypes making up about 80% of all LC cases globally.4

Imaging is a cornerstone in the diagnostic evaluation of patients with NSCLC. Standard imaging modalities such as chest X-ray (CXR) and computed tomography (CT) are often complimented by nuclear medicine techniques, including positron emission tomography- computed tomography (PET-CT).5 18F-Fluorodeoxyglucose (FDG) is the most commonly used PET tracer for evaluating pulmonary malignancies for staging, restaging, assessment of response post treatment. It is well known that FDG uptake reflects cellular glucose metabolism and is mediated by glucose transporters (GLUT-1 and GLUT-3) and hexokinase. Unfortunately, FDG uptake is not specific to malignancies, as it is also observed in inflammatory and infectious processes, leading to a high rate of false positives, especially in regions with a high prevalence of infectious lung diseases.6, 7, 8 Therefore, it becomes essential to explore imaging biomarkers for NSCLC patients that go beyond glucose metabolism.

New radiopharmaceuticals are being developed to enhance the sensitivity and specificity of PET CT imaging and many of these new tracers are now already in clinical use for various purposes.9,10 Tracers targeting hypoxia and proliferation are one of the most utilized non FDG, novel tracers currently in lung cancer patients. Although, none of the new tracers have yet been able to replace 18 F FDG PET-CT; their role in complementing 18F FDG PET-CT in various clinical scenarios is gaining wide popularity. In certain scenarios complimentary role of PET CT with hypoxia tracers (such as 18F -FMISO) and proliferative tracers (such as 18F-FLT) has already been established. 18F-FLT PET- CT has proven its value in diagnosing relapse after radiotherapy and is being used in conjunction with 18F FDG PET-CT for this purpose. Role of 18F-FMISO PET CT has been evaluated for radiotherapy planning with the aim to provide a radiotherapy boost dose to hypoxic tumors in patients of NSCLC undergoing chemoradiotherapy. The extra radiation doses during radiotherapy as indicated by the additional scan, can be delivered without exceeding tolerable doses to normal organs and without any high-grade adverse events or cardiac toxicity. PET tracer targeting receptors including epidermal growth factor receptor (EGFR), programmed cell death protein (PD-1) or its ligand (PD-L1) are also gaining interest to evaluate intralesional as well as differential distribution of the receptors in multiple lesions with the ultimate aim of optimizing the patient pathway including patient selection, improving treatment efficacy and reducing adverse effects of receptor specific targeting drugs which may otherwise be associated with significant toxicities.11, 12, 13

Conventionally, treatment options for NSCLC were limited, primarily involving surgery, radiotherapy, chemotherapy, or a combination of these approaches. Over the last few years multiple Programmed Death 1 (PD-1) / Programmed Death Ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) have been developed and tested.

Immune checkpoint inhibitors targeting PD-1 (such as nivolumab and pembrolizumab) and PD-L1 (such as durvalumab and atezolizumab) have demonstrated substantial improved efficacy in managing NSCLC.14 Clinical studies have indicated that immunotherapy targeting PD -1 and PD-L1 could provide a promising new way for the treatment of NSCLC. Antibodies blocking PD-1/PD-L1 pathway have shown enhanced antitumor immunity and their potential in achieving desired tumor killing is now evident. Additionally, combining different immunotherapy treatments, combination of immunotherapy with chemotherapy or with targeted treatment has also shown promising results in non-small cell lung cancer patients.15

Most of the immune checkpoint inhibitors (ICIs) currently approved by the Food and Drug Administration (FDA) are monoclonal antibodies (mAbs) that can bind to either PD-1 or PD-L1 with high specificity and affinity and block the interaction.16 Although, immunotherapy using mAbs has clearly demonstrated improved patient outcomes, this is not without some drawbacks. While they are considered more tolerable and less toxic as compared to conventional chemotherapy treatment, adverse events and even potentially fatal treatment induced toxicities can still occur in some patients.17 In addition, highly variable response rates among patients treated with PD-1/PD-L1 ICI have been reported, including some patients having no response at all, and some patients developing resistance to treatment after an initial positive response.18,19 The precise selection of patients for immunotherapy leading to improved patient outcomes still requires some attention. Currently centers rely on a combination of information from 18F FDG PET-CT, and Immunohistochemistry (IHC) to select patients for immunotherapy. IHC remains the most important tool and the information from the other scans has only secondary relevance. However, IHC also has its limitations and has been shown to be a poor discriminator of PD-L1 between tumors and healthy tissue.20

Noninvasive detection of PD-1 or PD-L1 status using radiolabelled tracers for PET-CT scanning could be complementary to IHC and clinical trials have focused on demonstrating its utility in NSCLC patients.21