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Non-Small Cell Lung Cancer (NSCLC): Recent Advances in Clinical Diagnosis and Treatment

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: 25 May 2026 | Viewed by 3511

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Prof. Dr. Cesare Guida

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Unit of Radiation Oncology, Ospedale del Mare, ASL Napoli 1 Centro, 80147 Naples, Italy
Interests: non-small cell lung cancer; radiodiagnosis; radiomics; precision medicine
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Special Issue Information

Dear Colleagues,

Non-small cell lung cancer (NSCLC) remains a leading cause of global cancer-related mortality, driving an urgent need for innovations in both diagnosis and therapy. The tissue biopsy remains the gold standard for initial diagnosis; liquid biopsy excels in tracking clonal evolution and emerging resistance mechanisms during treatment. The management of advanced non-small cell lung cancer (NSCLC) has been transformed by the synergy between targeted therapies and immunotherapy.

These include the approval of checkpoint inhibitors and a variety of targeted therapies, which require comprehensive biomarker testing. These advances collectively signify a shift towards more precise, dynamic, and patient-tailored NSCLC management. It is not only due to efforts in screening for detection of early-stage disease but also due to remarkable advances in the treatment of metastatic NSCLC.

Radiotherapy remains a cornerstone in the management of non-small cell lung cancer (NSCLC), with recent innovations reshaping its therapeutic role. Advanced delivery techniques such as IMRT, IGRT, and SBRT have enhanced precision, enabling higher tumor control with reduced toxicity. A major research focus is the integration of radiotherapy with systemic therapies, including chemotherapy, targeted agents, and immunotherapy. Synergistic effects have been observed, as radiotherapy can modulate the tumor microenvironment and enhance antigen presentation, thereby potentiating immune checkpoint inhibition. Clinical trials are exploring combinations with PD-1/PD-L1 and CTLA-4 inhibitors, showing promising outcomes in locally advanced and metastatic settings. Concurrent chemoradiotherapy remains the standard in unresectable stage III NSCLC, with subsequent consolidation immunotherapy further improving survival. Targeted therapies combined with radiotherapy are under investigation, particularly for tumors harboring EGFR or ALK alterations, though optimal sequencing and dosing strategies are still under definition. Adaptive radiotherapy and biomarker-driven selection may further refine patient stratification. Overall, the integration of radiotherapy with systemic agents is paving the way for more personalized, multimodal treatment paradigms in NSCLC.

This Special Issue will include articles and narrative reviews on the current treatment, as well as future perspectives for the management of NSCLC.

Prof. Dr. Cesare Guida
Guest Editor

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Keywords

novel screening tool
cancer biomarkers
predictive marker of immunotherapy
targeted therapy
radiotherapy
non-small cell lung cancer

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Published Papers (6 papers)

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Research

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14 pages, 916 KB

Open AccessArticle

Impact of Prior mRNA COVID-19 Vaccination on PFS2 in NSCLC Patients Receiving Second-Line Immune Checkpoint Inhibitors: A Real-World Analysis

by Selahattin Çelik, Engin Eren Kavak, Esra Zeynelgil, Gökşen İnanç İmamoğlu, İsmail Dilli, Salih Karatlı, Mehmetcan Atak, Mustafa Altınbaş and Tülay Eren

J. Clin. Med. 2026, 15(7), 2475; https://doi.org/10.3390/jcm15072475 - 24 Mar 2026

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Abstract

Background: Immune checkpoint inhibitors (ICIs) targeting the PD-1 axis represent standard second-line therapy for metastatic non-small cell lung cancer (NSCLC). Emerging data suggest that SARS-CoV-2 mRNA vaccines may enhance antitumor immunity through innate immune activation and type I interferon signaling, potentially sensitizing tumors to PD-1 blockade. The clinical impact of patients initiating second-line nivolumab remains unclear. Methods: In this retrospective single-center cohort study, 88 patients with recurrent stage IV NSCLC who received second-line nivolumab between 1 January 2023 and 1 January 2026 were analyzed. Vaccination exposure was defined using a 6-month pre-treatment window prior to nivolumab initiation (T0). Patients were stratified according to receipt of ≥2 versus 0–1 mRNA COVID-19 vaccine doses within the 6 months preceding T0 (n = 45 and n = 43, respectively). The primary endpoint was progression-free survival from nivolumab initiation (PFS2). Survival outcomes were estimated using the Kaplan–Meier method and evaluated using Cox regression models. Results: With a median follow-up of 22.4 months, median PFS2 for the overall cohort was 11.1 months (95% CI, 9.4–15.1). Patients receiving ≥2 mRNA doses had significantly longer PFS2 than those receiving 0–1 dose (14.0 vs. 9.6 months; p = 0.04). In multivariable analysis, ≥2 doses were independently associated with reduced risk of progression or death (aHR 0.52, 95% CI 0.31–0.88; p = 0.01). Non-adenocarcinoma histology and baseline brain metastasis were independently associated with shorter PFS2. Conclusions: Receipt of ≥2 mRNA vaccine doses within 6 months before nivolumab initiation was independently associated with prolonged PFS2 in metastatic NSCLC. Prospective multicenter validation is warranted. Full article

(This article belongs to the Special Issue Non-Small Cell Lung Cancer (NSCLC): Recent Advances in Clinical Diagnosis and Treatment)

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18 pages, 895 KB

Open AccessArticle

The Impact of the COVID-19 Pandemic on Diagnosis, Treatment, and Survival of Lung Cancer Patients in Thailand from 2019–2021

by Chaiyut Charoentum, Chawin Aksorn, Khemruthai Chaiwipassatorn, Khwanchanok Siroros, Kittipich Tiangtawat, Thanika Ketpueak, Thatthan Suksombooncharoen and Busayamas Chewaskulyong

J. Clin. Med. 2026, 15(6), 2277; https://doi.org/10.3390/jcm15062277 - 17 Mar 2026

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Background/Objectives: The COVID-19 pandemic emerged in early 2020, disrupting global cancer services. We aimed to assess the pandemic’s impact on lung cancer diagnosis and treatment, including clinical characteristics, diagnostic methods, treatment patterns, and survival outcomes. Methods: A retrospective analysis of 1832 patients visiting Maharaj Nakorn Chiang Mai Hospital from January 2019 to December 2021 with suspected lung cancer was conducted. We evaluated demographic characteristics, diagnostic methods, treatment modalities, and survival results across this period. Results: Among the 698 eligible patients, the pandemic led to a 13% to 17% decline in newly diagnosed lung cancer cases. However, demographic and lung cancer characteristics, including age, gender, and smoking status, remained unchanged. The pandemic also saw an increase in asymptomatic cases and a 1.3 to 2.2 times higher occurrence of early-stage non-small cell lung cancer cases. The rapid implementation of healthcare policies prioritized the diagnosis of suspected cancer patients and maintained cancer care throughout the pandemic, resulting in similar diagnostic methods and waiting times compared to the pre-pandemic era. Treatment patterns displayed continuity, with a notable rise in 2 to 3 times higher surgical interventions and an 8% to 11% decrease in the initial delivery of palliative care. The delivery of systemic therapy for patients with advanced-stage disease was also maintained. One-year survival rates remained consistent across various lung cancer stages during the pandemic. Conclusions: The COVID-19 pandemic led to a modest decrease in new diagnoses, with limited effects on the demographic and clinical profiles of lung cancer cases. Survival rates among patients diagnosed during the pandemic remained stable compared to those diagnosed before the pandemic. These findings underscore the adaptability of the healthcare system, alongside the capabilities of multidisciplinary teams, in providing timely and effective diagnosis and ensuring uninterrupted essential treatment of lung cancer during challenging circumstances. Full article

(This article belongs to the Special Issue Non-Small Cell Lung Cancer (NSCLC): Recent Advances in Clinical Diagnosis and Treatment)

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13 pages, 1081 KB

Open AccessArticle

Association of IL7 rs16906115 Polymorphism with Immune-Related Adverse Events in Patients with Advanced Lung Cancer Undergoing Immunotherapy

by Andrea González-Hernández, Guillermo Paz-López, Beatriz Martínez-Gálvez, Felipe Vaca Paniagua, Isabel Barragán, Elisabeth Pérez-Ruiz, José Carlos Benitez, Antonio Rueda-Dominguez and Javier Oliver

J. Clin. Med. 2026, 15(4), 1486; https://doi.org/10.3390/jcm15041486 - 13 Feb 2026

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Abstract

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced non-small cell lung cancer (aNSCLC). However, immune-related adverse events (irAEs) remain a clinical challenge in this context. Genetic variants acting as cis-eQTLs may predict toxicity risk, thereby enabling personalized treatment. Specifically, the interleukin 7 (IL7) rs16906115 variant has recently been implicated in ICI-related toxicity in other malignancies, like melanoma, although its role in lung cancer remains less defined. We investigated the association between the IL7 rs16906115 polymorphism, immune-related adverse events (irAEs), and survival outcomes in patients with aNSCLC receiving ICIs. Methods: This retrospective cohort study analyzed 153 patients with aNSCLC treated with ICIs (2018–2023) at two centers in Spain. The final analytical cohort included 124 patients with complete clinical follow-up. IL7 rs16906115 genotyping was performed using TaqMan assays. Associations between genotypes/alleles, irAEs, and survival (PFS/OS) were evaluated using logistic regression and Kaplan–Meier analysis. A clinical–genetic predictive model was developed. Results: The A allele frequency was 8.5%. Carriers of the A allele (AG/AA genotypes) had significantly higher irAEs rates compared to GG homozygotes (OR = 3.77, 95% CI: 1.16–12.6, p = 0.0081). The association remained significant after multivariable adjustment (OR = 4.64, 95% CI: 1.50–17.2, p = 0.0203). Crucially, A-allele carriers exhibited significantly shorter Progression-Free Survival compared to non-carriers (median 6.6 vs. 10 months, p = 0.0029). The combined clinical–genetic model achieved moderate predictive performance for toxicity (AUC = 0.67, 95% CI: 0.56–0.78) compared to clinical-only models (AUC = 0.57), stratifying patients into moderate- and high-risk groups, respectively. Conclusions: The IL7 rs16906115 polymorphism is a potential pharmacogenetic biomarker for predicting adverse events in aNSCLC immunotherapy. These findings identify the IL7 rs16906115 polymorphism as a candidate biomarker, suggesting its potential utility as an exploratory tool for risk stratification that warrants further validation. Full article

(This article belongs to the Special Issue Non-Small Cell Lung Cancer (NSCLC): Recent Advances in Clinical Diagnosis and Treatment)

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13 pages, 719 KB

Open AccessArticle

Prognostic Value of ¹⁸F-FDG PET/CT-Derived Secondary Lymphoid Organ Ratios and Hematologic Inflammation Markers in Advanced Non-Small Cell Lung Cancer Treated with Nivolumab

by Erkam Kocaaslan, Ali Kaan Güren, Fırat Akagündüz, Ahmet Demirel, Mustafa Alperen Tunç, Burak Paçacı, Yeşim Ağyol, Pınar Erel, Abdüssamed Çelebi, Selver Işık, Ezgi Çoban, Nazım Can Demircan, Salih Özgüven, Zeynep Ceren Balaban Genç, Nargiz Majidova, Nadiye Sever, Murat Sarı, Osman Köstek and Ibrahim Vedat Bayoğlu

J. Clin. Med. 2026, 15(2), 798; https://doi.org/10.3390/jcm15020798 - 19 Jan 2026

Viewed by 442

Abstract

Background/Objectives: This study aimed to evaluate the prognostic value of ¹⁸F-FDG PET/CT-based secondary lymphoid organ metabolic ratios—spleen/liver (SLR), bone marrow/liver (BLR), and ileocecal region/liver (ILR)—and hematological inflammation markers (neutrophil/lymphocyte ratio [NLR] and systemic immune-inflammation index [SII]) obtained before nivolumab treatment in relation to survival in patients with advanced non-small cell lung cancer (NSCLC). Methods: This retrospective single-center study included 79 advanced NSCLC patients who were treated with nivolumab monotherapy at Marmara University Faculty of Medicine Hospital between 2022 and 2024. Pretreatment SLR, BLR, and ILR ratios were calculated from ¹⁸F-FDG PET/CT examinations; NLR and SII values were obtained from hematological data. Survival outcomes were analyzed using the Kaplan–Meier method, and prognostic factors were assessed using Cox proportional hazards regression analysis. In a subset of patients, an exploratory longitudinal analysis was performed using early follow-up PET/CT to assess follow-up-to-baseline changes in immune-organ metabolic ratios in relation to overall survival. Results: High NLR and SII levels were significantly associated with shorter progression-free survival and overall survival. In contrast, no significant associations were observed between PET/CT-derived metabolic ratios (SLR, BLR, and ILR) and survival. Multivariate analysis identified the presence of liver metastases and a high NLR as independent adverse prognostic factors for overall survival. Conclusions: In this homogeneous real-world cohort treated exclusively with single-agent nivolumab, PET/CT-derived secondary lymphoid organ metabolic ratios showed limited prognostic value at baseline and during early on-treatment assessment. In contrast, hematological inflammation markers, especially high NLR levels, are strong prognostic indicators of survival and may complement established clinical factors in risk stratification. Full article

(This article belongs to the Special Issue Non-Small Cell Lung Cancer (NSCLC): Recent Advances in Clinical Diagnosis and Treatment)

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12 pages, 1782 KB

Open AccessArticle

Real-World Clinical Outcomes and Biopsy Patterns of Older Patients with Unresected Non-Small-Cell Lung Cancer Treated with Primary Stereotactic Body Radiotherapy

by Pragya Rai, Su Zhang, Yan Song, Chi Gao, Anya Jiang, Jiayang Li, Peixi Jiang, James Signorovitch, Ashwini Arunachalam, Andrew Song, Ayman Samkari and Megan E. Daly

J. Clin. Med. 2025, 14(23), 8604; https://doi.org/10.3390/jcm14238604 - 4 Dec 2025

Viewed by 590

Abstract

Background/Objectives: We describe the real-world survival and utilization of lung biopsy in Medicare patients with unresected stage I-IIB (N0) non-small-cell lung cancer (NSCLC) receiving primary stereotactic body radiotherapy (SBRT) in the US. Methods: Patients (aged ≥66 years) with unresected stage I-IIB (N0) NSCLC who received primary SBRT were identified in the SEER-Medicare database (2007–2020) and followed from SBRT initiation until death/data end. Outcomes included overall and disease-stage-specific real-world event-free survival (rwEFS), overall survival (OS), lung cancer-specific cumulative incidence of death, and time to death or distant metastasis (TDDM). rwEFS, OS, and TDDM were described using Kaplan–Meier analysis. Median times from lung biopsy to SBRT were summarized. Results: Of 3014 patients (median follow-up: 2.9 years), 2302 (76.4%), 454 (15.1%), 168 (5.6%), and 90 (3.0%) had stage IA, IB, IIA, and IIB disease, respectively. The mean age at diagnosis was 77.3 years, 37.7% were male, and 86.9% were White. Overall, the 5-year rwEFS rate was 23.8% (median 26.2 months), the 5-year OS rate was 42.3% (median 48.9 months), and the 5-year lung cancer-specific cumulative incidence of death was 25.3%. rwEFS and OS rates declined with more advanced disease stage at diagnosis. Most patients (90.1%) underwent lung biopsy within 12 months before SBRT. Conclusions: Among older US patients with unresected NSCLC receiving SBRT, prognosis remains limited, with many deaths due to non-lung cancer causes. Recurrence and survival were lower among subgroups with more advanced disease. These findings benchmark real-world outcomes for future studies assessing novel strategies in this patient population. Full article

(This article belongs to the Special Issue Non-Small Cell Lung Cancer (NSCLC): Recent Advances in Clinical Diagnosis and Treatment)

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Review

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39 pages, 3285 KB

Open AccessReview

Therapeutic Targeting of VEGFR-2, PD-L1, and EGFR–MET Pathways in Non-Small Cell Lung Cancer: Clinical Progress with Ramucirumab, Atezolizumab, and Amivantamab

by Piotr Kawczak and Tomasz Bączek

J. Clin. Med. 2026, 15(8), 3024; https://doi.org/10.3390/jcm15083024 - 15 Apr 2026

Viewed by 699

Abstract

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and remains a leading cause of cancer-related mortality worldwide. Advances in molecular characterization and tumor biology have driven the development of antibody-based therapies targeting immune checkpoints, angiogenesis, and oncogenic signaling pathways critical for tumor growth and progression. Among these agents, Ramucirumab, Atezolizumab, and Amivantamab have demonstrated significant clinical efficacy in selected NSCLC populations. This review summarizes the mechanisms of action, pivotal clinical trials, and current clinical evidence supporting the use of ramucirumab, atezolizumab, and amivantamab in the management of advanced NSCLC. Relevant literature was identified through searches of PubMed, clinical trial registries, and recent international conference proceedings, with an emphasis on therapeutic efficacy, safety profiles, and rational combination strategies. Ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor-2 (VEGFR-2), has shown a survival benefit when combined with docetaxel in patients with previously treated advanced NSCLC. Atezolizumab, a programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor (ICI), has become a cornerstone of NSCLC treatment across multiple disease stages, both as monotherapy and in combination with chemotherapy. Amivantamab, a bispecific antibody targeting both epidermal growth factor receptor (EGFR) and mesenchymal–epithelial transition factor (MET), has demonstrated robust and durable clinical activity in patients with EGFR exon 20 insertion–mutated NSCLC. Collectively, these agents highlight the expanding role of antibody-based therapies in NSCLC and underscore the importance of biomarker-driven patient selection and treatment personalization. Ongoing research into resistance mechanisms, predictive biomarkers, and combination approaches is expected to further refine the integration of antibody-based strategies in precision oncology for NSCLC. Full article

(This article belongs to the Special Issue Non-Small Cell Lung Cancer (NSCLC): Recent Advances in Clinical Diagnosis and Treatment)

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