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Clinical Trials and Outcomes for Non-Small Cell Lung Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Clinical Research of Cancer".

Deadline for manuscript submissions: 31 July 2026 | Viewed by 6709

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Special Issue Editors

Dr. Ana Rodrigues

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Guest Editor

Medical Oncology Department, Research Center Cancer Biology & Epigenetics Group and Clinical Trials Department, Institito Portugues de Oncologia do Porto (IPO-Porto), Porto, Portugal
Interests: lung cancer

Prof. Dr. António Araújo

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Co-Guest Editor

1. Centro Hospitalar Universitário do Porto, Porto, Portugal
2. Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
Interests: clinical and translational research; mechanisms and control of adverse events; strategies to improve cancer patients’ quality of life
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Special Issue Information

Dear Colleagues,

Non-Small Cell Lung Cancer (NCLC) treatment has changed dramatically in the last 2.5 decades. We evolved from an armamentarium that was limited to surgery, radiotherapy and chemotherapy, chosen according to the histologic subtype, to the integration of these with target therapies, immunotherapy, and combination of different systemic treatments, according to the presence of actionable oncogenic alterations and other biomarkers. The number of trials for NSCLC, in the early or advanced setting is increasing exponentially and rapidly, compromising the head-to-head comparations, as well comparations with a standard of care that is in permanent evolution. Furthermore, it has becoming of utmost importance the observation of the clinical trial results in the real-world daily clinics, and the publication of that real world data, particularly in special populations, like elderly or with ECOG PS 2. For the clinician it is a challenge to be updated with this fast-moving reality, instigated by an unprecedent drug development, the new paradigm of trial designs, new targets and biomarkers.

The aim of this issue is to divulgate and integrate clinical trials and outcomes in the knowledge of NSCLC treatment, specially translating these results for our daily practice.

We are pleased to invite you to collaborate with us.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following: clinical trials, real world data and reviews.

We look forward to receiving your contributions.

Dr. Ana Rodrigues
Prof. Dr. António Araújo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

non-small cell lung cancer
oncogenic alterations
clinical trial
systemic therapy
targeted therapy
immunotherapy
radiotherapy
real-world data
surgery
drug development

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Published Papers (7 papers)

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Research

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15 pages, 607 KB

Open AccessArticle

The Impact of Minimal Residual Disease (MRD) Testing on the Decision-Making Process in Non-Small-Cell Lung Cancer (NSCLC)

by Roni Gillis, Tamar Zahavi, Nir Peled, Adar Yaacov, Basel Afifi, Jaber Salim, Reham Basheer, Noam Asna, Arnon Makori, Michael Peer, Evgeni Gershman, Yoav Manaster, Osnat Moreh Rahav and Elizabeth Dudnik

Cancers 2026, 18(8), 1246; https://doi.org/10.3390/cancers18081246 - 14 Apr 2026

Viewed by 345

Abstract

Background: Minimal residual disease (MRD) assessment is an emerging tool for refining the risk of relapse following definitive therapy in non-small-cell lung cancer (NSCLC). However, data regarding its clinical impact on the decision-making process remain limited. We evaluated MRD feasibility and its impact in the real-world setting. Methods: A pooled retrospective analysis of longitudinal MRD data in NSCLC patients (n = 34: Signatera™ (Exome), n = 25, Guardant Reveal™, n = 9) was implemented. Co-primary endpoints: MRD feasibility and clinical impact on management (changes in surveillance intensity or therapy escalation/de-escalation). Secondary endpoints: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy for recurrence detection, and MRD lead time. Results: MRD was feasible in 32/34 patients (94.1%); longitudinal testing included two samples in 15 patients (44.1%) and three samples in 2 patients (5.9%). Signatera™ (Exome) failed in 2/25 (8.0%) due to insufficient tissue. MRD influenced management in 20/34 (58.8%) patients, most commonly supporting therapy de-escalation (15/34, 44.1%), followed by imaging surveillance modification (3/34, 8.8%) and therapy escalation (2/34, 5.9%). In univariable analysis, tumor grade and STAS were associated with MRD-driven management impact, but neither remained significant in multivariable analysis. With a median follow-up of 18.9 months (IQR 8.5–30.7), MRD was positive in 6/32 (18.8%), while recurrence/progression occurred in 10/32 (31.3%) patients. MRD yielded 21 true negatives, five true positives, five false negatives (including two isolated brain recurrences), and one false positive, corresponding to a sensitivity of 50.0%, specificity of 95.5%, PPV of 83.3%, NPV of 80.8%, and an accuracy of 81.3%. The median MRD lead time (n = 5) was 1.31 months (range, 0.46–5.52). Conclusions: In this real-world cohort, MRD testing was feasible and frequently guided clinical decisions, mainly supporting treatment de-escalation. MRD was highly specific but less sensitive. Prospective studies are needed to define optimal testing intervals and validate MRD-guided strategies. Full article

(This article belongs to the Special Issue Clinical Trials and Outcomes for Non-Small Cell Lung Cancer)

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17 pages, 1748 KB

Open AccessArticle

Dynamics of Pulmonary Perfusion and Function Following Radical Treatment for Lung Tumors: A Prospective Comparative Study of Surgery, Radiotherapy, and Thermal Ablation

by Aurimas Mačionis, Ieva Balčiūnaitė, Grytė Galnaitienė, Rūta Dubeikaitė, Gertrūda Maziliauskienė, Ieva Dimienė, Irena Nedzelskienė, Edita Mišeikytė-Kaubrienė, Lina Padervinskienė, Skaidrius Miliauskas, Donatas Vajauskas and Marius Žemaitis

Cancers 2026, 18(8), 1213; https://doi.org/10.3390/cancers18081213 - 10 Apr 2026

Viewed by 338

Abstract

Background/Objectives: Accurate assessment of pulmonary function is essential before planning radical lung cancer treatment. While spirometry reflects global lung function, perfusion imaging provides detailed information on regional perfusion patterns. This study aimed to characterize the pre-treatment profile of patients and compare the impact of surgical resection, radiotherapy, and thermal ablation on global pulmonary function and regional perfusion using SPECT/CT. Methods: In this prospective study of 68 patients, pre- and post-treatment assessments were conducted using lung perfusion SPECT/CT. While the entire cohort underwent imaging, longitudinal global pulmonary function (spirometry and gas diffusion) was analyzed for 45 patients who completed the three-month follow-up. Quantitative analysis included perfusion percentages and lung volumes, while a semi-quantitative scoring system evaluated the severity of perfusion defects. Results: In the overall cohort, the affected lung perfusion and volume significantly decreased (p = 0.002). Subgroup analysis revealed that the surgical resection group experienced significant reductions in perfusion (from 54.0% to 41.0%, p = 0.002) and volume (p < 0.001) of the affected lung, whereas no statistically significant changes were observed in the thermal ablation and radiotherapy groups (p > 0.05). Notably, 60.3% of patients presented with perfusion defects before treatment. Post-treatment spirometry parameters, particularly FEV1% (threshold 83.5%, AUC = 0.783), served as reliable predictors of persistent perfusion impairment. Conclusions: Radiotherapy and thermal ablation are lung-perfusion-sparing treatments compared to surgical resection. The high prevalence of pre-existing perfusion defects emphasizes the importance of incorporating lung perfusion SPECT/CT into routine pre-treatment evaluation to optimize treatment selection. Full article

(This article belongs to the Special Issue Clinical Trials and Outcomes for Non-Small Cell Lung Cancer)

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19 pages, 2315 KB

Open AccessArticle

A Real-World, Single-Center, Observational Retrospective Experience of Durvalumab Treatment After Concomitant Chemoradiation for Unresectable Stage III Non-Small Cell Lung Cancer

by Agnieszka Wojskowicz, Piotr Skalij, Dominika Hempel, Łukasz Zalewski, Monika Konopka-Filippow, Iwona Sidorkiewicz, Agnieszka Krzystyniak and Ewa Sierko

Cancers 2026, 18(6), 1044; https://doi.org/10.3390/cancers18061044 - 23 Mar 2026

Viewed by 526

Abstract

Background: Non-small cell lung cancer (NSCLC) constitutes about 80–85% of lung cancers, and ~60–70% of NSCLC patients are diagnosed at an advanced stage of the disease. Concurrent chemoradiotherapy (cCRT) followed by consolidation durvalumab has become the standard of care for unresectable stage III NSCLC, following the phase III PACIFIC trial, which demonstrated significantly improved progression-free survival (PFS) and overall survival (OS) with durvalumab. Methods: We conducted a single-center retrospective study with unresectable stage III NSCLC patients who received cCRT between January 2021 and December 2025 at the Białystok Oncology Center (Poland). Patients with an ECOG performance status of 0–1 and no disease progression (PD) after cCRT were treated with durvalumab consolidation up to 12 months or until PD or unacceptable toxicity. The clinical outcomes and treatment tolerance were analyzed. Results: Out of 94 cCRT-treated patients (pts), 78 received durvalumab consolidation therapy. The median age of the pts was 66.5 years; 64.1% pts were >65 years old. Squamous carcinoma was the predominant histology (56.4%). The median time from cCRT completion to durvalumab initiation was 45 days (range: 15–85). A majority (57.7%) of patients completed the full 12 months of durvalumab. With a median follow-up of 40 months, the median PFS was ~1224 days (40.2 months). At 3 years, PFS was 52.8%. There were no significant differences in PFS by age (<65 vs. ≥65 years), HR:0.65, clinical stage (IIIA vs. IIIB/IIIC) HR:1.01, histology (squamous vs. non-squamous carcinoma), HR:0.76; sex HR:0.6, ECOG 0 vs. 1 HR:0.82; or initiation of durvalumab ≤42 vs. >42 days after cCRT, HR:0.62 (p > 0.05 for all). The sole factor significantly affecting PFS was smoking status: ever-smokers had a longer PFS than never-smokers (median ~46 months vs. ~21 months, HR:2.11, p = 0.04). Durvalumab consolidation was generally well tolerated. Grade 3–4 adverse events (mainly pneumonitis and esophagitis) leading to permanent durvalumab discontinuation occurred in 7 patients (9%), almost all over 65 years old. Conclusions: Real-world data from our single-center study confirm that consolidation durvalumab therapy after cCRT provides substantial clinical benefit in unresectable stage III NSCLC, even in older patients. The PFS and safety outcomes in our cohort, which had a higher proportion of elderly and locally advanced cases, were comparable with those reported in clinical trials (PACIFIC) and observational studies (PACIFIC-R), underscoring the effectiveness and tolerability of this approach in routine practice. We acknowledge the limitations of the retrospective design and sample size, but our findings support the use of cCRT followed by durvalumab in eligible stage III NSCLC patients and highlight the need for further research on optimizing outcomes (e.g., the impact of smoking and other biomarkers). Full article

(This article belongs to the Special Issue Clinical Trials and Outcomes for Non-Small Cell Lung Cancer)

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20 pages, 2227 KB

Open AccessArticle

ATR Blockade Potentiates the Effects of Genotoxic Agents In Vitro and Promotes Antitumor Immunity in a Mouse Model of Non-Small Cell Lung Cancer

by Dimitra Mavroeidi, Christina Papanikolaou, Elisavet Deligianni, Panagiotis Malamos, Panagiota Stamou, Konstantinos N. Syrigos and Vassilis L. Souliotis

Cancers 2026, 18(5), 820; https://doi.org/10.3390/cancers18050820 - 3 Mar 2026

Viewed by 667

Abstract

Background/Objectives: Non-small cell lung cancer (NSCLC) is the most frequent type of lung cancer, and its main treatments include chemotherapy with genotoxic drugs and immunotherapy. Central to the cellular response to genotoxic stress is the DNA damage response (DDR) network, regulated by key kinases such as ataxia-telangiectasia mutated and Rad3-related (ATR). Herein, we tested the hypothesis that inhibition of ATR enhances the cytotoxicity of genotoxic agents and the antitumor immune response. Methods: DDR-related parameters and redox status, expressed as GSH/GSSG ratio, and apurinic/apyrimidinic lesions, were evaluated in human (A549, H1299) and murine (LLC) NSCLC cell lines after co-exposure to ATR inhibitor (AZD6738) and ultraviolet C (UVC) irradiation or cisplatin. Using a syngeneic LLC model, treatments of AZD6738 alone or in combination with cisplatin and/or anti-programmed cell death 1 antibody (anti-PD1) were examined. Results: In all cell lines, combined treatment with AZD6738 and cisplatin or UVC irradiation markedly decreased cell viability, DNA repair efficiency, and GSH/GSSG ratios; increased drug-induced DNA damage; and augmented apurinic/apyrimidinic lesions. In vivo, following treatment with AZD6738 and cisplatin, flow cytometry analysis performed in tumor cells revealed an increased infiltration of CD3⁺ and CD8⁺ T cells, with the triple combination of AZD6738, cisplatin, and anti-PD1 achieving the strongest antitumor effect. The CD3⁺CD4⁻CD8⁻ double-negative (DN) T cell population in tumor samples also emerged as a contributing factor in this context. Conclusions: These results demonstrate that ATR blockade concurrently enhances the efficacy of genotoxic agents and immune checkpoint inhibitors, thus paving the way for combination therapies in NSCLC. Full article

(This article belongs to the Special Issue Clinical Trials and Outcomes for Non-Small Cell Lung Cancer)

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12 pages, 1079 KB

Open AccessArticle

Real-World Comparative Study of Atezolizumab-Based Chemotherapy Regimens in Advanced Non-Small Cell Lung Cancer

by Ayaka Ohiwa, Tadashi Nishimura, Tadashi Sakaguchi, Hajime Fujimoto, Shuji Kodama, Atsushi Fujiwara, Hiroki Nakahara, Taichi Isobe, Takaya Hirai, Akihiko Yagi, Aiko Ebihara, Hidenori Ibata, Osamu Hataji, Masamichi Yoshida, Hisamichi Yuda, Taro Yasuma, Corina N. D’Alessandro-Gabazza, Esteban C. Gabazza and Tetsu Kobayashi

Cancers 2025, 17(22), 3630; https://doi.org/10.3390/cancers17223630 - 12 Nov 2025

Viewed by 1436

Abstract

Background/objective: Carboplatin, pemetrexed, and pembrolizumab are established as a key first-line regimen for metastatic non-small cell lung cancer, although selecting the optimal therapy for each patient remains challenging in real-world clinical practice. This retrospective multicenter study compared the efficacy and safety of two atezolizumab-based combination regimens, ACnP (carboplatin, nab-paclitaxel, atezolizumab) and ABCP (carboplatin, paclitaxel, bevacizumab, atezolizumab), in patients with non-small cell lung cancer in real-world clinical practice. Methods: A total of 91 patients treated between May 2018 and December 2023 at six Japanese hospitals were analyzed: 40 received ACnP and 51 received ABCP. Patient characteristics, treatment outcomes, and adverse events were compared, with subgroup analyses adjusted by inverse probability of treatment weighting using propensity scores. Results: The objective response rates were 55.0% with ACnP and 45.1% with ABCP. Median progression-free survival was 5.5 months for ACnP and 6.9 months for ABCP, while median overall survival was 16.2 and 18.3 months, respectively. Subgroup analyses showed significantly improved progression-free survival with ABCP in patients with brain metastases, liver metastases, EGFR-positive tumors, PD-L1-positive tumors, and impaired renal function (CCr < 45 mL/min). ABCP also conferred overall survival benefits in patients with brain and liver metastases. However, ACnP was associated with a lower incidence of neutropenia, peripheral neuropathy, and skin rash. Conclusions: These findings suggest that ABCP may offer superior efficacy in specific non-small cell lung cancer subgroups, while ACnP remains a valuable option for patients requiring a more tolerable safety profile. Full article

(This article belongs to the Special Issue Clinical Trials and Outcomes for Non-Small Cell Lung Cancer)

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19 pages, 6389 KB

Open AccessArticle

Research on the Precise Differentiation of Pathological Subtypes of Non-Small Cell Lung Cancer Based on ¹⁸F-FDG PET/CT Radiomics Features

by Wenbo Li, Linjun Ju, Shuxian Zhang, Zheng Chen, Yue Li, Yuyue Feng, Yuting Xiang, Tingxiu Xiang, Zhongjun Wu and Hua Pang

Cancers 2025, 17(20), 3311; https://doi.org/10.3390/cancers17203311 - 14 Oct 2025

Viewed by 1601

Abstract

Objectives: Employing 18F-FDG PET/CT radiomic properties both within and surrounding tumors, in conjunction with clinical attributes, to precisely differentiate among several pathological subtypes of non-small-cell lung cancer (NSCLC). Approaches: The study comprised 222 patients who received 18F-FDG PET/CT scans from January 2015 to December 2020 and were later diagnosed with NSCLC, encompassing 169 cases of lung adenocarcinoma (LUAD) and 53 cases of lung squamous cell carcinoma (LUSC). They were arbitrarily allocated into a training group and a validation group in a 7:3 ratio. Radiomics feature extraction was conducted on 18F-FDG PET/CT images of primary tumors and adjacent tumor regions with LIFE-x (5.2.0). A multivariate logistic regression analysis was employed to develop a nomogram for differentiating lung adenocarcinoma (LUAD) from lung squamous cell carcinoma (LUSC). The clinical efficacy of each model was assessed and contrasted utilizing accuracy (Acc), sensitivity (Sen), specificity (Spe), receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA). Outcomes: The nomogram model that integrates 18F-FDG PET/CT radiomics features with clinical characteristics showed superior efficacy in differentiating adenocarcinoma from squamous cell carcinoma in NSCLC patients, surpassing models based only on PET or CT radiomics. The validation set exhibited an Area under curve (AUC) of 0.880, an Acc of 0.929, a Sen of 0.808, and a Spe of 0.962. This model exhibits the most superior overall performance in DCA. Conclusions: A nomogram model integrating radiomic features derived from 18F-FDG PET/CT images of tumors and adjacent tissues with clinical characteristics can effectively differentiate between LUAD and LUSC. Full article

(This article belongs to the Special Issue Clinical Trials and Outcomes for Non-Small Cell Lung Cancer)

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Review

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32 pages, 1381 KB

Open AccessReview

Drug Development in Non-Oncogene-Addicted Non-Small Cell Lung Cancer

by Pedro Cruz, Cristina Boixareu, Diogo J. Silva, Joshua Ting, Rayssa Sena, Steph A. Pang, Stephanie Mullings and Anna Minchom

Cancers 2026, 18(5), 880; https://doi.org/10.3390/cancers18050880 - 9 Mar 2026

Viewed by 1001

Abstract

Non-oncogene-addicted non-small cell lung cancer therapy has seen major advances in recent years. New molecular targets and biomarkers have enabled the development of drugs as diverse as immunotherapies and antibody–drug conjugates, among others. With a pharmacological armamentarium so precise, phase I trials have also evolved from exclusively toxicological studies into early efficacy signal-seeking trials. Nonetheless, difficulties remain, with the frequent failure of new drugs when progressing to a phase III setting. Challenges are seen in the setting of later lines therapy (testing against docetaxel), of which there are several examples. These are being tackled with promising new drugs being developed, based on innovative biological rationales. We review the current state of the art of drug development in non-oncogene-addicted non-small cell lung cancer, including advances, new drugs and targets, challenges, and opportunities in drug development. Full article

(This article belongs to the Special Issue Clinical Trials and Outcomes for Non-Small Cell Lung Cancer)

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