Sequential chemo-durvalumab, reduced-dose RT, and consolidation durvalumab for unresectable stage III NSCLC unfit for PACIFIC regimen (DEDALUS trial) Francesco Agustoni, Jessica Saddi, Diego Luigi Cortinovis, Stefano Arcangeli, Luca Sala, et al. Jnci Cancer Spectrum, 2026 Background The PACIFIC study established the standard of care for unresectable, stage III non-small cell lung cancer (NSCLC). The DEDALUS trial is a phase 2, open-label, multicenter study enrolling patients who are eligible for sequential chemo-radiation therapy (CRT) plus immunotherapy. Methods Patients had unresectable stage IIIA-C NSCLC, regardless of PD-L1 status. After 3 cycles of chemo-durvalumab, responders received hypo-fractionated thoracic radiotherapy (45 Gy over 3 weeks) with durvalumab, then continued durvalumab for up to 12 months or until disease progression. Primary endpoint was safety, assessed by the incidence of grade 3 and 4 possibly related adverse events (PRAEs) within 6 months. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and quality of life (NCT05128630). Results Between February 2022 and August 2024, 28 patients were screened, and 25 enrolled across 3 Italian centers. Enrollment was halted early due to low recruitment. We recorded 9 grade 3-4 PRAEs, which accounted for 6.4% of all AEs; 7 patients (28%) experienced at least 1 grade 3-4 PRAE. Only 1 was immune-related, while the remaining PRAEs were related to chemotherapy, none to RT. Median PFS was 13.2 months (95% CI = 4.9 to 18.6), median OS was 17.5 months (95% CI = 10.7 to 18.6). Among the 16 patients who started maintenance without progression median PFS was 18.6 months (95% CI = 12.8 to not reached), median OS was not reached. Conclusions The early closure of the study and the reduced sample size make it difficult to draw significant conclusions. However, feasibility and safety seem to be acceptable, and early PFS and OS data are promising, especially for patients who completed the full treatment sequence.
Thyroid toxicity in lung cancer patients treated with immune-checkpoint inhibitors: a single-center retrospective analysis Niccolò Leandro Alessio, Gabriele Ferrari, Antonio Mastrelia, Virginia Valeria Ferretti, Giulia Gambini, et al. Frontiers in Immunology, 2026 Background Lung cancer is the leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) have radically changed the treatment of lung cancer gradually entering all treatment settings. Alongside their clinical benefits, ICIs are associated with immune-related adverse events (irAEs), among which endocrine toxicities, particularly thyroid dysfunctions, represent some of the most frequent. Methods We conducted a retrospective analysis of 420 lung cancer patients referred to the oncology unit of IRCCS Policlinico San Matteo in Pavia, between March 2016 and December 2024. Clinical and treatment-related data were reviewed to identify thyroid irAEs. Comparative analyses between patients with and without thyroid dysfunction were performed using descriptive statistics and survival outcomes. Results Among 420 lung cancer patients treated with ICIs, 69 (16.4%) developed thyroid irAEs. Most events occurred in the first 6 months, and the majority were grade 1–2 (G1 31.9%, G2 66.7%, G3 1.4%). Thyroid replacement therapy was required in 65.2%, while steroids were used in 13%. Male sex was associated with a lower incidence of thyroid irAEs (p 0.050), non-small cell lung cancer (NSCLC) not otherwise specified (NOS) histology was associated with a higher risk (p 0.021). Disease stage and treatment line were not significantly correlated. Patients experiencing thyroid irAEs were more likely to achieve an objective response (CR/PR) compared with those without (p 0.028). Moreover, patients with PD as best response showed a significantly lower incidence of thyroid irAEs compared to those with SD (p 0.010). Duration of response was significantly longer in patients with thyroid irAEs (median 34 vs 17 months; p 0.047). Time-dependent Cox models did not demonstrate a significant association between thyroid irAEs and progression-free survival - PFS (HR 1.08, p 0.66) or overall survival – OS (HR 1.02, p 0.89). Conclusions The occurrence of thyroid irAEs correlated with better tumor response rates and prolonged duration of response, while not significantly impacting PFS or OS. These findings support the hypothesis that thyroid irAEs may serve as a favorable immunologic and prognostic biomarker in the context of ICI therapy.
Transformer-based AI approach to unravel long-term, time-dependent prognostic complexity in patients with advanced NSCLC and PD-L1 ≥50%: insights from the pembrolizumab 5-year global registry Alessio Cortellini, Valentina Santo, Leonardo Brunetti, Edoardo Garbo, David J Pinato, et al. Journal for Immunotherapy of Cancer, 2025 Background With nearly one-third of patients with advanced non-small cell lung cancer (NSCLC) and PD-L1 Tumor Proportion Score≥50% surviving beyond 5 years following first-line pembrolizumab, long-term outcomes challenge traditional paradigms of cancer prognostication. The emergence of non-cancer-related factors and time-dependent trends underscores the need for advanced analytical frameworks to unravel their complex interplay. Methods We analyzed the Pembro-real 5Y registry, a global real-world dataset of 1050 patients treated across 61 institutions in 14 countries with a long-term follow-up and a large panel of baseline variables. Two complementary approaches were employed: ridge regression, chosen for its ability to address multicollinearity while retaining interpretability, and not another imputation method (NAIM), a transformer-based artificial intelligence model designed to handle missing data without imputation. Endpoints included risk of death at 6, 12, 24, 60 months and 5-year survival. Results The ridge regression model achieved a c-statistic of 0.66 (95% CI: 0.59 to 0.72) for the risk of death and an area under the curve (AUC) of 0.72 (95% CI: 0.65 to 0.78) for 5-year survival, identifying Eastern Cooperative Oncology Group Performance Status (ECOG-PS)≥2, increasing age, and metastatic burden as primary risk factors. However, wide CIs for some predictors highlighted statistical instability. NAIM demonstrated robust handling of missing data, with a c-index of 62.98±2.11 for risk of death and an AUC of 60.52±3.71 for 5-year survival. The comprehensive SHapley Additive exPlanations analysis revealed dynamic, time-dependent patterns, with early mortality dominated by acute factors (eg, ECOG-PS, steroids) and long-term outcomes increasingly influenced by systemic health markers (eg, absence of hypertension, increasing body mass index). Unexpected insights included the protective role of dyslipidemia (but not statins) and the nuanced impact of smoking status, reflecting evolving disease dynamics and host-tumor interplay. Conclusions Our integrative framework illuminates the complexity of long-term outcomes in patients with NSCLC treated with pembrolizumab, uncovering dynamic, non-linear prognostication trends. This analysis provides insights into patient trajectories, emphasizing the need for holistic, long-term management strategies.
Non-invasive PD-L1 stratification in non-small cell lung cancer using dynamic contrast-enhanced MRI Gaia Messana, Chandra Bortolotto, Sithin Thulasi Seetha, Alessandra Marrocco, Carlotta Pairazzi, et al. European Radiology, 2025 Objectives This study aimed to assess whether pharmacokinetic parameters derived from DCE-MRI can stratify Programmed Death-Ligand 1 (PD-L1) expression in NSCLC. The secondary aim was to identify a suitable pharmacokinetic model configuration for anisotropic temporally-spaced DCE-MRI sequences, considering Tofts variants, population-averaged arterial input functions (AIF), and bolus arrival time (BAT) estimation methods. Materials and methods From April 2021 to May 2023, patients with locally advanced non-small cell lung cancer (NSCLC) were prospectively enrolled. Tumors were categorized based on: PD-L1 absence/presence (threshold 1%) and hyperexpression/hypoexpression (threshold 50%). Pharmacokinetic parameters were extracted using several candidate configurations; fit quality was evaluated using coefficient of determination (R²). Mann–Whitney U-test and ROC-AUC were used to assess correlation with PD-L1 for the best-fit configuration. Results Thirty-eight patients (mean age 68 ± 9 years, 28 men) were included. PD-L1 expression was present in 25 patients (66%) and absent in 13 (34%). PD-L1 was hyperexpressed in 13 (34%) patients and hypoexpressed in 25 (66%). Voxel-wise pharmacokinetic parameters were extracted using the best-fit configuration—extended Tofts model (ETM) with Georgiou AIF and Peak-Gradient (PG) BAT estimation (R 2 = 0.79). Ktrans median (0.25 vs. 0.12 min−¹, p = 0.02), Ktrans standard deviation (0.32 vs. 0.23 min−¹, p = 0.01) and Kep median (1.09 vs. 0.59 min−¹, p = 0.02) were significantly higher in PD-L1 < 50% group (ROC-AUC 0.71–0.76). Conclusion DCE-MRI pharmacokinetic parameters could stratify PD-L1 hypo/hyperexpression in NSCLC. The ETM with PG BAT estimation method and Georgiou AIF was the best-performing pharmacokinetic configuration. Key Points Question Could Dynamic Contrast-Enhanced (DCE) MRI offer a safe and non-invasive way to assess Programmed Death-Ligand 1 (PD-L1) expression? Findings Quantitative DCE-MRI parameters K trans (the volume transfer rate) and Kep (the efflux rate constant) show potential for distinguishing PD-L1 hyperexpression from hypoexpression. Clinical relevance Preliminary results suggest that DCE-MRI could be a safe method to stratify PD-L1 hypo/hyperexpression in non-small cell lung cancer, potentially optimizing treatment decisions, given the high cost of immunotherapy. Graphical Abstract
Biomarker testing implementation for molecularly targeted therapy in non-small cell lung cancer patients Daniele Lorenzini, Gabriella Gaudioso, Alessandro Scardoni, Lorenzo Blandi, Alessandro Del Gobbo, et al. Tumori, 2025 Background: Recent advancements in identifying druggable molecular drivers in lung adenocarcinoma (LUAD), have transformed treatment paradigms. In recent years, Next Generation Sequencing (NGS) has gained momentum as an essential tool for in-depth simultaneous analysis of multiple genes, thereby streamlining the diagnostic process in LUAD. Despite this, the implementation of NGS testing in both the US and Europe remains suboptimal. Aims: In compliance with a decree issued by the Italian Ministry of Health, Lombardy Region recently launched an initiative to implement NGS testing in patients with advanced LUAD. In this context, a real-world prospective observational study was planned to assess the efficacy of the regional network of molecular laboratories in testing nine biomarkers ( KRAS p.G12C, EGFR , BRAF, HER2, MET mutations; ALK , ROS1 , NTRK1-3 , RET rearrangements), for on-label molecularly targeted drugs. Results: In 2023, out of the 2784 advanced/metastatic LUAD patients expected in Lombardy, 2343 (84.2%) were successfully evaluated with an NGS panel including all the nine biomarkers for on-label drugs. Actionable aberrations were identified in 45.5% of the patients (1068/2343), predominantly involving EGFR , KRAS , and ALK genes. Conclusion: Our data provide evidence that establishing a structured network of NGS hubs is mandatory to ensure access of advanced LUAD patients to molecularly targeted treatments.
