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Extensive stage-Small-Cell Lung Cancer (ES-SCLC) is an aggressive cancer with dismal prognosis. The addition of immune-checkpoint inhibitors (ICIs) to platinum-based chemotherapy have been consistently demonstrated to improve outcomes and survival, becoming the new standard in first – line treatment of ES-SCLC patients. However, despite positive results reported in the pivotal trials, longer benefit appears evident only for a selected group of patients. Several predictive biomarkers have been studied so far but the prospective identification of patients more likely to experience better outcome seems to be challenging in SCLC. Indeed, classical immune predictive biomarkers as PD-L1 and tumor mutational burden (TMB) seem not to correlate with outcomes. Recently, a new molecular classification of SCLC based on differential expression of genes associated with specific clinical behaviors and therapeutic vulnerability have been presented suggesting a new field to be investigated. Despite the achievements, these studies focused mainly on inter-tumoral heterogeneity, limiting the exploration of intra-tumoral heterogeneity and cell to cell interactions. New analysis methods are ongoing in order to explore subtypes plasticity. Analysis on single biopsies cannot catch the whole genomic profile and dynamic change of disease over time and during treatment. Moreover, the availability of tissue for translational research is limited due to the low proportion of patients undergoing surgery. In this context, liquid biopsy is a promising tool to detect reliable predictive biomarkers. Here, we reviewed the current available data on predictive role of tissue and liquid biomarkers in ES-SCLC patients receiving ICIs. We assessed latest results in terms of predictive and prognostic value of gene expression profiling in SCLC. Finally, we explored the role of liquid biopsy as a tool to monitor SCLC patients over time.

The human immunodeficiency virus (HIV) infection continues to be a social and public health problem. Thanks to more and more effective antiretroviral therapy (ART), nowadays HIV-positive patients live longer, thus increasing their probability to acquire other diseases, malignancies primarily. Senescence along with immune-system impairment, HIV-related habits and other oncogenic virus co-infections increase the cancer risk of people living with HIV (PLWH); in the next future non-AIDS-defining cancers will prevail, lung cancer (LC) in particular. Tumor in PLWH might own peculiar predictive and/or prognostic features, and antineoplastic agents’ activity might be subverted by drug-drug interactions (DDIs) due to concurrent ART. Moreover, PLWH immune properties and comorbidities might influence both the response and tolerability of oncologic treatments. The therapeutic algorithm of LC, rapidly and continuously changed in the last years, should be fitted in the context of a special patient population like PLWH. This is quite challenging, also because HIV-positive patients have been often excluded from participation to clinical trials, so that levels of evidence about systemic treatments are lower than evidence in HIV-uninfected individuals. With this review, we depicted the epidemiology, pathogenesis, clinical-pathological characteristics and implications for LC care in PLWH, offering a valid focus about this topic to clinicians.

Recent clinical trials demonstrated longer survival in extended small cell lung cancer (SCLC) patients treated with immunotherapy in addition to chemotherapy. However, the magnitude of benefit is modest and the impact in real-world setting has to be fully established. We collected clinical data and radiological imaging of patients affected by extended or relapsing SCLC and consecutively treated according to clinical practice between 2016 and 2023. As primary end-point, we compared pre-defined outcome indicators before and after the introduction of chemo-immunotherapy (May 2020): 6-month and 12-month progression free survival (PFS) rate, 12-month and 18-month overall survival (OS). Among those who were treated after May 2020, patients who did not receive immunotherapy according to treating physician's choice were included in the analysis to minimize clinical selection bias. The analysis included 214 patients: 132 (61.7%) were treated in an Academic cancer center and 82 (38.3%) in two community hospitals; 104 were treated before May 2020. Median PFS of the overall study population was 4.8 months (95% confidence interval [95% CI]: 4.4-5.4), median OS was 7.1 months (95% CI: 6.3-7.7). Estimated PFS and OS were significantly longer in patients treated after May 2020 with hazard ratio (HR) for PFS and OS of 0.61 (95% CI: 0.46-0.81, p < 0.001) and 0.70 (95% CI: 0.52-0.93, p = 0.015), respectively. 6-month PFS rate increased from 27% to 40% (p = 0.04) while 12-months PFS raised from 1% to 11% (p = 0.003). 12-month and 18-month OS rate increased from 15% to 28% (p = 0.03) and from 2.1% to 12% (p = 0.009), respectively. After May 2020 the median number of hospitalization days per patient decreased significantly and the incidence of severe AEs was similar. Among patients treated with chemo-immunotherapy, the onset of immune-related AEs was associated with improved PFS and OS (HR 0.55, 95% CI: 0.35-0.89, p = 0.012 and HR 0.47, 95%CI 0.28-0.77, p = 0.002, respectively). The real-world analysis shows a meaningful improvement of outcome indicators after the introduction of chemo-immunotherapy, with reduction of the duration of hospitalization, thus supporting the use of chemo-immunotherapy and the need for further biomarker research.

Background Atezolizumab (A) plus carboplatin-etoposide (CE) represents the new first-line treatment in extensive stage (ES)-Small Cell Lung Cancer (SCLC) patients. This study aims at identifying the association of baseline and dynamic changes of cfDNA, Tumor Fraction (TF) and variant allele frequency (VAF) of tumor-related mutations with median (m) overall (OS) and progression free survival (PFS) in SCLC patients treated with ACE. Materials and methods This is a single-center prospective exploratory study including treatment-naive ES-SCLC patients eligible to first-line ACE. Liquid biopsies were longitudinally collected at baseline (T0), after cycle 1 (T1) and 2 (T2), at disease progression (T3). cfDNA Next Generation Sequencing (NGS) analysis was performed; genomic profiles and TF were inferred from shallow WGS (sWGS). Results Thirty-two patients were included; mPFS and mOS were 5.19 and 7.96 months, respectively. Higher T0 cfDNA (HR 1.44, 95% CI 1.17–1.77, p  = 0.0006) and VAF (HR 2.6, 95% CI 1.36–4.93, p  = 0.0039) were associated with risk of death; higher T0 cfDNA (HR 1.29, 95% CI 1.08–1.54, p  = 0.0049), TF (HR 1.97, 95% CI 1.02–3.82, p  = 0.044) and VAF (HR 2.32, 95% CI 1.22–4.42, p  = 0.01) were predictors of risk of PD. Among the dynamic changes in the biomarkers under investigation, the association of 10-unit increase of VAF T0-T1 and T0-T2 with OS (HR 1.38, 95% CI 1.01–1.88, p  = 0.043; HR 1.56, 95% CI 1.21–2.16, p  = 0.008) and PFS (HR 1.69, 95% CI 1.18–2.43, p  = 0.004; HR 1.81, 95% CI 1.22–2.70, p  = 0.003) was estimated. Conclusion T0 and dynamic changes of cfDNA, TF and VAF may help physicians to stratify ES-SCLC patients receiving first-line ACE and to anticipate the clinical course of the disease.

Background/Objectives: To simplify the decision-making process in radiomics by employing RadiomiX, an algorithm designed to automatically identify the best model combination and validate them across multiple environments was developed, thus enhancing the reliability of results. Methods: RadiomiX systematically tests classifier and feature selection method combinations known to be suitable for radiomic datasets to determine the best-performing configuration across multiple train–test splits and K-fold cross-validation. The framework was validated on four public retrospective radiomics datasets including lung nodules, metastatic breast cancer, and hepatic encephalopathy using CT, PET/CT, and MRI modalities. Model performance was assessed using the area under the receiver-operating-characteristic curve (AUC) and accuracy metrics. Results: RadiomiX achieved superior performance across four datasets: LLN (AUC = 0.850 and accuracy = 0.785), SLN (AUC = 0.845 and accuracy = 0.754), MBC (AUC = 0.889 and accuracy = 0.833), and CHE (AUC = 0.837 and accuracy = 0.730), significantly outperforming original published models (p < 0.001 for LLN/SLN and p = 0.023 for MBC accuracy). When original published models were re-evaluated using ten-fold cross-validation, their performance decreased substantially: LLN (AUC = 0.783 and accuracy = 0.731), SLN (AUC = 0.748 and accuracy = 0.714), MBC (AUC = 0.764 and accuracy = 0.711), and CHE (AUC = 0.755 and accuracy = 0.677), further highlighting RadiomiX’s methodological advantages. Conclusions: Systematically testing model combinations using RadiomiX has led to significant improvements in performance. This emphasizes the potential of automated ML as a step towards better-performing and more reliable radiomic models.

EGFR tyrosine kinase inhibitors (TKIs) are the front-line treatment in EGFR mutation positive advanced non-small cell lung cancer (aNSCLC) patients. Generally, they are well-tolerated but skin toxicity is common (45–100% of patients) and may adversely affect quality of life. Pathogenesis of cutaneous side effects is usually linked to EGFR expression in normal cells of the epidermis and not immune-related. Subacute cutaneous lupus erythematosus (SCLE) is an autoimmune disease and about 40% of SCLE cases are drug related, but no reports are available involving osimertinib. Our report depicts a drug induced-SCLE (DI-SCLE) caused by erlotinib and worsened by osimertinib. The adverse event is characterized by the absence of systemic symptoms. Diagnosis has been performed by skin biopsy and the conditions improved with systemic steroids administration and EGFR-TKIs discontinuation. The report underlines the importance of a complete dermatologic diagnosis of skin lesions induced by EGFR inhibitors, according to symptom severity and timing of improving with standard clinical management. The diagnosis of immune-related skin toxicity in this context affects the treatment and the outcome of skin toxicity and must be taken into account when planning subsequent treatments, potentially including immune checkpoint inhibitors (ICIs).

Abstract Background Osimertinib became the standard treatment for patients with untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) following results reported in the phase III randomized FLAURA trial. Because of strict exclusion criteria, patient populations included in pivotal trials are only partially representative of real-world patients. Methods We designed an observational, prospective, multicenter study enrolling patients with EGFR-mutant aNSCLC receiving first-line osimertinib to evaluate effectiveness, safety, and progression patterns in the real-world. Results At data cutoff, 126 White patients from nine oncology centers were included. At diagnosis, 16 patients (12.7%) had a performance status (PS) ≥2 and 38 (30.2%) had brain metastases. Overall response rate (ORR) was 73%, disease control rate (DCR) 96.0%. After a median follow-up of 12.3 months, median time to treatment discontinuation (mTTD) was 25.3 months, median progression-free-survival (mPFS) was 18.9 months and median overall survival (mOS) was not reached (NR). One hundred and ten patients (87%) experienced adverse events (AEs), 42 (33%) of grade 3–4, with venous thromboembolism (VTE) as the most common (n = 10, 7.9%). No difference in rates of VTE was reported according to age, PS, comorbidity, and tumor load. We observed longer mTTD in patients without symptoms (NR vs. 18.8 months) and with fewer than three metastatic sites at diagnosis (NR vs. 21.4 months). Patients without brain metastases experienced longer mPFS (NR vs. 13.3 months). No difference in survival outcome was observed according to age, comorbidity, and type of EGFR mutation. Isolated progression and progression in fewer than three sites were associated with longer time to treatment discontinuation (TTD). Conclusion Osimertinib confirmed effectiveness and safety in the real world, although thromboembolism was more frequent than previously reported. The FLOWER study is an observational prospective multicenter study focusing on outcome, safety, progression pattern, and clinical management of untreated patients with EGFR-mutant advanced non-small cell lung cancer receiving first-line osimertinib in the real world.

Introduction Immune-related adverse events (irAEs) constitute a challenge in the clinical management of solid tumors. This study aims to collect real-world data on the occurrence of immune-mediated diarrhea and colitis (IMDC) in advanced non-small cell lung cancer (aNSCLC) treated with immune checkpoint inhibitors (ICIs) and to assess the clinical impact of a multidisciplinary approach (MDA) on IMDC management. Methods We retrospectively collected data on patients with aNSCLC consecutively treated with ICIs, either as single agent or in combination with chemotherapy, between September 2013 and July 2022. Among patients developing IMDC, we conducted blinded revision of colonic biopsies and evaluated the clinical impact of the introduction of MDA through predefined indicators. Results Among the 607 patients included, 84 (13.8%) experienced IMDC. Pathological review highlighted a high prevalence of microscopic colitis (28%), with a collagenous pattern linked to longer symptoms duration (P = .01). IMDC occurred more frequently in females (P = .05) and PD-L1 expressors (P = .014) and was correlated with longer progression-free survival (17.0 vs 5.8, P < .001) and overall survival (28.3 vs 9.5, P < .001). The introduction of MDA was associated with increased employment of diagnostical tools such as fecal calprotectin test (P < .001), colonoscopy (P < .001), and gastroenterological evaluation (P = .017) and a significant decrease in both grade 3 conversion rate (P = .046) and recurrence after rechallenge (P = .016). Hospitalization rate dropped from 17.2% to 3.8% (P: ns). Conclusion These findings highlight the clinical relevance of IMDC and support the incorporation of a MDA to optimize the clinical management of this irAE to improve patient care. Prospective validation has been planned. Immune-related adverse events are a challenge in the clinical management of solid tumors. This study collected real-world data on the occurrence of immune-mediated diarrhea and colitis in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors and assessed the clinical impact of a multidisciplinary approach on the management of this adverse event.

Abstract Introduction The observational multicenter prospective FLOWER study (NCT04965701) confirmed effectiveness and safety of osimertinib in the real-world (RW) management of untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) patients. Methods Herein, we report updated survival data, post-progression management, cost/effectiveness and budget impact (BI) of osimertinib compared with a RW population receiving gefitinib or erlotinib. Results Overall, 189 Caucasian patients receiving first-line osimertinib were included. After a follow-up of 20.7 months, 74(39.2%) patients discontinued osimertinib, median time-to-treatment discontinuation (mTTD) was 27.9 months, overall survival 36.8 months. At progression, tissue biopsy was performed in 29 (56.9%), liquid biopsy in 15 (29.4%) and both in 7 (13.7%) cases. The most frequent resistant mechanism was MET amplification (N = 14, 29.8%). At data cutoff, 13 (6.9%) patients were continuing osimertinib beyond progression; 52 (67.5%) received second-line treatment; no further treatments were administered in 25 (32.5%) cases. Thirty-three (63.4%) patients received chemotherapy, 12(23.1%) TKIs combination. Cost–effectiveness analysis showed a total cost per patient based on RW mTTD of 98,957.34€, 21,726.28€ and 19,637.83€ for osimertinib, erlotinib and gefitinib, respectively. The incremental cost-effectiveness ratio (ICER)/month for osimertinib was 359,806.0€/life-year-gained (LYG) and 197,789.77€/LYG compared to erlotinib and gefitinib. For osimertinib, the BI-gap between RW-TTD and theoretical-TTD was 16,501.0€ per patient. Conclusions This updated analysis confirms the effectiveness of osimertinib in RW. Although the ICER of osimertinib seems not cost-effective, additional costs for the management of disease progression to old generation TKIs were not considered in this study. The BI-gap suggests RW mTTD as a more reliable measure for expense estimation. This article reports updated survival data, post-progression diagnostic-therapeutic pathway, cost-effectiveness, and budget impact of osimertinib in patients treated with first-line osimertinib and included in the FLOWER study.