Background Lung neuroendocrine tumors (LNETs) span well-differentiated typical/atypical carcinoids (TC/AC) to poorly differentiated large-cell neuroendocrine carcinoma (LCNEC). Robust biomarkers for grading and prognostication are lacking. We hypothesized that differential metabolic pathways activation, reflected by protein expression, holds prognostic relevance.We conducted a monocentric translational study on resected LNETs to characterize biomarkers involved in glycolysis, fatty acid, and amino acid pathways across different grades of LNETs. Secondary endpoints included assessing clinical outcomes and correlating biomarker expression with patient prognosis. Methods Digital FFPE sections underwent standardized immunohistochemistry (IHC) and quantitative image analysis. Biomarkers included glycolysis (MCT1, MCT4, CD147), amino-acid metabolism (SLC1A5, SLC7A5, GLS), and fatty-acid synthesis (FAS, ACC). Expression was summarized by H-score and dichotomized. Associations with clinicopathologic variables, recurrence-free survival (RFS), and overall survival (OS) were tested using median and maximally selected rank statistics. Results Overall, 49 LNETs were included: 11 TC, 19 AC; 19 LCNEC. LCNEC showed marked upregulation of glycolytic and amino-acid transport markers versus TC/AC. Fatty-acid markers were generally low across subtypes. High MCT1 and SLC7A5 predicted shorter OS; MCT1 and CD147 predicted shorter RFS. In multivariable analysis, MCT1 remained independently associated with RFS. Notably, a subset of ACs with elevated glycolysis/amino-acid markers showed LCNEC-like outcomes, independent of Ki-67. GLS peaked in AC, suggesting divergent glutamine utilization along the spectrum. Conclusion Quantitative digital pathology reveals distinct metabolic signatures in LNETs. MCT1 and SLC7A5 emerge as prognostic biomarkers, with MCT1 independently predicting RFS. Integrating metabolic immunophenotyping with histopathology refines risk stratification—especially for AC—and highlights potentially actionable metabolic axes for future therapeutic interventions in LNETs.

BACKGROUND:SLFN11, highly expressed in SCLC, predicts sensitivity to DNA-damaging agents. Its role in other lung neuroendocrine neoplasms (NENs) (typical/atypical carcinoids - TC/AC and large cell neuroendocrine carcinoma- LCNEC) is unknown. This multicentre study assessed SLFN11 across lung NENs exploring its clinical-molecular associations. METHODS:SLFN11 immunohistochemistry (H-score 0-300) was assessed in 361 tumours (127 TC, 35 AC, 152 LCNEC, 47 SCLC). Ki67, pRb, cMYC, DLL3, ASCL1, HNF1a, OTP and NEUROD1, ASCL1, POU2F3, and YAP1 (NAPY; H-score > 50 as dominant subgroup) staining were integrated with clinicopathologic data and survival. Median SLFN11expression (exp) was used for survival analysis. RESULTS:SLFN11exp varied across histologies (p < 0.001), with median values of 0 in TC (range 0-20) and AC (0-40), 2.49 (0-250) in LCNEC, 35 (0-240) in SCLC. SLFN11 showed a positive correlation with Ki67 (R2 = 0.187) across all histologies. In TC/AC, SLFN11exp was enriched in A1 subgroup tumours (known for ASCL1exp) (p = 0.035) and not correlated with OTP, HNF1A, CD44 and SSTR2Aexp. In LCNEC, SLFN11exp was higher in ASCL1high tumors (median 17.2; 0-162.5, p = 0.003) and correlated with cMYCexp (p = 0.024), but not with pRB and DLL3 status. In SCLC, a trend toward higher SLFN11exp in ASCL1high tumours was observed. SLFN11exp was not prognostic in TC/AC or LCNEC. In SCLC, SLFN11exp ≥ median value was associated with improved OS (13.9 vs 6.8 months; HR = 0.48, 95%CI 0.26-0.90, p = 0.020). CONCLUSION:SLFN11exp in lung NENs is higher in SCLC > LCNEC > TC/AC, and correlated with Ki67. SLFN11exp was associated with ASCL1exp in all lung NENs. SLFN11 role in TC/AC and LCNEC remains to be defined.

Pleural mesothelioma (PM) is a rare asbestos-related malignancy characterized by complex diagnosis and poor prognosis, with survival strongly influenced by histological subtype and eligibility for a multimodality approach, reserved for highly selected patients. While platinum-pemetrexed chemotherapy or the combination of ipilimumab plus nivolumab represent standard first-line options for unresectable disease, pembrolizumab combined with platinum-pemetrexed has demonstrated improved survival in advanced PM (IND227/Keynote483 trial). In resectable PM, multimodality treatment including surgery and chemotherapy remains preferred, yet pathological complete response (pCR) rates remain low at approximately 5%, and the role of perioperative immunotherapy is still poorly defined. CHIMERA is a prospective, open-label, multicenter phase II single-arm trial evaluating neoadjuvant pembrolizumab combined with platinum-pemetrexed chemotherapy followed by surgery and adjuvant pembrolizumab in patients with treatment-naïve, resectable stage I-IIIA epithelioid or biphasic PM. Patients receive three cycles of neoadjuvant pembrolizumab plus cisplatin or carboplatin and pemetrexed every three weeks, followed by centralized pleurectomy/decortication or extended pleurectomy/decortication in two high-volume referral centers, and subsequently 14 cycles of adjuvant pembrolizumab. The primary endpoint is pCR, with secondary endpoints including major pathological response, objective response rate, event-free survival, overall survival, treatment feasibility, and safety; translational tissue- and blood-based biomarker analyses are planned. The study is powered to detect an increase in pCR from 5% to 18%, requiring 40 patients to account for potential dropouts. By focusing on pathological efficacy within a standardized multimodality framework, CHIMERA aims to clarify the role of perioperative chemo-immunotherapy and to improve outcomes for patients with resectable PM.

Schlafen 11 (SLFN11) is a gene encoding for a protein involved in the irreversible arrest of cell replication under DNA-damaging stress. SLFN11 is expressed differently across various cancers. When overexpressed, SLFN11 inhibits tumor replication and growth by early recruitment to stressed replication forks, making tumors more sensitive to a range of anti-cancer treatments, including topoisomerase I-II inhibitors, DNA alkylating agents, platinum salts, anti-metabolites, anti-tumor antibiotics, poly ADP-ribose polymerase (PARP) inhibitors and immunotherapies. SLFN11 expression can be silenced in cancer cells through different epigenetic mechanisms, resulting in SLFN11 downregulation and resistance to anti-cancer treatments. In this context, SLFN11 is increasingly being recognized as a promising biomarker for predicting cancer treatment responses. Its expression levels can inform clinical decisions, helping to identify patients most likely to benefit from therapies that exploit replication stress and to select new drug combinations that specifically aim to overcome SLFN11 deficiency.

Introduction Pleural mesothelioma (PM) is an aggressive neoplasm associated with asbestos exposure. Clinical management of PM poses major challenges due to the lack of reliable markers for early diagnosis and prognostic stratification. Here we evaluated circulating microRNAs (miRNAs) as minimally invasive biomarkers for PM detection and risk assessment. Methods Plasma samples were collected from 32 asbestos-exposed (AsbEX) individuals and 56 PM patients, including epithelioid (N = 45) and non-epithelioid (N = 11) subtypes. An initial discovery cohort (9 AsbEX and 9 PM) was screened for 92 miRNAs using quantitative RT-PCR. Candidate miRNAs were validated in the full cohort. Results Ratios calculated from the plasma levels of miR-24-3p, miR-146a-5p, miR-191-5p, miR-200a-3p, miR-222-3p, miR-223-3p, and miR-1260a robustly differentiated PM patients from asbestos-exposed controls with high accuracy and sensitivity. Furthermore, ratios of circulating miR-146a-5p, miR-200a-3p, miR-222-3p and miR-191-5p enabled stratification of epithelioid PM in high- and low-risk prognostic groups. Conclusion Circulating miRNA signatures represent promising non-invasive biomarkers for early PM detection and prognostic stratification, particularly in epithelioid cases. Incorporation of these biomarkers into clinical workflows could pave the way for more personalized treatment strategies and optimize patient selection for surgery.

TPS8122 Background: Pleural mesothelioma (PM) is a rare cancer related to asbestos exposure, marked by complex histopathological diagnosis and dismal prognosis. Patients’ survival is strongly influenced by the histological subtype and by the eligibility to a multimodal approach, which is reserved to very selected patients. Platinum-pemetrexed chemo-regimen or the immunotherapy combination ipilimumab+nivolumab are the available first-line treatment options for unresectable PM patients. In this setting, pembrolizumab in combination with platinum-pemetrexed showed an improved overall and progression free survival (IND227/Keynote483 trial). In patients with resectable PM, the multimodality approach with platinum-pemetrexed chemotherapy and surgery is usually preferred, achieving pathological complete response (pCR) in 5% of cases. To date, the role of perioperative immunotherapy for PM has not yet been extensively investigated. Methods: This is a phase II single arm trial enrolling patients with resectable PM from 8 high volume Italian centers, with 18 months of enrollment and 12 months of follow-up. Inclusion criteria will be the histologically confirmed diagnosis of surgical resectable stage I-IIIA treatment-naïve epithelioid/biphasic PM. Patients will receive 3 cycles of pembrolizumab 200 mg plus cisplatin (75 mg/sm) or carboplatin (AUC 5) and pemetrexed (500 mg/sm) every 3 weeks. The surgical procedure of pleurectomy/decortication will be centralized in 2 centers and will be performed within 6 weeks after the last neoadjuvant cycle. The adjuvant treatment will start within 10 weeks from surgery and will be based on 14 cycles of pembrolizumab 200 mg every 3 weeks. The primary endpoint will be the pCR; secondary endpoints will include: major pathological response, objective response rate, event free survival, OS, surgery feasibility, safety. Translational analysis on tissue and blood samples will also be performed. In order to investigate an improvement of pCR from 5% to 18%, 36 patients and a minimum number of 4 pCR are needed to verify this hypothesis with a least 80% power and a probability of type I error of 0.05. Considering a 10% patients dropped-out because of disease progression precluding surgery, a total number of 40 patients will be included in the study. The trial is currently ongoing since November 2024; 5 patients have been enrolled so far. This is the first clinical trial assessing the activity and safety of pembrolizumab in combination with platinum-pemetrexed for resectable PM patients. Clinical trial information: NCT06155279 .

INTRODUCTION:Lurbinectedin has recently emerged in the treatment landscape of extensive stage (ES) small cell lung cancer (SCLC). Here we report the outcomes and safety of lurbinectedin within a named patient program in a multicentric, international cohort. METHODS:Clinical data of all patients with ES-SCLC treated with lurbinectedin at the Erasmus Medical Center (EMC, Rotterdam-The Netherlands) and the Veneto Institute of Oncology (IOV, Padua-Italy) were collected. RESULTS:A total of 238 patients receiving lurbinectedin as second- (37 %), third- (45 %) or further-line (18 %) were included. Median number of cycles was 3 (1-22). The objective response rate was 23.1 %, the disease control rate 45.5 %. The median progression free survival (PFS) 2.2 months (95 %CI 1.6-2.8) and the median overall survival (OS) 5.4 months (95 %CI 4.5-6.3). Patients with a chemotherapy-free interval (CFI) ≥ 90 days showed a longer PFS (3.1 vs 1.8 months, HR 0.46, 0.30-0.71, p < 0.001) and OS (6.8 vs 4.5 months, HR 0.56, 0.37-0.85, p = 0.006). Patients with ECOG performance status (PS) ≥ 2 at lurbinectedin start, brain or liver metastasis showed a worse outcome. Adverse events were recorded in 218 (92 %) patients, with 29 % grade 3-4 events. CONCLUSION:Considering its safety profile and modest but consistent effectiveness, lurbinectedin represents a therapeutic option as compassionate use in patients with ES-SCLC, especially in those with a long CFI. Poor PS, CFI < 90 days, brain or liver metastases may affect the OS.

BACKGROUND:Treatment of advanced ALK + NSCLC has improved with increasingly effective ALK tyrosine-kinase inhibitors (TKIs). We report real-world treatment patterns and outcomes from the Italian ATLAS registry. METHODS:Clinical-pathological and treatment data were retrospectively and prospectively collected from 37 Italian centers. RESULTS:463 ALK + advanced NSCLC patients treated from 2019 to 2024 were included. 431 (93 %) patients received 1st line (1L) ALK TKIs, mostly alectinib (82.5 %). 1L treatment choice, reported in 142 cases, was driven by drug access as first (31 %) or subsequent lines (40.1 %) and by safety (21.8 %). Among 382 patients receiving 1L alectinib overall survival (OS) rate was 88.7 % and 73.3 % at 24 and 60 months, respectively. Median progression-free survival (mPFS) was 43.1 months (95 %CI: 29.5-57.0). Brain was a new site of progression in 11 (3.6 %) patients. Intracranial PFS rate was 73.1 % and 59.1 % at 24 and 36 months with a 64.7 % intracranial response rate. Grade ≥ 3 adverse events occurred in 41 (10.7 %) patients, mainly hepatic toxicity (13, 3.4 %) and asthenia (5, 1.3 %). At progression tissue and/or liquid biopsy were performed in 28 (23.5 %) and 20 (16.8 %) cases, respectively. Out of 80 patients receiving 2nd line therapy after alectinib, 67 (83.8 %) received lorlatinib achieving mPFS 7.5 (95 % CI: 6.2-8.8) and mOS 26.4 months (95 % CI: 19.1-33.7). 17 (15.5 %) patients died without second line therapy. CONCLUSIONS:Real-world data confirm the effectiveness and safety of alectinib, used as preferred upfront ALK-TKI. The recent 1L lorlatinib approval might change this scenario. Tissue/liquid biopsy at disease progression are underperformed in clinical practice.

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. 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). Thirty-two patients were included; mPFS and mOS were 5.19 and 7.96 months, respectively. Higher T0 cfDNA (HR 1.44, 95

Introduction ctDNA is a useful tool for NGS molecular profiling in advanced NSCLC patients. Its clinical applicability in patients with gene rearrangements is still limited due to a lower detection rate of these types of alterations compared to single SNVs or small indels. To this purpose, we performed a study in two Italian centers to assess the concordance between tissue and plasma samples in the detection of genes fusions (ALK, ROS, RET) and METexon14 mutations in advanced NSCLC patients. Methods Patients with a histological diagnosis of oncogene addicted (ALK, ROS1, RET positive or METexon14 mutated) advanced NSCLC were enrolled at the time of first line of TKI treatment. Plasma samples were harvested before the start of TKI treatment and NGS analysis on ctDNA samples using the AVENIO ctDNA Expanded kit was performed. The Positive Percent Agreement (PPA) between tissue and plasma was calculated. Results Fifty-eight rearranged or METexon14 mutated NSCLC patients were included and 57 ctDNA samples were successfully sequenced. An overall PPA of 37% (21/57) was obtained, with a best performance for RET fusion (80%), intermediate for METexon14 skipping mutations (40%) and ALK rearranged (36%) and a worst one for ROS1 rearranged samples (18%). We found TP53, APC and SMAD4 as most prevalent co-mutated genes (21%, 12% and 10% of patients, respectively). Among different factors considered, increased driver detection rate in patients with extra-thoracic metastases (p = 0.0049) was observed. Significantly shorter survival was observed in patients harboring co-occurring KRAS/NRAS mutations in ctDNA. Conclusions ctDNA testing to detect oncogenic fusions or METexon14 mutations in advanced NSCLC patients is useful, even if type of gene alterations and clinical characteristics could influence the driver detection rate. Liquid biopsy represents a complementary tool to tissue genotyping, however more sensitive approaches for gene fusions and METexon14 detection are needed to implement its strength and reliability.

Small cell lung cancer (SCLC) is characterized by a dismal prognosis. Many efforts have been made so far for identifying novel biomarkers for a personalized treatment for SCLC patients. Schlafen 11 (SLFN11) is a protein differently expressed in many cancers and recently emerged as a new potential biomarker. Lower expression of SLFN11 correlates with a worse prognosis in SCLC and other tumors. SLFN11 has a role in tumorigenesis, inducing replication arrest in the presence of DNA damage through the block of the replication fork. SLFN11 interacts also with chromatin accessibility, proteotoxic stress and mammalian target of rapamycin signalling pathway. The expression of SLFN11 is regulated by epigenetic mechanisms, including promoter methylation, histone deacetylation, and the histone methylation. The downregulation of SLFN11 correlates with a worse response to topoisomerase I and II inhibitors, alkylating agents, and poly ADP-ribose polymerase inhibitors in different cancer types. Some studies exploring strategies for overcoming drug resistance in tumors with low levels of SLFN11 showed promising results. One of these strategies includes the interaction with the Ataxia Telangiectasia and Rad3-related pathway, constitutively activated and leading to cell survival and tumor growth in the presence of low levels of SLFN11. Furthermore, the expression of SLFN11 is dynamic through time and different anticancer therapy and liquid biopsy seems to be an attractive tool for catching SLFN11 different expressions. Despite this, further investigations exploring SLFN11 as a predictive biomarker, its longitudinal changes, and new strategies to overcome drug resistances are needed.

The difference in circulating cytokines levels between epithelioid (E) or non-epithelioid (NE) Pleural Mesothelioma (PM) and their modulation after chemotherapy (ChT) or immune checkpoint inhibitors (ICIs) have not yet been described. This prospective translational study included patients (pts) with E or NE PM treated respectively with ChT and ICIs. The primary aim was to explore the prognostic role of cytokines levels, their dynamic change during ChT or ICIs and their correlation with progression-free survival (PFS). Blood samples were collected at baseline (T0) and at the end of ChT cycles or at first radiological imaging during ICIs (T1). Plasma levels of IL-1b, IL-2, IL-6, IL-8, IL-10, MCP1, HGF, TGFb1, TNFa, GM-CSF were quantified by enzyme-linked immunosorbent assay. A combined score (CS) of IL-8, IL-6 and HGF levels was calculated. Thirty-two pts were included, 18 (56%) treated with platinum-pemetrexed and 14 (44%) with ipilimumab-nivolumab. At T0, higher levels of IL-1b (p=0.039), IL-6 (p=0.001), IL-8 (p=0.007), IL-10 (p=0.015), and TNFa (p=0.001) were observed in NE vs E PM pts; no differences were seen for MCP1, GM-CSF, HGF, TGFb1 and IL-2. A trend was observed between lower levels of IL-8 and longer PFS with ChT (p=0.070). Plasma levels of IL-8 increased with ChT (p=0.004) and decreased with ICIs (p=0.002). Lower levels of IL-6 correlated with better PFS after ChT (p=0.054); a similar trend was seen with ICIs (p=0.164). HGF levels were not related to PFS, but HGF decreased at T1 after ICIs (p=0.014). Lower levels of IL-10 correlated with longer PFS after ICIs (p=0.049); T0-T1 levels of IL-10 increased after ChT (p=0.001) and ICIs (p=0.006). Lower levels of the CS of IL-8, IL-6 and HGF correlated with longer PFS after ChT (p=0.026); a trend with ICIs was seen (p=0.062). A T0-T1 decrease of the CS was seen in ICIs group (p=0.004). No relation between cytokines levels and neutrophil to lymphocyte ratio, platelet to lymphocyte ratio and immune related adverse events was seen. In this series, circulating cytokines were differently expressed in E vs NE pts; some cytokines showed a prognostic and predictive role after ChT or ICIs. ICIs may have a key role in decreasing some cytokines levels.

IntroductionRearranged during transfection (RET) gene rearrangements occur in 1%-2% of non-small cell lung cancer (NSCLC). Because of the results of the study LIBRETTO-001, selpercatinib has been approved as the first-line treatment for patients with RET fusion-positive advanced NSCLC. Selpercatinib demonstrated to be well tolerated. Despite this, gastrointestinal adverse events (AEs) are frequently reported, and no clinical-radiological and endoscopic features and their impact in terms of treatment discontinuations, interruptions, and dose reductions have been described so far. Case reportA 37-year-old never-smoker woman was treated in our institution with selpercatinib for a RET fusion-positive NSCLC. After 9 months of treatment, the patient referred abdominal pain of grade (G) 2, associated with nausea of G2, bilious vomiting of G3, and weight loss of G1. At computed tomography scan, the presence of important bowel wall thickening, free ascitic fluid, mesenteric congestion, and stranding was detected. The patient underwent an anterograde enteroscopy extended to jejunum with detection of lymphocytic duodenitis with sub-mucosal edema. Selpercatinib treatment was temporary interrupted with complete resolution of the symptoms and then re-administered with dose reduction, without relapsed of the gastrointestinal toxicity after 120 days. ConclusionTo our knowledge, this is the first case report of a patient with NSCLC treated with selpercatinib outside a clinical study who developed severe gastrointestinal toxicity characterized by small bowel edema and lymphocytic duodenitis, leading to treatment interruption and dose reduction. The gastrointestinal AE has been described by a radiological, endoscopic, and histopathological point of view. Further investigations are needed to better identify pathological mechanisms of gastrointestinal toxicity for an appropriate AE management.

Lung cancer (LC) is the leading cause of cancer-related death worldwide, mostly because the lack of a screening program so far. Although smoking cessation has a central role in LC primary prevention, several trials on LC screening through low-dose computed tomography (LDCT) in a high risk population showed a significant reduction of LC related mortality. Most trials showed heterogeneity in terms of selection criteria, comparator arm, detection nodule method, timing and intervals of screening and duration of the follow-up. LC screening programs currently active in Europe as well as around the world will lead to a higher number of early-stage Non Small Cell Lung Cancer (NSCLC) at the diagnosis. Innovative drugs have been recently transposed from the metastatic to the perioperative setting, leading to improvements in terms of resection rates and pathological responses after induction chemoimmunotherapy, and disease free survival with targeted agents and immune checkpoint inhibitors. The present review summarizes available evidence about LC screening, highlighting potential pitfalls and benefits and underlining the impact on the diagnostic therapeutic pathway of NSCLC from a multidisciplinary perspective. Future perspectives in terms of circulating biomarkers under evaluation for patients' risk stratification as well as a focus on recent clinical trials results and ongoing studies in the perioperative setting will be also presented.

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 98,957.34euro, 21,726.28euro and 19,637.83euro for osimertinib, erlotinib and gefitinib, respectively. The incremental cost-effectiveness ratio (ICER)/month for osimertinib was 359,806.0euro/life-year-gained (LYG) and 197,789.77euro/LYG compared to erlotinib and gefitinib. For osimertinib, the BI-gap between RW-TTD and theoretical-TTD was 16,501.0euro 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.

Aims: This study describes real-world outcomes of pretreated EGFR T790M-positive (T790M+) advanced non-small-cell lung cancer patients progressing after first- or second-generation tyrosine kinase inhibitors and receiving osimertinib, compared with T790M-negative (T790M-) patients. We have also described progression patterns and treatment sequences. Patients & methods: This is a retrospective multicenter Italian observational study including consecutive Caucasian patients referred between 2014 and 2018. Results: 167 patients were included. Median progression-free survival was 9.8 months (95% CI: 8.3-13.3) for T790M+ and 6.0 months (95% CI: 4.9-7.2) for T790M- patients, respectively. Median overall survival was 20.7 months (95% CI: 18.9-28.4) for T790M+ and 10.6 months (95% CI: 8.6-23.6) for T790M- patients, respectively. The T790M mutation correlated with absence of new sites of disease. After progression, most T790M+ patients continued osimertinib, whereas most T790M- patients received a different treatment line. Conclusion: Better outcomes were shown in patients receiving osimertinib. A more limited progression pattern for T790M+ was suggested.

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.