Background:Immunotherapy targeting the programmed cell death (ligand)-1 (PD-[L]1) pathway has improved outcomes in patients with advanced/metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGAs), especially those with high PD-L1 expression (≥50% of tumor cells [TC]). However, some patients have primary or acquired resistance to treatment and new therapeutic strategies are needed to address this. Datopotamab deruxtecan (Dato-DXd), a trophoblast cell surface antigen 2 (TROP2)-directed antibody-drug conjugate, and rilvegostomig, a bispecific anti-PD-1/anti-TIGIT antibody, have shown promising efficacy and manageable safety profiles in patients with advanced or metastatic NSCLC. Methods and design:TROPION-Lung10 (NCT06357533) is a phase 3, open-label, multicenter, randomized study evaluating the efficacy and safety of first-line Dato-DXd plus rilvegostomig versus standard-of-care pembrolizumab in patients with advanced/metastatic nonsquamous NSCLC with PD-L1 TC expression ≥50% and without AGAs. Approximately 675 adults with nonsquamous stage IIIB/C or IV NSCLC not amenable to curative surgery or definitive chemoradiation, PD-L1 TC ≥50%, and no AGAs will be enrolled. Patients will be randomized (2:1:2) to receive Dato-DXd (6 mg/kg intravenously [IV] every 3 weeks [Q3W]) plus rilvegostomig (750 mg IV Q3W), rilvegostomig alone (750 mg IV Q3W), or pembrolizumab (200 mg IV Q3W for up to 35 cycles/24 months). The dual primary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and overall survival (OS) in the TROP2 normalized membrane ratio (NMR) biomarker-positive population for Dato-DXd plus rilvegostomig versus pembrolizumab. The key secondary endpoints are PFS by BICR per RECIST v1.1 and OS in the full analysis set (FAS). Other secondary endpoints include the objective response rate and duration of response by BICR per RECIST v1.1, PFS2, patient-reported outcomes in the TROP2 NMR-positive population and FAS, and safety. Discussion:TROPION-Lung10 will assess first-line Dato-DXd plus rilvegostomig in patients with advanced/metastatic NSCLC with high PD-L1 expression and without AGAs. Clinical trial registration:ClinicalTrials.gov, identifier NCT06357533.

Lorlatinib is a third-generation tyrosine kinase inhibitor approved for first- and second-line treatment of ALK-positive advanced non-small cell lung cancer. The CROWN study demonstrated that first-line lorlatinib significantly improves progression-free survival and intracranial control compared to crizotinib, with sustained benefits observed over a follow-up period of up to 5 years. As lorlatinib is associated with a distinct adverse event (AE) profile, we aim to analyze lorlatinib's safety profile, focusing on AEs incidence, severity, timing and management. A comprehensive safety management framework is also outlined to address lorlatinib-associated toxicity, drawing on evidence from the literature and the clinical expertise of an Italian expert panel. The most frequent AEs associated with lorlatinib are hypercholesterolemia and hypertriglyceridemia, which emerge early after treatment initiation. The 5-year analysis of the CROWN study revealed minimal changes in most AE rates over time. Pharmacological and non-pharmacological approaches effectively resolved most AEs; lorlatinib dose reduction did not affect its efficacy. The proposed safety management framework emphasizes patient preparation and regular monitoring to predict AE occurrence, indicating AE-specific interventions, mitigation strategies and multidisciplinary collaboration to optimize outcomes. Lorlatinib's toxicity appears generally predictable and manageable; the safety framework offers pragmatic guidance to clinicians for appropriate management in clinical practice.

BACKGROUND:Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with high central nervous system penetration and activity against resistance mutations. Although its clinical efficacy as first-line treatment for ALK-positive advanced non-small cell lung cancer (NSCLC) has been demonstrated, its economic value within the Italian healthcare system remains to be fully established. This study evaluated the cost-effectiveness of lorlatinib compared with alectinib as first-line therapy in Italy. METHODS:A partitioned survival model with three health states (progression-free, progressed disease, and death) was developed from the Italian National Health Service and societal perspectives over a 30-year time horizon. Clinical efficacy inputs were derived from the CROWN trial and indirect treatment comparisons using network meta-analysis. Costs (2026 euros) included drug acquisition, subsequent treatments, healthcare resource use, adverse events, end-of-life care, and societal costs. Health outcomes were expressed as life-years (LYs) and quality-adjusted life-years (QALYs). Deterministic, probabilistic, and scenario analyses were conducted to assess uncertainty. RESULTS:In the base case, lorlatinib was dominant over alectinib, providing higher benefits (+2.01 LYs; +1.66 QALYs) at lower costs (-€19,210 per patient). This finding was robust across pricing scenarios. Probabilistic sensitivity analysis showed an almost 98,40% probability of cost-effectiveness at Italian willingness-to-pay thresholds. CONCLUSIONS:From both NHS and societal perspectives, lorlatinib represents a cost-saving and clinically superior first-line treatment option compared with alectinib for patients with ALK-positive advanced NSCLC in Italy.

In AEGEAN, perioperative durvalumab plus neoadjuvant chemotherapy, versus neoadjuvant chemotherapy alone, significantly improved event-free survival (EFS) and pathologic complete response in patients with resectable non-small cell lung cancer (R-NSCLC), with a safety profile consistent with the individual agents. We report EFS from a second planned interim analysis, interim disease-free survival (DFS) and overall survival (OS), and safety, after all patients completed/discontinued treatment. In this phase III, double-blind, placebo-controlled study, patients with treatment-naïve R-NSCLC (stage II-IIIB [N2]) were randomly assigned (1:1) to neoadjuvant platinum-based chemotherapy plus durvalumab/placebo (once every 3 weeks, four cycles) presurgery and then adjuvant durvalumab/placebo (once every 4 weeks, 12 cycles). Efficacy was analyzed in the modified intention-to-treat population (n = 740; for DFS, its resected subpopulation), which excluded patients with documented EGFR/ALK aberrations. As of May 10, 2024 (median follow-up, 25.9 months [censored patients]), EFS benefit favoring the durvalumab arm remained consistent (hazard ratio [HR], 0.69 [95% CI, 0.55 to 0.88]). Numerical improvement in DFS (HR, 0.66 [95% CI, 0.47 to 0.92]) and OS (HR, 0.89 [95% CI, 0.70 to 1.14]) favored the durvalumab arm. Maximum grade 3/4 adverse events occurred in 15.4% and 10.6% of the durvalumab and placebo arms, respectively, during adjuvant treatment. These results further support perioperative durvalumab plus neoadjuvant chemotherapy as a new treatment option.

Background: Sensitive detection of EGFR mutations in liquid biopsies of advanced non-small-cell lung cancer (aNSCLC) is vital for guiding targeted treatments. Real-time PCR offers a quick turnaround time but relatively low sensitivity while Next-Generation Sequencing (NGS) offers broader EGFR coverage, co-mutation evaluation and high sensitivity. Methods: This study evaluated the amplicon-based NGS Plasma-SeqSensei™ Solid Cancer In Vitro Diagnostics (IVD) Kit (Sysmex) against the real-time PCR-based cobas® EGFR Mutation Test v2 (Roche), the current routine standard at the Veneto Institute of Oncology IOV-IRCCS. We enrolled 130 patients with aNSCLC in the RARE Study between April 2022 and August 2025 who were referred to our institute. Liquid biopsies were taken at diagnosis or at progression and analyzed using two methods with the primary objective of assessing diagnostic concordance for EGFR profiling. Sysmex NGS libraries were sequenced on a NextSeq 550 sequencer (Illumina), with the NextSeq 500/550 Mid Output Kit v2.5 (150 Cycles) in single-end mode. Results: Among 129 evaluable samples, the NGS assay demonstrated a marginally higher EGFR mutation detection rate, identifying mutations in 31/129 cases (24.0%, 95% CI: 17–33), versus 28/129 (21.7%, 95% CI: 15–30) by cobas, specifically for variants covered by both assays. Overall concordance was almost perfect (Cohen’s Kappa = 0.89, 95% CI: 0.80–0.98), confirming the high reliability of both methods. Furthermore, we identified a cfDNA input threshold of at least 20 ng as critical for ensuring optimal assay sensitivity and reliable mutation detection (Odds Ratio = 4.41 for inputs ≥ 20 ng, p = 0.006). Conclusions: Ultimately, the Sysmex NGS proved to be a robust and highly sensitive assay. It delivers performance comparable to that of standard RT-PCR while providing the clinical advantage of concurrently detecting a broader spectrum of EGFR variants and actionable mutations in other genes.

The introduction of neoadjuvant immunotherapy in non-small cell lung cancer (NSCLC) has led to complex tumor responses that challenge conventional pathological assessment. Thus, traditional endpoints such as major pathological response (MPR) and pathological complete response (pCR) may become insufficient to capture the full spectrum of immune-mediated changes. Indeed, these parameters were originally developed in the context of cytotoxic chemotherapy and may not reflect immune-mediated phenomena and stromal remodeling which can significantly alter the appearance of the tumor bed. As a result, MPR and pCR may underrepresent the true extent of biological response in patients treated with immunotherapy. This review outlines current limitations in morphologic evaluation and highlights the need for immune-adapted criteria. Furthermore, it explores the additional value of digital pathology and AI that offer objective and reproducible quantification of histologic features. Integrating these tools with radiologic and molecular data supports a multidimensional approach to response assessment, aiming to refine prognostication, guide adjuvant therapy, and ensure consistency in clinical trial designs.

Pleural mesothelioma (PM) is a malignancy with a relevant genetic component, with germline mutations identified in up to 12

BACKGROUND:Immune checkpoint inhibitor (ICI) monotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with PD-L1 ≥ 50%; however, up to 30% of patients experience early progression or death, including cases of hyperprogressive disease (HPD). High baseline levels (≥ 30.5%) of circulating CD10- low-density neutrophils (LDNs) have been associated with increased HPD occurrence. Emerging evidence suggests that combining ICI with platinum-based chemotherapy (PCT) may mitigate the risk of HPD. Currently, no prospective studies have addressed HPD prevention in this context. PATIENTS AND METHODS:HYPERBOLIC (NCT07274384) is a phase 2, randomized, open-label, multicenter, international trial evaluating whether adding 3 cycles of PCT to first-line cemiplimab reduces HPD rate in stage IV NSCLC with PD-L1 ≥ 50% and CD10- LDNs (identified by flow cytometry as CD15⁺CD11b⁺ within the PBMC fraction, with immature cells defined by loss of CD10) ≥ 30.5%. Seventy-four patients will be randomized (1:1 ratio) to receive cemiplimab alone or cemiplimab plus 3 PCT cycles, followed by cemiplimab maintenance. Randomization will be stratified by Lung Immune Prognostic Index. The first computed tomography scan at week 7 after treatment start will assess HPD occurrence, defined as RECIST v 1.1. disease progression with a delta tumor growth rate (ΔTGR) ≥ 50% and/or TGR ratio ≥ 2. The primary endpoint will be the combined rate of HPD and early death (death within 12 weeks with no radiological evaluation). Secondary endpoints will be HPD rate according to alternative definitions, overall survival, progression free survival, objective response rate, and safety. An extensive translational research platform will include spatial transcriptomics of tumor tissue, single-cell RNA sequencing of PBMCs, circulating-free DNA and plasma factors profiling, and saliva/stool microbiome genomics and metabolomics, to longitudinally explore tumor-host dynamic interactions during treatment. CONCLUSION:to our knowledge, HYPERBOLIC is the first prospective, biomarker-driven trial investigating early treatment escalation based on HPD risk in PD-L1-high NSCLC.

Over the past decade, significant achievements in elucidating the molecular pathogenesis of non-small cell lung cancer (NSCLC) have catalyzed a paradigm shift from empiric therapies to precision oncology. In this context, HER2 alterations, including protein overexpression, gene amplification, and activating mutations, constitute distinct molecular subsets within NSCLC. In the past few years, targeted therapeutic modalities such as antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan (the first agent to be granted FDA approval for HER2-mutant NSCLC), alongside selective tyrosine kinase inhibitors (TKIs), including zongertinib and sevabertinib, have demonstrated robust systemic efficacy and notable intracranial penetration. This comprehensive review delineates the molecular landscape and clinical phenotypes of HER2-altered NSCLC, synthesizes interim and mature data from ongoing clinical trials evaluating anti-HER2 therapies, and critically examines efficacy and safety results from different classes of targeted agents. Further research is crucial to uncover potential mechanisms of resistance in NSCLC with HER2 mutations and define sequencing or combinatorial strategies pertinent to optimizing individualized patient management.

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.

BackgroundFollowing the ADAURA study results, showing that adjuvant osimertinib was associated with significant improvement in disease-free survival among patients with stage IB-IIIA epidermal growth factor receptor mutation positive (EGFRm+) non-small cell lung carcinoma (NSCLC), an Early Access Program (EAP) was activated in Italy to provide preapproval access to osimertinib.MethodsThe ELBA observational retrospective cohort study aims to describe the characteristics, diagnostic workup, mutation testing, and treatment patterns of the patients included in the ADAURA EAP. The retrospective observation period was from the day of the first procedure leading to the pathological diagnosis of NSCLC (index date) to osimertinib initiation and data were obtained from medical records or other original documents available at the sites.ResultsOverall, 71 patients were evaluable, mainly females (73.2%), with mean (SD) age of 67.5 (8.7) years. Age-adjusted Charlson Comorbidity Index scored 2 or 3 for 74.7% of patients without considering lung cancer. Forty-six (66.7%) out of 69 evaluable patients with available data were discussed at the multi-disciplinary team meeting. The median (25th-75th percentiles) time from the initial diagnostic suspicion to the index date was 52.0 (30.0-67.0) days and from index date to EGFR test prescription 20.0 (0.0-42.0) days. Among patients with available data (N = 69), the tests were mostly single-gene polymerase chain reaction mutation-specific test (63.8%) and next-generation sequencing (33.3%). Primary tumor surgery was mostly lobectomy (n/N=63/71, 88.7%). Pathological staging was IB for 21.1% of patients, II for 43.7% and III for 35.2%. Adjuvant chemotherapy prior to osimertinib was administered in 32.4% of patients. Osimertinib was started after a median (25th-75th percentiles) time from tumor resection of 2.9 (2.1-4.9) months.ConclusionsThe ELBA Study showed an evolving landscape in biomarker-driven and molecular targeted therapies in early-stage NSCLC management towards the integration of mutational testing into clinical practice, with a growing focus on an optimal definition of adjuvant treatment.

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.

Histopathologic assessment of the tumor bed following neoadjuvant therapy in non-small cell lung cancer (NSCLC) is increasingly relevant, but comparative data across treatment modalities remain limited. We evaluated tumor bed features and artificial intelligence (AI)-assisted stromal quantification in advanced NSCLC, comparing patients treated with immunotherapy, tyrosine kinase inhibitors (TKIs), and chemotherapy. This multicenter retrospective study included 71 patients with stage IIIB-IV NSCLC who underwent salvage surgery after neoadjuvant therapy at five Italian centers between 2018 and 2022. Thirty-eight patients received immune-based therapy, 16 received TKIs, and 17 received chemotherapy alone. Tumor bed response was assessed according to International Association for the Study of Lung Cancer recommendations, including residual viable tumor, necrosis, fibrosis, and inflammation. Immune-related features were recorded. AI-assisted morphometric analysis quantified fibrosis on Azan-Mallory staining and inflammatory burden on CD45 immunohistochemistry. The immunotherapy group showed the most favorable regression profile, with higher pathological complete response rates than the TKI and chemotherapy groups, respectively (40.5% vs 21.4% vs 11.8%), and lower residual viable tumor burden (median, 5% vs 45% vs 45%). This group also showed a more immune-reactive tumor bed phenotype and significantly higher AI-quantified inflammatory burden (p = 0.022). In the overall cohort, multivariable analysis identified residual viable tumor percentage (HR, 1.02; p = 0.018) and AI-derived fibrosis (HR, 0.97; p = 0.013) as independent predictors of recurrence. Tumor bed evaluation after neoadjuvant therapy provides prognostically relevant information beyond residual viable tumor alone. AI-assisted fibrosis quantification may complement viable tumor assessment and refine post-surgical risk stratification.

INTRODUCTION:Rare cancers, individually uncommon but collectively significant, pose major challenges due to their heterogeneity, low incidence, and fragmented expertise. This review addresses the complexities of managing and researching rare cancers, highlighting the necessity for collaborative networks. AREAS COVERED:A systematic literature search was conducted using PubMed to identify peer-reviewed articles from 2010 to 2025 focusing on rare cancers, collaborative clinical networks, European Reference Networks (ERNs), and thymic malignancies. The review examines key obstacles such as limited patient populations, uneven expertise distribution, funding challenges, and explores models of collaboration including ERNs and the Italian TYME network. These networks exemplify integrated efforts to improve clinical care, research efficiency, and patient involvement through coordinated governance, registries, and multidisciplinary approaches. EXPERT OPINION:Sustainable, transparent, and inclusive collaborative networks like TYME and ERNs are essential to overcoming rare cancer research barriers. They enable standardized care, robust data sharing, and enhanced clinical trials, ultimately improving outcomes. Continued investment, policy support, and expansion of interoperable digital infrastructures are critical to fully realize the transformative potential of these network models in rare cancer care.

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.

IntroductionChemo-immunotherapy is the standard frontline treatment of advanced non-squamous non-small cell lung cancer (nsq-NSCLC). Among oncogenic drivers, KRAS mutation accounts for approximately 25% of lung adenocarcinomas, with p.G12C being the most common variant. This study assessed clinical features and survival outcomes according to KRAS mutation in a real-life population of nsq-NSCLC patients treated with first-line platinum-pemetrexed-pembrolizumab.MethodsThis is a retrospective-prospective study including patients with nsq-NSCLC who received first-line platinum-pemetrexed-pembrolizumab from 4 September 2018 in 33 Italian Centers.ResultsAmong the 765 patients included in this analysis, 121 (15.8%) had KRAS p.G12C mutation, 201 (26.3%) KRAS non-p.G12C mutation and 443 (57.9%) KRAS WT. KRAS-mutated patients had more frequently a history of smoking (90.6% vs 84.1%, p=0.012) and bone metastases (44.1% vs 35.9%; p=0.022) compared to KRAS WT.Median Overall Survival (OS) was similar between KRAS-mutated and KRAS WT patients (16.7 vs 18.2 months; adjusted Hazard Ratio [HR] 1.19, 95% Confidence Interval [CI] 0.95-1.50, p=0.132). No difference in OS was found between KRAS p.G12C and KRAS non-p.G12C (15.9 vs 17.0 months, HR 0.93, 95% CI: 0.66-1.31, p=0.676).Median progression-free survival was significantly shorter in KRAS-mutated compared to KRAS WT patients (8.8 vs 10.8 months; adjusted HR 1.29, 95% CI 1.04-1.59, p=0.018), with no differences between KRAS p.G12C and KRAS non-p.G12C (8.8 vs 8.8 months, HR 0.95, 95% CI: 0.70-1.30, p=0.756).ConclusionsKRAS mutation showed a potential negative predictive role in advanced nsq-NSCLC treated with first-line chemo-immunotherapy. The impact of co-mutations and post-progression outcomes warrants further investigation.

BACKGROUND:Although rebiopsy at progression on osimertinib is recommended for patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC), its real-world impact on clinical outcomes remains unclear. Rebiopsy on Osi is a multicenter, retrospective study assessing rebiopsy patterns, resistance mechanisms, and their impact on second-line treatment choices and outcomes in routine clinical practice. METHODS:A total of 457 patients with advanced NSCLC harboring a common EGFR mutation (exon 19 deletion or L858R) who progressed on first-line osimertinib were identified from the Italian ATLAS registry. Patients were stratified according to rebiopsy status (tissue and/or plasma-based next-generation sequencing) and receipt of biomarker-driven adaptive second-line therapy. RESULTS:Rebiopsy was performed in 206 patients (45.1%), predominantly via tissue sampling (66.2%). A resistance mechanism was identified in 80 cases (38.8%), with higher detection rates with tissue rebiopsy (46.6%) than with liquid biopsy (13.5%). MET amplification/overexpression emerged as the most frequent actionable resistance mechanism. Among 239 patients treated with second-line therapy, 39 (16.3%) received adaptive treatment, including 29 of 39 patients (74.3%) with MET amplification/overexpression who were treated with a MET-TKI-based regimen. Median progression-free survival (PFS) and overall survival (OS) were longer with adaptive therapy (7.3 and 14.1 months) than with rebiopsy without treatment adaptation (6.5 and 12.2 months) or no rebiopsy (5.1 and 8.2 months). CONCLUSION:In real-world practice, rebiopsy identifies a resistance mechanism in slightly more than one third of patients, with actionable MET amplification/overexpression accounting for approximately one fifth of cases. Biomarker-driven adaptive therapy may improve clinical outcomes, supporting the implementation of rebiopsy in routine practice.

BACKGROUND:The treatment landscape for metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) is rapidly evolving, with the development of specific targeted therapies. The bispecific antibody amivantamab is the new standard of care for this population but real-world safety and efficacy data are lacking. METHODS:This is a multicenter, retrospective, observational study conducted on advanced NSCLC patients harboring EGFRex20ins who were included within the ATLAS Italian real-world registry between January and December 2024. Clinical-pathological features, treatment effectiveness, and safety outcomes were retrospectively collected and analyzed. RESULTS:A total of 119 advanced NSCLC patients harboring EGFRex20ins mutations were included. Seventy-six (63.9%) and 24 (20.2%) received first-line platinum-based chemotherapy with or without immunotherapy, respectively. Overall 64 of 119 patients received single agent amivantamab in the subsequent lines. Treatment-related adverse events (TRAEs) of any grade and grade 3-4 were reported in 68.8% and 10.9%, respectively, including skin rash (56%, G3 9.4%), asthenia (9%), peripheral edema (8%), and infusion-related reactions (9.4%, G3 1.5%). Dose interruptions, reductions, and discontinuations due to TRAEs occurred in 20.3%, 12.5%, and 3.1% patients, respectively. The objective response rate was 37.5%, the DCR was 66.2%, the median progression-free survival (mPFS) was 9.6 months, and the median overall survival was 16.9 months under amivantamab. Among the 23 patients with brain metastasis, 13% achieved a partial intracranial (ic) response and 43.5% a stable disease. The ic mPFS was 11.6 months. CONCLUSION:This data confirms the efficacy and safety profile of amivantamab observed in the CHRYSALIS trial, showing a meaningful clinical benefit in a heavily pretreated real-world population.