PURPOSE:Dabrafenib plus trametinib is a standard first-line treatment for BRAF V600E-mutated non-small cell lung cancer (NSCLC). The LiBRA study aimed to explore the role of liquid biopsy in detecting and monitoring BRAF V600E mutation, assessing its potential to predict treatment response and emerging resistance. MATERIALS AND METHODS:This prospective multicenter study enrolled patients with BRAF V600E-mutated NSCLC treated with first-line dabrafenib plus trametinib. Plasma samples were collected at baseline (t0), after 4 weeks (t1), and longitudinally until disease progression (PD). BRAF V600E was monitored by digital droplet PCR (ddPCR). Next-generation sequencing (NGS) was performed at t0 and PD to identify resistance mechanisms. RESULTS:Forty patients were enrolled. Dabrafenib plus trametinib achieved an overall response rate of 42.5%, with a median progression-free survival (PFS) and overall survival (OS) of 8.3 and 21.1 months, respectively. At t0, BRAF V600E was detectable by ddPCR in 24 (62%) of 39 patients. Among 21 shedders evaluated at t1, 17 (81%) cleared the mutation. Higher baseline BRAF V600E allele frequency was associated with shorter PFS (hazard ratio [HR], 1.09, P = .013) and OS (HR, 1.10, P = .010), whereas clearance at t1 correlated with longer PFS (8.3 v 1.4 months, P < .001) and OS (10.5 v 2.2 months, P < .001). Biological PD anticipated radiologic/clinical PD by a median of 4.9 weeks (IQR, 1.4-9.8). Baseline EGFR and MET CNVs were associated with shorter PFS and OS. Resistance mechanisms at PD included NRAS, KRAS, TP53 mutations and MET, EGFR, ERBB2 CNVs. CONCLUSION:The LiBRA study supports liquid biopsy as a prognostic and monitoring tool in BRAF V600E-mutated NSCLC undergoing targeted therapy.

Identifying predictive and resistance biomarkers remains one of the most relevant unmet needs in clinical cancer research. Artificial Intelligence (AI) represents a powerful tool to develop predictive algorithms tailored to individual patients. Thanks to its ability to process large quantities of heterogeneous, patient-level information, the AI-based approach is progressively fostering the growth of a data-driven paradigm to complement traditional, hypothesis-driven clinical research. However, the development of reliable AI models requires access to large, high-quality, and continuously updated datasets. Despite this necessity, no infrastructure currently exists to enable federated, multi-omic, standardized, prospective, and large-scale collection and analysis of real-world clinical and biological data in the context of lung cancer. We established the APOLLO11 consortium, a distributed, nationwide, updated Italian lung cancer network designed to build a decentralized, long-term, population-based, real-world data repository and a multilevel biobank, locally stored and centrally annotated. This strategy seeks to lay the foundation for the clinical implementation of data-driven research, ultimately advancing precision oncology.

Introduction: Data from two global protocols under the expanded access program, Study-436 and Study-442, evaluating the safety and efficacy of sotorasib in patients with advanced KRAS G12C-mutated NSCLC beyond the traditional registrational trial setting are presented. Methods: Patients were enrolled in 90 centers globally. Baseline characteristics and safety data for Study-436 and Study-442 and efficacy data for Study-436 were estimated. All data were summarized descriptively. Results: A total of 268 patients (n = 150 [Study-436] and n = 118 [Study-442]) received oral sotorasib (960 mg daily). At baseline, 21.3% and 31.0% of patients had Eastern Cooperative Oncology Group performance status (ECOG PS) 2 and a history of central nervous system (CNS) metastases, respectively.Treatment-related adverse events occurred in 64.9% of patients; diarrhea (31.3%) was the most common. The incidence of treatment-related adverse events was similar between patients with ECOG PS 0 to 1 (67.8%) and PS 2 (54.4%) and those with (69.9%) and without (62.7%) a history of CNS metastases. The median real-world progression-free survival and overall survival was 6.3 and 9.5 months, respectively. The median real-world progression-free survival was numerically similar in patients with ECOG PS 0 to 1 versus PS 2 (6.5 versus 5.6 mo) and in patients with versus without a history of CNS metastases (5.7 versus 6.5 mo); median overall survival followed similar trends. Improvement from ECOG PS 2 to ECOG PS 0 to 1 was observed by the end of first cycle of treatment (57.9%). Conclusions: Safety and efficacy outcomes of sotorasib in this study were not affected with ECOG PS 2 and the history of CNS metastases and were consistent with those reported in key clinical trials.

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.

Background/Objectives: Alterations of the phosphatidylinositol 3-kinase catalytic subunit alpha gene (PIK3CA) are identified in approximately 2-4% of non-small cell lung cancer (NSCLC) cases; however, their biological and clinical relevance in NSCLC remains incompletely understood. This study aimed to comprehensively characterize the clinical and molecular features, as well as outcomes, of patients with PIK3CA-altered NSCLC across different disease stages. Methods: We conducted a retrospective multicenter analysis of 62 patients with histologically confirmed early-stage or advanced NSCLC-harboring PIK3CA alterations (mutations and/or gene amplifications) treated between 2015 and 2022 at three Italian institutions. Demographic, clinical, pathological, and molecular variables were systematically collected and analyzed. Results: PIK3CA mutations accounted for the majority of alterations (90.3%), while amplifications represented 9.7%. The most frequent mutations involved exon 9 (66.1%), predominantly E545K and E542K, followed by exon 20 (16.1%). Most patients were current or former smokers, and concomitant oncogenic alterations were detected in 59.7% of cases, most commonly KRAS mutations. A history of prior malignancy was reported in 24.6% of cases. In the metastatic setting, adenocarcinoma histology was associated with significantly longer overall survival (OS) compared with non-adenocarcinoma histologies (18.4 vs. 5.5 months; p = 0.02). Patients with PD-L1-negative tumors demonstrated a numerically longer OS than those with PD-L1-positive tumors; however, this difference did not reach statistical significance (19.1 vs. 5.4 months; p = 0.05). No statistically significant survival differences were observed according to specific PIK3CA mutation subtypes or treatment strategies. Conclusions: PIK3CA-altered NSCLC represents a molecularly heterogeneous and clinically understudied subgroup, frequently characterized by co-occurring oncogenic alterations. In this study, no definitive prognostic or predictive role for PIK3CA alterations could be established. Nevertheless, these findings provide a descriptive real-world characterization of this molecular subset and support the need for validation in larger, prospectively designed, molecularly stratified studies.

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: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.

BACKGROUND:This study describes clinical characteristics, treatment patterns as well as safety outcomes of NSCLC patients harboring PD-L1 ≥ 50% who received adjuvant atezolizumab within the Italian real-world scenario. METHODS:Patients with surgically resected NSCLC harboring EGFR/ALK wild type disease and PD-L1 TPS ≥ 50%, who received at least one cycle of adjuvant atezolizumab were included. Clinical-pathological and molecular data, safety and efficacy outcomes were collected from the Italian ATLAS real-world registry. RESULTS:A total of 132 patients were included across 45 Italian centers between July 2022 and August 2024. Lobectomy was performed in 81.1% of cases, with 8.3% pathological stage IIA, 40.2% stage IIB, 43.9% stage IIIA, and 7.6% stage IIIB, according to the eighth TNM staging edition. The median number of atezolizumab cycles was 12.5 (range: 1-20). Treatment related adverse events (TRAEs) during atezolizumab were reported in 44 patients (33.3%), including 11 (8.3%) who experienced multiple TRAEs. Grade ≥ 3 TRAEs were reported in 21 cases (15.9%), leading to treatment discontinuation in 18 (13.6%). The median time to the first onset of TRAEs was 89 days (range: 3-390 days). 15 patients experienced a disease recurrence, including 6 locoregional-only and 9 distant relapses, with a median time since surgery of 13.3 months. CONCLUSION:This study showed that the safety profile of adjuvant atezolizumab outside of a clinical trial context was comparable to the IMPower-010 study, highlighting the value of the Italian ATLAS registry as source of real-word evidence to optimize the clinical management of NSCLC patients.

Background Immune checkpoint inhibitors (ICI) improved survival of patients with non-small cell lung cancer (NSCLC), yet many patients do not respond to treatment. The identification of markers for ICI response remains an unmet clinical need. This study hypothesizes that host genetics influences the response to ICI, contributing to the variability in efficacy among individuals.Methods We conducted a genome-wide association study (GWAS) in patients with NSCLC on ICI monotherapy with nivolumab, pembrolizumab, or atezolizumab, to identify germline variants associated with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) at 24 months after the start of ICI therapy. Genomic DNA was genotyped using Axiom Precision Medicine Research Arrays. Raw data were processed with Axiom Analysis Suite, and quality checked with PLINK software. Imputation to the whole genome was done on the Michigan Imputation Server. Association analyses were performed for ORR (logistic regression with PLINK2 software) and survival (Cox proportional hazards model, with GenAbel package in R environment), with appropriate covariates. Variants were annotated for functional significance using SNPnexus and FUMA. Post-GWAS analyses, including colocalization, were performed to explore the function of the identified variants. Their possible role as expression quantitative trait loci was investigated in different databases (GTEx, eQTLGen, TCGA).Results No genome-wide significant associations were found for ORR or PFS, while a locus on chromosome 2 (lead variant: rs111648355) showed near genome-wide significance (p value=6.3×10⁻⁸) for OS. Patients with minor alleles of these variants exhibited significantly worse OS (HR=5.1, 95% CI: 2.9 to 9.2). Functional annotation linked these variants to regulatory effects on genes including MSH2, MSH6, PPP1R21, FBXO11, and STON1. These genes play a role in mismatch repair, endosomal trafficking, or major histocompatibility complex class II regulation, and might influence the response to immunotherapy.Conclusions This study identifies an association between a genomic locus on chromosome 2 and OS in patients with NSCLC treated with ICI. Although these results need validation in larger cohorts and functional studies to elucidate the underlying mechanisms, they highlight the potential of germline variants as predictive biomarkers of response to ICI.

Background/Objectives: Lung cancer (LC) remains one of the most lethal malignancies worldwide, with both environmental and occupational exposures contributing to its incidence. While oncogene-addicted tumors-defined by single driver mutations-have garnered attention due to their therapeutic implications, less is known about the mutational landscape of tumors potentially arising from occupational exposure to carcinogens. This real-life observational study aimed to assess whether previous occupational exposure to lung carcinogens correlates with distinct LC phenotypes, particularly non-oncogene-addicted (nOA) profiles. Methods: A total of 199 LC patients were enrolled across two specialized oncology centers in Northern Italy between 2021 and 2023. Each participant underwent detailed occupational history taking and molecular characterization using next-generation sequencing. Patients were stratified into nonexposed (NE), low exposed (LE), and high exposed (HE) to carcinogens for lung based on standardized questionnaires and sector-specific assessments. Results: No significant differences were found in histological subtypes across exposure groups. However, people with adenocarcinoma and high occupational exposure to lung carcinogens were more frequently characterized by a nOA phenotype compared to those with low occupational exposure. Logistic regression models-adjusted for age, sex, and smoking habits-confirmed that HE patients had a significantly higher likelihood of developing nOA tumors (OR = 3.07; 95% CI: 1.16-8.11; p = 0.023). This association persisted after adjusting for smoking habits Exposures occurring 5-10 years before diagnosis seemed to be associated with an increased nOA profile. Conclusions: These findings suggest that high levels of exposure to occupational carcinogens impact LC phenotypes. Indeed, these phenotypes are more complex to treat and show the worst prognosis. Assessing the occupational exposure to lung carcinogens during work may offer prognostic insights and support the request for more adequate compensation for the patients. Further studies are warranted to validate these results and to explain the mechanisms that produce the differences observed in LC phenotypes in people with high exposure to occupational carcinogens.

8015 Background: Stage III Non-Small Cell Lung Cancer (NSCLC) is a heterogeneous group of tumors with a wide spectrum of clinical presentations and no single definitive therapeutic approach. The role of neoadjuvant alectinib in stage III ALK-positive NSCLC is still unclear. Here, we present the final analysis of the phase II, open-label, single-arm, multicenter study aimed at investigating the activity and safety of alectinib in potentially resectable locally advanced stage III ALK-positive NSCLC patients (ALNEO trial, EUDRACT number 2020-003432-25). Methods: Treatment-naïve patients with potentially resectable stage III ALK-positive NSCLC, ECOG PS≤1 were registered to receive neoadjuvant alectinib for 2 cycles (8 weeks) followed by surgery and adjuvant alectinib for 24 cycles (96 weeks). The primary endpoint was major pathological response (MPR) by Blinded Independent Central Review (BICR). Secondary endpoints included pathological complete response (pCR) by BICR, objective response (OR), event-free survival (EFS), disease-free survival (DFS), overall survival (OS) and adverse events (AEs). According to the Simon’s design (P0=20%, P1=40%), 18 and 33 patients were required for the first and second stage, respectively. Results: A total of 33 patients were registered in 20 Italian Oncology Centers from May 2021 to July 2024. Median age was 62 years (Interquartile Range [IQR], 49–74 years), 23 (70%) patients were female and 17 (52%) were never smokers. Clinical stage according to the 8th AJCC TNM was IIIA in 21 (64%) and IIIB in 12 (36%) patients. The most represented stage was T3N2 (n=8, 24%), followed by T1aN2 (n=4, 12%), T2aN2 (n=4, 12%), T4N0 (n=4, 12%) and T4N2 (n=4, 12%). All the patients completed the neoadjuvant phase and 28 (85%) underwent surgery, which consisted of lobectomy in 21 (64%), pneumonectomy in 3 (9%) and other surgery in 4 (12%) patients. Among patients who completed surgery, R0 was achieved in 24 (86%) patients. According to the BICR, MPR was documented in 15 (46%, 90% Confidence Interval [CI]: 31%–61%) patients and pCR in 4 (12%, 95% CI: 3%–28%) patients. Overall, an OR was observed in 22 (67%) patients. Adjuvant treatment was started in 26 (79%) patients with a median interval from surgery of 5.1 weeks (IQR, 3.6–6.0 weeks). After a median follow-up of 15.2 months (IQR, 6.8–27.8 months), 31 (94%) patients were alive and 5 (19%) patients completed the adjuvant treatment. Median EFS and OS were not reached. A total of 6 (18%) patients experienced disease progression/recurrence. Grade≥3 AEs occurred in 3 (9%) and 2 (8%) patients during neoadjuvant and adjuvant phase, respectively. Conclusions: ALNEO study met its primary endpoint, suggesting alectinib as a feasible peri-operative option in resectable locally advanced stage III ALK-positive NSCLC patients. The study was partially supported by Roche S.p.A. Clinical trial information: NCT05015010 .

Importance:Patients with advanced RET fusion-positive (RET+) non-small cell lung cancer (NSCLC) who experience disease progression following treatment with RET inhibitors (RETis) have limited treatment options. Identifying membrane protein targets may support the assessment of novel therapies, such as antibody-drug conjugates and bispecific antibodies. Objective:To evaluate membrane target expression in RET+ NSCLC. Design, Setting, and Participants:This multicenter cohort study used centralized immunohistochemistry (IHC) on archival tissue samples and whole transcriptome sequencing (WTS) in an independent cohort. Tissue samples were collected from 12 European centers, and WTS was performed on globally sourced patient samples submitted for molecular profiling. This study included samples from patients with RET+ NSCLC and RET-wild-type (RET-wt) adenocarcinoma controls that were analyzed by IHC and 203 RET+ and 19 579 RET-wt samples analyzed by WTS. Exposures:Membrane protein expression of MET, ERBB2 (formerly HER2), epidermal growth factor receptor (EGFR), human epidermal growth factor 3 (HER3), and trophoblastic cell surface antigen 2 (TROP2) was evaluated using IHC, with samples scored on a scale of 0 to 3. Scores of 2 or greater were considered positive. Target expression as analyzed by WTS was expressed as median transcript per million scores. Main Outcomes and Measures:Biomarker positivity, coexpression of biomarkers, dynamic changes in paired biopsies, and clinical correlates with survival outcomes. Results:A total of 189 patients were included in the study (among 81 patients with RET+ NSCLC, the median [IQR] age was 62 [55-70] years, and there were 49 female individuals [60%]). In 93 samples from 81 patients with RET+ NSCLC, positive IHC scores were observed for MET in 51 of 86 (59%), ERBB2 in 3 of 84 (3.6%), EGFR in 24 of 84 (29%), HER3 in 31 of 82 (38%), and TROP2 in 59 of 65 (91%). Compared with RET-wt adenocarcinoma (n = 112), RET+ tumors showed higher MET (59% vs 43%; P = .03) and lower ERBB2 expression (3.6% vs 15%; P = .01). The WTS analysis from the independent cohort confirmed these results. Of 61 evaluable samples, 59 of 61 (97%) had at least 1 positive biomarker, 60 of 77 (78%) when excluding TROP2. MET/EGFR coexpression occurred in 17 of 79 evaluable samples (21.5%). Dynamic change in biomarker expression was observed in paired biopsy specimens. No significant survival differences based on target expression emerged in patients treated with RETi in the IHC and the WTS cohorts. Conclusions and Relevance:The results of this cohort study suggest that RET+ NSCLC tumors frequently express MET and TROP2, with MET positivity enriched vs RET-wt controls. Coexpression and biomarker dynamics highlight the need for membrane target screening and novel therapeutic strategies for this population.

Background BRAF mutations identify a small subgroup of patients (pts) with non-small cell lung cancer (NSCLC). Dabrafenib/trametinib (D/T) combination is associated with high response rates and durable anti-tumor activity in BRAF-V600-mutants. Several open questions still remain unanswered in clinical practice, including the efficacy of treatments based on clinical and molecular characteristics, the activity in patients with brain metastases, the optimal sequence with immunotherapy-based therapies. Here we present outcomes among advanced BRAF-mutant NSCLC patients from the Italian ATLAS registry. Methods Patients with metastatic BRAF-mutated NSCLC were included. Clinical-pathological features, treatment effectiveness and safety outcomes were retrospectively collected from the Italian real-world ATLAS registry. Results A total of 244 BRAF-mutated NSCLC pts were enrolled, including 70% V600E mutations. The median PFS of first line D/T was 19.8 months (95% CI: 10.7-29.0), with a 2-year OS rate of 65.4% and a PFS2 of 6.6 months (95% CI: 0-14.3). The activity of D/T differs among sex (mPFS was 13.6 mos and 25.3 mos and 2-yr OS rate were 54.9% and 72.3% in males and females, respectively) and smoking status (mPFS was 18.4 mos, 25.6 mos and 24 mos in never, former and current smokers, respectively). Concomitant MET amplification was associated with a shorter median PFS (mPFS was 13.6 mos vs. 44.3 mos with and without MET amplification respectively) in pts treated with D/T as 1st line. Conclusions These data confirm the efficacy and safety of first line D/T in BRAF V600E-mutated pts in the real-world setting consistently with prior studies, suggesting a differential activity among key clinical-molecular subgroups.

INTRODUCTION:Despite several therapeutic efforts, lung cancer remains a highly lethal disease. Novel therapeutic approaches encompass immune-checkpoint inhibitors, targeted therapeutics and antibody-drug conjugates, with different results. Several studies have been aimed at identifying biomarkers able to predict benefit from these therapies and create a prediction model of response, despite this there is a lack of information to help clinicians in the choice of therapy for lung cancer patients with advanced disease. This is primarily due to the complexity of lung cancer biology, where a single or few biomarkers are not sufficient to provide enough predictive capability to explain biologic differences; other reasons include the paucity of data collected by single studies performed in heterogeneous unmatched cohorts and the methodology of analysis. In fact, classical statistical methods are unable to analyze and integrate the magnitude of information from multiple biological and clinical sources (eg, genomics, transcriptomics, and radiomics).METHODS AND OBJECTIVES:APOLLO11 is an Italian multicentre, observational study involving patients with a diagnosis of advanced lung cancer (NSCLC and SCLC) treated with innovative therapies. Retrospective and prospective collection of multiomic data, such as tissue- (eg, for genomic, transcriptomic analysis) and blood-based biologic material (eg, ctDNA, PBMC), in addition to clinical and radiological data (eg, for radiomic analysis) will be collected. The overall aim of the project is to build a consortium integrating different datasets and a virtual biobank from participating Italian lung cancer centers. To face with the large amount of data provided, AI and ML techniques will be applied will be applied to manage this large dataset in an effort to build an R-Model, integrating retrospective and prospective population-based data. The ultimate goal is to create a tool able to help physicians and patients to make treatment decisions.CONCLUSION:APOLLO11 aims to propose a breakthrough approach in lung cancer research, replacing the old, monocentric viewpoint towards a multicomprehensive, multiomic, multicenter model. Multicenter cancer datasets incorporating common virtual biobank and new methodologic approaches including artificial intelligence, machine learning up to deep learning is the road to the future in oncology launched by this project.

e20604 Background: Oncogene-addicted non-small cell lung cancer (NSCLC) is an heterogeneous group including different molecular alterations. Most single agent (IO) and combination immunotherapy (CT-IO) trials excluded specific oncogene-addicted NSCLCs such as ALK and EGFR; however, it is likely that other oncogene driven tumours were not tested for but included in these trials and could be actually treated with IO in clinical practice. Methods: Among 428 patients treated with IO or CT-IO as first-line treatment, 30 patients were identified to harbour rare molecular alterations (37% non-smokers, 63% former or current smokers): METex14 skipping mutation (n = 10), MET amplifications (n = 4), BRAF other than V600E mutations (n = 7), HER2 exon 20 insertions (n = 5), RET fusions (n = 2), EGFR exon 20 insertions (n = 2). We analyzed progression-free survival (PFS) and overall survival (OS) in patients harbouring these mutations who underwent first-line IO (if PD-L1≥50%; n = 23) or CT-IO (if PD-L1 < 1-49% n = 2 or < 1% n = 5). Results: In whole population median PFS was 5,1 months (95%CI: 2,39-11,29) and median OS 25,5 months (95%CI: 8,80-60,98); 13 patients experienced progressive disease as best response, the disease control rate (DCR) was 56,7%. Patients treated with IO (n = 22) had a mPFS of 4,7 m (95%CI: 2,13-23,48) and a mOS of 29,8 months (95%CI: 10,08-60,98); those treated with CT-IO (n = 8) had a mPFS of 5,1 m (95%CI: 2,29-6,01) and a mOS of 8,5 m (95%CI: 7,68-12,51). Among the most represented molecular alterations, MET alterations (n = 14, 3 treated with CT-IO and 11 with IO) had a mPFS of 5,1 m (95%CI: 1,67-23,90) and a mOS of 25,5 m (95%CI: 8,80-60,72). In particular METex14 skipping mutations had a mPFS of 5,1 m and a mOS of 25,5 m, while MET amplifications had a mPFS of 2,4 m and mOS of 10,3 m. BRAF nonV600E mutations (n = 7, 2 treated with CT-IO and 5 with IO) had a mPFS 5,3 m and mOS not reached. HER2 exon 20 insertions (n = 5, 2 treated with CT-IO and 3 with IO) had a similar mPFS (6,0 m) but a poorer OS outcome (8,5 m). ( Table 1) Conclusions: Our results show a limited effectiveness of both IO alone and CT-IO as first-line treatment in oncogene addicted mNSCLC, even taking into account survival outcomes of upfront CT compared to targeted agents in pivotal trials. [Table: see text]

The advent of immunotherapy has transformed the treatment paradigm for metastatic non-small cell lung cancer (NSCLC). In the past few years, several studies have investigated the potential role of immune checkpoint inhibitors (ICIs) in resectable and unresectable locally advanced disease, achieving remarkable results that led to their approval in clinical practice. However, there is limited evidence on immunotherapy rechallenge after recurrence, with the majority of available knowledge coming from retrospective studies which involve heavily pretreated patients with advanced NSCLC. The recent introduction in the curative setting and the potential regulatory restrictions raise questions about the optimal choice of first-line and subsequent therapies for patients with systemic relapse. The role of immunotherapy readministration in this new scenario needs to be clarified, as well as the identification of patients for whom it is more appropriate, including clinical characteristics, duration of response, switching to other ICIs, reasons for discontinuation and immune-related toxicity. Here, we review literature on rechallenge with immunotherapy, including efficacy, safety profile and potential predictive factors of response.

Aims: This retrospective study aims to identify a possible predictive role of KRAS mutations in non-small-cell lung cancer in response to first-line pembrolizumab, either as monotherapy or combined with chemotherapy. Methods: Patients received pembrolizumab alone (n = 213) or associated with chemotherapy (n = 81). Results: A mutation in the KRAS gene was detected in 27% of patients. In patients on pembrolizumab alone, median progression-free survival in KRAS-mutated cases was longer than in wild-type cases (11.3 vs 4.4 months; p = 0.019), whereas median overall survival did not reach statistical significance (22.1 vs 12.5 months; p = 0.119). Patients receiving chemo-immunotherapy with KRAS-positive tumors had a similar progression-free survival (9.7 vs 7.3 months; p = 0.435); overall survival data were immature. Conclusion: This study suggests a correlation between KRAS status and response to pembrolizumab.

Recently targeted therapy and immunotherapy have been demonstrated to improve survival in non-operable, non-small cell lung cancer (NSCLC) patients. The results of salvage lung resection in patients with initially unresectable advanced NSCLC after immune checkpoint inhibitor (ICI) or Target Therapy (TT) treatment remain limited and unclear. We aimed to define the outcomes of patients undergoing salvage surgery in a real-life setting. A case series study evaluation of clinical data from patients submitted to salvage surgery was performed. Patients included in the study were judged inoperable, according to a multidisciplinary tumor board decision, before being submitted to ICI or TKI treatment. Data were analyzed using Chi-squared, Fisher’s and Wilcoxon rank-sum tests, where appropriate. Eighteen patients were enrolled. Sixty-seven per cent were Stage IIIB and IV. Fifty per cent of cases received TKI treatment, the remaining patients received ICI alone or with chemo- and/or radiotherapy. Twenty-two per cent of cases were scheduled and successfully performed by minimal invasive approach without needing for conversion. Overall, 5 patients (28