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Colorectal cancer (CRC), like other tumor types, is a highly heterogeneous disease. Within the tumor bulk, intra-tumoral heterogeneity is also ascribable to Cancer Stem Cells (CSCs) subpopulation, characterized by high chemoresistance and the unique ability to retain tumorigenic potential, thus associated to tumor recurrence. High dynamic plasticity of CSCs, makes the development of winning therapeutic strategies even more complex to completely eradicate tumor fuel. Rimonabant, originally synthesized as antagonist/inverse agonist of Cannabinoid Receptor 1, is able to inactivate Wnt signaling, both in vitro and in vivo, in CRC models, through inhibition of p300-histone acetyltransferase activity. Since Wnt/β-Catenin pathway is the main player underlying CSCs dynamic, this finding candidates Rimonabant as potential modulator of cancer stemness, in CRC. In this work, using established 3D cultures of primary colon CSCs, taking into account the tumor heterogeneity through monitoring of Wnt activity, we demonstrated that Rimonabant was able to reduces both tumor differentiated cells and colon CSCs proliferation and to control their survival in long term cultures. Interestingly, in ex vivo model of wild type human organoids, retaining both architecture and heterogeneity of original tissue, Rimonabant showed no toxicity against cells from healthy colon epithelium, suggesting its potential selectivity toward cancer cells. Overall, results from this work provided new insights on anti-tumor efficacy of Rimonabant, strongly suggesting that it could be a novel lead compound for CRC treatment.

Introduction: During the recent INTERACTION group congress held on February 16-17, 2024, in Milan, Italy, many aspects of early-stage lung cancer treatment were explored. This review delves into perioperative treatment, a rapidly evolving field with an expanding therapeutic arsenal that includes chemotherapy, target therapy, and immunotherapy. The challenge remains in tailoring treatment strategies to individual patients, identifying patients best suited for surgery versus those necessitating trimodal treatment, particularly in distinguishing surgical candidates from those requiring multimodal approaches and not suitable for surgical approach., Materials and Methods: We conducted a literature review of phase III trials on immunotherapy and target therapy in early-stage non-small cell lung cancer (NSCLC), searching in MEDLINE, EMBASE and LILACS, adding the latest data from the European Society of Medical Oncology (ESMO) 2023 and 2024, American Society of Clinical Oncology (ASCO) 2024, and the World Conference on Lung Cancer (WCLC) 2024 conferences. A guidance on unresolved and controversial issues from the panel has been reported, also highlighting the remaining limitations that warrant further investigation and refinement in this field., Results: Most recent data on early-stage NSCLC have been critically reviewed. The panel emphasized the importance of distinguishing, from the outset in a multidisciplinary setting, patients who are suitable for surgical treatment from those who are not. In this context, the importance of accurate staging at the time of diagnosis was highlighted. A paradigm shifts regarding the timing of molecular NGS DNA and RNA testing is strongly recommended., Conclusion: Decisions regarding perioperative treatment in early-stage lung cancer demand early consideration, involving a multidisciplinary team and require an upfront NGS analysis. Such an approach ensures personalized care aligned with each patient's unique characteristics, optimizing treatment efficacy and overall well-being., Competing Interests: Declaration of Competing Interest None., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background : The treatment landscape for non-small cell lung cancer (NSCLC) has evolved significantly with the advent of immunotherapy. Nonetheless, uncertainty regarding optimal first-line treatments, special populations, and the feasibility of rechallenge remains. This study aims to investigate Italian oncologists' opinions on these aspects through a Delphi Survey. Methods : A steering committee (SC) of six oncologists identified three topics of interest, namely NSCLC (first line) therapeutic choice, NSCLC special populations, and NSCLC immunotherapy rechallenge), and drafted several topic-related statements to be voted in the Delphi Survey by the 61 oncologists forming the Delphi Panel. The survey included two rounds, wherein the experts rated their agreement/disagreement with the statements on a 5-point Likert scale. Consensus was defined as agreement/disagreement by at least 75% of the panel. Results : The SC drafted 69 statements for the first round, of which 16 (23.2%) met the agreement threshold, 5 (7.2%) met the disagreement threshold, and 48 (69.6%) did not reach consensus. The SC revised the latter statements and drafted 37 for the second round. Overall, 5 (13.5%) statements met the agreement threshold, 1 (2.7%) met the disagreement threshold, and 31 (83.8%) did not reach consensus in the second round. Conclusions : The survey showed agreement on the necessity of molecular characterization, mutations, smoke, the role of steroid therapy, and immunotherapy rechallenge, and revealed several areas of uncertainty among Italian oncologists on the use of immunotherapy in NSCLC. Statements-where consensus was not met-can be used to guide future clinical research in resolving the issues.

This review delves into the intricate landscape of pleural mesothelioma (PM), emphasizing the need for nuanced therapeutic strategies. While platinum-based chemotherapy remains a cornerstone, the advent of immune checkpoint inhibitors (ICIs), notably through the Checkmate 743 trial, has reshaped treatment paradigms. Challenges persist due to patient heterogeneity and a lack of specific biomarkers. Targeting genotypic and phenotypic alterations emerges as a promising avenue, demanding precision oncology in this rare disease. CDKN2A loss, prevalent in PM, may respond to CDK4/6 inhibitors. Defects in MMR and HR suggest tailored approaches with ICI or PARP inhibitors, respectively. Ongoing trials explore novel inhibitors and promising targets like mesothelin. Implementing these strategies requires overcoming challenges in patient selection, combination therapies, biomarker identification, and cost considerations. Collaboration is crucial for transforming these insights into impactful clinical interventions, heralding the era of personalized and precision medicine for PM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Immunotherapy represented a turning point for treating extensive small-cell lung cancer (ES-SCLC). Although, many issues remain debated., Methods: A group of Italian medical and radiation oncologists with expertise in managing patients with ES-SCLC developed a list of statements divided in six areas of interest. The Delphi method was used to assess the consensus on the defined list of statements., Results: 32 statements were included in the final list to be voted by the Delphi panel, and 26 reached a consensus on the agreement. A prompt involvement of a multidisciplinary team is a priority to provide an integrated treatment strategy. First-line recommended treatment is immunotherapy in combination with platinum-based chemotherapy and etoposide for four cycles followed by maintenance immunotherapy., Conclusions: While awaiting new data from clinical trials and real-world studies, these recommendations can represent a useful tool to guide the management of ES-SCLC patients in daily practice., Competing Interests: Declaration of Competing Interest Francesco Agustoni received a grant for an advisory role from Roche. Lucia Bonomi received honoraria from Bristol-Myers Squibb/Celgene, MSD Oncology, AstraZeneca, Astellas Pharma, Janssen Oncology; fee for consulting or advisory roles from Janssen Oncology, Ipsen, Roche. Paolo Borghetti received honoraria from AstraZeneca, Roche. Giovanni Luca Ceresoli received fees for speaker engagements from Bristol Myers Squibb, Merck Sharp & Dohme, Novocure, AstraZeneca, Bayer, and Astellas; and fees for advisory roles from Bristol Myers Squibb, Novocure, and AstraZeneca. Andrea Riccardo Filippi received fees as speakers’ bureau from Astra Zeneca, MSD, Roche, Ipsen; fees for advisory role from Astra Zeneca, Roche; and research funding from Astra Zeneca. He also participated (no financial interest) in sponsored research from Astra Zeneca, Roche, MSD. Giovanna Finocchiaro received personal fees for speaker engagements from AstraZeneca and for advisory roles from MSD, and AMGEN. Letizia Gianoncelli received personal fees for speaker engagements from AstraZeneca, Bristol Myers Squibb, MSD, and Roche. Salvatore Grisanti received a fee for an advisory board from Roche. Fabio Pagni received consulting or advisory fees from Lilly, Amgen, Roche, MSD, Novartis, and Janssen. Prof Pagni participated in the paper during his involvement as PI of the Italian MUR Dipartimenti di Eccellenza 2023–2027 (l. 232/2016, art. 1, comma 314 - 337). Claudia Proto received consulting or advisory fees from AstraZeneca, Roche, MSD, BMS, and Janssen; research funding from Roche, AstraZeneca, Pfizer, Celgene, MSD, BMS, Daichii; fees for travel, accommodation, and expenses from AstraZeneca, Roche, and MSD. Erika Rijavec received honoraria from Bristol-Myers Squibb, AstraZeneca MSD, and Roche; advisory board fees from Sanofi; and travel grants from Daichii Sankyo. All other authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Background: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted., Patients and Methods: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method., Results: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy., Conclusion: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various cancers. ICI treatment is associated with the incidence of immune-related adverse events (irAEs) which can affect any organ. Data on irAEs occurrence in relation to sex- differentiation and their association with gender-specific factors are limited., Aims: The primary objective of the G-DEFINER study is to compare the irAEs incidence in female and male patients who undergo ICI treatment. Secondary objectives are: to compare the irAEs incidence in pre- and postmenopausal female patients; to compare the irAEs incidence in female and male patients according to different clinical and gender-related factors (lifestyle, psychosocial, and behavioral factors). Exploratory objectives of the study are to compare and contrast hormonal, gene-expression, SNPs, cytokines, and gut microbiota profiles in relation to irAEs incidence in female and male patients., Methods and Results: The patients are recruited from Fondazione IRCCS Istituto Nazionale dei Tumori, Italy, St Vincent's University Hospital, Ireland, Oslo University Hospital, Norway, and Karolinska Insitutet/Karolinska University Hospital, Sweden. The inclusion of patients was delayed due to the Covid pandemic, leading to a total of 250 patients recruited versus a planned number of 400 patients. Clinical and translational data will be analyzed., Interpretation: The expected outcomes are to improve the management of cancer patients treated with ICIs, leading to more personalized clinical approaches that consider potential toxicity profiles. The real world nature of the trial makes it highly applicable for timely irAEs diagnosis.

Introduction: We evaluated efficacy and safety of cabozantinib plus atezolizumab or cabozantinib alone in advanced NSCLC previously treated with an immune checkpoint inhibitor (ICI)., Methods: COSMIC-021 (NCT03170960) is a phase 1b, multicenter study in advanced solid tumors. This analysis included patients with stage IV non-squamous NSCLC without actionable genomic aberrations in EGFR, ALK, ROS1 , or BRAF - V600E who progressed on one prior ICI and less than or equal to two prior lines of systemic anticancer therapy. Patients received cabozantinib 40 mg orally/day plus atezolizumab 1200 mg intravenously every three weeks (combination cohort) or cabozantinib 60 mg orally/day (single-agent cabozantinib cohort). Primary end point of the combination cohort was objective response rate per Response Evaluation Criteria in Solid Tumors v1.1 by investigator. Outcomes in the single-agent cabozantinib cohort were exploratory., Results: Eighty-one patients assigned to combination therapy and 31 assigned to single-agent cabozantinib received greater than or equal to one dose of study treatment. Median (range) follow-up was 26.1 months (12.1-44.2) and 22.4 months (1.5-29.0), respectively. Objective response rate was 20% (95% confidence interval: 11.7%-30.1%) in combination cohort and 6% (95% confidence interval: 0.8%-21.4%) in single-agent cabozantinib cohort. Treatment-related adverse events (TRAEs) occurred in 86% of patients in the combination cohort and 90% in the single-agent cabozantinib cohort; grade 3/4 TRAEs were 44% and 48%, respectively. There were two grade 5 TRAEs: pneumonitis (n = 1, combination) and gastric ulcer hemorrhage (n = 1, single-agent). Neither PD-L1 expression in tumor cells nor tumor mutation burden correlated with outcomes., Conclusions: Cabozantinib plus atezolizumab demonstrated modest clinical activity and manageable toxicity in advanced NSCLC after progression on prior ICI., Competing Interests: Dr. Neal reported receiving honoraria from Biomedical Learning Institute CME, Clinical Care Options, CME Matter, Medscape CME, MJH Life Sciences CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge CME, Research to Practice CME, Rockpointe CME, Medical Educator Consortium, HMP Education, a consulting or advisory role with AstraZeneca, Blueprint Pharmaceuticals, Calithera Biosciences, D2G Oncology, Exelixis, Genentech, Roche, Jounce Therapeutics, Eli Lilly and Company, Natera, Regeneron, Sanofi, Surface Oncology, Takeda Pharmaceuticals, Turning Point Therapeutics, and receiving institutional research funding from 10.13039/100006483AbbVie, Adaptimmune, Boehringer Ingelheim, 10.13039/100010544Exelixis, 10.13039/100004328Genentech, 10.13039/100004337Roche, GSK, 10.13039/100005565Janssen, 10.13039/100004334Merck, Nektar Therapeutics, 10.13039/100004336Novartis, Takeda Pharmaceuticals. Dr. Armando Santoro reported having a consulting or advisory role with Sanofi, Incyte, receiving honoraria from AbbVie, Amgen, ArQule, AstraZeneca, Bayer, BMS, Celgene, Eisai, Gilead Sciences, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, Servier, Takeda, and participating in a data safety or advisory board with BMS, Servier, Gilead, Pfizer, Eisai, Bayer, MSD. Dr. Maria Gonzalez-Cao reported receiving grants or contracts from Roche, AstraZeneca, and Novartis, honoraria from Bristol Myers Squibb, MSD, AstraZeneca, Novartis, and Pierre Fabre, support for travel, accommodations, and expenses from MSD, AstraZeneca, and Pierre Fabre, and having a leadership or fiduciary role with the Spanish Melanoma Group. Dr. Ryan D. Gentzler reported receiving honoraria from Targeted Oncology, OncLive, Clinical Care Options, Society for Immunotherapy of Cancer, American Society of Clinical Oncology, MedStar Health, Aptitude Health, support for attending meetings from International Association for the Study of Lung Cancer, American Society of Clinical Oncology, Dava Oncology, Tempus, having a consulting or advisory role with AstraZeneca, Daiichi Sankyo, Gilead, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, OncoCyte, Sanofi, Takeda, Merus, Regeneron, receiving institutional research funding from 10.13039/100002429Amgen, Alliance Foundation, 10.13039/100004325AstraZeneca, Big Ten Research Consortium, 10.13039/100002491Bristol Myers Squibb, 10.13039/100010795Chugai, 10.13039/501100022274Daiichi Sankyo, 10.13039/100008130Helsinn Therapeutics, Hoosier Cancer Research Network, 10.13039/100005565Janssen, 10.13039/100016765Jounce Therapeutics, Merck, 10.13039/100016957Mirati Therapeutics, 10.13039/100004319Pfizer, 10.13039/100008199RTI International, Takeda, Dizal, Puma, and having leadership or committee roles with Hoosier Cancer Research Network, ASCO, Journal of Clinical Oncology, NCI Investigational Drug Steering Committee, and International Association for the Study of Lung Cancer. Dr. Jerome Goldschmidt reported receiving honoraria from G1 Therapeutics, and support for travel, accommodations, and expenses from Sara Cannon Research Institute. Dr. Claudia Proto reports receiving honoraria from AstraZeneca, Bristol Myers Squibb, MSD, Roche, Sanofi, having a consulting or advisory role with AstraZeneca, MSD and Roche, institutional research funding from MSD, Lilly, Pfizer, support for travel, accommodations, expenses from AstraZeneca, MSD, and Roche, and is the principal investigator in clinical trials for Janssen, Pfizer, Lilly, Spectrum Pharmaceuticals, Roche, MSD, BMS, and AstraZeneca. Dr. Shiven Patel reported receiving a consulting or advisory role with AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Regeneron, Sanofi, TerSera Therapeutics LLC, Total Health Conferencing, Natera, Takeda, Merck, BMS, and receiving institutional research funding from AstraZeneca, Janssen, Merck, and Takeda. Dr. Sonam Puri reported having an institutional consulting or advisory role with Jazz Pharma, receiving consulting fees from G1 Therapeutics, Pfizer, Bristol-Myers Squibb, receiving honoraria from Aptitude Health, and support for travel, accommodations, and expenses from Dava Oncology. Dr. Stephen V. Liu reported having a consulting or advisory role with AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Catalyst, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech, Roche, Gilead Sciences, Guardant Health, Janssen Oncology, Jazz Pharmaceuticals, Merck, Merus, Mirati, Novartis, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics, receiving institutional research funding from AbbVie, 10.13039/100018529Alkermes, Elevation Oncology, Ellipses, Genentech, Roche, 10.13039/100005564Gilead Sciences, Merck, Merus, Nuvalent, Inc., RAPT Therapeutics, and Turning Point Therapeutics, and participation in a data safety monitoring board or advisory board with Candel Therapeutics. Dr. Erminia Massarelli reported receiving honoraria from AstraZeneca, Merck, Eli Lilly and Company, Takeda Pharmaceuticals, Mirati, and having a consulting or advisory role with Bristol Myers Squibb, Daiichi Sankyo Co., Fusion Therapeutics, Janssen, Eli Lilly and Company, Sanofi, AbbVie, Iovance Therapeutics, and Mirati. Ms. Denise Williamson, Drs. Martin Schwickart, Christian Scheffold, and Svetlana Adrianova are employees of and reported having stock with Exelixis. In addition, Dr. Christian Scheffold reported a patent: Combinations of Cabozantinib and Atezolizumab to Treat Cancer; patent number 11198731. Dr. Enriqueta Felip reported having a consulting or advisory role with AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GlaxoSmithKline, Janssen, Merck Serono, MSD, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point, Daiichi Sankyo, honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, MSD, Peervoice, Pfizer, Sanofi, Takeda, Touch Oncology, and receiving support for travel, accommodations, and expenses from AstraZeneca, Janssen, Roche. The remaining authors declare no conflict of interest., (© 2024 The Authors.)

Background: Specific components of lipid profile seem to differently impact on immune activity against cancer and unraveling their prognostic role in patients with solid cancer treated with immune checkpoint inhibitors (ICIs) is needed., Materials and Methods: We retrospectively collected baseline clinicopathological characteristics including circulating lipid profile (total cholesterol [TC], triglycerides [TG], low-density lipoproteins [LDL], high-density lipoproteins [HDL]) of patients with consecutive solid cancer treated with ICIs, and we investigated their role in predicting clinical outcomes., Results: At a median follow-up of 32.9 months, among 430 enrolled patients, those with TC ≥ 200 mg/dl showed longer median progression-free survival (mPFS; 6.6 vs. 4.7 months, P = .4), although not reaching statistical significance, and significantly longer median overall survival (mOS; 19.4 vs. 10.8 months, P = .02) compared to those with TC < 200 mg/dl. Conversely, patients with TG ≥150 mg/dl displayed shorter PFS (3.4 vs. 5.1 months, P = .02) and OS (7.1 vs. 12.9 months, P = .009) compared to those with TG <150 mg/dl. TC and TG were then combined in a "LIPID score" identifying three subgroups: good-risk (GR) (TC ≥200 mg/dl and TG <150 mg/dl), intermediate-risk (IR) (TC <200 mg/dl and TG <150 mg/dl or TC ≥200 mg/dl and TG ≥150 mg/dl) and poor-risk (PR) (TC <200 mg/dl and TG ≥150 mg/dl). The mPFS of GR, IR, and PR groups was 7.8, 4.3, and 2.5 months, respectively (P = .005); mOS of GR, IR, and PR was 20.4, 12.4, and 5.3 months, respectively (P < .001). At multivariable analysis, the PR profile represented an independent poor prognostic factor for both PFS and OS., Conclusions: We developed a lipid score that defined subgroups of patients with cancer who differently benefit from ICIs. Further mechanistic insights are warranted to clarify the prognostic and predictive role of lipid profile components in patients treated with ICIs., (© The Author(s) 2023. Published by Oxford University Press.)

Background: The widespread use of immune checkpoint inhibitors (ICIs) has revolutionised treatment of multiple cancer types. However, selecting patients who may benefit from ICI remains challenging. Artificial intelligence (AI) approaches allow exploitation of high-dimension oncological data in research and development of precision immuno-oncology., Materials and Methods: We conducted a systematic literature review of peer-reviewed original articles studying the ICI efficacy prediction in cancer patients across five data modalities: genomics (including genomics, transcriptomics, and epigenomics), radiomics, digital pathology (pathomics), and real-world and multimodality data., Results: A total of 90 studies were included in this systematic review, with 80% published in 2021-2022. Among them, 37 studies included genomic, 20 radiomic, 8 pathomic, 20 real-world, and 5 multimodal data. Standard machine learning (ML) methods were used in 72% of studies, deep learning (DL) methods in 22%, and both in 6%. The most frequently studied cancer type was non-small-cell lung cancer (36%), followed by melanoma (16%), while 25% included pan-cancer studies. No prospective study design incorporated AI-based methodologies from the outset; rather, all implemented AI as a post hoc analysis. Novel biomarkers for ICI in radiomics and pathomics were identified using AI approaches, and molecular biomarkers have expanded past genomics into transcriptomics and epigenomics. Finally, complex algorithms and new types of AI-based markers, such as meta-biomarkers, are emerging by integrating multimodal/multi-omics data., Conclusion: AI-based methods have expanded the horizon for biomarker discovery, demonstrating the power of integrating multimodal data from existing datasets to discover new meta-biomarkers. While most of the included studies showed promise for AI-based prediction of benefit from immunotherapy, none provided high-level evidence for immediate practice change. A priori planned prospective trial designs are needed to cover all lifecycle steps of these software biomarkers, from development and validation to integration into clinical practice., Competing Interests: Disclosure AP declares training of personnel role for AstraZeneca and Italfarma; advisory board role for BMS, travel grant from Janssen; and speaker’s engagement for Roche. FT declares full or part-time employment with Politecnico di Milano as researcher and lecturer for high-level education; and as cofounder of MLcube. CG declares advisory board role for Amgen, Roche, Sanofi, Takeda; speaker’s engagement from AstraZeneca, Bristol Myers Squibb, Eli Lilly, Merck-Sharp-Dohme, and Novartis; institutional funding from AstraZeneca and Bristol Myers Squibb; institutional research grant from Italian Ministry of Health; clinical trials PI for AstraZeneca and Roche; and non-remunerated activities as member or AIOM, AIOT, ASCO, FONICAP, IASLC, and ISLB. SER declares speaker’s engagement from Amgen, BMS, Astellas, and GSK; writer’s engagement from BMS and Amgen; and travel and accommodation from Janssen and MSD. LC-B declares full time employment with ESMO as Scientific and Medical division Fellow. JD declares consultant role for MJH Life Sciences at ASCO Clinical Congress Consultants at ASCO 2022. ATP declares advisory board role for Abbvie, Elevar, Prelude Therapeutics, and Privo; institutional research grant from Abbvie and Kura; and non-renumerated activity as PI for Adenoid Cystic Carcinoma Research Foundation and Cancer Research Foundation. GLR declares advisory board role for AstraZeneca, BMS, MSD, Novartis, Pfizer, Roche, and Sanofi; speaker’s engagement from Italfarnaco; institutional funding as local PI for Amgen, AstraZeneca, BMS, Celgene, GSK, MSD, Novartis, Roche and Sanofi. CP declares personal fees from Italfarmaco, AstraZeneca, BMS, Merck Sharp and Dohme, and Janssen; and institutional funding from Novartis. ST declares speaker’s engagement from IDEA Pharma, Merck, MSD, Roche, and Ventana; institutional funding from Andy Quick Charitable fund, Complete genomics, CRUK, CRUK training and career development board, CRUK Welcome Trust, Harry J Lloyd Charitable Trust Career Development Award, NIHR, RMH/ICR/BRC/Imperial AHSC/Faculty of Medicine, Rosetrees Trust, The Francis Crick Institute, The Robert McAlpine Foundation, and Ventana. MK declares advisory board role for Bayer, MSD, Pierre Fabre, Servier; speaker’s engagement for BMS, Merck; institutional funding from Amgen, BMS, Merck, Nordic Farma, Novartis, Pierre Fabre, Servier; institutional research grant from Bayer, Bristol Myers Squibb, Personal Genomics Diagnostics, Pierre Fabre, Roche, Servier, Sirtex; trial chair for Servier; non-remunerated activities for Leadership Role for Dutch Colorectal Cancer Group and ESMO; advisory role for KWF, Patient representative organization (Kanker.nl), ZiNNL; and non-remunerated activity as ESMO faculty member. SD declares advisory board role for AstraZeneca, Besins Healthcare, Cellectis, Elsan, Isis/Servier, Novartis, Orion, Pierre Fabre, Rappta, Sanofi; speaker’s engagement for AstraZeneca, Exact Sciences, Gilead, Lilly, MSD, Pfizer, Seagen; institutional funding as steering committee member for AstraZeneca, BMS, Pfizer, Puma, Sanofi, Roche Genentech; institutional funding as local PI for Orion; institutional funding as coordinating PI for Taiho; institutional funding from GE; non-remunerated activity as PI for European Commission; and non-remunerated activity as Board of Directors member for SFSPM. JNK declares advisory board role for DoMore Diagnostics, Owkin, and Panakeia; and speaker’s engagement from Eisai, Fresenius, and MSD. FGMDeB declares speaker’s engagement from Ambrosetti, Amgen, BMS, Dephaforum, ESO, Healthcare Research & Pharmacoepidemiology, Incyte, Merck Group, MSD, Nadirex, Pfizer, Roche, Sanofi, Seagen, and Servier; consultation/advisory role from Mattioli 1885, AstraZeneca, BMS, EMD Serono, Incyte, Menarini, MSD, NMS Nerviano Medical Science, Novartis, Pierre Fabre, Roche, Sanofi, and Taiho; funding as coordinating PI from Basilea Pharmaceutica International AG, BMS, DAICHI SANKIO Dev. Limited, Exelixis Inc, F. Hoffman-LaRoche Ltd, Ignyta Operating INC, IQVIA, Janssen-Cilag International NV, Kymab, LOXO Oncology Incorporated, MedImmune LCC, Merck KGaA, Merck Sharp & Dohme Spa, MSD, Novartis, Pfizer, and Tesaro; and think tank funding from MCCann Health. MCG declares speaker’s engagement from AstraZeneca, ecancer, GrupoPacifico-Secretaria Tecnica ICAPEM/AstraZeneca, Medscape, MSD, MSD Italia, S.O.S S.r.l, WebMD, WebMD Oncology/Takeda; consultation/advisory role from AstraZeneca/MedImmune, Daiichi Sankyo, AstraZeneca Poland, AstraZeneca UK, Bayer Healthcare Pharmaceuticals, Blueprint Medicines, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Incyte, Mirati Therapeutics, MSD, Pfizer, Regeneron Pharmaceuticals, Roche, Sanofi/Prex, Sanofi Genzyme corporation, Seagen International GmbH, and Takeda; institutional funding as local PI for Phase III studies from Amgen, AstraZeneca, Bluprint, BMS, GlaxoSmithkline, Incyte Corporation, IPSEN Bioscience, MedImmune LCC, Novartis, Roche, and Sanofi; institutional funding as local PI for Phase II studies from AstraZeneca, Celgene Corporation, Daiichi Sankyo Development, MedImmune LCC, Merck KGaA, Merck Serono, Spectrum Pharmaceuticals, and Turning Point Therapeutics; institutional funding as local PI for Phase I studies from Exelixis Inc., Janssen; institutional funding as local PI from Bayer, Janssen, Merck, Pfizer, Otsuka Pharmaceutical Italy; institutional funding as Coordinating PI from AstraZeneca, MSD; steering committee member of the MK-3475 KN671 Steering Committee (KEYNOTE-671) from MSD, MK-3475 KN671 Steering Committee from MSD, Steering Committee ML41118 from Roche, and steering committee of Pfizer Global Lung Cancer Educational Programme; personal financial interests as PACIFIC-R Scientific Committee from AstraZeneca, PACIFIC-R Global Scientific Committee from AstraZeneca, Pacific 6 International Coordinating Investigator from AstraZeneca, steering Committee member and Co-chair at the AstraZeneca Lung Cancer Summit 2019, GSK-Garassino-ZEAL Steering Committee 2020-23, GSK Lung Cancer Global Council, Jannesen Scientific Advisory Board and Therapeutic Area Steering Committee Meeting on Lung Cancer, Seattle Genetics Lung Cancer Platform Study; travel, accommodations and expenses from AstraZeneca, Pfizer, and Roche; non-remunerated activities as principal investigator of AO Spedali Civili Brescia, Eli Lilly Studio TYME trial, European Thoracic Oncology Platform (ETOP) phase III trial, GOIRC Studio CHANCE trial, GOIRC RAME trial, GUSTAVE-ROUSSY PARIGI LIPI TRIAL, Istituto dei Tumori Pascale MILES 5 trial, Istituto dei Tumori Pascale IND227 trial, Istituto dei Tumori Pascale Beverly trial, Istituto Nazionale dei Tumori Progetto Timoma trial, Istituto Nazionale dei Tumori APOLLO trial, Istituto Nazionale dei Tumori Bando finalizzata Mesotelioma trial, Istituto Nazionale dei Tumori POST-ALK trial, Istituto Nazionale dei Tumori TERAVOLT trial, Istituto Nazionale dei Tumori FAME trial, MSD People, Pfizer STYLE trial, and Sant’Orsola Malpighi Creta trial; non-remunerated activities as member of AIOM, AIOT, ASCO, EMA Scientific Advisory Group, ESMO, IPOP, TUTOR, WCLC, Women for Oncology Italy; and non-remunerated activities as Scientific Programme Committee of AACR. GP declares full time employment from ESMO. ALGP declares personal financial interests for stocks/shares as cofounder of Agade s.r.l. and AllyArm s.r.l; institutional financial interests for co-funding of the Professorship Chair by Associazione Univerlecco and Congregazione Suore Infermiere dell’Addolorata; institutional financial interests for licensing/royalties as co-inventor of Patent No. 10201900000848 (Load compensation device, registered with Politecnico di Milano, surrendered in January 2023 with a royalty return plan), Patent No. 102018000006950 (System for detection and kinematic monitoring of body movements in water, and relative method, registered with Politecnico di Milano and Fondazione per la Ricerca Scientifica Termale; PCT/EP2019/067618) and Patent No. 102017000027918 (Device for controlled assistance of the grip; PCT/IB2018/051652); and non-financial interests as a member of the International Conference of Rehabilitation Robotics, member of the Institute of Electrical and Electronics Engineers (IEEE), IEEE Robotics and Automation Society, IEEE Engineering in Medicine and Biology Society and IEEE Women in Engineering. All other authors have declared no conflicts of interest., (Copyright © 2023 European Society for Medical Oncology. All rights reserved.)

Patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor gene ( EGFR ) Exon 20 insertions (Exon20ins) at the second line and beyond (2L+) have an unmet need for new treatment. Amivantamab, a bispecific EGFR- and MET-targeted antibody, demonstrated efficacy in this setting in the phase 1b, open-label CHRYSALIS trial (NCT02609776). The primary objective was to compare the efficacy of amivantamab to the choices made by real-world physicians (RWPC) using an external control cohort from the real-world evidence (RWE) chart review study, CATERPILLAR-RWE. Adjustment was conducted to address differences in prognostic variables between cohorts using inverse probability weighting (IPW) and covariate adjustments based on multivariable regression. In total, 114 patients from CHRYSALIS were compared for 55 lines of therapy from CATERPILLAR-RWE. Baseline characteristics were comparable between the amivantamab and IPW-weighted RWPC cohorts. For amivantamab versus RWPC using IPW adjustment, the response rate ratio for the overall response was 2.14 ( p = 0.0181), and the progression-free survival (PFS), time-to-next-treatment (TTNT) and overall survival (OS) hazard ratios (HRs) were 0.42 ( p < 0.0001), 0.47 ( p = 0.0063) and 0.48 ( p = 0.0207), respectively. These analyses provide evidence of clinical and statistical benefits across multiple outcomes and adjustment methods, of amivantamab in platinum pre-treated patients with advanced NSCLC harboring EGFR Exon20ins. These results confirm earlier comparisons versus pooled national registry data.

Importance: After the PACIFIC trial, concurrent chemo-radiotherapy followed by consolidation therapy with durvalumab for 1 year (limited to PD-L1 tumour proportion score ≥ 1% in the EMA region) is the firmly established standard of care treatment for unresectable NSCLC patients. Several relevant questions are emerging with the growing use of this approach, posing novel challenges in clinical practice. Treatment of oncogene-addicted NSCLCs, management of mediastinal disease recurrence after surgery and the optimal management of patients progressing during or after durvalumab are now some of the most clinically relevant issues., Observations: Patients with unresectable NSCLC harbouring EGFR and HER2 mutations or ALK/ROS1/RET /NTRK1,2,3 rearrangements are unresponsive to immunotherapy. Importance of knowing the tumour genotyping (NGS, preferable DNA and RNA) from the earliest stages of NSCLC, also for the possible use of immunotherapy both in the adjuvant and perioperative setting. In case of mediastinal disease recurrence after surgery, re-biopsy is essential to re-determine the histological and biological characteristics of the disease and the distinction of recurrence in curable and non-curable disease is of pivotal important for the optimal management of subsequent treatments., Conclusions and Relevance: Treatment of stage III NSCLC has always been controversial and challenging: Multidisciplinary approach is mandatory and defining resectability is a critical issue. Chemo-radiotherapy followed by maintenance Durvalumab is now the standard of treatment. Herein, we provide a comprehensive overview of the key challenges and open questions that we are currently facing in clinical practice, in unresectable stage III and in early-stage NSCLC, identifying the knowledge gaps and the possible solutions., Competing Interests: Declaration of Competing Interest Dr Catania reports advisory board role for AstraZeneca and compensated activity for projects for AstraZeneca. Dr Russo reports advisory board role for AstraZeneca, BMS, Novartis, Pfizer, and MSD, speaker bureau for AstraZeneca and BMS, and compensated activity for editorial projects for AstraZeneca, MSD, Novartis, and Roche., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Thymic malignancies are rare tumors with few therapeutic options. The STYLE trial was aimed to evaluate activity and safety of sunitinib in advanced or recurrent type B3 thymoma (T) and thymic carcinoma (TC)., Methods: In this multicenter, Simon 2 stages, phase 2 trial, patients with pretreated T or TC were enrolled in two cohorts and assessed separately. Sunitinib was administered 50 mg daily for 4 weeks, followed by a 2-week rest period (schedule 4/2), until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Progression-free survival, overall survival, disease control rate and safety were secondary endpoints., Results: From March 2017 to January 2022, 12 patients with T and 32 patients with TC were enrolled. At stage 1, ORR was 0% (90% confidence interval [CI]: 0.0-22.1) in T and 16.7% (90% CI: 3.1-43.8) in TC, so the T cohort was closed. At stage 2, the primary endpoint was met for TC with ORR of 21.7% (90% CI: 9.0%-40.4%). In the intention-to-treat analysis, disease control rate was 91.7% (95% CI: 61.5%-99.8%) in Ts and 89.3% (95% CI: 71.8%-97.7%) in TCs. Median progression-free survival was 7.7 months (95% CI: 2.4-45.5) in Ts and 8.8 months (95% CI: 5.3-11.1) in TCs; median overall survival was 47.9 months (95% CI: 4.5-not reached) in Ts and 27.8 months (95% CI: 13.2-53.2) in TCs. Adverse events occurred in 91.7% Ts and 93.5% TCs. Grade 3 or greater treatment-related adverse events were reported in 25.0% Ts and 51.6% TCs., Conclusions: This trial confirms the activity of sunitinib in patients with TC, supporting its use as a second-line treatment, albeit with potential toxicity that requires dose adjustment., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Chemoimmunotherapy represents the standard of care for patients with advanced non-small cell lung cancer (NSCLC) and programmed death-ligand 1 (PD-L1) <50%. Although single-agent pembrolizumab has also demonstrated some activity in this setting, no reliable biomarkers yet exist for selecting patients likely to respond to single-agent immunotherapy. The main purpose of the study was to identify potential new biomarkers associated with progression-free-survival (PFS) within a multiomics analysis., Methods: PEOPLE (NTC03447678) was a prospective phase II trial evaluating first-line pembrolizumab in patients with advanced EGFR and ALK wild type treatment-naïve NSCLC with PD-L1 <50%. Circulating immune profiling was performed by determination of absolute cell counts with multiparametric flow cytometry on freshly isolated whole blood samples at baseline and at first radiological evaluation. Gene expression profiling was performed using nCounter PanCancer IO 360 Panel (NanoString) on baseline tissue. Gut bacterial taxonomic abundance was obtained by shotgun metagenomic sequencing of stool samples at baseline. Omics data were analyzed with sequential univariate Cox proportional hazards regression predicting PFS, with Benjamini-Hochberg multiple comparisons correction. Biological features significant with univariate analysis were analyzed with multivariate least absolute shrinkage and selection operator (LASSO)., Results: From May 2018 to October 2020, 65 patients were enrolled. Median follow-up and PFS were 26.4 and 2.9 months, respectively. LASSO integration analysis, with an optimal lambda of 0.28, showed that peripheral blood natural killer cells/CD56dimCD16+ (HR 0.56, 0.41-0.76, p=0.006) abundance at baseline and non-classical CD14dimCD16+monocytes (HR 0.52, 0.36-0.75, p=0.004), eosinophils (CD15+CD16-) (HR 0.62, 0.44-0.89, p=0.03) and lymphocytes (HR 0.32, 0.19-0.56, p=0.001) after first radiologic evaluation correlated with favorable PFS as well as high baseline expression levels of CD244 (HR 0.74, 0.62-0.87, p=0.05) protein tyrosine phosphatase receptor type C (HR 0.55, 0.38-0.81, p=0.098) and killer cell lectin like receptor B1 (HR 0.76, 0.66-0.89, p=0.05). Interferon-responsive factor 9 and cartilage oligomeric matrix protein genes correlated with unfavorable PFS (HR 3.03, 1.52-6.02, p 0.08 and HR 1.22, 1.08-1.37, p=0.06, corrected). No microbiome features were selected., Conclusions: This multiomics approach was able to identify immune cell subsets and expression levels of genes associated to PFS in patients with PD-L1 <50% NSCLC treated with first-line pembrolizumab. These preliminary data will be confirmed in the larger multicentric international I3LUNG trial (NCT05537922)., Trial Registration Number: 2017-002841-31., Competing Interests: Competing interests: GLR provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom received honoraria or education grants: Merck Sharp and Dohme, Takeda, Amgen, Eli Lilly, BMS, Roche, Italfarmaco, Novartis, Sanofi, Pfizer and AstraZeneca. AP declares personal fees from AstraZeneca, Italfarmaco, Roche, BMS. RF declares advisory role from Merck Sharp and Dohme. FDB provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom received honoraria or education grants: Amgen, AstraZeneca, Boehringer-Ingelheim, BMS, Eli Lilly, F. Hoffmann-La Roche, Ignyta, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer.CP declares personal fees from Italfarmaco, AstraZeneca, BMS and Merck Sharp and Dohme.MCG declares personal financial interests with the following organizations: AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati, Daiichi Sankyo, Regeneron, Merck, Ose Immuno Therapeutics, Blueprint, Jansenn, Sanofi; she also declares Institutional financial interests with the following organizations: Eli Lilly, MSD, Pfizer (MISP); AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Ignyta, Incyte, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine, Glaxo Smith Kline GSK, Spectrum pharmaceuticals., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Artificial Intelligence (AI) methods are being increasingly investigated as a means to generate predictive models applicable in the clinical practice. In this study, we developed a model to predict the efficacy of immunotherapy (IO) in patients with advanced non-small cell lung cancer (NSCLC) using eXplainable AI (XAI) Machine Learning (ML) methods., Methods: We prospectively collected real-world data from patients with an advanced NSCLC condition receiving immune-checkpoint inhibitors (ICIs) either as a single agent or in combination with chemotherapy. With regards to six different outcomes - Disease Control Rate (DCR), Objective Response Rate (ORR), 6 and 24-month Overall Survival (OS6 and OS24), 3-months Progression-Free Survival (PFS3) and Time to Treatment Failure (TTF3) - we evaluated five different classification ML models: CatBoost (CB), Logistic Regression (LR), Neural Network (NN), Random Forest (RF) and Support Vector Machine (SVM). We used the Shapley Additive Explanation (SHAP) values to explain model predictions., Results: Of 480 patients included in the study 407 received immunotherapy and 73 chemo- and immunotherapy. From all the ML models, CB performed the best for OS6 and TTF3, (accuracy 0.83 and 0.81, respectively). CB and LR reached accuracy of 0.75 and 0.73 for the outcome DCR. SHAP for CB demonstrated that the feature that strongly influences models' prediction for all three outcomes was Neutrophil to Lymphocyte Ratio (NLR). Performance Status (ECOG-PS) was an important feature for the outcomes OS6 and TTF3, while PD-L1, Line of IO and chemo-immunotherapy appeared to be more important in predicting DCR., Conclusions: In this study we developed a ML algorithm based on real-world data, explained by SHAP techniques, and able to accurately predict the efficacy of immunotherapy in sets of NSCLC patients., Competing Interests: MCG: declares personal financial interests with the following organizations: AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, Roche, Takeda. FB declares: Consultant Advisory Board for Ignyta, BMS, Daiichi Sankyo, Pfizer, Octimet Oncology, Incyte, Teofarma, Pierre Fabre, Roche, EMD Serono, Sanofi, NMS Nerviano Medical Science, Pharm Research Associated U.K Ltd; as a Speaker BMS, Roche, MSD, Ignyta, Bayer, ACCMED, Dephaforum S.r.l., Nadirex, Merck, Biotechspert Ltd, PriME Oncology, Pfizer, Servier, Celgene, Tesaro, Loxo Oncology Inc., Sanofi, Healthcare Research & Pharmacoepidemiology, as P.I for Novartis, Roche, BMS, Celgene, Incyte, NMS, Merck KGAA, Kymab, Pfizer, Tesaro, MSD. AP declares personal fees from Roche, AstraZeneca and BMS outside the submitted work. CP declares personal fees from BMS and MSD, outside the submitted work. G.LR. declares personal fees from BMS, MSD and Astra Zeneca outside the submitted work. DS declares personal fees from AstraZeneca, Boehringer Ingelheim and BMS, outside the submitted work. DS: Consulting, advisory role: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Sanofi. Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Roche, Merck Sharp & Dohme. Principal Investigator in clinical trial sponsored by Bristol-Myers Squibb, Merck Sharp & Dohme, Eli Lilly. Travel, Accommodations: AstraZeneca, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer. DS consulting, advisory role: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Sanofi. Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Roche, Merck Sharp & Dohme. Principal Investigator in clinical trial sponsored by Bristol-Myers Squibb, Merck Sharp & Dohme, Eli Lilly. Travel, Accommodations: AstraZeneca, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Prelaj, Galli, Miskovic, Pesenti, Viscardi, Pedica, Mazzeo, Bottiglieri, Provenzano, Spagnoletti, Marinacci, De Toma, Proto, Ferrara, Brambilla, Occhipinti, Manglaviti, Galli, Signorelli, Giani, Beninato, Pircher, Rametta, Kosta, Zanitti, Di Mauro, Rinaldi, Di Gregorio, Antonia, Garassino, de Braud, Restelli, Lo Russo, Ganzinelli, Trovò and Pedrocchi.)

PD-L1 in tumor cells is the only used biomarker for anti PD1/PD-L1 immune-checkpoints inhibitors (ICI) in Non Small Cell Lung Cancer (NSCLC) patients. However, this parameter is inaccurate to predict response, especially in patients with low tumor PD-L1. Here, we evaluated circulating EVs as possible biomarkers for ICI in advanced NSCLC patients with low tumoral PD-L1. EVs were isolated from plasma of 64 PD-L1 low, ICI-treated NSCLC patients, classified either as responders (R; complete or partial response by RECIST 1.1) or non-responders (NR). EVs were characterized following MISEV guidelines and by flow cytometry. T cells from healthy donors were triggered in vitro using patients' EVs. Unsupervised statistical approach was applied to correlate EVs' and patients' features to clinical response. R-EVs showed higher levels of tetraspanins (CD9, CD81, CD63) than NR-EVs, significantly associated to better overall response rate (ORR). In multivariable analysis CD81-EVs correlated with ORR. Unsupervised analysis revealed a cluster of variables on EVs, including tetraspanins, significantly associated with ORR and improved survival. R-EVs expressed more costimulatory molecules than NR-EVs although both increased T cell proliferation and partially, activation. Tetraspanins levels on EVs could represent promising biomarkers for ICI response in NSCLC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Signorelli, Ghidotti, Proto, Brambilla, De Toma, Ferrara, Galli, Ganzinelli, Lorusso, Prelaj, Occhipinti, Viscardi, Capizzuto, Pontis, Petraroia, Ferretti, Colombo, Torri, Sozzi, Garassino, Jachetti and Fortunato.)

Introduction: Adding bevacizumab to erlotinib prolonged progression-free survival (PFS) of patients with EGFR-mutated advanced NSCLC in the Japanese JO25567 trial, but limited data were available in non-Asian patients. BEVERLY is an Italian, multicenter, randomized, phase 3 investigating the addition of bevacizumab to erlotinib as first-line treatment of advanced EGFR-mutated NSCLC., Methods: Eligible patients were randomized 1:1 to erlotinib plus bevacizumab or erlotinib alone. Investigator-assessed PFS and blinded independent centrally reviewed PFS were coprimary end points. With 80% power in detecting a 0.60 hazard ratio and two-sided α error of 0.05, 126 events of 160 patients were needed. The trial was registered as NCT02633189 and EudraCT 2015-002235-17., Results: From April 11, 2016, to February 27, 2019, a total of 160 patients were randomized to erlotinib plus bevacizumab (80) or erlotinib alone (80). At a median follow-up of 36.3 months, median investigator-assessed PFS was 15.4 months (95% confidence interval [CI]: 12.2-18.6) with erlotinib plus bevacizumab and 9.6 months (95% CI: 8.2-10.6) with erlotinib alone (hazard ratio = 0.66, 95% CI: 0.47-0.92). Blinded independent centrally reviewed PFS analysis confirmed this result. A statistically significant interaction with treatment effect was found for smoking habit (p = 0.0323), with PFS prolongation being clinically significant only among current or previous smokers. Hypertension (grade ≥3: 24% versus 5%), skin rash (grade ≥ 3: 31% versus 14%), thromboembolic events (any grade: 11% versus 4%), and proteinuria (any grade: 23% versus 6%) were more frequent with the combination., Conclusions: The addition of bevacizumab to first-line erlotinib prolonged PFS in Italian patients with EGFR-mutated NSCLC; toxicity was increased with the combination but without unexpected safety issues., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Clinical and laboratory biomarkers in patients with advanced non-small-cell lung cancer (aNSCLC) receiving chemo-immunotherapy (CIT) are still poorly explored. Materials & methods: All consecutive aNSCLC patients who received at least one cycle of first-line CIT were enrolled. The impact of several clinical and laboratory biomarkers on outcomes was evaluated through Cox proportional hazard models. Results: Higher neutrophil-to-lymphocyte ratio was shown to be an independent prognostic biomarker of both worse progression-free survival and worse overall survival. The EPSILoN score was able to divide patients into three different prognostic groups, with a median overall survival of 73.2, 45.6 and 8.6 months for the favorable, intermediate and poor groups, respectively. Conclusion: The neutrophil-to-lymphocyte ratio and EPSILoN score were shown to have a prognostic value in aNSCLC patients treated with CIT.

Among the several next-generation tyrosine kinase inhibitors (TKIs) tested against uncommon EFGR alterations, poziotinib has been demonstrated to be a powerful agent for metastatic non-small-cell lung cancer (mNSCLC) with aberrations in HER2 exon 20, and FDA approval is being sought in the previously-treated population. Poziotinib has also shown activity in mNSCLC with aberrations in EGFR exon 20. Herein, we report the first published case of a patient affected by mNSCLC harbouring an EGFR exon 20 insertion (EGFRex20ins) mutation who achieved a complete response (CR) under treatment with poziotinib as part of the ZENITH20 trial. In January 2021, a former smoker 62-year-old female patient was diagnosed with relapse, after two surgeries and post-operative chemotherapy of mNSCLC, at liver and retroperitoneal nodes. Given the identification by Next Generation Sequencing (NGS) of EGFRex20ins mutation, she was enrolled in ZENITH20-cohort 5 trial, a phase 2 multicentre study aimed to assess the efficacy and safety of poziotinib in patients with EGFR or HER2 exon 20 insertion mutations. Poziotinib as first-line systemic therapy for metastatic disease was initiated at the end of January 2021 and administrated at the initial dosage of 8 mg orally twice daily (BID). The most common side effects from the beginning of the treatment included alopecia, macular skin rash, diarrhoea, xerostomia, and conjunctivitis. Due to these adverse events, poziotinib was discontinued during the first 3 months and then reduced to 6 mg orally BID in April 2021. After the dose de-escalation, the adverse events ameliorated, and the patient better tolerated the treatment without further interruption. Since the first reevaluation (after 4 weeks of therapy), the treatment with poziotinib resulted to be remarkably effective, with a partial response (PR) subsequently confirmed in May and July 2021. Then, in October 2021, a CT scan confirmed a CR, maintained with good tolerance at the last reevaluation in February 2022. Treatment is still ongoing at the same dosage. In this case, poziotinib has represented a successful and well-tolerated first-line treatment alternative to chemotherapy in this patient with EGFR exon 20 insertion mutated mNSCLC., Competing Interests: AP declares personal fees from Roche, AstraZeneca and BMS outside the submitted work. GL declares personal fees from BMS, MSD and Astra Zeneca outside the submitted work. CP declares personal fees from BMS and MSD, outside the submitted work. GB declares employment and stock ownership at Spectrum Pharmaceuticals, Inc. RW was employed by Spectrum Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Prelaj, Bottiglieri, Bhat, Washington, Calareso, Greco, Ferrara, Brambilla, De Toma, Occhipinti, Manglaviti, Soro, Ganzinelli, Lo Russo and Proto.)

Treatment of stage III non-small cell lung cancer (NSCLC) has traditionally been controversial and challenging: multidisciplinary approach is mandatory and defining resectability is a critical issue; furthermore, patients are often frail due to age or comorbidities. After PACIFIC trial publication, a new therapeutic path has been defined for patients with unresectable NSCLC, with a prominent prognostic advantage. A trimodality treatment, with chemo-radiotherapy followed by maintenance durvalumab is now the standard of care, recommended by international guidelines. However, despite an impressive activity, the use of consolidative immunotherapy after concurrent chemoradiotherapy is highly debated in some clinically-relevant situations, including patients harboring EGFR mutations, older and/or frail patients not suitable for combined treatment, PD-L1 tumor expression. Here we report an expert virtual Italian meeting summary, where six medical oncologists and six radiation oncologists discussed all these aspects trying to underline the critical aspects and to find the possible clinical solutions., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Tumour testing of the BRCA1/2 genes is routinely performed in patients with different cancer histological subtypes. To accurately identify patients with tumour-detected germline pathogenic variants (PVs) is a relevant issue currently under investigation. This study aims at evaluating the performance of the tumour-to-germline diagnostic flowchart model defined at our Institutional Molecular Tumour Board (MTB). Results from tumour BRCA sequencing of 641 consecutive unselected cancer patients were discussed during weekly MTB meetings with the early involvement of clinical geneticists for appropriate referral to genetic counselling. The overall tumour detection rate of BRCA1/2 PVs was 8.7% (56/641), ranging from 24.4% (31/127) in high-grade ovarian cancer to 3.9% (12/304) in tumours not associated with germline BRCA1/2 PVs. Thirty-seven patients with PVs (66%) were evaluated by a clinical geneticist, and in 24 of them (64.9%), germline testing confirmed the presence of the PV in blood. Nine of these patients (37.5%) were not eligible for germline testing according to the criteria in use at our institution. Cascade testing was subsequently performed on 18 relatives. The tumour-to-germline diagnostic pipeline, developed in the framework of our institutional MTB, compared with guideline-based germline testing following genetic counselling, proved to be effective in identifying a higher number of germline BRCA PVs carriers., Competing Interests: FB: Consultant Advisory Board: Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, MSD, Novartis, Incyte, BMS, Menarini. Speaker: BMS, Healthcare Research & Pharmacoepidemiology, Merck Group, ACCMED, Nadirex, MSD, Pfizer, Servier, Sanofi, Roche, AMGEN, Incyte, Dephaforum. Principal Investigator for Novartis, F.Hoffmann-LaRoche Ltd, BMS, Ignyta Operating INC, Merck Sharp & Dohme Spa, Kymab, Pfizer, Tesaro, MSD, MedImmune LCC, Exelixis Inc., LOXO Oncology Incorporated, DAICHI SANKIO Dev. Limited, Basilea Pharmaceutica International AG, Janssen-Cilag International NV, Merck KGAA MN: Travel expenses from Celgene, speaker honorarium from Accademia della Medicina and consultant honoraria from EMD Serono, Basilea Pharmaceutica, Incyte and MSD Italia. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Azzollini, Vingiani, Agnelli, Tamborini, Perrone, Conca, Capone, Busico, Peissel, Rosina, Ducceschi, Mantiero, Lopez, Raspagliesi, Niger, Duca, Damian, Proto, de Braud, Pruneri and Manoukian.)

(1) Background: In advanced non-small cell lung cancer (aNSCLC), programmed death ligand 1 (PD-L1) remains the only biomarker for candidate patients to immunotherapy (IO). This study aimed at using artificial intelligence (AI) and machine learning (ML) tools to improve response and efficacy predictions in aNSCLC patients treated with IO. (2) Methods: Real world data and the blood microRNA signature classifier (MSC) were used. Patients were divided into responders (R) and non-responders (NR) to determine if the overall survival of the patients was likely to be shorter or longer than 24 months from baseline IO. (3) Results: One-hundred sixty-four out of 200 patients (i.e., only those ones with PD-L1 data available) were considered in the model, 73 (44.5%) were R and 91 (55.5%) NR. Overall, the best model was the linear regression (RL) and included 5 features. The model predicting R/NR of patients achieved accuracy ACC = 0.756, F1 score F1 = 0.722, and area under the ROC curve AUC = 0.82. LR was also the best-performing model in predicting patients with long survival (24 months OS), achieving ACC = 0.839, F1 = 0.908, and AUC = 0.87. (4) Conclusions: The results suggest that the integration of multifactorial data provided by ML techniques is a useful tool to select NSCLC patients as candidates for IO.

Aim: Diagnostic laboratories are progressively introducing next-generation sequencing (NGS) technologies in the routine workflow to meet the increasing clinical need for comprehensive molecular characterization in cancer patients for diagnosis and precision medicine, including fusion-transcripts detection. Nevertheless, the low quality of messenger RNA (mRNA) extracted from formalin-fixed paraffin-embedded (FFPE) samples may affect the transition from traditional single-gene testing approaches [like fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), or polymerase chain reaction (PCR)] to NGS. The present study is aimed at assessing the overall accuracy of RNA fusion transcripts detection by NGS analysis in FFPE samples in real-world diagnostics., Methods: Herein, NGS data from 190 soft tissue tumors (STTs) and carcinoma cases, discussed in the context of the institutional Molecular Tumor Board, are reported and analyzed by FusionPlex © Solid tumor kit through the manufacturer's pipeline and by two well-known fast and accurate open-source tools [Arriba (ARR) and spliced transcripts alignment to reference (STAR)-fusion (SFU)]., Results: The combination of FusionPlex © Solid tumor with ArcherDX ® Analysis suite (ADx) analysis package has been proven to be sensitive and specific in STT samples, while partial loss of sensitivity has been found in carcinoma specimens., Conclusions: Albeit ARR and SFU showed lower sensitivity, the use of additional fusion-detection tools can contribute to reinforcing or extending the output obtained by ADx, particularly in the case of low-quality input data. Overall, our results sustain the clinical use of NGS for the detection of fusion transcripts in FFPE material., Competing Interests: The authors declare that they have no conflicts of interest., (© The Author(s) 2022.)

In the immunotherapy era, considering the prolonged survival benefit and responses observed with immunecheckpoint inhibitors (ICI) in many cancer types, the identification of patients with rapid progression (PD) and deaths upon ICI has found some skepticism and resistance among the scientific community. Nevertheless, an acceleration of tumour during ICI, defined as hyperprogressive disease (HPD), has been recognized across different cancer types and evidence regarding rapid PDs and deaths are emerging in patients with malignant pleural mesothelioma (MPM), small cell lung cancer (SCLC) and thymic malignancies and in uncommon non-small cell lung cancer (NSCLC) populations. Of note, PD and early deaths (ED) rates upon single agent ICI were up to 60% and 30% in MPM and 70% and 38% in SCLC patients, respectively. Similarly, rapid PDs and deaths were observed in clinical trials and retrospective studies including patients with poor performance status (PS), HIV infection and rare NSCLC histologies. Atypical patterns of response, such as pseudoprogression (PsPD) may also occur in other thoracic malignancies (MPM) and in some uncommon populations (i.e., HIV patients), however probably at lower rate compared to HPD. The characterizations of HPD and PsPD mechanisms and the identification of common definition criteria are the next future challenges in this area of cancer research., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-636). The series “Immunotherapy in other thoracic malignancies and uncommon populations” was commissioned by the editorial office without any funding or sponsorship. Dr. RF reports personal fees from MSD, outside the submitted work. Dr. DS reports personal fees and non-financial support from Astra Zeneca, personal fees and non-financial support from Merck Sharp & Dohme, personal fees and non-financial support from Bristol Myers Squibb, non-financial support from Roche, outside the submitted work. Dr. CP reports personal fees and other from ROCHE, personal fees and other from BMS, other from MSD, outside the submitted work. Dr. AP reports personal fees from Roche, personal fees from AstraZeneca, personal fees from BMS, outside the submitted work. Dr. MCG reports grants and personal fees from Eli Lilly, personal fees from Boehringer Ingelheim, grants and personal fees from Otsuka Pharma, grants and personal fees from Astra Zeneca, grants and personal fees from Novartis, grants and personal fees from BMS, grants and personal fees from Roche, grants and personal fees from Pfizer, grants and personal fees from Celgene, grants and personal fees from Incyte, personal fees from Inivata, personal fees from Takeda, grants from Tiziana Sciences, grants from Clovis, grants from Merck Serono, grants and personal fees from Bayer, grants and personal fees from MSD, grants and personal fees from GlaxoSmithKline S.p.A., grants and personal fees from Sanofi-Aventis, grants and personal fees from Spectrum Pharmaceutcials, grants and personal fees from Blueprint Medicine, personal fees from Seattle Genetics, personal fees from Daiichi Sankyo, grants from United Therapeutics Corporation, grants from Merck KGaA, personal fees from Janssen, non-financial support from MSD, non-financial support from Eli-Lilly, grants from Turning Point, grants from Ipsen, grants from MedImmune, grants from Exelisis, grants from Array (Pfizer), personal fees from Mirati Therapeutics, outside the submitted work. Dr. GLR reports personal fees from MSD, other from BMS, personal fees from AstraZeneca, other from ROCHE, outside the submitted work. The authors have no other conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

(1) Background. The onset of a drug-drug interaction (DDI) may affect treatment efficacy and toxicity of advanced non-small-cell lung cancer (aNSCLC) patients during epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) use. Here we present the use of Drug-PIN ® (Personalized Interactions Network) software to detect DDIs in aNSCLC patients undergoing EGFR-TKIs. (2) Methods. We enrolled patients with Stage IV aNSCLC already treated with or candidates to receive EGFR-TKIs, in any line; ECOG PS 0-2; taking at least one concomitant drug. Cancer treatments, concomitant drugs, and clinical and laboratory data were collected and inserted in Drug-PIN ® . (3) Results. Ninety-two patients, median age of 68.5 years (range 43-89), were included. In total, 20 clinically relevant DDIs needing medical intervention in a total of 14 patients were identified; the 14 major DDIs were related to a high-grade interaction between TKIs and SSRIs, antipsychotics, antiepileptics, H2-receptor antagonist and calcium antagonists. A negative association between statin intake and PFS was identified ( p = 0.02; HR 0.281, 95% CI 0.096-0.825). (4) Conclusions. This is the first retrospective study assessing the prevalence of DDIs, the clinical need for medical intervention and the impact of concomitant drugs on EGFR-TKIs survival in aNSCLC.

This study is a meta-analysis of randomized controlled trials involving first-line studies in which immune checkpoint inhibitors were added to chemotherapy and were compared with chemotherapy alone. The primary end point was overall survival (OS). The analyses used random-effects models and the Grading of Recommendations Assessment, Development, and Evaluation system to rate the quality of the evidence. Nine articles were included for qualitative and quantitative synthesis. A meta-analysis of the nine randomized trials showed a significant benefit in terms of OS (hazard ratio: 0.75 [95% CI: 0.66-0.85]; p < 0.01). Only programmed death ligand-1 positive-high cancers derive a significant OS benefit. In this meta-analysis, there is moderate evidence that the addition of immune checkpoint inhibitors to chemotherapy may improve both OS compared with chemotherapy alone.

Target therapies completely changed the clinical approach in EGFR mutated and ALK rearranged non-small cell lung cancer, ensuring these patients exceptional outcomes with a better toxicity profile compared to conventional chemotherapy. In recent years, beyond EGFR and ALK alterations, new data are emerging about less common alterations, new drugs have been already approved and others agents have been recently investigated or are currently under investigation. In this review we will discuss some uncommon alterations in non-small cell lung cancer such as ROS1, BRAF, RET, HER2, NTRK, MET and other targets that are in an early evaluation phase. We will summarize the characteristics of patients harboring these alterations, the already approved or under investigation therapies and the related resistance mechanisms., (Copyright © 2021. Published by Elsevier B.V.)

First-line immune-checkpoint inhibitor (ICI)-based therapy has deeply changed the treatment landscape and prognosis in advanced non-small cell lung cancer (aNSCLC) patients with no targetable alterations. Nonetheless, a percentage of patients progressed on ICI as monotherapy or combinations. Open questions remain on patients' selection, the identification of biomarkers of primary resistance to immunotherapy and the treatment strategies to overcome secondary resistance to first-line immunotherapy. Local ablative approaches are the main therapeutic strategies in oligoprogressive disease, and their role is emerging in patients treated with immunotherapy. Many therapeutic strategies can be adapted in aNSCLC patients with systemic progression to personalize the treatment approach according to re-characterization of the tumors, previous ICI response, and type of progression. This review's aim is to highlight and discuss the current and potential therapeutic approaches beyond first-line ICI-based therapy in aNSCLC patients based on the pattern of disease progression (oligoprogression versus systemic progression).