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Introduction: Anaplastic lymphoma kinase (ALK) gene-rearrangements are identified in about 3-5% of non-small cell lung cancers (NSCLC), and ALK-rearranged NSCLC is to be considered an oncogene-addicted cancer with peculiar clinical characteristics., Areas Covered: Several ALK inhibitors have been studied and approved for use in the treatment of advanced ALK-rearranged NSCLC with reported superiority in terms of efficacy and safety profile compared with chemotherapy. Second- and third-generation ALK inhibitors (alectinib, brigatinib, and lorlatinib) offer to NSCLC patients a clinically meaningful prolongment of survival with a very good quality of life profile. However, resistances to these agents always occur, with less satisfying options for second-line treatments. Direct comparisons among these agents are not available, and the choice among brigatinib, alectinib, and lorlatinib as first-line treatment remains challenging. Very recently, alectinib has been demonstrated to improve efficacy outcomes compared with chemotherapy also in resected stage IB-IIIA ALK-rearranged NSCLC, extending the clinical benefit offered by ALK inhibitors also to the adjuvant setting., Expert Opinion: Future development of ALK inhibitors in NSCLC treatment includes the search for optimal management of acquired resistance to first-line treatments and the extension of use of ALK inhibitors also to neoadjuvant and preferably to perioperative setting.

Background: MAURIS is an Italian multicenter, open-label, phase IIIb ongoing trial, aiming at evaluating the safety and effectiveness of atezolizumab + carboplatin/etoposide in patients with newly diagnosed, extensive-stage small-cell lung cancer (ES-SCLC). The primary objective is the safety evaluation., Materials and Methods: Patients received atezolizumab + carboplatin/etoposide Q3W for 4-6 cycles in the induction phase, followed by atezolizumab maintenance Q3W. We presented the interim analysis on safety (referring to the induction phase) and clinical effectiveness, in all patients (N = 154) and in subgroups that received ≤3 (N = 23), 4 (N = 43), and 5-6 cycles (N = 89) of induction., Results: At a median follow-up of 10.5 months, 139 patients (90.3%) discontinued treatment. Serious adverse events occurred in 29.9% of patients overall, and the rate was lower in patients with 5-6 cycles (19.1%) than in those with 4 (34.9%) or ≤3 (63.6%) cycles. Immune-mediated adverse events were reported in 14.9%, 15.7%, 11.6%, and 18.2% of patients, overall and by subgroup, respectively. The median overall survival and progression-free survival were 10.7 and 5.5 months, respectively. Overall, 111 patients (71.6%) had a tumor response., Conclusions: Interim results provide further evidences about safety and efficacy profile of atezolizumab + carboplatin/etoposide treatment in a ES-SCLC patient population closer to that observed in clinical practice., Clinical Trial Registration: Eudract No. 2019-001146-17, NCT04028050., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Oncologists tend to under-report subjective symptoms during cancer treatment. This study describes the under-reporting rate of selected symptoms and explores its association with overall survival (OS). A secondary aim is to test the association of patient-reported symptoms with OS., Patients and Methods: This is a post hoc analysis on data pooled from 12 randomized trials, promoted by the National Cancer Institute of Naples (Italy), enrolling patients between 2002 and 2019, with published primary analyses. Occurrence and grade of six side-effects (anorexia, nausea, vomiting, constipation, diarrhea and fatigue) reported by physicians were compared with corresponding symptoms reported by patients in quality-of-life (QoL) questionnaires. Under-reporting was defined as the rate of cases reported grade 0 by the physician while grade ≥1 by the patient. Prognostic value was tested in a multivariable model stratified by trial, including age, sex and performance status as confounders. A landmark threshold was defined for OS analyses., Results: 3792 patients with advanced lung, ovarian, pancreatic, breast or colorectal cancer were pooled; 2603 (68.6%) were eligible having at least one toxicity assessment and one QoL questionnaire, before the first planned disease restaging. Concordance between physicians' and patients' reporting was low with Cohen's k coefficients ranging from 0.03 (fatigue) to 0.33 (vomiting). Under-reporting ranged from 52.7% (nausea) to 80.5% (anorexia), and was not associated with OS. Patient-reported anorexia, vomiting and fatigue ('a little' or more) were significantly associated with shorter OS., Conclusions: Under-reporting of treatment side-effects is frequent, but it does not affect OS. Patients' reported symptoms should be used for prognostic evaluation., Competing Interests: Disclosure LA: honoraria from Pfizer, EliLilly. RDL: honoraria from Astellas, Pfizer, Janssen. PDP: Honoraria from Lilly, Gilead, MSD, Roche, Exact Sciences, Novartis; support for attending meetings from Gilead, Lilly, Istituto Gentili, MSD. CG: honoraria as speaker bureau or advisory board member or consultant from MSD, BMS, AstraZeneca, Roche, Eli Lilly, Pfizer, Amgen, Novartis, GSK, Takeda, Boehringer, Menarini, Karyopharm, Sanofi. AM: honoraria for speaker’s bureau or advisory board from Roche, AstraZeneca, BMS, Pfizer, MSD, Boehringer, Takeda, Novartis, Lilly, Sanofi. SP: honoraria from AstraZeneca, MSD, Roche, GSK, Pharmamar; research funding from Roche, AstraZeneca, MSD, Pfizer, GSK. FN: honoraria from Seagen. AA: honoraria from Amgen, MSD, Eisai, Bristol-Meyers; consulting or advisory role: Amgen, AstraZeneca, MSD, Eisai, Bayer. AG: honoraria from Janssen. MDM: honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche, Takeda, Amgen, Merck for consultancy or participation to advisory boards; direct research funding from Tesaro/GlaxoSmithKline; institutional funding for work in clinical trials/contracted research from Beigene, Exelixis, MSD, Pfizer and Roche. FP: institutional support or grants for clinical trials from Roche, Bayer, AstraZeneca, Pfizer, Incyte, Tesaro/GSK, Merck; honoraria for participation on advisory boards from Bayer, Pierre Fabre, AstraZeneca, Incyte, Ipsen, Clovis, Astellas, Sanofi, Roche, Pfizer. MCP: institutional funding for clinical research from Roche, AstraZeneca, Bayer; honoraria for educational activities from Astellas, Pfizer, Ipsen, AstraZeneca; support for attending meetings from Menarini. All other authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Patients with radically resected stage II and III NSCLC are exposed to a high risk of disease recurrence. Thus, adjuvant cisplatin-based chemotherapy is routinely offered to this patient population, although it results in an absolute increase in 5-year survival rate of only 4%. This modest improvement in survival rate makes it challenging to communicate to our patients about the decision to be treated with adjuvant chemotherapy or not. Nowadays, the decision to administer adjuvant chemotherapy or not in resected NSCLC is almost never completely shared with patients because its role is very difficult to explain. The risk-benefit ratio becomes clearly unfavourable in elderly and unfit patients. Recently, the phase III ADAURA trial demonstrated a clinically significant disease-free survival and overall survival benefit with adjuvant osimertinib (with or without adjuvant chemotherapy) versus a placebo in EGFR-mutated stage IB-IIIA resected NSCLC. In this patient population, the decision to administer chemotherapy or not is much more challenging given the great benefit offered by osimertinib alone. Thus, it is time now to improve our communication tools to explain the role of adjuvant chemotherapy to our patients, especially in the EGFR-mutated population, in order to undertake real shared decision making in a clinical context in which the opportunity to administer toxic chemotherapy is debatable and subjective.

Background: The combination of platinum-based chemotherapy with immune-checkpoint inhibitors (ICIs) is a standard of care option in the front-line treatment of advanced non-small cell lung cancer (NSCLC). Positive efficacy and safety results have been demonstrated with different chemo-ICI combinations in the corresponding clinical trials, however no randomized prospective comparison is available and there is no evidence on how to choose among the available regimens., Methods: A virtual International Expert Panel took place in July 2023 to review data on chemo-ICI regimens available in the first-line setting in patients with NSCLC, and reach common considerations both in clinical practice and in research setting., Results: Overall, all panelists agreed that safety of the chemo-immunotherapy combination regimens is supported by reviewed data, showing no additional toxicity concerns over those of the individual components of each regimen and highlighting differences in toxicity profile based on ICI component (single anti-PD-1 versus double anti-PD-1 and anti-CTLA-4). Among disease characteristics, PD-L1 value (<1%) but not histology was considered a potential selection factor in favor of the combination with dual ICI. With regards to clinical features, the panelists agreed that chemotherapy, whichever the ICI combination regimen, remains the backbone to counteract disease-related symptoms included those conditioning worse performance status. The panelists defined high, medium, and low priorities in clinical research. High priority was attributed to prospectively evaluating the impact of the addition of anti-CTLA-4 on brain metastasis, biomarker subgroups, and the optimal duration and schedule of combination regimens., Conclusions: Based on the available evidence, the panelists reached common considerations on strengths and differences between chemotherapy plus single agent ICI and chemotherapy plus double agent ICIs in patients with advanced NSCLC. In the absence of direct comparison, different toxicity profile and subgroup analysis by PD-L1 are considered as the main potential features to select among the two regimens, however to be confirmed by recommended prospective randomized clinical research., Competing Interests: Declaration of competing interest C. Gridelli received honoraria as speaker bureau or advisory board member or as consultant from MSD, BMS, Roche, Astra Zeneca, Novartis, Pfizer, Menarini, Boehringer, Karyopharm, Eli Lilly, Amgen, Sanofi, GSK, Boehringer Ingelheim. S. Peters received education grants, provided consultation, attended advisory boards and/or provided lectures for the following organizations: AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, Beigene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Imedex, IQVIA, Incyte, iTeos, Janssen, Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, Peerview, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, Vaccibody. T. Mok received education grants, honoraria, provided consultation, attended advisory boards and/or provided lectures for the following organizations: AstraZeneca, Aurora Tele-Oncology Platform, Lunit, ACT Genomics-Sanomics Group, HUTCHMED, Alpha Biopharma, ACEA Pharmaceutical Research, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, Fishawack Facilitate, InMed, Lilly, Merck Sharp & Dohme, Novartis, Origimed, Pfizer, Prime Oncology, Roche, Sanofi Aventis GmbH, Taiho Pharmaceutical, Takeda, Lucence, Medscape, Permanyer Publications, PeerVoice, Physicans' Education Resource, Research to Practice, Shanghai BeBirds Translation & Consulting, Liangyihui Network Technology Co, Ltd, AbbVie, Berry Oncology, Blueprint Medicines, C4 Therapeutics, CStone Pharmaceuticals, Curio Science, D3, Eisai, Gilead Sciences, Gritstone Bio, Guardant Health, touchIME, Hengrui Therapeutics, Ignyta, Incyte, Inivata, IQvia, Lilly, Loxo, Lunit, Merck Serono, Mirati Therapeutics, Puma Biotechnology, SFJ Pharmaceuticals Group, Vertex, Yuhan, Qiming Development (HK) Ltd, G1 Therapeutics, Janssen, geneDecode. Stock and Other Ownership Interests: Aurora Tele-Oncology Platform, HUTCHMED, ACT Genomics-Sanomics Group. MC Garassino received education grants, honoraria, provided consultation, attended advisory boards and/or provided lectures for the following organizations: MSD Oncology, AstraZeneca/MedImmune, GlaxoSmithKline, Takeda, Roche, Bristol Myers Squibb, Novartis, Tiziana Life Sciences, Sanofi, Celgene, Daiiki Sankyo, Inivata, Incyte, Pfizer, Seattle Genetics, Lilly, GlaxoSmithKline, Bayer, Blueprint Medicines, Janssen, Regeneron, Otsuka, AstraZeneca, Roche/Genentech, Spectrum Pharmaceuticals, Ipsen, Exelixis, Amgen. Luis Paz-Ares reports institutional research support from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharpe & Dohme, and Laboratorios Pfizer Ltda.; personal fees (self/family) from Altum Secuency, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly and Company, Genomica, Ipsen Biopharmaceuticals Inc., Janssen Biotech, Merck Sharpe & Dohme, Mirati, Novartis, Laboratorios Pfizer Ltda., PharmaMar, Roche, Servier Pharmaceuticals, and Takeda Oncology; and serves as a board member at Genómica and Altum all outside the submitted work. F. de Marinis received honoraria or consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Novartis, Takeda, Xcovery, and Roche. Dr. Attili reports no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: MET (MET Proto-Oncogene, Receptor Tyrosine Kinase) exon 14 skipping mutation represents one of the most common MET alterations, accounting for approximately 1-3% of all mutations in advanced lung adenocarcinomas. While until 2020 no specific treatment was available for this subset of patients, as of today, three MET Tyrosine Kinase Inhibitors (TKIs) are currently approved in this setting, namely capmatinib, tepotinib and savolitinib., Objective: This article aims to provide an extensive overview of the current therapeutic standard of care for exon 14 skipped advanced Non-small Cell Lung Cancer (NSCLC) patients, alongside with mentions of the main future challenges and opportunities., Conclusion: FDA-approved MET-TKIs currently represent the best option for treating exon 14 skipped advanced NSCLC patients, thanks to their excellent efficacy profile, alongside their manageable safety and tolerability. However, we currently lack specific agents to treat patients progressing on capmatinib or tepotinib, due to a limited understanding of the mechanisms underlying both on- and off-target resistance. In this respect, on-target mutations presently constitute the most explored ones from a mechanistic point of view, and type II MET-TKIs are currently under investigation as the most promising agents capable of overcoming the acquired resistance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum-pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum-pemetrexed would improve overall survival in patients with pleural mesothelioma., Methods: We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m 2 ] or carboplatin [area under the concentration-time curve 5-6 mg/mL per min] with pemetrexed 500 mg/m 2 , every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02784171, and is closed to accrual., Findings: Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66-75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3-27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4-21·3] with pembrolizumab vs 16·1 months [13·1-18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64-0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20-33%) with pembrolizumab and 17% (13-24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group., Interpretation: In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum-pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma., Funding: The Canadian Cancer Society and Merck & Co., Competing Interests: Declaration of interests MP has received grants for research to institution from AstraZeneca and Roche; payment for educational events from Astellas, Pfizer, and AstraZeneca; and received drugs for research from Roche and AstraZeneca. GLR received consulting fees from MSD, BMS, AstraZeneca, Roche, Novartis, Lilly, Amgen, Sanofi, Pfizer, Takeda, GSK, and Italfarmaco; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from MSD, BMS, AstraZeneca, Roche, Novartis, Lilly, Amgen, Sanofi, Pfizer, Takeda, GSK, and Italfarmaco; received support for attending meetings or travel from Roche, MSD, BMS, and Amgen; has participated on a Data Safety Monitoring Board or Advisory Board for MSD, BMS, AstraZeneca, Roche, Novartis, Lilly, Amgen, Sanofi, Pfizer, Takeda, GSK, and Italfarmaco; and has other financial or non-financial interests from MSD, BMS, AstraZeneca, Roche, Novartis, Amgen, Sanofi, Pfizer, Takeda, and GSK. YL holds stock or stock options from Merck. SL received consulting fees from Lilly, MSD, Sanofi, and AbbVie and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca. AS received grants or contracts (payments to institution) from MSD, BMS, AstraZeneca, Roche, and Amphera; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, BMS, MSD, and Roche; received support for attending meetings or travel from AstraZeneca, BMS, MSD, and Roche; and participated on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, BMS, MSD, and Roche. MF received consulting fees from AstraZeneca, BMS, and Takeda and received honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, BMS, and Takeda. SAL has participated on a Data Safety Monitoring Board or Advisory Board for Sanofi and Bayer. JRG received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca and BMS. PB received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Merck and participated on a Data Safety Monitoring Board or Advisory Board for Mirati and AbbVie. NL has received editorial support from EMD Serono; received grants to institute (unrelated) from Amgen, AstraZeneca, Bayer, BMS, Eli Lilly, EMD Serono, Guardant Health, Inivata, Janssen, Merck/MSD, Novartis, Pfizer, Roche, and Takeda; received honoraria or travel funding for CME lectures (unrelated) from AstraZeneca, Beigene, BMS, Janssen, Merck, Novartis, and Takeda; and participated on a Data Safety Monitoring Board or Advisory Board for Mirati, Helsinn, and Daichii Sankyo. LS has received grants or contracts to institution to support clinical trial from AstraZeneca, Merck, Bayer, Novartis, Repare, GSK, and Janssen and holds stock or stock options from AstraZeneca. DED has received research grants from CIHR, CancerCare Manitoba Foundation, and AstraZeneca; received research grants and salary awards from Manitoba Medical Services Foundation; received payment for educational events from Roche, Boehringer Ingelheim, and BMS; served on an advisory board for Merck, AstraZeneca, Pfizer, Jazz Pharmaceuticals, and Novartis; has acted in a leadership or fiduciary role in a board, society, committee or advocacy group, paid or unpaid for Lung Cancer Canada (Medical Advisory Committee), Canadian Association of Medical Oncologists (Chair, Fellowship Committee), and Canadian Cancer Trials Group (Chair, Small Cell Lung Cancer Working Group); and received equipment, materials, drugs, medical writing, gifts, or other services from AstraZeneca (Medical writing assistance on a small-cell lung cancer paper). QC has received grants to institution from Alkermes, Amgen, Apollomics, Astellas, AstraZeneca, Bicycle, BMS, Conjupro, Decipher, Eli Lilly, Esperas, Exactis, GSK, iTEOS, Kelun, Merck, Mirati, Nuvalent, Ocellaris, Pfizer, Rvolution Medicines, Roche, SeaGen, Spectrum, and Treadwell; received consulting fees from Amgen, AnHeart, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GSK, Jazz Pharmaceuticals, Janssen, Merck and Co, Novartis, Pfizer, Roche, and Takeda; received payment for speaking or presentations from AstraZeneca; acted on an advisory board for Amgen, AnHeart, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GSK, Jazz Pharmaceuticals, Janssen, Merck and Co, Novartis, Pfizer, Roche, and Takeda; acted on a Data Safety Monitoring Committee for Merck and KGaA; and occupied a leadership or fiduciary role in a board, society, committee, or advocacy group, paid or unpaid for Lung Cancer Canada and Canadian Mesothelioma Foundation. CWL has served as a member of the Board of Directors for Canadian Mesothelioma Foundation. LG received grants or contracts to institution from BMS, MSD, Takeda, Pfizer, Roche, Amgen, Sanofi, Janssen, Lilly, and Novartis; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, Takeda, Pfizer, Roche, Amgen, Sanofi, Janssen, Lilly, and Novartis; received support for attending meetings or travel from Pfizer, MSD, AstraZeneca, and Takeda; and participated on a Data Safety Monitoring Board or Advisory Board for Inhatarget Therapeutics. XQ received support for attending meetings or travel from Pfizer (ESMO 2022), Janssen (ASCO 2022), and Sanofi (ASCO 2023). VW received consulting fees from Amgen; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Bristol Myers Squibb, MSD, Roche, and Sanofi; received support for attending meetings or travel from AstraZeneca, Bristol Myers Squibb, Janssen, MSD, Roche, and Sanofi; and participated on a Data Safety Monitoring Board or Advisory Board for Amgen, AstraZeneca, and Ipsen. GZ received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Inventiva Pharma, Lilly, MSD Oncology, Pfizer, and Roche; acted in a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Da Volterra, Inventiva Pharma, MSD Oncology, Pfizer, and Roche; received research funding from AstraZeneca, Bristol-Myers Squibb, Pfizer, Roche, and Takeda; and received travel, accommodations, and expenses from AbbVie, AstraZeneca, Bristol-Myers Squibb, Lilly, Pfizer, and Roche. MLS received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from BMS and support for attending meetings or travel from Pfizer (ESMO 2022). AM received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Roche, AstraZeneca, BMS, MSD, Pfizer, Takeda, Boehringer, Sanofi, Lilly, Novartis, and Italfarmaco and participated on a Data Safety Monitoring Board or Advisory Board for Roche, AstraZeneca, Pfizer, MSD, and Takeda. FG received consulting fees from Novocure, BMS, Novartis, PharmaMar, Pierre Fabre, and MSD; received payment for speaker bureau from Novocure; received support for attending meetings or travel from Novartis, MSD, BMS, PharmaMar, and Pierre Fabre. SD received payment for presentations from Novartis, Pierre-Fabre, and BMS and travel and accommodation support during meetings from Istituto Gentili, Novartis, Pierre-Fabre, and BMS. GLC received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Novocure and BMS and participated on a Data Safety Monitoring Board or Advisory Board for Novocure. PAZ received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck Sharp and Dohme, Astellas, Janssen, Sanofi, Ipsen, Pfizer, Novartis, Bristol Meyer Squibb, Amgen, AstraZeneca, Roche, and Bayer; received support for attending meetings or travel from Merck Sharp and Dohme, Astellas, Janssen, Sanofi, Ipsen, Pfizer, Novartis, Bristol Meyer Squibb, Amgen, AstraZeneca, Roche, and Bayer; and participated on a Data Safety Monitoring Board or Advisory Board for Merck Sharp and Dohme, Astellas, Janssen, Sanofi, Ipsen, Pfizer, Novartis, Bristol Meyer Squibb, Amgen, AstraZeneca, Roche, and Bayer. MM received support for attending meetings or travel from Roche, Pfizer, and Novartis. FLC received consulting fees from Takeda, Amgen, Novartis, AstraZeneca, and Roche; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Takeda, Amgen, Novartis, AstraZeneca, and Roche; and received support for attending meetings or travel from Takeda and Amgen. CG received consulting fees from Karyopharm, Menarini, and Roche; received payment or honoraria for lectures, presentations, speakers' bureaux, manuscript writing, or educational events from MSD, BMS, Novartis, Amgen, Sanofi, Eli Lilly, GSK, Roche, Takeda, Boehringer, AstraZeneca, and Pfizer; and participated on a Data Safety Monitoring Board or Advisory Board for MSD, BMS, Novartis, Amgen, Sanofi, Eli Lilly, GSK, Roche, Takeda, Boehringer Ingelheim, AstraZeneca, and Pfizer. FP received partial funding to institution and experimental study drug from Pfizer; received financial support to institution from Roche, Bayer, AstraZeneca, Pfizer, Incyte, Tesaro/GSK, and Merck; and received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bayer, Pierre Fabre, AstraZeneca, Incyte, Ipsen, Clovis, Astellas, Sanofi, Roche, and Pfizer. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Lung cancer is the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) as the most common subtype. In the past decades, immunotherapy deeply changed paradigms for care of newly diagnosed advanced NSCLC patients without oncogenic driver mutations. An immunotherapy-based regimen alone or in combination to chemotherapy was crowned as the preferred option to choice, according to worldwide guideline., Areas Covered: Newly diagnoses of advanced NCSLC occurred predominantly in elderly patients, representing over half of patients treated in daily practice. However, data on older patients' treatments are still lacking, because they are under-represented in clinical trials. This leads to a 'black hole' of knowledge about efficacy and safety of immune-checkpoint inhibitors use in this cohort of population., Expert Opinion: According to available data from subgroup analyses, immunotherapy as single agent seem to work in elderly similarly to younger patients, with no excess of toxicities. In contrast, the real impact - and not least the safety - of an immune-chemo combination use in elderly population was still unclear. Awaiting data from dedicated clinical trials, this review will discuss available results from randomized phase III clinical trials comparing immune-chemo combinations to chemotherapy alone, focusing on elderly subgroup enrolled.

Background: The treatment of stage III non-small cell lung cancer (NSCLC) is very challenging because it is a heterogeneous group of diseases. This study was to investigative whether concurrent immunotherapy with chemoradiotherapy was associated with improved outcomes compared to consolidative immunotherapy following chemoradiotherapy in patients with unresectable stage III NSCLC, which may provide evidence-based medical evidence for the treatment of stage III NSCLC., Methods: A total of 78 epidermal growth factor receptor or anaplastic lymphoma kinase (EGFR/ALK) negative patients from the clinical database of the shanghai pulmonary hospital with locally advanced unresectable NSCLC and we evaluated them for baseline clinical factors, follow-up. Patients underwent concurrent immunotherapy with chemoradiotherapy or consolidative immunotherapy after chemoradiotherapy. Patients were classified based on initial site of progression (primary versus non-primary site). The study endpoints were progression-free survival (PFS) and time to death or distant metastasis (TDDM). Cox proportional hazards analysis was used to assess the factors affecting PFS and TDDM., Results: The median follow-up time for both groups was 26 months, and there was no significant difference in baseline clinical characteristics (P>0.05). The patients receiving concurrent immunotherapy (n=36) had a longer PFS than those receiving consolidative immunotherapy (n=42) (median 32.4 vs. 15.5 months; P<0.01). The TDDM was also longer in patients with concurrent immunotherapy than those with consolidative immunotherapy (median 57.3 vs. 31.0 months; P=0.01). Furthermore, in a subset of patients with initial site of progression at a non-primary-site, patients undergoing concurrent immunotherapy had longer PFS than those undergoing consolidative immunotherapy (median 22.7 vs. 11.9 months; P=0.03)., Conclusions: Concurrent immunotherapy with chemoradiotherapy may be associated with improved disease progression outcomes as compared to consolidative immunotherapy following chemoradiotherapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-575/coif). C.G. received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events for MSD, BMS, Amgen, Novartis, Astra Zeneca, Roche, Sanofi, Pfizer, Eli Lilly, Takeda, Boehringer. C.G. reports participation on a Data Safety Monitoring Board or Advisory Board for MSD, BMS, Amgen, Novartis, Astra Zeneca, Roche, Sanofi, Pfizer, Eli Lilly, Takeda, Boehringer, Karyopharm, GSK and received consulting fees for Menarini. H.S.P. has received institutional grants from RefleXion and Merck, and personal fees from AstraZeneca (consulting, advisory board), Bristol Myers Squibb (honoraria), Daiichi Sankyo (honoraria), G1 Therapeutics (honoraria), Galera (advisory board), and RefleXion (consulting). The other authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Background: ALK tyrosine kinase inhibitors (TKIs) have revolutionized the treatment and largely improved the survival outcomes of patients with NSCLC harboring ALK rearrangements. Different ALK TKI compounds have demonstrated antitumor activity in these patients and are available in clinical practice. However, clinical expertise across countries varies according to local regulatory approval of different drugs, identifying multiple treatment scenarios to comply with international guidelines and clinical practice., Methods: A virtual webinar was held on July 2023 to discuss the state of the art and future perspectives in the treatment of ALK rearrangement in advanced NSCLC in Italy. The faculty hosting the webinar was composed of eight medical oncologists from different regions of Italy with clinical expertise in treating patients with lung cancer. Live-shared notes were used to produce a report to serve as the basis of a review manuscript on the topic., Results: Alectinib and brigatinib are the preferred front-line treatment options in Italy, pending approval of the front-line medicine lorlatinib, which would be considered among the choices. Due to a local regulatory limitation of second-line lorlatinib, which is not allowed after front-line brigatinib, alectinib is commonly the preferred front-line choice to follow a sequence of alectinib, followed by lorlatinib, followed by platinum plus pemetrexed chemotherapy. Age and performance status were not considered per se as clinical features influencing treatment choice. However, treatment compliance is deemed a relevant factor in decision making with regard to the number of pills to be administered. In general, given the availability of alternative choices, the spectrum of patients' comorbidities and polypharmacotherapy interactions should be taken into account in treatment selection according to the toxicity profile of each compound. In addition, several issues were debated with regard to improving treatment outcomes, including testing, brain metastases, and management of an oligoprogressive disease., Conclusions: The treatment scenario of ALK-positive disease is dynamically evolving. Furthermore, not all FDA- and EMA-approved compounds are approved in Italy with the same indications. This influences therapeutic opportunities and increases the need for greater clinical expertise to help and guide treatment selection.

Taking into account the huge epidemiologic impact of lung cancer (in 2020, lung cancer accounted for 2,206,771 of the cases and for 1,796,144 of the cancer-related deaths, representing the second most common cancer in female patients, the most common cancer in male patients, and the second most common cancer in male and female patients) and the current lack of recommendations in terms of prognostic factors for patients selection and management, this article aims to provide an overview of the current landscape in terms of currently available immunotherapy treatments and the most promising assessed prognostic biomarkers, highlighting the current state-of-the-art and hinting at future challenges.

Immune checkpoint inhibitors have activity in mesothelioma. IND.227 was a phase 2 trial (120 patients planned) comparing progression-free survival of standard platinum and pemetrexed (CP) versus CP + pembrolizumab (pembro) versus pembro. Accrual to the pembro arm was discontinued on the basis of interim analysis (IA-16 wk disease control rate). CP + pembro was tolerable, with progression-free survival similar between arms and median survival and overall response rate higher than those of CP alone (19.8 mo [95% confidence interval or CI: 8.4-41.36] versus 8.9 mo [95% CI: 5.3-12.8] and 47% [95% CI: 24%-71%] versus 19% [95% CI: 5%-42%], respectively). The subsequent phase 3 trial has completed accrual; results are expected in 2023., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitors have changed the history of NSCLC treatment by becoming, alone or in combination with platinum-based chemotherapy, a mainstay of first-line therapy for advanced NSCLC. This increasingly dictates the identification of predictive biomarkers of response that can guide patient selection, in order to rationalize and personalize therapies, particularly in elderly patients. Immunotherapy in these patients raises questions of efficacy and tolerability related to aging, which is accompanied by a progressive decline in various body functions. Physical, biological and psychological changes contribute to individual validity status and, preferably, 'fit' patients are generally enrolled in clinical trials. In elderly patients, especially frail and complex patients with more than one chronic disease, data are poor and specific prospective studies are needed. This review reports the main available results on the use of immune checkpoint inhibitors in older patients with advanced NSCLC, in terms of efficacy and toxicity, and aims to highlight the need to better predict which patients might benefit from immunotherapy agents by probing knowledge and integrating information on immune system changes and age-related physiopathological modifications.

Background: The use of immune checkpoint inhibitors (ICIs) in the front-line treatment of advanced non-small-cell lung cancer (NSCLC) is currently the standard of care. However, as clinical trials include a very limited number of elderly patients, evidence on the safety and efficacy of using ICI-based regimens is still limited., Methods: A virtual International Expert Panel took place in July 2022 to review the available evidence on the use of ICI-based regimens in the first-line setting in elderly patients with NSCLC and provide a position paper on the field both in clinical practice and in a research setting., Results: All panelists agreed that age per se is not a limitation for ICI treatments, as the elderly should be considered only as a surrogate for other clinical factors of frailty. Overall, ICI efficacy in the elderly population is supported by reviewed data. In addition, the panelists were confident that available data support the safety of single-agent immunotherapy in elderly patients with NSCLC. Conversely, concerns were expressed on the safety of chemo + ICI-based combination, which were considered mainly related to the toxicities of chemotherapy components. Therefore, suggestions were proposed to tailor combined approaches in the elderly patients with NSCLC. The panelists defined high, medium, and low priorities in clinical research. High priority was attributed to implementing the real-world assessment of elderly patients treated with ICIs, who are mostly underrepresented in pivotal clinical trials., Conclusions: Based on the current evidence, the panelists outlined the significant limitations affecting the clinical practice in elderly patients affected by NSCLC, and reached common considerations on the feasibility, safety, and effectiveness of ICI monotherapy and ICI combinations in the first-line setting., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: CTLA-4/PD-1/PD-L1- directed immune checkpoint inhibitors (ICIs) are one of the standard therapies for the treatment of advanced non-small cell lung cancer (NSCLC). However, some new classes of monoclonal antibodies are emerging as promising therapies for advanced NSCLC., Areas Covered: Therefore, this paper aims to provide a comprehensive review of the recently approved as well as emerging monoclonal antibody immune checkpoint inhibitors for the treatment of advanced NSCLC., Expert Opinion: Further and larger studies will be needed to explore the promising emerging data on new ICIs. Future phase III trials could allow us to properly assess the role of each immune checkpoints in the wider context of the tumor microenvironment and thus the best new ICIs to use, the best approach and the most effective subset of patients to select.

RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib have revolutionized the landscape of RET-positive (RET+) advanced non-small cell lung cancer (NSCLC) treatment, thanks to their efficacy and safety profiles. This class of medications currently represents the standard of care for both naïve and patients that have not received selective RET-TKIs in the first-line setting. However, we presently lack a satisfactory understanding of resistance mechanism developing after selective RET-TKIs usage, as well as a specific treatment for patients progressing on selpercatinib or pralsetinib. Chemotherapy ± immunotherapy is considered as a recommended subsequent second-line regimen in these patients. Therefore, it is of paramount importance to better define and understand the resistance mechanisms triggered by RET-TKIs. With this in mind, the present review article has been conceived to provide a comprehensive overview about RET+ advanced NSCLC, both from a therapeutic and molecular point of view. Besides comparing the clinical outcome achieved in RET+ advanced NSCLC patients after multikinase inhibitors (MKIs) and/or RET-selective TKIs' administration, we focused on the molecular mechanisms accountable for their long-term resistance. Finally, a critical perspective on many of today's most debated issues and concerns is provided, with the purpose of shaping the possible pharmacological approaches for tomorrow's therapies.

Background/aim: Lung cancer is one of the most common malignant neoplastic diseases and by far the leading cause of cancer death worldwide. Recently, immune checkpoint inhibitors (ICIs) have received increasing attention for playing a crucial role in non-small cell lung cancer (NSCLC). Biomarkers, such as programmed cell death-ligand 1 (PD-L1) and tumor mutational burden (TMB), seemed to be helpful in selecting patients who are more likely to benefit from ICI treatment: however, their role has not yet been fully clarified., Patients and Methods: In this retrospective study, we evaluated the relationship between pre-treatment peripheral blood neutrophil-to-lymphocyte ratio (NLR) and survival in 252 patients suffering from advanced NSCLC who had received pembrolizumab as their first-line immunotherapy., Results: Compared to their NLR low counterparts who had a median overall survival (OS) of 34.8 months, patients with NLRs above 4.8 had a median OS of 7.6 months (HR=3.26, 95%Cl=2.3-4.6, p-value<0.0000001). In multivariate Cox regression analysis, alongside other variables, such as metastatic sites, age, and sex, NLR and PD-L1 predicted progression-free survival and OS; furthermore, a very high NLR - over 10 - seemed to forecast a very dismal prognosis in patients undergoing immunotherapy, with sudden deaths in the days immediately following therapy (median OS=3.8 months)., Conclusion: NLR acts as a valuable and reliable prognostic factor in non-small cell lung carcinoma patients undergoing first line immunotherapy with pembrolizumab. Additional investigation is necessary to fully elucidate the underlying biological rationale, which can be found in myeloid derived suppressor cells, a heterogeneous population of cells with neutrophil-like immunophenotypic features., Competing Interests: The Authors have no conflicts of interest to declare in relation to this study., (Copyright 2023, International Institute of Anticancer Research.)

Background: Brigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor with demonstrated efficacy in locally advanced and metastatic non-small cell lung cancer (NSCLC) in crizotinib-refractory and ALK inhibitor-naive settings. This analysis assessed brigatinib in Asian vs. non-Asian patients from the first-line ALTA-1L trial., Patients and Methods: This was a subgroup analysis from the phase III ALTA-1L trial of brigatinib vs. crizotinib in ALK inhibitor-naive ALK+ NSCLC. The primary endpoint was progression-free survival (PFS) as assessed by blinded independent review committee (BIRC). Secondary endpoints included confirmed objective response rate (ORR) and overall survival (OS) in the overall population and BIRC-assessed intracranial ORR and PFS in patients with brain metastases., Results: Of the 275 randomized patients, 108 were Asian. Brigatinib showed consistent superiority in BIRC-assessed PFS vs. crizotinib in Asian (hazard ratio [HR]: 0.35 [95% CI: 0.20-0.59]; log-rank P = .0001; median 24.0 vs. 11.1 months) and non-Asian (HR: 0.56 [95% CI: 0.38-0.84]; log-rank P = .0041; median 24.7 vs. 9.4 months) patients. Results were consistent with investigator-assessed PFS and BIRC-assessed intracranial PFS. Brigatinib was well tolerated. Toxicity profiles and dose modification rates were similar between Asian and non-Asian patients., Conclusion: Efficacy with brigatinib was consistently better than with crizotinib in Asian and non-Asian patients with locally advanced or metastatic ALK inhibitor-naive ALK-+ NSCLC. There were no clinically notable differences in overall safety in Asian vs. non-Asian patients., (Copyright © 2022. Published by Elsevier Inc.)

As of today, only two antiangiogenic monoclonal antibodies plus epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) combinations are FDA and EMA-approved and are recommended by American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network for the first-line treatment of EGFR+ advanced non-small cell lung cancer patients: erlotinib plus bevacizumab and erlotinib plus ramucirumab. However, all treated patients eventually become unresponsive to such drugs, due to several different acquired resistance mechanisms, mainly represented by T790M substitutions and MET amplifications. While osimertinib treatment in T790M+ patients still represents the only approved treatment, MET-TKIs will likely change this status quo in the near future. In fact, existing clinical data strongly support a role for MET-TKI-based combinations in EGFR+ MET-amplified patients, possibly revolutionizing our current treatment algorithm. Chemotherapy plus immunotherapy plus antiangiogenic therapy combinations could also represent another useful addition., Competing Interests: Dr. Gridelli C received honoraria as speaker bureau and advisory board member from Astra Zeneca, BMS, MSD, Roche, Sanofi, GSK, Menarini, Karyopharm, Amgen, Pfizer, Eli Lilly, Takeda, Novartis; all the other authors have no conflicts of interest to declare., (© The Author(s) 2022.)

Objective: The primary goal of the Campania Oncology Network (ROC) was to reduce cancer delay and care fragmentation through the establishment of cancer-specific multidisciplinary oncologic groups (GOMs) and diagnostic and therapeutic assistance paths (PDTAs)., Methods: Five cancer centres of the ROC, with their own cancer specific GOM, were selected. In our analysis, we have focused on four neoplasms: lung, colon, ovarian and prostate cancers. The median time for pre-GOM and GOM Times was calculated for each tumour site. Univariate and multivariate logistic regressions were performed to individuate risk factors for pre-GOM and GOM Time., Results: Significant differences were observed for prostate cancer compared to other patients either for pre-GOM or GOM Times. Significant risks were found for ovarian and prostate cancers in pre-GOM time and for prostate cancer in GOM-Time., Conclusions: This experience will produce knowledge and data to guide decision-making and to manage more effectively the challenges of fighting cancer in Campania region. The Valutazione Percorso Rete Oncologica Campana (ValPeROC) study evaluates, for the first time, the ROC activity, through the analysis of key performance indices. Pre-GOM and GOM Time represent the quality of the entire regional health system and are useful to define models, which can evaluate the performance of the ROC over time., (© 2022 John Wiley & Sons Ltd.)

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.)

Aim: ALK , ROS1 , NTRK  and RET gene fusions and MET exon 14 skipping alterations represent novel predictive biomarkers for advanced non-small-cell lung cancer (NSCLC). Therefore, testing patients for these genetic variants is crucial for choosing the best selective treatment. Over the last couple of decades, next-generation sequencing (NGS) platforms have emerged as an extremely useful tool for detecting these variants. Materials & methods: In the present study, we report our NGS molecular records produced during a year of diagnostic activity. Results: Overall, our in-house developed NGS workflow successfully analyzed n = 116/131 (88.5%) NSCLC samples. Of these, eight (6.8%) and five (4.3%) out of 116 patients harbored ALK and RET gene rearrangements, respectively: one case harbored ROS1 gene fusion (0.7%). Conclusion: Our results highlight that an RNA-based NGS analysis can reliably detect gene fusion alterations, thereby playing a pivotal role in the management of NSCLC patients.

Background: Immune-checkpoint inhibitors (ICIs) have increased and improved the treatment options for patients with non-oncogene-addicted advanced stage non-small cell lung cancer (NSCLC). However, the role of ICIs in oncogene-addicted advanced stage NSCLC patients is still debated. In this study, in an attempt to fill in the informational gap on the effect of ICIs on other driver mutations, we set out to provide a molecular landscape of clinically relevant oncogenic drivers in programmed death-ligand 1 (PD-L1) positive NSCLC patients., Methods: We retrospectively reviewed data on 167 advanced stage NSCLC PD-L1 positive patients (≥1%) who were referred to our clinic for molecular evaluation of five driver oncogenes, namely, EGFR , KRAS , BRAF , ALK and ROS1 ., Results: Interestingly, n = 93 (55.7%) patients showed at least one genomic alteration within the tested genes. Furthermore, analyzing a subset of patients with PD-L1 tumor proportion score (TPS) ≥ 50% and concomitant gene alterations ( n = 8), we found that n = 3 (37.5%) of these patients feature clinical benefit with ICIs administration, despite the presence of a concomitant KRAS gene alteration., Conclusions: In this study, we provide a molecular landscape of clinically relevant biomarkers in NSCLC PD-L1 positive patients, along with data evidencing the clinical benefit of ICIs in patient NSCLC PD-L1 positive alterations.

Competing Interests: FdM has served in a consultant/advisory role for Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Merck Sharp & Dohme, Novartis, Roche Genentech, Takeda and Pfizer, outside the submitted work. CG received honoraria as speaker bureau or advisory board member or as consultant from MSD, BMS, Roche, AstraZeneca, Novartis, Pfizer, Menarini, Boehringer, Karyopharm and Eli Lilly. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.

Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-527/coif). CZ serves as an Editor-in-Chief of Translational Lung Cancer Research from August 2014 to July 2022. SHL serves as an unpaid editorial board member of Translational Lung Cancer Research from September 2019 to September 2023. GM serves as an unpaid editorial board member of Translational Lung Cancer Research from February 2016 to July 2023. CG serves as an unpaid editorial board member of Translational Lung Cancer Research from September 2019 to September 2023, and received honoraria as speaker bureau or advisory board member or consulting fees form Menarini, Roche, Eli Lilly, Boehringer, Amgen, Pfizer, Novartis, MSD, BMS, Astra Zeneca, Takeda, Novartis, GSK, Karyopharm. Qing Z received lecture and presentations fees from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, and Sanofi. AB received consulting fees as an Advisory Board with Astra Zeneca, BD, Ethicon, Medtronic, Roche, and is the president of European Society of Thoracic Surgeons. TJ received consulting fees from Roche, Merck, MSD, Puma, AstraZeneca, BMS, Amgen, Gilead, Specialised Therapeutics. DHO reports research funding (to institution) from Genentech, BMS, Merck, Pfizer, Palobiofarma, and Onc. AI. MR received honoraria for lectures and expert meetings from Astrazeneca, and also received honoraria for lectures and expert meetings as well as travel expenses from Abex. KS received a research grant from Boehringer-Ingelheim, through Kindai University Faculty of Medicine, has received consulting fees from AstraZeneca, and has received honoraria from Chugai, Taiho, and AstraZeneca. FT received speaker bureau from AstraZeneca. The other authors have no conflicts of interest to declare.

Background and Objective: The genetic nature of cancer provides the rationale to support the need for molecular diagnosis and patient selection for individualised antineoplastic treatments that are the best in both tolerability and efficacy for each cancer patient, including non-small cell lung cancer (NSCLC) patients. Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations represent the prevalent oncogenic driver in NSCLC, being detected in roughly one-third of cases and KRAS G12C is the most frequent mutation found in approximately 13% of patients., Methods: This paper gives an overview of the numerous scientific efforts in recent decades aimed at KRAS inhibition., Key Content and Findings: Sotorasib is the first approved KRAS G12C inhibitor that has been shown to provide a durable clinical benefit in patients with pre-treated NSCLC with KRAS G12C mutation. Together with the development of new targeted drugs, the development of strategies to control resistance mechanisms is one of the major drivers of research that is exploring the use of KRAS inhibitors not only alone, but also in combination with other targeted therapies, chemotherapy and immunotherapy., Conclusions: This review will describe the major therapeutic developments in KRAS mutation-dependent NSCLC and will analyse future perspectives to maximise benefits for this group of patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-21-948/coif). CG received honoraria as speaker bureau, advisory board member or consultant by: MSD, BMS, Roche, Astra Zeneca, Pfizer, Amgen, Novartis, GSK, Menarini, Karyopharm, Boehringer, Sanofi, Takeda, Eli Lilly. PM received honoraria for educational events by: Astra Zeneca, BMS, Boehringer, MSD. The other authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

Introduction : Approximately 5% of all diagnosed non-small cell lung cancer (NSCLC) patients harbor a genetic rearrangement between the ALK and EML4 genes, representing a specific molecular, histological and clinical subgroup (ALK+ NSCLC). To date, upfront treatment with ALK-tyrosine-kinase inhibitors (ALK-TKIs) has replaced chemotherapy in the first line setting for this subset of patients with excellent results. However, all treated patients eventually develop acquired resistance mechanisms to these agents (mainly resistance mutations) and experience progression of the disease. Areas covered : This paper provides a comprehensive state-of-the-art review about first-line approved ALK-TKIs, furthermore, it discusses the most promising ALK-TKIs under development designed to overcome resistance mutations and their implications. Expert opinion : Alectinib should currently be regarded as the standard of care for the first-line treatment of ALK+ NSCLC, considering its superior efficacy and safety profile. Regarding developing agents, lorlatinib and ensartinib appear to be the most promising ones, even though the data from their trials are still immature.

Introduction: Chemo-immunotherapy combinations have revolutionized our treatment algorithm with respect to naïve advanced NSCLC; however, given the great number of developed and approved combinations, the question arises as to which combinations provide the best efficacy and safety., Areas Covered: This review assesses and discusses the available data concerning chemo-immunotherapy combinations in the treatment of naïve advanced NSCLC, as well as presenting the most promising data involving combinations currently under investigation., Expert Opinion: Pembrolizumab-containing chemo-immunotherapy combinations are associated with the most mature data available and presently represent the standard treatment in clinical practice in naïve advanced NSCLC-affected patients. The nivolumab plus ipilimumab plus short-course chemotherapy combination, more recently approved by regulatory agencies, is an appealing alternative, thanks to the reduced rate of grade 3-5 TRAEs and the limited chemotherapy administration. The new chemo-immunotherapy combinations currently under investigation will help us to better identify both the best immune checkpoints to target and the most effective combinations to administer.