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The ever-growing knowledge regarding NSCLC molecular biology has brought innovative therapies into clinical practice; however, the treatment situation in the non-metastatic setting is rapidly evolving. Indeed, immunotherapy-based perioperative treatments are currently considered the standard of care for patients with resectable NSCLC in the absence of EGFR mutations or ALK gene rearrangements. Recently, data have been presented on the use of tyrosine kinase inhibitors (TKIs) in the adjuvant and locally advanced setting for patients with NSCLC harboring such driver gene alterations. The aim of the current work is to review the available evidence on the use of targeted treatments in the non-metastatic setting, together with a summary of the ongoing trials designed for actionable gene alterations other than EGFR and ALK . To date, 3-year adjuvant osimertinib treatment has been demonstrated to improve DFS and OS and to reduce CNS recurrence in resected EGFR -mutated NSCLC in stage IB-IIIA (TNM 7th edition). The use of osimertinib after chemo-radiation in stage III unresectable EGFR -mutated NSCLC showed the relevant PFS improvement. In the ALK -positive setting, 2-year alectinib treatment was shown to clearly improve DFS compared to adjuvant standard chemotherapy in resected NSCLC with stage IB (≥4 cm)-IIIA (TNM 7th edition). Several trials are ongoing to establish the optimal adjuvant TKI treatment duration, as well as neoadjuvant TKI strategies in EGFR- and ALK -positive disease, and (neo)adjuvant targeted treatments in patients with actionable gene alterations other than EGFR or ALK . In conclusion, our review depicts how the current treatment scenario is expected to rapidly change in the context of non-metastatic NSCLC with actionable gene alterations, hence appropriate molecular testing from the early stages has become crucial to establish the most adequate approaches both in the perioperative and the locally advanced disease.

RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1-2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the 'old' multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events.

Background: Actionable driver mutations account for 40-50% of NSCLC cases, and their identification clearly affects treatment choices and outcomes. Conversely, non-actionable mutations are genetic alterations that do not currently have established treatment implications. Among co-occurring alterations, the identification of concurrent actionable genomic alterations is a rare event, potentially impacting prognosis and treatment outcomes. Methods: We retrospectively evaluated the prevalence and patterns of concurrent driver genomic alterations in a large series of NSCLCs to investigate their association with clinicopathological characteristics, to assess the prognosis of patients whose tumor harbors concurrent alterations in the genes of interest and to explore their potential therapeutic implications. Results: Co-occurring driver alterations were identified in 26 out of 1520 patients with at least one gene alteration (1.7%). Within these cases, the incidence of concurrent actionable gene alterations was 39% (0.7% of the overall cohort). Among compound actionable gene mutations, EGFR was the most frequently involved gene (70%). The most frequent association was EGFR mutations with ROS1 rearrangement. Front-line targeted treatments were the preferred approach in patients with compound actionable mutations, with dismal median PFS observed (6 months). Conclusions: Advances in genomic profiling technologies are facilitating the identification of concurrent mutations. In patients with concurrent actionable gene alterations, integrated molecular and clinical data should be used to guide treatment decisions, always considering rebiopsy at the moment of disease progression.

Background: Platinum-based chemotherapy is the current standard treatment option in patients with EGFR -mutant non-small-cell lung cancer (NSCLC) who progress on osimertinib. However, outcomes with chemotherapy are dismal, and the treatment of central nervous system (CNS) disease is an unmet need in this setting., Methods: Patients with EGFR -mutant NSCLC who were candidates to receive osimertinib in the metastatic setting at our Center from 2015 to 2022 were retrospectively evaluated to identify patients who received standard platinum-based chemotherapy post-osimertinib. Data were collected on treatment outcomes, with a focus on brain metastases and progression patterns., Results: A total of 220 patients received indication for osimertinib in the study period; n = 176 had adequate follow-up data. Overall, n = 117 patients experienced disease progression on osimertinib. The median time to osimertinib progressive disease (PD) was 15 months (95% confidence interval CI 13-18). Of them, 51 patients (45%) had no access to further treatments. Of the remaining patients, n = 8 received experimental treatments, and n = 55 received standard platinum-based chemotherapy and were considered for this study. Median duration of chemotherapy was 3 months (95% CI 2-5); the best responses among 53 evaluable patients were observed as follows: 15% partial response/complete response (PR/CR), 40% stable disease (SD), 45% PD. Median progression-free survival (PFS) and overall survival (OS) were 3 (95% CI 2-5) and 10 (95% CI 6-15) months, respectively. All patients had baseline and follow-up brain radiologic assessments, and n = 23 had brain metastases at the start of chemotherapy. With a median follow-up of 13 months, intracranial PD occurred in 47% patients, being the first site of PD in 59% of cases. The median time for intracranial (IC) PD was 2 months (95% CI 2-7). IC PD occurred as oligometastatic in 29%, whereas in 71% of cases, it was associated with systemic PD., Conclusions: Access to subsequent treatments and CNS progression are confirmed unmet needs in EGFR -mutant NSCLC patients. Clinical and CNS-specific outcomes in patients receiving standard chemotherapy after the failure of osimertinib are dismal. Novel upfront treatment options with demonstrated prolonged PFS and better CNS outcomes may help address this important issue.

Various next-generation ALK TKIs are available as first-line options for ALK-positive NSCLC, with alectinib and lorlatinib being commonly preferred. However, no direct comparison between them has been conducted, making it impossible to pick a winner. We performed an analytic, 'non-comparative' assessment of the two phase 3 pivotal clinical trials showing superiority of alectinib (ALEX) and lorlatinib (CROWN) in comparison to crizotinib. Overall, the two studies were very similar in the study design and patient characteristics, with the exception of the selection and evaluation of brain metastases. PFS hazard ratios numerically favored lorlatinib, both according to the investigator and to BICR. Notably, the 3-year PFS rate was numerically higher with lorlatinib (64%) than with alectinib (46.4%). Despite similar response rates and overall intracranial response, the rate of complete intracranial response was higher with lorlatinib, with a cumulative incidence risk of CNS disease progression at 12 months of 9.4% with alectinib and 2.8% with lorlatinib. The peculiar toxicities of lorlatinib were related to lipidic profile alterations, peripheral oedema and cognitive effects, with no impact on cardiovascular risk nor impairment in quality of life versus crizotinib. Furthermore, the rate of permanent treatment discontinuation due to adverse events was numerically higher with alectinib (26%) than with lorlatinib (7%). In conclusion, despite the immature OS data for both drugs, the efficacy of lorlatinib appears higher than alectinib while maintaining a manageable toxicity profile., Competing Interests: I. Attili received consulting fees from Bristol-Myers Squibb 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 outside the submitted work. A. Passaro reports personal fees, as a speaker bureau or advisor, for AstraZeneca, Agilent/Dako, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly, Merck Sharp & Dohme, Janssen, Novartis, Pfizer and Roche Genentech outside the submitted work. 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 funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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.)

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma accounting for 15% of lung cancers with dismal survival outcomes. Minimal changes in therapy and prognosis have occurred in SCLC for the past four decades. Recent progress in the treatment of extensive-stage disease (ES-SCLC) has been marked by incorporating immune checkpoint inhibitors (ICIs) into platinum-based chemotherapy, leading to modest improvements. Moreover, few second-line-and-beyond treatment options are currently available. The main limitation for the molecular study of SCLC has been the scarcity of samples, because only very early diseases are treated with surgery and biopsies are not performed when the disease progresses. Despite all these difficulties, in recent years we have come to understand that SCLC is not a homogeneous disease. At the molecular level, in addition to the universal loss of retinoblastoma (RB) and TP53 genes, a recent large molecular study has identified other mutations that could serve as targets for therapy development or patient selection. In recent years, there has also been the identification of new genetic subtypes which have shown us how intertumor heterogeneity exists. Moreover, SCLC can also develop intratumoral heterogeneity linked mainly to the concept of cellular plasticity, mostly due to the development of resistance to therapies. The aim of this review is to quickly present the current standard of care of ES-SCLC, to focus on the molecular landscapes and subtypes of SCLC, subsequently present the most promising therapeutic strategies under investigation, and finally recap the future directions of ongoing clinical trials for this aggressive disease which still remains a challenge.

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.)

Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring most driver gene alterations. Starting from the first generation, research rapidly moved to the development of newer, more selective generations of TKIs, obtaining improved results in terms of disease control and survival. However, the use of novel generations of TKIs is not without limitations. We reviewed the main results obtained, as well as the ongoing clinical trials with TKIs in oncogene-addicted NSCLC, together with the biology underlying their potential strengths and limitations. Across driver gene alterations, novel generations of TKIs allowed delayed resistance, prolonged survival, and improved brain penetration compared to previous generations, although with different toxicity profiles, that generally moved their use from further lines to the front-line treatment. However, the anticipated positioning of novel generation TKIs leads to abolishing the possibility of TKI treatment sequencing and any role of previous generations. In addition, under the selective pressure of such more potent drugs, resistant clones emerge harboring more complex and hard-to-target resistance mechanisms. Deeper knowledge of tumor biology and drug properties will help identify new strategies, including combinatorial treatments, to continue improving results in patients with oncogene-addicted NSCLC.

Non-Small-Cell Lung Cancer (NSCLC) can harbour different MET alterations, such as MET overexpression (MET OE), MET gene amplification (MET AMP), or MET gene mutations. Retrospective studies of surgical series of patients with MET-dysregulated NSCLC have shown worse clinical outcomes irrespective of the type of specific MET gene alteration. On the other hand, earlier attempts failed to identify the 'druggable' molecular gene driver until the discovery of MET exon 14 skipping mutations (METex14). METex14 are rare and amount to around 3% of all NSCLCs. Patients with METex14 NSCLC attain modest results when they are treated with immune checkpoint inhibitors (ICIs). New selective MET inhibitors (MET-Is) showed a long-lasting clinical benefit in patients with METex14 NSCLC and modest activity in patients with MET AMP NSCLC. Ongoing clinical trials are investigating new small molecule tyrosine kinase inhibitors, bispecific antibodies, or antibodies drug conjugate (ADCs). This review focuses on the prognostic role of MET, the summary of pivotal clinical trials of selective MET-Is with a focus on resistance mechanisms. The last section is addressed to future developments and challenges.

Background: Since their first introduction in clinical practice, immune checkpoint inhibitors showed limited benefit in patients with NSCLC harboring EGFR mutations. With the rationale of increasing immune activation, combinatorial ICI strategies have been evaluated also in this subgroup of patients., Methods: We performed a systematic review on efficacy of ICI-based strategies in EGFR-mutant NSCLC according to most updated evidence., Results: Overall, ICI monotherapy and ICI plus chemotherapy confirm to be ineffective in EGFR-mutant NSCLC, whereas the combination of ICI with antiangiogenic and chemotherapy showed promising results. Limited data are available with alternative ICI combination strategies, driven by strong biological rationale of modulating the tumor immune microenvironment., Conclusions: To date, the available evidence do not support the use of ICI in patients with NSCLC harboring EGFR mutations. Clinical trials are ongoing to define which is the best timing and exploring novel combinations with ICI in this specific disease., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A. Passaro reports personal fees, as speaker bureau or advisor, for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly, Merck Sharp & Dohme, Janssen, Novartis, Pfizer and Roche Genentech, outside the submitted work; F. de Marinis 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. 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., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

ALK translocation amounts to around 3-7% of all NSCLCs. The clinical features of ALK+ NSCLC are an adenocarcinoma histology, younger age, limited smoking history, and brain metastases. The activity of chemotherapy and immunotherapy is modest in ALK+ disease. Several randomized trials have proven that ALK inhibitors (ALK-Is) have greater efficacy with respect to platinum-based chemotherapy and that second/third generation ALK-Is are better than crizotinib in terms of improvements in median progression-free survival and brain metastases management. Unfortunately, most patients develop acquired resistance to ALK-Is that is mediated by on- and off-target mechanisms. Translational and clinical research are continuing to develop new drugs and/or combinations in order to raise the bar and further improve the results attained up to now. This review summarizes first-line randomized clinical trials of several ALK-Is and the management of brain metastases with a focus on ALK-I resistance mechanisms. The last section addresses future developments and challenges.

Background: Following the introduction of immunotherapy (IO) in the first-line (1L) treatment in patients with non-small cell lung cancer (NSCLC) without sensitizing EGFR/ALK mutations, increasing real-world data depict how difficult it is to replicate data from clinical trials to clinical practice, with high rates of early treatment failure. In the context of chemo-IO, our study aims to compare platinum-pemetrexed-pembrolizumab combination to platinum-doublet alone in patients with low PD-L1 (<50%)., Methods: We retrospectively collected medical records from patients with stage IV non-squamous NSCLC with PD-L1<50%, consecutively treated at our Centre from 2016 to 2021. Patients were grouped according to 1L treatment received: chemo-IO (group A) or platinum-doublet (group B). Survival outcomes were analyzed and compared among the two groups., Results: Overall, 105 patients were included: 49 in group A and 56 in group B. At data cut-off, median follow-up was 12.4 and 34.8 months, with 32/49 and 52/56 events for progression-free survival (PFS) and 21/49 and 29/56 events for overall survival (OS), respectively. No difference in PFS was observed between group B and group A (6.6 versus 8 months, HR 1.12, 95%CI 0.57-1.40). Patients receiving 1L platinum-doublet had significantly longer OS compared to those receiving chemo-IO (median OS 23.8 vs 14.9 months, HR 0.47, 95% CI 1.15- 3.98, p=0.01). 12 month-OS was 58% (95% CI 44-76%) in group A and 78% (95% CI 68-91%) in group B (p=0.040). Subgroup analysis identified KRAS G12C mutation as potentially affecting PFS in patients receiving chemo-IO (HR 0.29, 95% CI 0-10-0.91). The OS benefit of platinum-doublet was consistent across subgroups, with particular benefit in female sex, liver or pleural metastases, PD-L1 negative. Overall, only 46.9% of patients with progression received subsequent treatment in group A (15/32), compared to 86.5% in group B (45/52, all receiving 2L IO), with no difference in PFS to 2L (group A 3.7months, group B 4.1months, p=0.3)., Conclusions: Despite small study population and differential follow-up, our study demonstrates that sequential use of 1L platinum-doublet and 2L IO is not inferior to 1L chemo-IO in non-squamous NSCLC with PD-L1<50%. In addition, we identified subgroups who might benefit differentially from the two approaches., (Copyright © 2022 Attili, Valenza, Santoro, Antonarelli, Trillo Aliaga, Del Signore, Catania, Spitaleri, Passaro and de Marinis.)

Surgery is the best option for patients with early stage non-small cell lung cancer (NSCLC). However, the rate of local and metastatic recurrences following surgery alone is high, especially in NSCLC patients with N2 lymph node involvement. A recent American study showed that 60% of lung cancers are diagnosed in an advanced stage, and less than 20% are diagnosed in an early, resectable stage. The same study reported the 5 year survival of patients with stage IV NSCLC was 6% compared to 50% in patients with resectable NSCLC depending by stage. The addition of adjuvant or neoadjuvant chemotherapy only improves 5 year survival by 5%-10%. Recently, immunotherapy with or without chemotherapy and novel targeted therapies have yielded excellent results, in terms of both progression-free survival and overall survival, in advanced NSCLC. Published studies have shown a benefit in using immunotherapy and targeted therapy in both the adjuvant and neoadjuvant settings with many further studies still ongoing. Here we review the published data on immunotherapy and targeted therapy in the adjuvant and neoadjuvant settings in patients with operable NSCLC., Competing Interests: Declaration of Competing Interest All authors have no conflicts of interest regarding this paper. All authors participated equally in writing this paper., (Copyright © 2021. Published by Elsevier Inc.)