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Immune checkpoint inhibitors have significantly improved overall survival with an acceptable safety profile in a substantial proportion of non-small cell lung cancer (NSCLC) patients. However, not all patients are sensitive to immune checkpoint blockade and, in some cases, programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors accelerate tumor progression. Several combination strategies are under evaluation, including the concomitant or sequential evaluation of chemotherapy or radiotherapy with immunotherapy. The current review provides an overview on the molecular rationale for the investigation of combinatorial approaches with chemotherapy or radiotherapy. Moreover, the results of completed clinical studies will be reported.

Patients with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) have a higher risk of developing brain metastases (BMs) than patients with other NSCLC sub-types. ALK inhibitors have activity in BMs due to ALK+ NSCLC. We performed a systematic review of the literature with the aim of assessing the efficacy of ALK inhibitors on BMs. A systematic search of the literature was performed using the databases Pubmed, EMBASE, Web of Science, The Cochrane Library, and SCOPUS. Relevant publications reporting activity of ALK inhibitors in NSCLC BMs were retrieved. Data were pooled using the number of events/number of evaluable patients according to fixed or random effect models. Intracranial tumour response was assessed through overall response rate (ORR), disease control rate (DCR: ORR + stable disease rate), median progression-free survival (PFS), and overall survival (OS). The primary endpoint was intracranial overall response rate (IC ORR). A total of 1,016 patients with BMs from 21 studies were analysed. In patients receiving ALK inhibitors in the first line setting, the pooled IC ORR was 39.17% (95%CI 13.1-65.2%), while the pooled IC ORR observed in further lines was 44.2% (95%CI 33.3-55.1%). Intracranial disease control rate (IC DCR) was 70.3% and 78.2% in naïve and pre-treated patients, respectively. Patients who had not received brain radiation attained an IC ORR of 49.0%. Based on these data, ALK inhibitors are effective in both naive and pre-treated patients with similar IC ORR and IC DCR, irrespective of the line of therapy.

An established multivariate serum protein test can be used to classify patients according to whether they are likely to have a good or poor outcome after treatment with EGFR tyrosine-kinase inhibitors. We assessed the predictive power of this test in the comparison of erlotinib and chemotherapy in patients with non-small-cell lung cancer. From Feb 26, 2008, to April 11, 2012, patients (aged ≥18 years) with histologically or cytologically confirmed, second-line, stage IIIB or IV non-small-cell lung cancer were enrolled in 14 centres in Italy. Patients were stratified according to a minimisation algorithm by Eastern Cooperative Oncology Group performance status, smoking history, centre, and masked pretreatment serum protein test classification, and randomly assigned centrally in a 1:1 ratio to receive erlotinib (150 mg/day, orally) or chemotherapy (pemetrexed 500 mg/m2, intravenously, every 21 days, or docetaxel 75 mg/m2, intravenously, every 21 days). The proteomic test classification was masked for patients and investigators who gave treatments, and treatment allocation was masked for investigators who generated the proteomic classification. The primary endpoint was overall survival and the primary hypothesis was the existence of a significant interaction between the serum protein test classification and treatment. Analyses were done on the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00989690. 142 patients were randomly assigned to chemotherapy and 143 to erlotinib, and 129 (91%) and 134 (94%), respectively, were included in the per-protocol analysis. 88 (68%) patients in the chemotherapy group and 96 (72%) in the erlotinib group had a proteomic test classification of good. Median overall survival was 9·0 months (95% CI 6·8–10·9) in the chemotherapy group and 7·7 months (5·9–10·4) in the erlotinib group. We noted a significant interaction between treatment and proteomic classification (pinteraction=0·017 when adjusted for stratification factors; pinteraction=0·031 when unadjusted for stratification factors). Patients with a proteomic test classification of poor had worse survival on erlotinib than on chemotherapy (hazard ratio 1·72 [95% CI 1·08–2·74], p=0·022). There was no significant difference in overall survival between treatments for patients with a proteomic test classification of good (adjusted HR 1·06 [0·77–1·46], p=0·714). In the group of patients who received chemotherapy, the most common grade 3 or 4 toxic effect was neutropenia (19 [15%] vs one [<1%] in the erlotinib group), whereas skin toxicity (one [<1%] vs 22 [16%]) was the most frequent in the erlotinib group. Our findings indicate that serum protein test status is predictive of differential benefit in overall survival for erlotinib versus chemotherapy in the second-line setting. Patients classified as likely to have a poor outcome have better outcomes on chemotherapy than on erlotinib. Italian Ministry of Health, Italian Association of Cancer Research, and Biodesix.

Compared to other malignancies, few studies have investigated the role of family history of cancer (FHC) in patients with lung cancer, yielding largely heterogeneous results. We performed a systematic literature review in accordance with PRISMA guidelines, searching the PubMed and Scopus databases from their inception to November 25, 2023, to identify studies reporting on the role of FHC in patients with lung cancer. A total of 53 articles were included, most with a retrospective design and encompassing a variety of geographical areas and ethnicities. Thirty studies (56.6%) assessed patients with non-small cell lung cancer (NSCLC), while 17 studies (32.1%) assessed patients with mixed histologies. Overall, the rates of FHC ranged from 8.3 to 68.9%, and the rates of family history of lung cancer ranged from 2 to 46.8%. Twenty-seven studies investigated FHC as a potential risk factor for lung cancer, with more than half reporting an increased risk for subjects with FHC. Five studies reported on the potential role of FHC in determining clinical outcomes, and twelve studies examined the relationship between FHC and germline mutations. Notably, only one study reported a significantly increased rate of germline mutations, including ATM , BRCA2 , and TP53 , for patients with a family history of lung cancer compared to those without, but both groups had a low prevalence of mutations (< 1%). The FAHIC—Lung (NCT06196424) is the first cross-sectional/prospective study specifically developed to identify FHC patterns and within-family clusters of other risk factors, including smoking, to guide patients with NSCLC to systematic genetic counseling. Acknowledging the largely heterogeneous results of our systematic review and considering the clinical implications of detecting pathogenic germline variants (PGVs), the FAHIC-lung study aims to identify patients potentially enriched with PGVs/likely PGVs to direct them to germline screening outside of the research setting.

The ability to identify the broadest range of targetable gene fusions is crucial to facilitate personalized therapy selection for advanced lung adenocarcinoma (LuADs) patients harboring targetable receptor tyrosine kinase (RTK) genomic alterations. In order to evaluate the most effective testing approach for LuAD targetable gene fusion detection, we analyzed 210 NSCLC selected clinical samples, comparing in situ (Fluorescence In Situ Hybridization, FISH, and ImmunoHistoChemistry, IHC) and molecular (targeted RNA Next-Generation Sequencing, NGS, and RealTime-PCR, RT-PCR) approaches. The overall concordance among these methods was high (>90%), and targeted RNA NGS was confirmed to be the most efficient technique for gene fusion identification in clinical practice, allowing the simultaneous analysis of a large set of genomic rearrangements at the RNA level. However, we observed that FISH was useful to detect targetable fusions in those samples with inadequate tissue material for molecular testing as well as in those few cases whose fusions were not identified by the RNA NGS panel. We conclude that the targeted RNA NGS analysis of LuADs allows accurate RTK fusion detection; nevertheless, standard methods such as FISH should not be dismissed, as they can crucially contribute to the completion of the molecular characterization of LuADs and, most importantly, the identification of patients as candidates for targeted therapies.

Background: Lung cancer represents a significant health concern, particularly among the elderly population. With global life expectancy increasing, the number of very elderly patients is rising. Robotic-assisted thoracic surgery (RATS) offers potential advantages over both traditional and video-assisted thoracoscopic surgery (VATS). This study aims to evaluate the feasibility and safety of RATS in very elderly patients (VEP) diagnosed with lung cancer. Methods: This retrospective study included patients who underwent major lung resections using RATS between 2015 and 2022 at two specialized centers. Patients were divided into very elderly patients (VEP, ≥80 years) and non-elderly patients (NEP, <80 years). Demographic, clinical, and surgical data were analyzed. Propensity score matching (PSM) at a 1:3 ratio was performed using clinically relevant variables that were significantly different at baseline to balance the two groups. Results: This study included 340 patients: 28 VEP and 312 NEP. Before PSM, VEP had higher ASA scores, more advanced disease stages, and increased comorbidities. Despite these differences, postoperative outcomes were comparable. Complications occurred in 42.9% of VEP and 29.8% of NEP (p = 0.16), but grade III complications were observed in 14.3% of VEP and 6.4% of NEP (p = 0.12), and grade IV complications were observed in 0% of VEP and 0.9% of NEP (p = not estimable). The mean hospital stay was 4 days in both groups (p = 0.99). Even after PSM (26 VEP vs. 71 NEP), complications, hospital stay, and 90-day mortality (3.9% in VEP, 0% in NEP) were similar. Multivariable analysis identified reduced FEV1 as a predictor of complications, while pathological stage I and lobectomy were associated with a decreased risk of complications, both before and after PSM. Conclusions: RATS is a safe and feasible option for selected very elderly patients with lung cancer, yielding outcomes comparable to younger patients.

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.

Lung cancer remains the first cause of cancer-related deaths worldwide. Thanks to the improvement in the knowledge of the biology of non-small cell lung cancer (NSCLC), patients’ survival has significantly improved. A growing number of targetable molecular alterations have been identified. Next-generation sequencing (NGS) has become one of the methodologies entered in clinical practice and was recently recommended by the European society for medical oncology (ESMO) to perform a comprehensive molecular characterization in patients with cancer. The current review provides an overview of the clinical trials that have explored the impact of NGS in patients with cancer, its limits, and advantages.

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

The advent of immune checkpoint inhibitors gave rise to a new era in oncology and general medicine. The increasing use of programmed death-1 (PD-1) inhibitors in non-small cell lung cancer and in other malignancies means clinicians have to face up to new challenges in managing immune-related adverse events (irAEs), which often resemble autoimmune diseases. Neurological irAEs represent an emerging toxicity related to immunotherapy, and it is mandatory to know how to monitor, recognize, and manage them, since they can rapidly lead to patient death if untreated. Guidelines for the diagnosis and treatment of these irAEs have been recently published but sharing some of the most unusual clinical cases is crucial, in our opinion, to improve awareness and to optimize the approach for these patients. A literature review on the diagnosis and treatment of immune-related neurotoxicity’s has been conducted starting from the report of four cases of neurological irAEs regarding cases of polyneuropathy, myasthenia gravis, Bell’s palsy, and encephalopathy, all of which occurred in oncological patients receiving PD-1 inhibitors (pembrolizumab and nivolumab) for the treatment of non-oncogene addicted advanced non-small cell lung cancer. The exclusion of other differential diagnoses and the correlation between the suspension of immunotherapy and improvement of symptoms suggest that immunotherapy could be the cause of the neurological disorders reported.