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In a randomized trial involving patients with ALK -rearranged lung cancer, brigatinib was associated with longer progression-free survival and more activity against central nervous system disease than crizotinib.

Small-cell lung cancer (SCLC) is the most lethal histologic subtype of lung cancer. It is characterized by rapid tumor growth and early metastatic dissemination, resulting in an extremely poor prognosis. The addition of immunotherapy to standard chemotherapy has led to a modest improvement in survival for patients with extensive-stage disease. However, the overall clinical benefit remains limited due to both primary and acquired resistance to immunotherapy. Indeed, the efficacy of immune checkpoint inhibitors is influenced by multiple factors, including tumor heterogeneity, an immunosuppressive tumor microenvironment, and intrinsic molecular characteristics of the disease. In recent years, active research has been conducted to identify and therapeutically overcome resistance mechanisms to immunotherapy, and accumulating suggestive evidence is lighting the way for new strategies for clinical management of patients with SCLC. In this review article, we summarize and discuss the substantial obstacle to immunotherapy clinical efficacy, with a particular emphasis on the published and ongoing clinical trials that investigated the potential strategies to overcome mechanisms of resistance to immunotherapy. Moreover, we report and discuss the new therapeutic approaches tested, especially the use of antibody–drug conjugates, bi-specific antibodies, adoptive cell therapies and combination strategies.

Non-Small-Cell Lung Cancer (NSCLC) is the primary cause of cancer-related death worldwide. Oncogene-addicted patients usually benefit from targeted therapy, but primary and acquired resistance mechanisms inevitably occur. Tumor protein 53 (TP53) gene is the most frequently mutated gene in cancer, including NSCLC. TP53 mutations are able to induce carcinogenesis, tumor development and resistance to therapy, influencing patient prognosis and responsiveness to therapy. TP53 mutants present in different forms, suggesting that different gene alterations confer specific acquired protein functions. In recent years, many associations between different TP53 mutations and responses to Epidermal Growth Factor Receptor (EGFR) targeted therapy in NSCLC patients have been found. In this review, we discuss the current landscape concerning the role of TP53 mutants to guide primary and acquired resistance to Tyrosine-Kinase Inhibitors (TKIs) EGFR-directed, investigating the possible mechanisms of TP53 mutants within the cellular compartments. We also discuss the role of the TP53 mutations in predicting the response to targeted therapy with EGFR-TKIs, as a possible biomarker to guide patient stratification for treatment.

Background Despite sensitivity to first-line chemotherapy, most small-cell lung cancer (SCLC) patients relapse. In this setting, topotecan demonstrated modest activity with significant toxicity. Paclitaxel was also active. This study was designed to evaluate activity and safety of nab-paclitaxel in relapsed SCLC. Methods In this multicentre prospective Phase 2 trial, patients with refractory or sensitive SCLC progressed to first-line platinum-based chemotherapy received nab-paclitaxel 100 mg/smq on days 1, 8, 15 every 4 weeks up to six cycles, progressive disease or intolerable toxicity. Primary endpoint was investigator-assessed objective tumour response. Secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). Results Of the 68 patients treated, partial response was 8% in the refractory cohort and 14% in the sensitive cohort. Most common toxicities of any grade were fatigue (54%), anaemia (38%), neutropenia (29%), leukopenia (26%) and diarrhoea (21%). Median PFS was similar in both refractory (1.8 months) and sensitive cohorts (1.9 months), while median OS was longer in sensitive one (6.6 versus 3.6 months). Conclusions Although nab-paclitaxel has shown some modest anti-tumour activity in relapsed SCLC, associated with a favourable toxicity profile, the primary end-point of the study was not met. Clinical Trial registration Clinical Trial registration number is ClinicalTrials.gov Identifier: NCT03219762.

Immunotherapy has become the standard of care for non-small cell lung cancer (NSCLC) patients. Some patients experience primary resistance to immunotherapy. Currently, we lack a marker of resistance to immunotherapy. Myeloid-derived suppressive-like cells (MDSCs) can reduce tumor response rate and survival outcomes. This is an exploratory prospective observational study on metastatic NSCLC patients starting immunotherapy. Baseline peripheral blood samples were collected. Monocytic (M)-MDSCs were analyzed by flow cytometry. The main clinical outcomes were tumor response, progression-free survival (PFS), and overall survival (OS). The association between MDSC levels and tumor response was assessed. The association of PFS with OS was investigated using the Kaplan-Meier method and the Cox proportional hazards model. Twenty-two patients were included. The median M-MDSC value was higher in patients with progressive disease than patients with stable disease or partial response, p = 0.045. The median MDSC value in the overall population was 1.9. We found worse PFS (HR = 2.51; p = 0.046) and OS (HR = 2.68; p = 0.042) in patients with M-MDSC values higher than the median. In this exploratory analysis, high M-MDSC levels are strongly associated with primary resistance to immunotherapy. If validated in larger studies, MDSC levels in blood samples could help to select NSCLC patients for higher benefit from immunotherapy.

BackgroundBone metastases (BoM) are a negative prognostic factor in non-small-cell lung cancer (NSCLC). Beyond its supportive role, bone is a hematopoietic organ actively regulating immune system. We hypothesized that BoM may influence sensitivity to immunotherapy.MethodsPretreated non-squamous (cohort A) and squamous (cohort B) NSCLCs included in the Italian Expanded Access Program were evaluated for nivolumab efficacy according to BoM.ResultsCohort A accounted for 1588 patients with non-squamous NSCLC, including 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 371 patients with squamous histology including 120 BoM+ (32%) and 251 (68%) BoM- cases. BoM+ had lower overall response rate (ORR; Cohort A: 12% versus 23%, p <  0.0001; Cohort B: 13% versus 22%, p = 0.04), shorter progression free survival (PFS; Cohort A: 3.0 versus 4.0 months, p <  0.0001; Cohort B: 2.7 versus 5.2 months, p <  0.0001) and overall survival (OS; Cohort A: 7.4 versus 15.3 months, p <  0.0001; Cohort B: 5.0 versus 10.9 months, p < 0.0001). Moreover, BoM negatively affected outcome irrespective of performance status (PS; OS in both cohorts: p < 0.0001) and liver metastases (OS cohort A: p < 0.0001; OS Cohort B: p = 0.48). At multivariate analysis, BoM independently associated with higher risk of death (cohort A: HR 1.50; cohort B: HR 1.78).ConclusionsBoM impairs immunotherapy efficacy. Accurate bone staging should be included in clinical trials with immunotherapy.

Non-small-cell lung cancer (NSCLC) patients with mutated or rearranged oncogene drivers can be treated with upfront selective inhibitors achieving higher response rates and longer survival than chemotherapy. The RET gene can undergo chromosomal rearrangements in 1%-2% of all NSCLC patients, involving various upstream fusion partners such as KIF5B, CCDC6, NCOA4, and TRIM33. Many multikinase inhibitors are active against rearranged RET. Cabozantinib, vandetanib, sunitinib, lenvatinib, and nintedanib achieved tumor responses in about 30% of these patients in retrospective studies. Prospective phase II trials investigated the activity and toxicity of cabozantinib, vandetanib, sorafenib, and lenvatinib, and did not reach significantly higher response rates. VEGFR and EGFR inhibition represented the main ways of developing off-target toxicity. An intrinsic resistance emerged according to the type of RET fusion partners, as KIF5B-RET fusion is the most resistant. Also acquired mutations in rearranged RET oncogene developed as resistance to these multikinase inhibitors. Interestingly, RET fusions have been found as a resistance mechanism to EGFR-TKIs in EGFR-mutant NSCLC patients. The combination of EGFR and RET inhibition can overcome this resistance. The limitations in terms of activity and tolerability of the various multikinase inhibitors prompted the investigation of new highly selective RET inhibitors, such as RXDX-105, BLU-667, and LOXO-292. Some data emerged about intracranial antitumor activity of BLU-667 and LOXO-292. If these novel drugs will achieve high activity in RET rearranged NSCLC, also these oncogene-addicted tumors can undergo a significant survival improvement.

Pleural mesothelioma (PM) is an aggressive and rare disease, characterized by a very poor prognosis. For almost two decades, the world standard treatment regimen for unresectable PM has consisted of a platinum-based drug plus pemetrexed, leading to an overall survival of approximately 12 months. The dramatic therapeutic scenario of PM has recently changed with the entry into the clinic of immune checkpoint inhibition, which has proven to be an effective approach to improve the survival of PM patients. The aim of the present review is to provide a comprehensive overview of the most promising immunotherapeutic-based strategies currently under investigation for advanced PM.

Over the past decades, significant progress has been made in the understanding of non-small cell lung cancer (NSCLC) biology and tumor progression mechanisms, resulting in the development of novel strategies for early detection and wide-ranging care approaches. Since their introduction, over 20 years ago, targeted therapies with tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for NSCLC. Nowadays, targeted therapies remain the gold standard for many patients, but still they suffer from many adverse effects, including unexpected toxicity and intrinsic acquired resistance mutations, which lead to relapse. The adoption of immune checkpoint inhibitors (ICIs) in 2015, has offered exceptional survival benefits for patients without targetable alterations. Despite this notable progress, challenges remain, as not all patients respond favorably to ICIs, and resistance to therapy can develop over time. A crucial factor influencing clinical response to immunotherapy is the tumor microenvironment (TME). The TME is pivotal in orchestrating the interactions between neoplastic cells and the immune system, influencing tumor growth and treatment outcomes. In this review, we discuss how the understanding of this intricate relationship is crucial for the success of immunotherapy and survey the current state of immunotherapy intervention, with a focus on forthcoming and promising chimeric antigen receptor (CAR) T cell therapies in NSCLC. The TME sets major obstacles for CAR-T therapies, creating conditions that suppress the immune response, inducing T cell exhaustion. To enhance treatment efficacy, specific efforts associated with CAR-T cell therapy in NSCLC, should definitely focus TME-related immunosuppression and antigen escape mechanisms, by combining CAR-T cells with immune checkpoint blockades.

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.