Search

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic horizons of various cancers. However, immune-related adverse events have been reported, including interstitial lung diseases. Our aim was to describe the clinical and radiological features and survival of a multicentre cohort of patients who developed ICI-related lung toxicity. Methods: Six Italian centres were involved in the study. Patients who were treated with anti-PD-1/PD-L1 and CTLA-4 mAbs and developed ICI-related lung toxicity were recruited retrospectively to study clinical, radiological, immunological and survival data. Results: A total of 41 patients (25 males, 66.8 ± 9.9 years) were enrolled. Lung toxicity occurred after 204.3 ± 208.3 days of therapy, with ground glass opacities being the most common HRCT pattern (23 cases). Male sex, lung cancer and acute respiratory failure were associated with a shorter latency of toxicity (p = 0.0030, p = 0.0245 and p = 0.0390, respectively). Patients who required high-flow oxygen therapy showed significantly worse survival (p = 0.0028). Conclusions: Our cohort showed heterogeneous clinical and radiological aspects of ICI-related lung toxicity, with a latency not limited to the first year of treatment. Severity was mainly mild to moderate, although life-threatening events did occur. Our data indicate that strict long-term follow-up is needed to enable early diagnosis and appropriate management. [ABSTRACT FROM AUTHOR]

Simple Summary: Around 2–4% of lung adenocarcinoma harbors BRAF mutations. Dabrafenib and Trametinib represent the first treatment-choice for BRAF V600Emut NSCLC, regardless of the line of therapy, while non-V600Emut receive standard immunotherapy or chemo-immunotherapy. Our real-life multicenter study on 44 BRAF mutant NSCLC responds to the urgent need to characterize this subset of patients in-depth, potentially offering new valuable biological and clinical insights. We specifically focused on similarities/discrepancies between V600E and non-V600E populations, providing consistent data about clinicopathologic characteristics, treatment response, and survival outcome. Introduction: BRAF mutation involved 2–4% of lung adenocarcinoma. Differences in clinicopathologic features and patient outcome exist between V600E and non-V600E BRAF mutated NSCLC. Thus, we sought to assess the frequency and clinical relevance of BRAF mutations in a real-life population of advanced-NSCLC, investigating the potential prognostic significance of distinct genetic alterations. Materials and Methods: The present multicenter Italian retrospective study involved advanced BRAF mutant NSCLC. Complete clinicopathologic data were evaluated for BRAF V600E and non-V600E patients. Results: A total of 44 BRAFmut NSCLC patients were included (V600E, n = 23; non-V600E, n = 21). No significant differences in survival outcome and treatment response were documented, according to V600E vs. non-V600E mutations, although a trend towards prolonged PFS was observed in the V600E subgroup (median PFS = 11.3 vs. 6.0 months in non-V600E). In the overall population, ECOG PS and age significantly impacted on OS, while bone lesions were associated with shorter PFS. Compared to immunotherapy, first-line chemotherapy was associated with longer OS in the overall population, and especially in the BRAF V600E subtype. Conclusions: Here, we report on real-life data from a retrospective cohort of advanced-NSCLC harboring BRAF alterations. Our study offers relevant clues on survival outcome, therapeutic response, and clinicopathologic correlations of BRAF-mutant NSCLC. [ABSTRACT FROM AUTHOR]

Immunotherapy, and in particular immune-checkpoints blockade therapy (ICB), represents a new pillar in cancer therapy. Antibodies targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) and Programmed Death 1 (PD-1)/Programmed Death Ligand-1 (PD-L1) demonstrated a relevant clinical value in a large number of solid tumors, leading to an improvement of progression free survival and overall survival in comparison to standard chemotherapy. However, across different solid malignancies, the immune-checkpoints inhibitors efficacy is limited to a relative small number of patients and, for this reason, the identification of positive or negative predictive biomarkers represents an urgent need. Despite the expression of PD-L1 was largely investigated in various malignancies, (i.e., melanoma, head and neck malignancies, urothelial and renal carcinoma, metastatic colorectal cancer, and pancreatic cancer) as a biomarker for ICB treatment-patients selection, it showed an important, but still imperfect, role as positive predictor of response only in nonsmall cell lung cancer (NSCLC). Importantly, other tumor and/or microenvironments related characteristics are currently under clinical evaluation, in combination or in substitution of PD–L1 expression. In particular, tumor-infiltrating immune cells, gene expression analysis, mismatch- repair deficiency, and tumor mutational landscape may play a central role in predicting clinical benefits of CTLA-4 and/or PD-1/PD-L1 checkpoint inhibitors. In this review, we will focus on the clinical evaluation of emerging biomarkers and how these may improve the naïve vision of a single- feature patients-based selection. [ABSTRACT FROM AUTHOR]

After an initial benefit, non-small-cell lung cancer ( NSCLC) patients receiving therapy with tyrosine kinase inhibitors develop drug resistance through a variety of mechanisms. Among these, tumor histology changes are a mechanism of acquired resistance in epidermal growth factor receptor-mutated and anaplastic lymphoma kinase-rearranged NSCLC cases. The current availability of therapeutic approaches to overcome tyrosine kinase inhibitor resistance in oncogenic-driven lung cancers justifies secondary tumor biopsy in these patients. On the other hand, little is known about the mechanism of disease progression in non-oncogenic driven NSCLC. Nevertheless, NSCLC lacking 'druggable' genetic alterations are not considered for secondary biopsy, as it is commonly believed that these tumors cannot develop histologic or molecular changes. Herein, we report two paradigmatic cases of wild-type NSCLC showing histologic 'change' on secondary biopsy, allowing for a successful switch in therapeutic strategy. [ABSTRACT FROM AUTHOR]

ROS proto-oncogene 1 (ROS1) rearrangements are reported in about 1–2% of non-squamous non-small-cell lung cancer (NSCLC). After efficacy of crizotinib was demonstrated, identification of ROS1 translocations in advanced disease became fundamental to give patients the chance of specific and effective treatment. Different methods are available for detection of rearrangements, and probably the real prevalence of ROS1 rearrangements is higher than that reported in literature, as our capacity to detect gene rearrangements is improving. In particular, with next generation sequencing (NGS) techniques, we are currently able to assess multiple genes simultaneously with increasing sensitivity. This is leading to overcome the "single oncogenic driver" paradigm, and in the very near future, the co-existence of multiple drivers will probably emerge more frequently and represent a therapeutic issue. Since recently, crizotinib has been the only available therapy, but today, many other tyrosine kinase inhibitors (TKI) are emerging and seem promising both in first and subsequent lines of treatment. Indeed, novel inhibitors are also able to overcome resistance mutations to crizotinib, hypothesizing a possible sequential strategy also in ROS1-rearranged disease. In this review, we will focus on ROS1 rearrangements, dealing with diagnostic aspects, new therapeutic options, resistance issues and the coexistence of ROS1 translocations with other molecular alterations. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have changed history and management of different tumor types, including non-small cell lung cancer (NSCLC). Response patterns may be more heterogeneous than those seen with cytotoxic chemotherapy. Besides atypical response patterns, new types of outcome should be taken into account such as pseudo-progression (PP) and hyper-progressive disease (HPD). PP is described as initial tumor increase or appearance of new lesions followed by their shrinkage during immunotherapy treatment while HPD is a rapid and severe pattern of progression with a not yet univocal definition. Physiopathology and underlying mechanism of these phenomena are not completely understood and in absence of reliable clinical and biological markers of response to immunotherapy, radiological evaluation remains a key point in clinicians' decision-making process but further efforts would be useful to identify a unique system of evaluation.In this review we summarize the main radiological criteria available in the evaluation of response to checkpoint inhibitors and we describe peculiar response patterns such PP and HPD with a focus on lung cancer. [ABSTRACT FROM AUTHOR]

The occurrence of secondary EGFR mutation T790 M in exon 20 and histologic “transformation” are common mechanisms underlying resistance to EGFR first- or second-generation tyrosine kinase inhibitors (TKI). We describe here on a hitherto unreported mechanism of EGFR TKI resistance synchronously combining squamous-cell carcinoma change and occurrence of the EGFR exon 20 S768I secondary mutation in a 43 year-old woman with stage IV adenocarcinoma harbouring EGFR exon 21 L858R mutation. After 8 months of response to gefitinib, the patient experienced EGFR TKI resistance and died of leptomeningeal neoplastic dissemination. [ABSTRACT FROM AUTHOR]

The aim of this multi-center, retrospective/prospective cohort observational study was to evaluate outcomes in routine clinical practice of first-line chemo-immunotherapy with cis/carboplatin, pemetrexed and pembrolizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) in 33 Italian centers. The outcome measure was to evaluate overall survival (OS) in a real-world patient population. Secondary endpoints were: progression-free survival (PFS), objective response rate (ORR), duration of response (DoR) and incidence of treatment-related adverse events (AEs). 1068 patients were enrolled at the time of data cut-off (January 31st, 2023), and 812 (76.0%) belonged to the retrospective cohort. Median age was 66 years (27−85), ECOG PS was ≥ 2 in 91 (8.6%) patients; 254 (23.8%) patients had brain metastases at baseline; 38 (3.6%) patients had tumor with PD-L1 expression ≥ 50%. After a median follow-up of 17.0 months (95% CI, 16.1–17.9), median OS was 16.1 months (95% CI, 14.4–18.8) and PFS was 9.9 months (95% CI, 8.8–11.2). Median DoR (n = 493) was 14.7 months (95% CI, 13.6–17.1). ORR was 43.4% (95% CI, 40.4–46.4). Any-grade AEs occurred in 636 (59.6%) patients and grade ≥ 3 in 253 (23.7%) patients. Most common grade ≥ 3 AEs were neutropenia (6.3%) and anemia (6.3%). First-line chemo-immunotherapy was effective and tolerable in this large, real-world Italian study of patients with advanced non-squamous NSCLC. Our results were in line with the KEYNOTE-189 registration study, also considering the low number of PD-L1 ≥ 50% patients included in our study. [Display omitted] • Chemo-immunotherapy is the standard front-line treatment for advanced non-squamous NSCLC. • Real-world data about platinum, pemetrexed and pembrolizumab regimen are needed. • We conducted a retrospective-prospective real-world study in 33 Italian Centers. • KEYNOTE-189 regimen was effective and safe in daily clinical practice. [ABSTRACT FROM AUTHOR]

Immunotherapy has widely changed the management of different malignancies. However, efficacy and safety of immune checkpoint inhibitors (ICIs) are not well established in people living with HIV (PLWH). Population of HIV-positive patients has deeply changed after the introduction of modern antiretroviral therapy (ART) and available data of immunotherapy in this subgroup are inadequate considering that cancer has become a leading cause of death and morbidity in this population. Moreover, there are many similarities between cancer and infectious antigen stimulation so that ICIs are even under evaluation as specific HIV treatment. Most of literature on this topic is based on small case series that suggest that immunotherapy for PLWH seems to be as effective as in HIV-negative population with a good safety profile. In this article we review literature on HIV and immunotherapy and we collect many case series available in different malignancies, with a brief focus on lung cancer. [ABSTRACT FROM AUTHOR]