The Role of Immunotherapy in the First-Line Treatment of Elderly Advanced Non-Small Cell Lung Cancer.

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.

The treatment of advanced non-small cell lung cancer harboring KRAS mutation: a new class of drugs for an old target-a narrative review.

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.

Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of 6 randomized trials.

BACKGROUND: Chemotherapy-induced neutropenia (CIN) has been demonstrated to be a prognostic factor in several cancer conditions. We previously found a significant prognostic value of CIN on overall survival (OS), in a pooled dataset of patients with advanced non-small-cell lung cancer (NSCLC) receiving first line chemotherapy from 1996 to 2001. However, the prognostic role of CIN in NSCLC is still debated. METHODS: We performed a post hoc analysis pooling data prospectively collected in six randomized phase 3 trials in NSCLC conducted from 2002 to 2016. Patients who never started chemotherapy and those for whom toxicity data were missing were excluded. Neutropenia was categorized on the basis of worst grade during chemotherapy: absent (grade 0), mild (grade 1-2), or severe (grade 3-4). The primary endpoint was OS. Multivariable Cox model was applied for statistical analyses. In the primary analysis, a minimum time (landmark) at 180 days from randomization was applied in order to minimize the time-dependent bias. RESULTS: Overall, 1529 patients, who received chemotherapy, were eligible; 572 of them (who received 6 cycles of treatment) represented the landmark population. Severe CIN was reported in 143 (25.0%) patients and mild CIN in 135 (23.6%). At multivariable OS analysis, CIN was significantly predictive of prognosis although its prognostic value was entirely driven by severe CIN (hazard ratio [HR] of death 0.71; 95%CI: 0.53-0.95) while it was not evident with mild CIN (HR 1.21; 95%CI: 0.92-1.58). Consistent results were observed in the out-of-landmark group (including 957 patients), where both severe and mild CIN were significantly associated with a reduced risk of death. CONCLUSION: The pooled analysis of six large trials of NSCLC treatment shows that CIN occurrence is significantly associated with a longer overall survival, particularly in patients developing severe CIN, confirming our previous findings.

Combining immunotherapies to treat non-small cell lung cancer.

Introduction: In recent years, immunotherapy has become an integral part of the treatment of many cancers, including non-small cell lung cancer (NSCLC). Precious therapeutic weapons impacting survival are monoclonal antibodies directed against the programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) immune checkpoint. Areas covered: Unfortunately, not all patients treated with checkpoint inhibitors have durable clinical responses. However, a better understanding of the complexity of interactions between the immune system and cancer, the latter capable of adopting evasion mechanisms, indicates different opportunities to enhance anti-tumor immunity. Expert opinion: In this paper, we review multiple strategies of combining immunotherapies that exploit not only additional immune checkpoint receptors and ligands but also other synergistic approaches such as vaccines or indoleamine 2,3-dioxygenase (IDO) inhibitors with the potential to extend the number of NSCLC patients achieving successful outcomes.

The optional approach of oncogene-addicted non-small cell lung cancer with brain metastases in the new generation targeted therapies era.

In recent years, the study of the molecular characteristics of non-small cell lung cancer (NSCLC) has highlighted a specific role of some genes that represent important therapeutic targets, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS-1) and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF). Patients with oncogene-addicted cancer benefit more from therapy with tyrosine kinase inhibitors (TKIs) than from chemotherapy. The brain is a preferred site for tumor spread in these patients. In addition, given greater control of extracranial disease and prolonged survival, the brain is often the first site of progression. Therefore, there is great interest in therapeutic approaches that optimize the control of intracranial disease associated with systemic drugs that, by penetrating the blood-brain barrier (BBB), may improve local control. On the latter, radiotherapy provides excellent efficacy but following the results of clinical trials with new brain penetrant drugs, the question of how and especially when to perform brain radiotherapy in patients with oncogene-addicted NSCLC remains open. Prospective studies may indicate which patients are most likely to benefit from combined use or in what sequence they will undergo systemic and radiotherapy treatment. Due to the heterogeneity of patients and the introduction of new generation TKIs, a multidisciplinary assessment for the best management of therapies in NSCLC patients with molecular driver alterations and brain metastases (BM) is required.

Evolution in the treatment landscape of non-small cell lung cancer with ALK gene alterations: from the first- to third-generation of ALK inhibitors.

INTRODUCTION: The medical treatment of non-small cell lung cancer (NSCLC) has radically changed over the last 10 years thanks to new molecular-targeted drugs able to act on biological mechanisms involved in tumor development. One such mechanism is the aberrant anaplastic lymphoma kinase (ALK) activation: patients with ALK-driven NSCLC benefit from treatments that selectively inhibit its pathogenetic mechanism. Areas covered: The first-generation ALK inhibitor is crizotinib, initially used in Europe as second-line treatment for ALK-positive metastatic NSCLC patients, then approved as the standard first-line (already approved in the USA as front-line therapy). However, most patients eventually experience disease progression due to the emergence of secondary resistance, partly linked to ALK-dependent mechanisms, hence the development of second- and third-generation ALK inhibitors: ceritinib, alectinib, and brigatinib are approved for ALK-positive NSCLC, lorlatinib is currently being evaluated while others are under development. Expert opinion: Despite the considerable responses to these new inhibitors, however, resistance mechanisms are described. Thus, while the therapeutic scenario of NSCLC has been soon revolutionized introducing next-generation ALK inhibitors in the first-line setting, future research should identify combined therapies or new generation drugs overcoming resistance in pretreated patients.

Lung cancer, elderly and immune checkpoint inhibitors.

Lung cancer is predominantly a disease of the elderly with about 50% of diagnoses in patients aged ≥70 years and about 14% in those older than 80. Medical and physiological characteristics of elderly cancer patients make the choice of their better treatment more challenging. Furthermore, aging is accompanied by the so called "immunosenescence" phenomenon, the age-related decline in the immune system that is one of the potential reasons of increase of the incidence and prevalence of most cancers. There is a growing interest in understanding of immunosenescence and how it may correlate with the use of immune checkpoint inhibitors in elderly non-small cell lung cancer (NSCLC) patients. The survival benefit achieved by immunotherapy in all histologies and therapy line settings, added to its manageable toxicity profile, has dramatically changed the scenario of advanced NSCLC treatment. At subgroup analyses of randomized clinical trials, elderly NSCLC population seems to benefit from anti-programmed death-1 (anti-PD-1)/anti-programmed death ligand-1 (anti-PD-L1) agents' treatment. These efficacy data were also confirmed by studies in real-life setting. The key-points of aging and immunosenescence are described, focusing on the role of immune checkpoint inhibitors in elderly NSCLC population.

Cancer drug related cardiotoxicity during breast cancer treatment.

INTRODUCTION: Breast cancer (BC) is the most common cancer in women. Although therapeutic armamentarium like chemotherapy, endocrine and target agents have increased survival, cardiovascular side effects have been observed. A comprehensive risk assessment, early detection and management of cardiac adverse events is therefore needed. AREAS COVERED: In this review we focus on cardiotoxicity data deriving from Phase III randomized trials, systematic reviews and meta-analysis in BC patients. We provide insight into advances that have been made in the molecular mechanisms, clinical presentation and management of such adverse event. EXPERT OPINION: Despite the large number of data from Phase III trials about cardiac events incidence, there are poor evidences for detection, monitoring and management of cardiotoxicity during BC treatment. Future cardiotoxicity-oriented clinical cancer research can help to predict the risk of cardiac adverse events and improve patients' outcome. Multidisciplinary approach as well as integration of blood biomarkers with imaging will be desirable.