Brigida Stanzione

Epidermal growth factor receptor (EGFR) mutations are described in 10–15% of Caucasian patients and in 50% of Asian patients with non-squamous non-small cell lung cancer (NSCLC). The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the therapeutic scenario and has changed the natural history of the disease. Despite the results obtained with osimertinib, a third-generation TKI, most patients experience disease progression. The search for new therapeutic strategies both to enhance first-line treatment and to ensure adequate second-line therapies represents an unmet medical need, towards which all efforts are being concentrated. In this review, we describe the main strategies identified to improve the prognosis of patients with EGFR-mutated NSCLC.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. The discovery of specific driver mutations has revolutionized the treatment landscape of oncogene-addicted NSCLC through targeted therapies, significantly improving patient outcomes. However, immune checkpoint inhibitors (ICIs) have demonstrated limited effectiveness in this context. Emerging evidence, though, reveals significant heterogeneity among different driver mutation subgroups, suggesting that certain patient subsets may benefit from ICIs, particularly when combined with other therapeutic modalities. In this review, we comprehensively examine the current evidence on the efficacy of immunotherapy in oncogene-addicted NSCLC. By analyzing recent clinical trials and preclinical studies, along with an overview of mechanisms that may reduce immunotherapy efficacy, we explored potential strategies to address these challenges, to provide insights that could optimize immunotherapy approaches and integrate them effectively into the treatment algorithm for oncogene-addicted NSCLC.

The treatment of Non Small Cell Lung Cancer (NSCLC) has been revolutionised by the introduction of targeted therapies. With the improvement of response and frequently of overall survival, however, a whole new set of adverse events emerged. In fact, due to the peculiar mechanism of action of each one of the tyrosine kinase inhibitors and other targeted therapies, every drug has its own specific safety profile. In addition, this safety profile could not fully emerge from clinical trials data, as patients in clinical practice usually have more comorbidities and frailties. Cardiotoxicity is a well-known and established adverse event of anti-cancer therapies. However, only recently it has become a central topic for targeted therapies in NSCLC, due to the unknown real range and frequency. Management of this toxicity begins with prevention, and must balance the need of continuing an effective anticancer treatment versus low risk of even fatal events and the preservation of long-term quality of life. The aim of this review is to summarise the current knowledge focusing on currently used targeted therapies in NSCLC.

Since the discovery of the first-generation ALK inhibitor, many other tyrosine kinase inhibitors have been demonstrated to be effective in the first line or further lines of treatment in patients with advanced non-small cell lung cancer with EMLA4-ALK translocation. This review traces the main milestones in the treatment of ALK-positive metastatic patients and the survival outcomes in the first-line and second-line settings with different ALK inhibitors. It presents the two options available for first-line treatment at the present time: sequencing different ALK inhibitors versus using the most potent inhibitor in front-line treatment. The efficacy outcomes of different ALK inhibitors in the first-line setting; the molecular profile of the disease, including mutation resistances and ALK variants and co-mutations; and patients’ co-morbidities and inhibitor toxicities should be taken into account to address the choice of the first-line treatment, as suggested in this review.

Although rare in non-small cell lung cancer (NSCLC), BRAF mutations present considerable therapeutic challenges. While the use of BRAF and MEK inhibitor combinations has significantly improved survival outcomes in patients with BRAF V600E mutations, no targeted therapies are currently available for class II and III mutations, leaving the optimal treatment strategy and prognosis for these patients uncertain. Additionally, despite immunotherapy typically showing limited benefit in patients with other activating genomic alterations, it appears to deliver comparable efficacy in BRAF-mutated NSCLC, emerging as a potentially viable treatment option, particularly in patients with a history of smoking. However, resistance to BRAF pathway inhibitors is inevitable, leading to disease progression, and a well-defined strategy to overcome these resistance mechanisms is lacking. This review aims to explore the critical challenges in the management of BRAF-mutated NSCLC, providing a comprehensive summary of the current evidence and highlighting ongoing clinical trials that aim to address these critical gaps.

Mesothelioma (MM) is an aggressive and lethal disease with few therapeutic opportunities. Platinum-pemetrexed chemotherapy is the backbone of first-line treatment for MM. The introduction of immunotherapy (IO) has been the only novelty of the last decades, allowing an increase in survival compared to standard chemotherapy (CT). However, IO is not approved for epithelioid histology in many countries. Therefore, therapy for relapsed MM remains an unmet clinical need, and the prognosis of MM remains poor, with an average survival of only 18 months. Increasing evidence reveals MM complexity and heterogeneity, of which histological classification fails to explain. Thus, scientific focus on possibly new molecular markers or cellular targets is increasing, together with the search for target therapies directed towards them. The molecular landscape of MM is characterized by inactivating tumor suppressor alterations, the most common of which is found in CDKN2A, BAP1, MTAP, and NF2. In addition, cellular targets such as mesothelin or metabolic enzymes such as ASS1 could be potentially amenable to specific therapies. This review examines the major targets and relative attempts of therapeutic approaches to provide an overview of the potential prospects for treating this rare neoplasm.

ROS proto-oncogene 1 (ROS1) rearrangements occur in 0.9–2.6% of patients with non small cell lung cancer (NSCLC), conferring sensitivity to treatment with specific tyrosine-kinase inhibitors (TKI). Crizotinib, a first-generation TKI, was the first target-therapy approved for the first-line treatment of ROS1-positive NSCLC. Recently, entrectinib, a multitarget inhibitor with an anti-ROS1 activity 40 times more potent than crizotinib and better activity on the central nervous system (CNS), received approval for treatment-naive patients. After a median time-to-progression of 5.5–20 months, resistance mechanisms can occur, leading to tumor progression. Therefore, newer generation TKI with greater potency and brain penetration have been developed and are currently under investigation. This review summarizes the current knowledge on clinicopathological characteristics of ROS1-positive NSCLC and its therapeutic options.

Tissue biopsy is essential for NSCLC diagnosis and treatment management. Over the past decades, liquid biopsy has proven to be a powerful tool in clinical oncology, isolating tumor-derived entities from the blood. Liquid biopsy permits several advantages over tissue biopsy: it is non-invasive, and it should provide a better view of tumor heterogeneity, gene alterations, and clonal evolution. Consequentially, liquid biopsy has gained attention as a cancer biomarker tool, with growing clinical applications in NSCLC. In the era of precision medicine based on molecular typing, non-invasive genotyping methods became increasingly important due to the great number of oncogene drivers and the small tissue specimen often available. In our work, we comprehensively reviewed established and emerging applications of liquid biopsy in NSCLC. We made an excursus on laboratory analysis methods and the applications of liquid biopsy either in early or metastatic NSCLC disease settings. We deeply reviewed current data and future perspectives regarding screening, minimal residual disease, micrometastasis detection, and their implication in adjuvant and neoadjuvant therapy management. Moreover, we reviewed liquid biopsy diagnostic utility in the absence of tissue biopsy and its role in monitoring treatment response and emerging resistance in metastatic NSCLC treated with target therapy and immuno-therapy.

The severe prognosis linked with a lung cancer diagnosis has changed with the discovery of oncogenic molecularly driven subgroups and the use of tailored treatment. ALK-translocated advanced lung cancer is the most interesting model, having achieved the longest overall survival. Here, we report the most important paradigmatic shifts in the prognosis and treatment for this subgroup population occurred among lung cancer.

Osimertinib is currently the preferred first-line therapy in patients with non-small cell lung cancer (NSCLC) with common epidermal growth factor receptor (EGFR) mutation and the standard second-line therapy in T790M-positive patients in progression to previous EGFR tyrosine kinase inhibitor. Osimertinib is a highly effective treatment that shows a high response rate and long-lasting disease control. However, a resistance to the treatment inevitably develops among patients. Understanding the secondary mechanisms of resistance and the possible therapeutic options available is crucial to define the best management of patients in progression to osimertinib. We provide a comprehensive review of the emerging molecular resistance mechanism in EGFR-mutated NSCLC pre-treated with osimertinib and its future treatment applications.