Alessandro Del Conte

PURPOSE: Dabrafenib plus trametinib is a standard first-line treatment for BRAF V600E–mutated non–small cell lung cancer (NSCLC). The LiBRA study aimed to explore the role of liquid biopsy in detecting and monitoring BRAF V600E mutation, assessing its potential to predict treatment response and emerging resistance. MATERIALS AND METHODS: This prospective multicenter study enrolled patients with BRAF V600E–mutated NSCLC treated with first-line dabrafenib plus trametinib. Plasma samples were collected at baseline (t0), after 4 weeks (t1), and longitudinally until disease progression (PD). BRAF V600E was monitored by digital droplet PCR (ddPCR). Next-generation sequencing (NGS) was performed at t0 and PD to identify resistance mechanisms. RESULTS: Forty patients were enrolled. Dabrafenib plus trametinib achieved an overall response rate of 42.5%, with a median progression-free survival (PFS) and overall survival (OS) of 8.3 and 21.1 months, respectively. At t0, BRAF V600E was detectable by ddPCR in 24 (62%) of 39 patients. Among 21 shedders evaluated at t1, 17 (81%) cleared the mutation. Higher baseline BRAF V600E allele frequency was associated with shorter PFS (hazard ratio [HR], 1.09, P = .013) and OS (HR, 1.10, P = .010), whereas clearance at t1 correlated with longer PFS (8.3 v 1.4 months, P < .001) and OS (10.5 v 2.2 months, P < .001). Biological PD anticipated radiologic/clinical PD by a median of 4.9 weeks (IQR, 1.4-9.8). Baseline EGFR and MET CNVs were associated with shorter PFS and OS. Resistance mechanisms at PD included NRAS , KRAS , TP53 mutations and MET , EGFR , ERBB2 CNVs. CONCLUSION: The LiBRA study supports liquid biopsy as a prognostic and monitoring tool in BRAF V600E–mutated NSCLC undergoing targeted therapy.

Background: Chemoimmunotherapy combinations represent the standard first-line treatment for non-oncogene addicted metastatic NSCLC (mNSCLC). However, evidence in elderly patients remains limited and conflicting. We conducted an analysis of the efficacy and safety of chemoimmunotherapy in patients aged ≥75 years enrolled in the Real-Combo Lung study, an observational study including patients with non-oncogene-addicted mNSCLC and PD-L1 expression < 50%. Patients and Methods: The primary objective of the study was to compare progression-free survival (PFS) and overall survival (OS) between patients aged ≥75 (elderly cohort) and those aged p = 0.29). The median OS was 17.5 months (95% CI: 14.7–NR) versus 21.4 months (95% CI: 17–NR), respectively (unadjusted HR 1.09, 95% CI: 0.76–1.56, p = 0.63). In multivariable analysis, ECOG PS ≥ 2 and baseline use of steroids were significantly associated with a worse outcome in the elderly cohort for both PFS and OS. Safety data did not differ significantly between cohorts. Conclusions: In this real-world study, elderly patients with mNSCLC derived outcomes comparable to those of younger patients, with similar efficacy and a manageable safety profile when treated with chemoimmunotherapy combinations.

Objective: The Italian Drug Agency (AIFA) Determination n. 589 of 2015 (Note 79) establishes that the use of bisphosphonates or denosumab is necessary for the primary prevention of bone fractures in postmenopausal patients with early breast cancer (EBC) undergoing adjuvant endocrine therapy (ET). Since adherence to the 2015 AIFA recommendation was still very low in 2019, a new bone health management model was identified to improve adherence to this recommendation. Methods: The aim of this project (Predict & Prevent) was to increase the percentage of patients with early breast cancer (EBC) with hormone receptor-positive (HR+) tumors treated. The project identified a new bone health model of management including the following: training of breast multidisciplinary teams and bone health specialists; presentation and implementation of this model in cancer centers; evaluation, at baseline and 12 months after the implementation of the project, of two key performance indicators (KPIs): rate of HR+ EBC patients assessed for bone health within 30 days from the start of adjuvant ET (KPI-1) and rate of HR+ breast cancer patients receiving bisphosphonates or denosumab within 90 days from the start of adjuvant ET (KPI-2). The primary endpoints of this study were the assessment of the rates of the two key performance indicators (KPIs) 12 months after the start of the project (T3) in comparison with the rates recorded at time 0 (T0) in each participating cancer center and the bone fracture rates at 5 years. In this first analysis, we reported the rates of two KPIs 12 months after the start of the new model (T3) and the comparison with the rates recorded at time 0 (T0) in each participating cancer center, to assess whether these percentages had increased after the implementation of the new organizational model. The rates of bone fractures will be evaluated after five years from implementation of this project in every cancer center. Results: From 2020 to 2022, 10 Italian cancer centers were involved in this project. As of September 2023, 9 cancer centers reported rates relative to two KPIs assessed in each hospital. In 6 hospitals (Negrar, Brescia, Bergamo, Aviano, Turin, Rome), the rates relative to KPI-1 and to KPI-2 increased progressively from time T0 (at baseline) to time T3 (after 12 months from the start of the project), due to training of multidisciplinary teams and implementation of a new bone health management model. In the other three cancer centers (Ancona, Genoa, Naples), where the rate of evaluation of bone health (KPI-1) and the indication for bisphosphonates/denosumab (KPI-2) in HR+ EBC patients were already high at time T0, the rates remained high even after 12 months from the start of this project. Conclusions: After 12 months from the implementation of this new organizational model of bone health management, an increase in the rate of postmenopausal HR+ EBC patients on adjuvant ET assessed for bone health and the rate of patients treated with bisphosphonate/denosumab were reported in six out of nine cancer centers. In the other three cancer centers, where the rates were high at baseline, the rates also remained high after 12 months from the new model implementation. This new model should be adopted in all cancer centers to allow adequate management of bone health in all postmenopausal HR+ EBC patients undergoing adjuvant ET, with the ultimate goal of reducing the rate of bone fractures in these patients in subsequent years.

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.