Circulating biomarkers as predictors of response to immune checkpoint inhibitors in NSCLC: Are we on the right path?

Immune checkpoints inhibitors (ICIs) have markedly improved the therapeutic management of advanced NSCLC and, more recently, they have demonstrated efficacy also in the early-stage disease. Despite better survival outcomes with ICIs compared to standard chemotherapy, a large proportion of patients can derive limited clinical benefit from these agents. So far, few predictive biomarkers, including the programmed death-ligand 1 (PD-L1), have been introduced in clinical practice. Therefore, there is an urgent need to identify novel biomarkers to select patients for immunotherapy, to improve efficacy and avoid unnecessary toxicity. A deeper understanding of the mechanisms involved in antitumor immunity and advances in the field of liquid biopsy have led to the identification of a wide range of circulating biomarkers that could potentially predict response to immunotherapy. Herein, we provide an updated overview of these circulating biomarkers, focusing on emerging data from clinical studies and describing modern technologies used for their detection.

Challenges and pitfalls in the management of endocrine toxicities from immune checkpoint inhibitors: a case presentation of synchronous thyrotoxicosis and primary adrenal insufficiency in a melanoma patient.

BACKGROUND: Immune checkpoint inhibitors have revolutionized the therapeutic approach to several solid tumors, becoming the standard of care for cancer treatment in different disease settings. Despite the fact that these agents are better tolerated than conventional chemotherapy, their use is associated with a specific toxicity profile, so-called immune-related adverse events (irAEs), that can involve several organs. Endocrine irAEs are among the most frequent toxicities (around 10 to 16%) and include hypophysitis, thyroid disorders, adrenalitis, and diabetes mellitus. Some of them may be life-threatening if not promptly recognized (such as diabetic ketoacidosis and acute adrenal crisis). CASE PRESENTATION: A 55-year-old woman with a personal history of euthyroid Hashimoto's thyroiditis was diagnosed with a metastatic melanoma, BRAF wild type. Under treatment with anti-PD-1 pembrolizumab, she developed thyrotoxicosis followed by hypothyroidism due to destructive thyroiditis and concurrent primary adrenal insufficiency due to adrenalitis. CONCLUSIONS: The simultaneous occurrence of adrenal and thyroid autoimmune diseases, resembling autoimmune polyendocrine syndrome type 2, may occur as a rare but serious side effect of ICI treatment. It often presents with abrupt onset and rapid evolution towards polyglandular insufficiency. Physicians should be aware of the potential association of two or more endocrine disorders and careful monitoring of endocrine function is needed during ICI therapy.

Therapeutic strategies for HER2-positive breast cancer with central nervous system involvement: a literature review and future perspectives.

Background and Objective: Brain metastases (BMs) are present in approximately 55% of patients with HER2-positive breast cancer (HER2+ BC). The introduction of anti-HER2 agents has radically changed the prognosis of these patients by prolonging overall survival. Methods: In this review, we describe the biology of central nervous system (CNS) spreading in patients with HER2+ BC. We also provide a literature review of current treatment strategies of brain metastatic BC, focusing on HER2+ disease, and future perspectives. Key Content and Findings: Treatment of symptomatic BMs includes traditionally neurosurgery and/or radiotherapy, depending on the number of metastases, performance status and systemic disease control. Local treatments, such as surgical excision of BM and stereotactic radiosurgery (SRS), when feasible, are preferred over whole-brain radiotherapy, because of related cognitive impairment. These treatments can lead to a local control of the disease, however, systemic relapses can affect the prognosis of these patients. Recently, new anti-HER2 agents have demonstrated to be effective on BMs, thereby leading to improved survival outcomes with an acceptable quality of life. Despite the clinical benefit of these approaches, BMs still represent a cause of death and effective therapeutic strategies are needed. Conclusions: Different targeted agents have demonstrated significant efficacy with tolerable safety profiles in HER2+ BC patients with BM, and have already been approved for clinical use in this setting. A better understanding of the molecular mechanisms underlying the onset of BMs could suggest novel targeted approaches in order to prevent CNS localization or delay progression to CNS in HER-2 metastatic patients.

Targeting MET in Non-Small Cell Lung Cancer (NSCLC): A New Old Story?

In recent years, we have seen the development and approval for clinical use of an increasing number of therapeutic agents against actionable oncogenic drivers in metastatic non-small cell lung cancer (NSCLC). Among them, selective inhibitors, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting the mesenchymal-epithelial transition (MET) receptor, have been studied in patients with advanced NSCLC with MET deregulation, primarily due to exon 14 skipping mutations or MET amplification. Some MET TKIs, including capmatinib and tepotinib, have proven to be highly effective in this molecularly defined subgroup of patients and are already approved for clinical use. Other similar agents are being tested in early-stage clinical trials with promising antitumor activity. The purpose of this review is to provide an overview of MET signaling pathways, MET oncogenic alterations primarily focusing on exon 14 skipping mutations, and the laboratory techniques used to detect MET alterations. Furthermore, we will summarize the currently available clinical data and ongoing studies on MET inhibitors, as well as the mechanisms of resistance to MET TKIs and new potential strategies, including combinatorial approaches, to improve the clinical outcomes of MET exon 14-altered NSCLC patients.

Overview on Therapeutic Options in Uncommon EGFR Mutant Non-Small Cell Lung Cancer (NSCLC): New Lights for an Unmet Medical Need.

The majority of epidermal growth factor receptor (EGFR) mutations (85-90%) are exon 19 deletions and L858R point mutations of exon 21, characterized by high sensitivity to EGFR-tyrosine kinase inhibitors (TKIs). Less is known about uncommon mutations (10-15% of EGFR mutations). The predominant mutation types in this category include exon 18 point mutations, exon 21 L861X, exon 20 insertions, and exon 20 S768I. This group shows a heterogeneous prevalence, partly due to different testing methods and to the presence of compound mutations, which in some cases can lead to shorter overall survival and different sensitivity to different TKIs compared to simple mutations. Additionally, EGFR-TKI sensitivity may also vary depending on the specific mutation and the tertiary structure of the protein. The best strategy remains uncertain, and the data of EGFR-TKIs efficacy are based on few prospective and some retrospective series. Newer investigational agents are still under study, and there are no other approved specific treatments targeting uncommon EGFR mutations. Defining the best treatment option for this patient population remains an unmet medical need. The objective of this review is to evaluate existing data on the outcomes, epidemiology, and clinical characteristics of lung cancer patients with rare EGFR mutations, with a focus on intracranial activity and response to immunotherapy.

Immunotherapy in Early-Stage Non-Small Cell Lung Cancer (NSCLC): Current Evidence and Perspectives.

Lung cancer is the leading cause of cancer deaths in the world. Surgery is the most potentially curative therapeutic option for patients with early-stage non-small cell lung cancer (NSCLC). The five-year survival for these patients remains poor and variable, depending on the stage of disease at diagnosis, and the risk of recurrence following tumor resection is high. During the last 20 years, there has been a modest improvement in the therapeutic strategies for resectable NSCLC. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, have become the cornerstone for the treatment of metastatic NSCLC patients. Recently, their clinical development has been shifted in the neoadjuvant and adjuvant settings where they have demonstrated remarkable efficacy, leading to improved clinical outcomes. Based on the positive results from phase III trials, ICIs have become a therapeutic option in neoadjuvant and adjuvant settings. On October 2021 the Food and Drug Administration (FDA) approved atezolizumab as an adjuvant treatment following surgery and platinum-based chemotherapy for patients with NSCLC whose tumors express PD-L1 ≥ 1%. In March 2022, nivolumab in combination with platinum-doublet chemotherapy was approved for adult patients with resectable NSCLC in the neoadjuvant setting. The current review provides an updated overview of the clinical trials exploring the role of immunotherapy in patients with early-stage NSCLC, focusing on the biological rationale for their use in the perioperative setting. We will also discuss the role of potential predictive biomarkers to personalize therapy and optimize the incorporation of immunotherapy into the multimodality management of stage I-III NSCLC.

Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development-a narrative review.

Background and Objective: Non-small cell lung cancer (NSCLC) with Kirsten rat sarcoma viral oncogene homolog (KRAS) driver alterations harbors a poor prognosis with standard therapies, including chemotherapy and/or immunotherapy with anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) antibodies. Selective KRAS G12C inhibitors have been shown to provide significant clinical benefit in pretreated NSCLC patients with KRAS G12C mutation. Methods: In this review, we describe KRAS and the biology of KRAS-mutant tumors and review data from preclinical studies and clinical trials on KRAS-targeted therapies in NSCLC patients with KRAS G12C mutation. Key Content and Findings: KRAS is the most frequently mutated oncogene in human cancer. The G12C is the most common KRAS mutation found in NSCLC. Sotorasib is the first, selective KRAS G12C inhibitor to receive approval based on demonstration of significant clinical benefit and tolerable safety profile in previously treated, KRAS G12C-mutated NSCLC. Adagrasib, a highly selective covalent inhibitor of KRAS G12C, has also shown efficacy in pretreated patients and other novel KRAS inhibitors are being under evaluation in early-phase studies. Similarly to other oncogene-directed therapies, mechanisms of intrinsic and acquired resistance limiting the activity of these agents have been described. Conclusions: The discovery of selective KRAS G12C inhibitors has changed the therapeutic scenario of KRAS G12C-mutant NSCLC. Various studies testing KRAS inhibitors in different settings of disease, as single-agent or in combination with targeted agents for synthetic lethality and immunotherapy, are currently ongoing in this molecularly-defined subgroup of patients to further improve clinical outcomes.

Cardiotoxicity Induced by Immune Checkpoint Inhibitors: What a Cardio-Oncology Team Should Know and Do.

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic scenario for several malignancies. However, they can be responsible for immune-related adverse events (irAEs), involving several organs, with a pooled incidence ranging between 54% and 76%. The frequency of cardiovascular system involvement is <1%. Among the cardiovascular irAEs, myocarditis is the most common and the most dangerous but other, less common manifestations of ICI-related cardiotoxicity include pericardial disease, arrhythmias, Takotsubo-like syndrome, and acute myocardial infarction, all of which remain poorly explored. Both oncologists and cardiologists, as well as the patients, should be aware of the possible occurrence of one or more of these complications, which in some cases are fatal, in order to implement effective strategies of cardiac surveillance. In this review, we summarize the latest studies and recommendations on the pathogenesis, clinical manifestation, diagnosis, and management of ICI-related cardiotoxicity in order to realize a complete and updated overview on the main aspects of ICI-related cardiotoxicity, from surveillance to diagnosis to management, useful for both oncologists and cardiologists in their clinical practice. In particular, in the first part of the review, we realize a description of the pathogenetic mechanisms and risk factors of the main cardiovascular irAEs. Then, we focus on the management of ICI-related cardiotoxicity by analyzing five main points: (1) identifying and evaluating the type and severity of the cardiotoxicity; (2) deciding whether to withhold ICI therapy; (3) initiating steroid and immunosuppressive therapy; (4) starting conventional cardiac treatment; and (5) restarting ICI therapy. Finally, we discuss the existing evidence on surveillance for ICI-related cardiotoxicity and propose a surveillance strategy for both short- and long-term cardiotoxicity, according to the most recent guidelines.

Management of Endocrine and Metabolic Toxicities of Immune-Checkpoint Inhibitors: From Clinical Studies to a Real-Life Scenario.

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of solid tumors. However, although ICIs are better tolerated than conventional chemotherapy, their use is associated with a peculiar toxicity profile, related to the enhancement of the immune response, affecting several organs. Among immune-related adverse events (irAEs), up to 10% involve the endocrine system. Most of them are represented by thyroid disorders (hypothyroidism and hyperthyroidism), mainly correlated to the use of anti-PD-1 and/or anti-PD-L1 agents. Less common endocrine irAEs include hypophysitis, adrenalitis, and metabolic irAEs. A deeper understanding of endocrine toxicities is a critical goal for both oncologists and endocrinologists. A strict collaboration between these specialists is mandatory for early recognition and proper treatment of these patients. In this review we will provide a comprehensive overview of endocrine and metabolic adverse events of ICIs, with particular interest in the pathogenesis, predisposing factors and clinical presentation of these irAEs, and their impact on clinical outcomes of patients. Furthermore, we will summarize the most recent studies and recommendations on the clinical approach to immune-related endocrinopathies with the purpose to optimize the diagnostic algorithm, and to help both oncologists and endocrinologists to improve the therapeutic management of these unique types of irAEs, in a real-life scenario.