Immunotherapy with antibodies against PD-1 or PD-L1, either alone or in combination with chemotherapy, has revolutionized treatment paradigms of non-small cell lung cancer (NSCLC) patients without oncogenic driver alterations. These agents, namely immune checkpoint inhibitors (ICIs), have also widely demonstrated a remarkable efficacy in locally advanced as well as in early-stage NSCLC. Assessment of tumor PD-L1 expression by immunohistochemistry has entered into routine clinical practice to select patients for immunotherapy, even though its predictive role has long been debated. Despite improved survival outcomes over standard chemotherapy, treatment with ICIs is associated with initial low response rate, with a significant proportion of patients not responding to these agents. Hence, novel appealing predictive biomarkers, such as those related to tumor cell signaling pathways, metabolism or the tumor microenvironment, have emerged as potentially useful to select those patients most likely to benefit from immunotherapy. Moreover, most patients ultimately develop acquired resistance to ICI treatment over time and novel therapeutic strategies are urgently needed to overcome or delay resistance. Herein, we provide an overview on recent advances in immunotherapy in NSCLC, focusing on updated results from studies on ICIs in different disease settings and at different lines of treatment. We further describe currently emerging predictive biomarkers, beyond PD-L1, to optimize patient selection and novel strategies to improve clinical outcomes.

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.

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.

Capillary leak syndrome (CLS) is a rare disorder associated with an increased capillar permeability due to an endothelial damage, causing leakage of plasma and proteins into the interstitial compartment. CLS is characterized by rapidly developing edema, hypotension and hypoproteinemia. We observed CLS in a 54-year-old man affected by muscle-invasive bladder cancer who received neoadjuvant treatment with CISPLATIN and GEMCITABINE. Treatment with infusion of albumin and increasing corticosteroid doses and diuretics led to a complete regression of all signs and symptoms related to the disorder. Of note, the patient showed an objective complete response to chemotherapy and underwent radical surgery on schedule.

Immune checkpoint inhibitors (ICIs) deeply changed the treatment landscape of breast cancer (BC). In particular, anti-programmed-death (ligand) 1 antibodies were approved for the treatment of triple-negative breast cancer (TNBC), both in first line for metastatic disease and in neoadjuvant setting, on the basis of a demonstrated improvement of the survival outcomes. In light of these results, current clinical trials aim at improving this benefit investigating novel combinations and strategies, at exploring the role of ICIs beyond TNBC, and at better selecting the patients in order to spare non-responders from avoidable toxicities. This narrative review aims at summarizing and discussing the evolving landscape of immunotherapeutic treatments for BC, highlighting the current challenges and the future perspectives.