The advent of immunotherapy has transformed the treatment paradigm for metastatic non-small cell lung cancer (NSCLC). In the past few years, several studies have investigated the potential role of immune checkpoint inhibitors (ICIs) in resectable and unresectable locally advanced disease, achieving remarkable results that led to their approval in clinical practice. However, there is limited evidence on immunotherapy rechallenge after recurrence, with the majority of available knowledge coming from retrospective studies which involve heavily pretreated patients with advanced NSCLC. The recent introduction in the curative setting and the potential regulatory restrictions raise questions about the optimal choice of first-line and subsequent therapies for patients with systemic relapse. The role of immunotherapy readministration in this new scenario needs to be clarified, as well as the identification of patients for whom it is more appropriate, including clinical characteristics, duration of response, switching to other ICIs, reasons for discontinuation and immune-related toxicity. Here, we review literature on rechallenge with immunotherapy, including efficacy, safety profile and potential predictive factors of response.

Background/Objectives: Alterations of the phosphatidylinositol 3-kinase catalytic subunit alpha gene (PIK3CA) are identified in approximately 2–4% of non-small cell lung cancer (NSCLC) cases; however, their biological and clinical relevance in NSCLC remains incompletely understood. This study aimed to comprehensively characterize the clinical and molecular features, as well as outcomes, of patients with PIK3CA-altered NSCLC across different disease stages. Methods: We conducted a retrospective multicenter analysis of 62 patients with histologically confirmed early-stage or advanced NSCLC-harboring PIK3CA alterations (mutations and/or gene amplifications) treated between 2015 and 2022 at three Italian institutions. Demographic, clinical, pathological, and molecular variables were systematically collected and analyzed. Results: PIK3CA mutations accounted for the majority of alterations (90.3%), while amplifications represented 9.7%. The most frequent mutations involved exon 9 (66.1%), predominantly E545K and E542K, followed by exon 20 (16.1%). Most patients were current or former smokers, and concomitant oncogenic alterations were detected in 59.7% of cases, most commonly KRAS mutations. A history of prior malignancy was reported in 24.6% of cases. In the metastatic setting, adenocarcinoma histology was associated with significantly longer overall survival (OS) compared with non-adenocarcinoma histologies (18.4 vs. 5.5 months; p = 0.02). Patients with PD-L1–negative tumors demonstrated a numerically longer OS than those with PD-L1–positive tumors; however, this difference did not reach statistical significance (19.1 vs. 5.4 months; p = 0.05). No statistically significant survival differences were observed according to specific PIK3CA mutation subtypes or treatment strategies. Conclusions: PIK3CA-altered NSCLC represents a molecularly heterogeneous and clinically understudied subgroup, frequently characterized by co-occurring oncogenic alterations. In this study, no definitive prognostic or predictive role for PIK3CA alterations could be established. Nevertheless, these findings provide a descriptive real-world characterization of this molecular subset and support the need for validation in larger, prospectively designed, molecularly stratified studies.

Background/Objectives: Anti–PD-1/PD-L1 blockers have revolutionized the treatment landscape of non–small cell lung cancer (NSCLC) lacking oncogene-addicted alterations, particularly in tumors with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%). Cemiplimab is approved as first-line monotherapy in this setting. However, real-world data remain scarce. This study aimed to evaluate the efficacy and safety of single-agent cemiplimab in a multicenter Spanish cohort and compare outcomes with a historical pembrolizumab cohort. Methods: Cemi-SPA is a retrospective multicenter study including 150 patients with advanced NSCLC and PD-L1 ≥ 50% treated with cemiplimab as first-line monotherapy across 21 Spanish centers. Clinical outcomes were analyzed and compared with a historical cohort of 144 patients treated with pembrolizumab. Propensity score matching (PSM) was performed to adjust for baseline differences. Results: Median progression-free survival (PFS) and overall survival (OS) were 8.1 and 12.6 months, respectively. ECOG performance status ≥ 2 was independently associated with worse outcomes, whereas the development of immune-related adverse events correlated with improved PFS and OS. After PSM, no significant differences were observed between cemiplimab and pembrolizumab in terms of efficacy. Conclusions: Cemiplimab demonstrated comparable real-world efficacy and safety to pembrolizumab in patients with advanced NSCLC and PD-L1 ≥ 50%. ECOG performance status emerged as the strongest prognostic factor, highlighting the importance of patient selection in routine clinical practice.

Cancer is among the major causes of death after heart transplant (HTx). Risk factors for cancer occurrence in this setting are not well established. This was a retrospective observational study of patients who underwent HTx between 2006 and 2019 and were followed up until May 2024. Clinical variables possibly associated with cancer were assessed with univariable and multivariable analyses. Survival analysis was carried out drawing Kaplan Meier curves and a Cox regression with time‐varying covariates were performed to overcome the immortal‐time‐bias. Three‐hundred‐thirty‐five HTx recipients were included, of whom 42 (12.5%) developed cancer after a median of 6.3 years. In univariable analysis, older age at HTx, smoking history, alcohol use, male sex, ischemic heart disease before HTx, use of cyclosporine rather than tacrolimus, and increased length of follow‐up were associated with cancer. Upon multivariable analysis, ischemic heart disease (OR 2.70 [1.19–6.11], p = 0.017) and length of follow‐up (OR 1.02 [1.00–1.04], p = 0.007) were independently associated with cancer occurrence. Cox regression revealed a higher risk of mortality among patients with cancer (HR 3.400, [2.026–5.709], p < 0.001). HTx recipients with prior ischemic cardiomyopathy and a longer survival time after transplant show a higher risk of developing cancer. Cancer significantly impairs post‐transplant survival.