Immunotherapy has significantly changed the treatment paradigm for solid tumors, with immune checkpoint inhibitors now established in the management of many malignancies. Despite initial success, durable responses remain limited to a subset of patients, often less than 30%, due to both intrinsic and acquired resistance mechanisms. These challenges have prompted the development of next-generation immunotherapies. Recent efforts have expanded the scope of immunotherapy beyond PD-1/PD-L1 and CTLA-4 inhibition, focusing on new immune targets currently under investigation in early phase clinical trials. These include novel immune checkpoint inhibitors, immunomodulators targeting the tumor microenvironment, and bispecific antibodies. This review provides a comprehensive overview of emerging immune targets currently being investigated in early drug development, discussing their mechanisms of action, preliminary clinical outcomes, and potential future directions.

Introduction: Hotspots (HS) mutations in the PIK3CA gene may lead to poorer oncological outcomes and endocrine resistance in advanced breast cancer (BC), but their prognostic role in early‐stage disease remains controversial. The overall agreement within plasma and tissue methods has not been well explored. Our aim was to correlate tissue and plasma approaches and to analyze the prognostic impact of PIK3CA mutations (PIK3CAm) in HR+/HER2− BC.Methods: A retrospective and unicentric analysis of PIK3CA mutational status in tissue and plasma samples by Cobas®PIK3CA Mutation Kit in patients with HR+/HER2− BC.Results: We analyzed 225 samples from 161 patients with luminal BC. PIK3CA mutations were identified in 62 patients (38.5%), of which 39.6% were found in tissue and 11.8% in plasma. In advanced disease, plasma and tissue correlation rate was performed in 64 cases, with an overall agreement of 70.3%. Eighty patients were treated with CDK4/6 inhibitors + endocrine therapy. We observed a moderately worse progression‐free survival (PFS) in PIK3CAm versus wild‐type (WT) (24 m vs. 30 m; HR = 1.39, p = 0.26). A subanalysis was carried out based on exons 9 and 20, which showed a statistically poorer PFS in PIK3CAm exon 9 versus 20 population (9.7 m vs. 30.3 m; HR = 2.84; p = 0.024). Furthermore, detection of PIK3CAm in plasma was linked to a worse PFS vs PIK3CAm detection just in tissue (12.4 vs. 29.3; HR = 2.4; p = 0.08).Conclusions: Our findings suggest the PIK3CA evaluation in tissue as the diagnostic method of choice, however, additional investigations are required to improve the role of liquid biopsy in the PIK3CA assessment. PIK3CAm show worse outcomes in advanced luminal BC, especially in exon 9 mutation carriers, despite visceral involvement, prior exposure to endocrine therapy or detection of PIK3CAm in plasma, with an unclear prognosis in early‐stage disease. Nonetheless, this should be validated in a prospective cohort study.

Genomic assays (GA) guide chemotherapy (CT) use in stage I-II endocrine receptor-positive (ER+)/HER2-negative (HER2-) breast cancer (BC). In tumors N0/intermediate-risk or N1/low-to-intermediate-risk, randomized trials with OncotypeDX® showed a CT benefit only for women aged≤ 50 years/premenopausal. Comparable data for the Prosigna® GA are lacking. We retrospectively included 567 women aged≤ 50 years with stage I-II ER+ /HER2 - BC tested with Prosigna® across 10 hospitals in Spain/Italy (2014-2023). Patients received endocrine therapy (ET) with/without (neo)adjuvant CT. Event-free survival (EFS) was analyzed using Kaplan-Meier curves, log-rank tests, and Cox regression. Propensity score matching (PSM) was applied. 5-year EFS rates were numerically compared with those of OncotypeDX® trials. Of 567 patients, 73.7% were N0 and 26.3% N1, 39.7% were Prosigna risk-of-relapse (ROR)-low (RL), 33.0% ROR-intermediate (RI), 27.3% ROR-high (RH) and 48.3% received CT. CT independently improved EFS in N0/RI and N1/RL-RI (5-year EFS 97.9% vs. 86.6%; adjusted hazard ratio=0.07, p = 0.018). In premenopausal women, CT benefit persisted only when adjuvant gonadotropin-releasing hormone analogue was not administered (p = 0.008), especially in N0/RI (p = 0.023). Results were confirmed after PSM. CT-treated N0/RH showed similar EFS to CT-treated N0/RI+N1/RL-RI, while N1/RH showed poor prognosis despite CT use. 5-year EFS rates were generally consistent with OncotypeDX® trials. Prosigna can help identify young women with stage I-II ER+ /HER2- BC who gain benefit from (neo)adjuvant CT and those in need of further escalated treatments. In premenopausal N0/RI and N1/RL-RI disease, the effect of CT seems to be driven by ovarian function suppression. Prospective validation is required.

Background: Immune checkpoint inhibitors (ICIs) have reshaped the management of advanced non-small cell lung cancer (NSCLC), yet only a subset of patients derive durable benefit and reliable predictive biomarkers remain limited. AT-rich interaction domain 1A (ARID1A) alterations have been identified as potential modulators of tumor immunogenicity, although clinical evidence of durable benefit in NSCLC remains limited. We report a case of sustained and complete remission following chemo-immunotherapy in a patient with ARID1A-mutant lung adenocarcinoma treated at the time of locoregional recurrence. Case Description: A 52-year-old Caucasian male was diagnosed with stage IIB lung adenocarcinoma with 30% programmed death-ligand 1 (PD-L1) expression and no common oncogenic driver mutations. He received neoadjuvant cisplatin-pemetrexed followed by left upper lobectomy and adjuvant chemotherapy. Two years later, surveillance imaging revealed mediastinal nodal recurrence. Next-generation sequencing (NGS) performed on the diagnostic and recurrent tumor samples identified a pathogenic ARID1A frameshift mutation. The patient was treated with carboplatin, pemetrexed, and pembrolizumab, achieving a complete metabolic response after four cycles. Maintenance therapy was administered for 20 months (27 cycles) and subsequently discontinued per patient preference. After 2 years off treatment, the patient remains asymptomatic with no radiologic evidence of relapse. Conclusions: This case supports a potential association between ARID1A alterations and enhanced sensitivity to immune checkpoint inhibition in NSCLC. Incorporation of ARID1A assessment into comprehensive genomic profiling is warranted, although its predictive value requires further validation studies.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i)-ribociclib, abemaciclib, palbociclib-are the standard of care for metastatic breast cancer. Although hepatotoxicity is a frequent adverse event, data on CDK4/6i drug-induced liver injury (DILI) remain scarce. We aimed to define the incidence, clinical presentation, severity, management, and relapse of CDK4/6i-related DILI in a large real-world cohort. Retrospective multicentre study including all patients who developed ≥grade 2 DILI (alanine aminotransferase/aspartate aminotransferase >3 × upper limit of normal) while receiving CDK4/6i between January/2018 and December/2022. Severity was assessed according to Common Terminology Criteria for Adverse Events version 5 (CTCAEv5) and DILI-International Expert Working Group criteria. Among 2,222 CDK4/6i-treated patients, 100 (4.5%, 95% CI 3.7-5.4%) developed DILI. Incidence was significantly higher for ribociclib (8.3%, 95% CI 6.3-10.7%) and abemaciclib (6.7%, 95% CI 4.6-9.3%) than for palbociclib (1.4%, 95% CI 0.8-2.2%) (Difference, p 2 × ULN, n = 12) occurred with all three CDK4/6i. The most frequent pattern was hepatocellular, whereas cholestatic was mainly observed with abemaciclib. Liver biopsy findings (n = 11) were heterogeneous and, together with biochemical results, did not support an immune-mediated mechanism as the primary driver. Corticosteroids (n = 20) did not impact time to grade 1 or alanine aminotransferase normalisation. DILI recurred in 28.2% of CDK4/6i rechallenges (n = 85). Among patients treated with ribociclib, rechallenge with an alternative CDK4/6i was associated with lower risk of recurrence (p = 0.010). DILI caused by ribociclib and abemaciclib are more common that with palbociclib. The absence of immune-mediated features and the limited benefit of corticosteroids question their routine use. After CDK4/6i reintroduction, DILI recurrence rate was 28%. Standardised management is needed, particularly following the approval of ribociclib and abemaciclib as adjuvant therapy. Although hepatotoxicity is a frequent adverse event, real-world data on CDK4/6i DILI remain scarce. DILI associated with ribociclib and abemaciclib is more common than for palbociclib, although moderate DILI (bilirubin >2 × normality) was observed with the three drugs. The absence of immune-mediated features and the limited benefit of corticosteroids question their routine use in CDK4/6i DILI. Relapse of DILI after rechallenge with a CDK4/6i was 28%, with all cases presenting as mild. The increasing use of CDK4/6i (metastatic breast cancer and ribociclib and abemaciclib as adjuvant therapy) highlights the need of standardising the management of CDK4/6i DILI.