Alpelisib 150mg tablets

BackgroundPediatric vascular malformations are rare, heterogeneous disorders increasingly driven by somatic mutations affecting key molecular pathways, particularly the PI3K-AKT-mTOR and RAS-MAPK signaling cascades. Advances in genomic profiling have enabled the use of targeted pharmacological therapies, but the available evidence remains fragmented.ObjectiveTo systematically review the clinical outcomes and safety of genotype-directed targeted systemic therapies in pediatric patients with genetically characterized vascular malformations.MethodsA systematic literature search was conducted in PubMed, Embase, and Scopus from database inception to November 21, 2025. Eligible studies included case reports, case series, cohort studies, and prospective investigations reporting genotype-directed targeted therapy in patients aged 0-18 years. Data on genetic alterations, targeted therapies, clinical and radiologic outcomes, and adverse events were extracted and synthesized qualitatively.ResultsFifty-two studies were included, reporting pediatric patients from the neonatal period to 18 years of age. The most frequently identified genetic alterations involved the PI3K-AKT-mTOR and RAS-MAPK pathways, predominantly PIK3CA and RAS-pathway mutations. Sirolimus, alpelisib, and trametinib were the most commonly used targeted agents. Many patients demonstrated clinical improvement and radiologic stabilization or lesion reduction following targeted therapy. Grade 3-4 adverse events were uncommon and generally manageable with dose modification or temporary treatment interruption.ConclusionsGenotype-directed targeted therapies appear to provide clinical and radiologic benefit in pediatric vascular malformations with acceptable safety profiles. However, the current evidence is largely derived from observational studies and requires prospective validation through standardized investigations.

Abstract licence: CC BY-NC-ND

Dysregulation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway has been implicated in oncogenesis, treatment resistance, and disease progression, making it an attractive target for anticancer drug development. Early experiences with PI3K/AKT/mTOR inhibitors have highlighted challenges associated with their modest efficacy, as well as safety and tolerability issues; however, several effective next-generation PI3K/AKT/mTOR inhibitors have now been approved for patients with breast cancer. As a result, there is a growing need to understand the presentation, characteristics, and management of common toxicities (hyperglycemia, rash, stomatitis, and diarrhea). This review summarizes available safety data from phase III randomized clinical trials for approved PI3K/AKT/mTOR pathway-targeted therapies (everolimus, alpelisib, capivasertib, and inavolisib), including incidence, severity, adverse event-related dose modifications, and time to onset. We also provide guidance for preparation, monitoring, and management strategies for integrating these therapies into clinical practice, with the hope that appropriate support will allow patients to tolerate higher PI3K/AKT/mTOR inhibitor dose intensities, which has the potential to translate to improved patient outcomes.

Abstract licence: CC BY-NC-ND

Background: Alpelisib plus fulvestrant improves outcomes in PIK3CA-mutated, hormone receptor-positive, HER2-negative metastatic breast cancer. However, on-target hyperglycemia often leads to dose modification or discontinuation. We aimed primarily to determine whether evening alpelisib after a ≥5 h fast with low-carbohydrate guidance reduces severe hyperglycemia versus standard morning dosing, and secondarily, to assess time to first grade 3-4 hyperglycemia, efficacy, and quality of life (QoL). Methods: ITACA was an open-label, randomized, phase IIb trial in three Croatian centers. Patients progressing on endocrine therapy were randomized 1:1 to evening alpelisib 300 mg after a ≥5 h fast with low-carbohydrate guidance or standard morning alpelisib, both with fulvestrant. The primary endpoint was the exposure-adjusted incidence rate (EAIR) of first grade 3-4 hyperglycemia within 90 days or 30 days post-discontinuation. Secondary endpoints were time to first grade 3-4 hyperglycemia, efficacy, and QoL. Results: Forty-two patients were randomized (21 per arm). Median age was 60 vs. 63 years in the evening vs. morning arms. In the safety set, EAIR of first grade 3-4 hyperglycemia was 378 vs. 742 per 100 person-years (11/21 vs. 14/20 patients with ≥1 event, unadjusted IRR 0.51, 95% CI 0.23-1.12). Adjusted Poisson models favored evening dosing. Analyses suggested delayed onset (median 73 vs. 9.5 days), with no detriment in efficacy or QoL. Conclusions: Evening alpelisib preceded by fasting and low-carbohydrate guidance may improve metabolic tolerability without compromising efficacy or QoL. These findings support evaluation in a larger trial incorporating prospective metabolic adherence and pharmacokinetic assessments.

Abstract licence: CC BY