Aeliya Mirza

Objectives: Pirtobrutinib, a noncovalent Bruton tyrosine kinase inhibitor, was developed to overcome resistance mutations that limit covalent BTK inhibitors and to offer improved tolerability. Three phase III randomized trials (BRUIN CLL-321, CLL-313, and CLL-314) have evaluated pirtobrutinib against distinct comparators in different chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) populations, but no pooled evidence exists, as of now. Methods: Following PRISMA 2020 guidance for systematic reviews without meta-analysis, we searched Embase, Scopus, and PubMed from inception to July 2026 for double-arm randomized trials of pirtobrutinib in CLL/SLL. We extracted safety and efficacy data from the trials and synthesized it narratively. Results: Of 500 identified records, 3 trials met eligibility criteria. In relapsed/refractory patients previously treated with a covalent BTK inhibitor (CLL-321), pirtobrutinib reduced progression or death by 46% versus investigator’s-choice therapy (HR: 0.54). In treatment-naive patients (CLL-313), pirtobrutinib reduced risk by 80% versus bendamustine-rituximab (HR: 0.20). In CLL-314, pirtobrutinib was noninferior to ibrutinib on objective response rate (87.0% vs. 78.5%) with a favorable early progression-free survival trend (HR: 0.57). Overall survival data remained inconclusive across trials, complicated by substantial crossover. Importantly, pirtobrutinib consistently showed lower rates of grade ≥3 adverse events, discontinuations, and cardiovascular toxicity, including markedly reduced atrial fibrillation versus ibrutinib. Conclusions: Pirtobrutinib demonstrates consistent efficacy and a favorable safety profile across relapsed/refractory and treatment-naive CLL/SLL settings, with the strongest evidence in patients who progressed on covalent BTK inhibitors. However, longer follow-up and head-to-head comparisons with other covalent inhibitors are warranted to establish its frontline role in this population.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have emerged as novel agents in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer. Palbociclib, when used in combination with endocrine therapy (ET), has shown promising results in this domain; however, conclusive evidence is still inadequate. We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines, comparing palbociclib plus ET with ET alone in HR+/HER2− advanced breast cancer patients. A total of 15 studies comprising 13,827 patients were included. Palbociclib plus ET significantly improved overall survival (HR=0.83, 95% CI: 0.76-0.91; P P P P P P =0.0005). No significant differences were observed for complete response or stable disease. In addition, palbociclib plus ET was associated with significantly increased adverse events, including neutropenia, leukopenia, thrombocytopenia, anemia, and febrile neutropenia. Palbociclib plus ET exhibits supremacy over ET alone in terms of survival and disease-control outcomes in HR+/HER2− advanced or metastatic breast cancer. However, there exists a significant trade-off in terms of increased adverse events, especially hematological toxicity, in the palbociclib plus ET group as compared with the ET group.

Autoimmune disorders exhibit intricate pathology. Their mechanisms are complex, which attenuates the need for novel therapeutic interventions. Frexalimab, a potent monoclonal antibody targeting the dysregulated CD40-CD40L pathway, stands out as a formidable weapon against the assault of inflammation and tissue devastation. Diverse electronic databases were searched using relevant keywords to extract data on the role of Frexalimab in combating various autoimmune diseases. This review highlights Frexalimab’s efficacy in improving various disability indicators of relapsing multiple sclerosis (RMS), alleviating fatigue in primary Sjögren’s syndrome (PSJS), and improving glycemic control in diabetic patients. Across multiple trials, its favorable safety profile has proven its superiority over first-generation drugs in minimizing side effects. Indeed, Frexalimab has become a harbinger of hope in the fight against autoimmune diseases and has pioneered a unique and unchallenging way for tackling complex autoimmune diseases in the clinical realm, however, further large-scale trials are needed to establish its therapeutic benefits across different autoimmune conditions.