The Safety Profiles of Two First-Generation NTRK Inhibitors: Analysis of Individual Case Safety Reports from the FDA Adverse Event Reporting System (FAERS) Database.

The first-generation tropomyosin receptor kinase (TRK) inhibitors, larotrectinib and entrectinib, represent exciting new developments in cancer treatment that offer relevant, rapid, and long-lasting clinical benefits. Larotrectinib and entrectinib are recommended as first-line treatments for locally advanced or metastatic non-small cell lung cancer (NSCLC) patients with positive TRK gene fusions. In this study, using the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database between 2019 and 2022, a retrospective analysis was conducted to evaluate the safety profiles of these drugs. During our study period, 807 individual case safety reports (ICSRs) related to larotrectinib or entrectinib were retrieved from the FAERS database, of which 48.7% referred to females and 24.7% referred to adult patients (18-64 years) with a median age of 61.0 years. A total of 1728 adverse drug reactions (ADRs) were identified. The most frequently reported ADRs were dizziness and pain, which belong to the System Organ Classes (SOCs) "nervous system disorders" and "general disorders and administration site conditions". Regarding all ADRs, the median time to onset was 37.0 days for larotrectinib and 12.0 days for entrectinib. No evident safety concerns emerged in the long-term safety profiles (>365 days). Only 18 ICSRs were related to pediatric populations (≤16 years), of which 94.0% of the ICSRs were related to larotrectinib. The median age was 10.5 years, while most patients were female (44.4%). Our results show favorable risk-benefit profiles for larotrectinib and entrectinib. Considering the increased use of neurotrophic tyrosine receptor kinase (NTRK) inhibitors, continuous safety monitoring of larotrectinib and entrectinib is required for the detection of possible new adverse drug reactions.

Late relapse after CAR-T cell therapy for adult patients with hematologic malignancies: A definite evidence from systematic review and meta-analysis on individual data.

Chimeric Antigen Receptor (CAR)-modified T lymphocytes represent one of the most innovative and promising approaches to treating hematologic malignancies. CAR-T cell therapy is currently being used for the treatment of relapsed/refractory (r/r) B-cell malignancies including Acute Lymphoblastic Leukemia, Large B-Cell Lymphoma, Follicular Lymphoma, Multiple Myeloma and Mantle Cell Lymphoma. Despite the unprecedented clinical success, one of the major issues of the approved CAR-T cell therapy - tisagenlecleucel, axicabtagene, lisocabtagene, idecabtagene, ciltacabtagene and brexucabtagene - is the uncertainty about its persistence which in turn could lead to weak or no response to therapy with malignancy recurrence. Here we show that the prognosis of patients who do not respond to CAR-T cell therapy is still an unmet medical need. We performed a systematic review and meta-analysis collecting individual data on Duration of Response from at least 12-month follow-up studies. We found that the pooled prevalence of relapse within the first 12 months after CAR-T infusion was 61% (95% CI, 43%-78%); moreover, one year after the infusion, the analysis highlighted a pooled prevalence of relapse of 24% (95% CI, 11%-42%). Our results suggest that identifying potential predictive biomarkers of response to CAR-T therapy, especially for patients affected by the advanced stage of blood malignancies, could lead to stratification of the eligible population to that therapy, recognizing which patients will benefit and which will not, helping regulators to make decision in that way.