Final results of the double-blind placebo-controlled randomized phase 2 LOTUS trial of first-line ipatasertib plus paclitaxel for inoperable locally advanced/metastatic triple-negative breast cancer.

PURPOSE: In LOTUS (NCT02162719), adding the oral AKT inhibitor ipatasertib to first-line paclitaxel for locally advanced/metastatic triple-negative breast cancer (aTNBC) improved progression-free survival (PFS; primary endpoint), with an enhanced effect in patients with PIK3CA/AKT1/PTEN-altered tumors (FoundationOne next-generation sequencing [NGS] assay). We report final overall survival (OS) results. METHODS: Eligible patients had measurable previously untreated aTNBC. Patients were stratified by prior (neo)adjuvant therapy, chemotherapy-free interval, and tumor immunohistochemistry PTEN status, and were randomized 1:1 to paclitaxel 80 mg/m2 (days 1, 8, 15) plus ipatasertib 400 mg or placebo (days 1-21) every 28 days until disease progression or unacceptable toxicity. OS (intent-to-treat [ITT], immunohistochemistry PTEN-low, and PI3K/AKT pathway-activated [NGS PIK3CA/AKT1/PTEN-altered] populations) was a secondary endpoint. RESULTS: Median follow-up was 19.0 versus 16.0 months in the ipatasertib-paclitaxel versus placebo-paclitaxel arms, respectively. In the ITT population (n = 124), median OS was numerically longer with ipatasertib-paclitaxel than placebo-paclitaxel (hazard ratio 0.80, 95% CI 0.50-1.28; median 25.8 vs 16.9 months, respectively; 1-year OS 83% vs 68%). Likewise, median OS favored ipatasertib-paclitaxel in the PTEN-low (n = 48; 23.1 vs 15.8 months; hazard ratio 0.83) and PIK3CA/AKT1/PTEN-altered (n = 42; 25.8 vs 22.1 months; hazard ratio 1.13) subgroups. The ipatasertib-paclitaxel safety profile was unchanged. CONCLUSIONS: Final OS results show a numerical trend favoring ipatasertib-paclitaxel and median OS exceeding 2 years with ipatasertib-paclitaxel. Overall, results are consistent with the reported PFS benefit; interpretation within biomarker-defined subgroups is complicated by small sample sizes and TNBC heterogeneity.

Pharmacokinetics and Safety of Valganciclovir in Pediatric Heart Transplant Recipients 4 Months of Age and Younger.

BACKGROUND: Valganciclovir (VGCV) effectively prevents cytomegalovirus disease in adult and pediatric solid organ transplant recipients. A dosing algorithm for VGCV for pediatric patients, based on body surface area and renal function, provides a personalized dose using age-appropriate formulations. The suitability of this dosing algorithm has not been assessed specifically in infants and neonates 4 months of age and younger receiving a solid organ transplant. METHODS: This multicenter prospective study evaluated the pharmacokinetics (PK) and safety of VGCV oral solution in 17 heart transplant recipients 4 months of age and younger who received 2 doses of VGCV on consecutive days using the pediatric dosing algorithm. Plasma concentrations of ganciclovir (GCV) were analyzed at specified times up to 24 hours post VGCV administration. RESULTS: GCV concentration data were available from 16 patients. The combined data from this study and historic study datasets were used to establish a 2-compartment population PK model with first-order formation to describe the PK of GCV after oral VGCV administration in patients across all pediatric age ranges, including those younger than 4 months of age. Estimated mean area under the curve during the 0-24 hours dosing interval for these patients was 68.1 µg·h/mL. CONCLUSIONS: The pediatric dosing algorithm for VGCV (utilizing individuals' body surface area and renal function) provides systemic GCV exposures in patients younger than 4 months that are similar to those observed in older pediatric populations. The data indicate that this dosing algorithm is appropriate across the entire pediatric age range, including this youngest age group.