Abstract Background: Trazimera™ (PF-05280014) is a trastuzumab biosimilar. This multinational, randomized, double-blind, parallel-group study (NCT01989676) compared Trazimera with reference trastuzumab (Herceptin®) sourced from the EU (Herceptin-EU), each plus paclitaxel, in the first-line treatment of HER2-positive metastatic breast cancer (MBC). Equivalence between the two groups was previously demonstrated for the primary efficacy endpoint of objective response rate, evaluating responses achieved by Week 25 and confirmed by Week 33 (Pegram et al, Br J Cancer 2019). Furthermore, using data collected up to 378 days after randomization, there were no notable differences in progression-free survival, overall survival (OS), safety, or immunogenicity. Here, we report additional cumulative safety and OS data collected up to 5 years after the first patient was screened. Methods: Eligible patients were randomized 1:1 to receive intravenous Trazimera or Herceptin-EU, each plus paclitaxel. Randomization was stratified by prior trastuzumab exposure and estrogen receptor status. Trazimera or Herceptin-EU treatment could continue until objective disease progression per RECIST 1.1. In addition to evaluating safety and OS in the overall study population, we assessed safety in the subgroup of patients still ongoing in the study after Day 378 (including only adverse events starting after this time point). We also compared time to discontinuation from Trazimera or Herceptin-EU. Results: Of 707 patients randomized (Trazimera, n=352; Herceptin-EU, n=355), 83 (11.7%) were ongoing in the study as of the data cutoff on February 25, 2019 (Trazimera, n=41 [11.6%]; Herceptin-EU, n=42 [11.8%]). Overall, 637 (90.1%) patients discontinued trastuzumab treatment (Trazimera, n=319 [90.6%]; Herceptin-EU, n=318 [89.6%]). The most frequent reason for discontinuing trastuzumab was objective progression (Trazimera, n=245 [69.6%]; Herceptin-EU, n=245 [69.0%]). Estimated median time to discontinuation from trastuzumab was 12.25 months for Trazimera and 12.06 months for Herceptin-EU (stratified hazard ratio [HR] 1.014; 95% confidence interval [CI] 0.867-1.186; log-rank P=0.569). In total, 58 (16.5%) patients in the Trazimera group and 67 (18.9%) patients in the Herceptin-EU group died. There was no statistically significant difference in OS (stratified HR 0.888; 95% CI 0.624-1.264; log-rank P=0.254). Estimated 2-year survival rates were 82.26% for Trazimera and 77.50% for Herceptin-EU; corresponding estimated 3-year rates were 77.17% and 75.33%. Among patients who received treatment (Trazimera, n=349; Herceptin-EU, n=353), there were no notable differences in incidences of treatment-emergent adverse events (TEAEs; 98.3% vs. 96.6%), grade 3 or higher TEAEs (40.7% vs. 42.5%), or serious TEAEs (19.2% vs. 19.3%). Rates of cardiac failure (1.4% vs. 2.8%), infusion-related reaction (IRR; 9.7% vs. 9.1%), and decreased ejection fraction (13.2% vs. 13.0%) were similar. Comparable proportions of patients had ≥1 occasion of an absolute decrease in left ventricular ejection fraction of ≥16% from baseline (6.3% vs. 5.4%) or ≥10% from baseline and below the lower limit of normal (4.0% vs. 5.1%). In the subgroup ongoing after Day 378 (Trazimera, n=265; Herceptin-EU, n=264), rates of cardiac failure (0.0% vs. 1.1%), IRR (0.0% vs. 0.8%), and decreased ejection fraction (3.4% vs. 4.2%) remained balanced. Conclusion: Long-term safety and OS data were consistent with previous results from this ongoing comparative study of Trazimera and Herceptin-EU, demonstrating no clinically meaningful differences between treatment groups. These results represent the longest known follow-up data reported for a trastuzumab biosimilar study in patients with HER2-positive MBC. Funding: This study was sponsored by Pfizer. Citation Format: Rubi K Li, Oleg Lipatov, Hryhoriy Adamchuk, Vladimir Vladimirov, Eduardo Yanez, Patricia Banchero, Amy Freyman, Fiona Hilton, Alexandra Thiele, Alicia Vana. Trazimera (a trastuzumab biosimilar) in HER2-positive metastatic breast cancer: Long-term safety and overall survival data [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-08.
Three single-dose and one multiple-dose phase I studies were conducted in subjects with primary hypercholesterolemia to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.The dosing schedules for hypercholesterolemic subjects randomized in the four phase I studies were (1) ascending, single, intravenous (IV) bococizumab (0.3, 1, 3, 6, 12, or 18 mg/kg), or placebo (N = 48; baseline low-density lipoprotein cholesterol [LDL-C] ≥130 mg/dL); (2) single, IV bococizumab (0.5 or 4 mg/kg; no placebo) added to ongoing atorvastatin 40 mg/day (N = 24); (3) single, fixed, subcutaneous (SC) bococizumab (100 or 200 mg), or IV bococizumab (200 mg; no placebo; N = 49; baseline LDL-C ≥130 mg/dL); and (4) weekly IV bococizumab (0.25, 0.5, 1, or 1.5 mg/kg) or placebo for 4 weeks (N = 67; baseline LDL-C ≥130 mg/dL).Bococizumab pharmacokinetics were well characterized following single IV or SC doses and following multiple IV doses. Exposure to single-dose bococizumab increased slightly greater than dose-proportionally and clearance decreased with increasing dose. In the single-dose studies, maximal mean percent reductions from baseline in LDL-C ranged from 43% (0.3 mg/kg) to 84% (18 mg/kg) in bococizumab-treated subjects, compared with 2% for placebo. For the multiple-dose study, maximal reductions in LDL-C ranged from 55% (0.25 mg/kg) to 66% (1 mg/kg) in bococizumab-treated subjects, compared with 9% for placebo. In all studies, adverse events were infrequent, transient, and not dose-related.Bococizumab was generally safe and well tolerated. Bococizumab lowered LDL-C levels substantially in all four studies.
Insulin‐like growth factors (IGFs) are important trophic factors during development as well as in the adult or damaged nervous system. Their trophic actions are modulated by interactions with six distinct IGF binding proteins. The mRNA expression profiles of binding proteins 2, 4 and 5 in the normal developing and adult CNS are well characterized and are shown to have distinctive, non‐overlapping distributions. The IGF binding protein‐6 (BP6) is also expressed in the CNS, however, details regarding its mRNA expression distribution in the developing and adult nervous system is limited. BP6 has the unique property of preferentially binding the IGF‐II ligand. Coupled with the fact that this ligand is the most abundantly expressed IGF in the adult CNS, this suggests that the IGF‐II/BP6 complex has a unique role in modulating IGF‐II function in the adult brain. In this report the anatomical distribution of BP6 messenger RNA in the developing and adult rat nervous system is presented. In the embryonic animal the CNS expression is tightly restricted to trigeminal ganglia and, relative to the rest of the embryo, this structure has the highest expression. The expression in the forebrain and cerebellum does not occur until after postnatal day 21 and then is primarily associated with GABAergic interneurons, The highest levels of expression in the adult animal are in the hindbrain, spinal cord, cranial ganglia, and dorsal root ganglia. These nuclei in the hindbrain and periphery that express BP6 are all associated with the coordination of sensorimotor function in the cerebellum, which indicates an important role for the BP6/IGF‐II complex in the function and maintenance of these systems.
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