Biosimilars are designed to be highly similar to approved or licensed (reference) biologics and are evaluated based on the totality of evidence from extensive analytical, nonclinical and clinical studies. As part of the stepwise approach recommended by regulatory agencies, the first step in the clinical evaluation of biosimilarity is to conduct a pharmacokinetics similarity study in which the potential biosimilar is compared with the reference product. In the context of biosimilar development, a pharmacokinetics similarity study is not necessarily designed for a comparative assessment of safety. Development of PF-05280014, a potential biosimilar to trastuzumab, illustrates how a numerical imbalance in an adverse event in a small pharmacokinetics study can raise questions on safety that may require additional clinical trials.
This randomised, double-blind study compared PF-05280014 (a trastuzumab biosimilar) with reference trastuzumab (Herceptin®) sourced from the European Union (trastuzumab-EU), when each was given with paclitaxel as first-line treatment for HER2-positive metastatic breast cancer.Between 4 April 2014 and 22 January 2016, 707 participants were randomised 1:1 to receive intravenous PF-05280014 plus paclitaxel (PF-05280014 group; n = 352) or trastuzumab-EU plus paclitaxel (trastuzumab-EU group; n = 355). PF-05280014 or trastuzumab-EU was administered weekly (first dose 4 mg/kg, subsequent doses 2 mg/kg), with the option to change to a 3-weekly regimen (6 mg/kg) from Week 33. Treatment with PF-05280014 or trastuzumab-EU could continue until disease progression. Paclitaxel (starting dose 80 mg/m2) was administered on Days 1, 8 and 15 of 28-day cycles for at least six cycles or until maximal benefit of response. The primary endpoint was objective response rate (ORR), evaluating responses achieved by Week 25 and confirmed by Week 33, based on blinded central radiology review.The risk ratio for ORR was 0.940 (95% CI: 0.842-1.049). The 95% CI fell within the pre-specified equivalence margin of 0.80-1.25. ORR was 62.5% (95% CI: 57.2-67.6%) in the PF-05280014 group and 66.5% (95% CI: 61.3-71.4%) in the trastuzumab-EU group. As of data cut-off on 11 January 2017 (using data up to 378 days post-randomisation), there were no notable differences between groups in progression-free survival (median: 12.16 months in the PF-05280014 group vs. 12.06 months in the trastuzumab-EU group; 1-year rate: 54% vs. 51%) or overall survival (median: not reached in either group; 1-year rate: 89.31% vs. 87.36%). Safety outcomes and immunogenicity were similar between the treatment groups.When given as first-line treatment for HER2-positive metastatic breast cancer, PF-05280014 plus paclitaxel demonstrated equivalence to trastuzumab-EU plus paclitaxel in terms of ORR.ClinicalTrials.gov, NCT01989676.
The role of brain insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in neuroprotection was further investigated using in vitro and in vivo models of cerebral ischemia by assessing the effects of IGF-I, IGF-II, and high affinity IGFBP ligand inhibitors (the peptide [Leu 24, 59, 60 , Ala 31 ]hIGF-I (IGFBP-LI) and the small molecule NBI-31772 (1-(3,4-dihydroxybenzoyl)-3-hydroxycarbonyl-6, 7-dihydroxyisoquinoline), which pharmacologically displace and elevate endogenous, bioactive IGFs from IGFBPs. Treatment with IGF-I, IGF-II, or IGFBP-LI (2 μg/mL) significantly ( P < 0.05) reduced CA1 damage in organotypic hippocampal cultures resulting from 35 minutes of oxygen and glucose deprivation by 71%, 60%, and 40%, respectively. In the subtemporal middle cerebral artery occlusion (MCAO) model of focal ischemia, intracerebroventricular (icv) administration of IGF-I and IGF-II at the time of artery occlusion reduced ischemic brain damage in a dose-dependent manner, with maximum reductions in total infarct size of 37% ( P < 0.01) and 38% ( P < 0.01), respectively. In this model of MCAO, icv administration of NBI-31772 at the time of ischemia onset also dose-dependently reduced infarct size, and the highest dose (100 μg) significantly reduced both total (by 40%, P < 0.01) and cortical (by 43%, P < 0.05) infarct volume. In the intraluminal suture MCAO model, administration of NBI-31772 (50 μg icv) at the time of artery occlusion reduced both cortical infarct volume (by 40%, P < 0.01) and brain swelling (by 24%, P < 0.05), and it was still effective when treatment was delayed up to 3 hours after the induction of ischemia. These results further define the neuroprotective properties of IGFs and IGFBP ligand inhibitors in experimental models of cerebral ischemia.
PF-05280014 was compared with trastuzumab sourced from the European Union (trastuzumab-EU), each plus paclitaxel, as first-line treatment for human epidermal growth factor receptor 2-positive metastatic breast cancer in a phase III study. Equivalence between treatment groups was demonstrated. The aim of this study was to report long-term safety and overall survival (OS) over 6 years after the first patient was screened. Randomized patients received intravenous PF-05280014 or trastuzumab-EU, each plus paclitaxel, until objective disease progression. OS, long-term safety, subgroup safety (patients ongoing after day 378), and time-to-treatment discontinuation (TTD) were assessed based on the final statistical analysis plan amended for the ad-hoc analyses. Of 707 randomized patients (n = 352, PF-05280014; n = 355, trastuzumab-EU), 252 (71.6%) in the PF-05280014 and 251 (70.7%) in the trastuzumab-EU group discontinued treatment due to objective progression. Overall, 451 (63.8%) patients completed the study. Between groups (PF-05280014; trastuzumab-EU), estimated median TTDs were 12.25 and 12.06 months (p = 0.692); 61 (17.3%) and 67 (18.9%) patients died; stratified hazard ratio for OS was 0.929 (95% confidence interval 0.656–1.316; p = 0.339); estimated survival rates were 82.3 and 77.4% at 2 years and 77.2 and 75.3% at 3 years. The incidences of treatment-emergent adverse events (TEAEs) overall (98.6%; 96.6%) and for grades ≥3 (41.0%; 43.1%) were comparable between groups. In patients (n = 265; n = 264) ongoing after day 378, the incidences of any TEAEs, grade ≥3 TEAEs, and serious TEAEs were comparable between the treatment groups. Long-term safety and OS were consistent with previous results and demonstrated no clinically meaningful differences between treatment groups. ClinicalTrials.gov: NCT01989676 (21 November 2013); and EudraCT: 2013-001352-34 (18 December 2013).
Abstract Glutamate is the major excitatory neurotransmitter in the central nervous system and is tightly regulated by cell surface transporters to avoid increases in concentration and associated neurotoxicity. Selective blockers of glutamate transporter subtypes are sparse and so knock‐out animals and antisense techniques have been used to study their specific roles. Here we used WAY‐855, a GLT‐1‐preferring blocker, to assess the role of GLT‐1 in rat hippocampus. GLT‐1 was the most abundant transporter in the hippocampus at the mRNA level. According to [ 3 H]‐ l ‐glutamate uptake data, GLT‐1 was responsible for approximately 80% of the GLAST‐, GLT‐1‐, and EAAC1‐mediated uptake that occurs within dissociated hippocampal tissue, yet when this transporter was preferentially blocked for 120 h with WAY‐855 (100 µ m ), no significant neurotoxicity was observed in hippocampal slices. This is in stark contrast to results obtained with TBOA, a broad‐spectrum transport blocker, which, at concentrations that caused a similar inhibition of glutamate uptake (10 and 30 µ m ), caused substantial neuronal death when exposed to the slices for 24 h or longer. Likewise, WAY‐855, did not significantly exacerbate neurotoxicity associated with simulated ischemia, whereas TBOA did. Finally, intrahippocampal microinjection of WAY‐855 (200 and 300 nmol) in vivo resulted in marginal damage compared with TBOA (20 and 200 nmol), which killed the majority of both CA1–4 pyramidal cells and dentate gyrus granule cells. These results indicate that selective inhibition of GLT‐1 is insufficient to provoke glutamate build‐up, leading to NMDA receptor‐mediated neurotoxic effects, and suggest a prominent role of GLAST and/or EAAC1 in extracellular glutamate maintenance.
TPS1129 Background: Substantial improvement in survival outcomes has been achieved with cyclin-dependent kinase (CDK) 4/6 inhibitors plus endocrine therapy (ET) in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced/metastatic breast cancer (BC); however, resistance to this therapy ultimately occurs. PF-07220060 is an oral, highly potent, selective, next generation inhibitor of CDK4 with sparing of CDK6. A first-in-human phase 1/2a study evaluated PF-07220060 (300/400 mg BID) plus ET in patients with HR+/HER2− advanced/metastatic BC who progressed on a prior CDK4/6 inhibitor plus ET (n = 26). At the data cutoff date of November 1, 2022, in patients with measurable disease (n = 21), 6 (29%) had confirmed objective response (OR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and 11 (52%) had a clinical benefit response (CBR). Of all patients (n = 26), median progression-free survival (PFS) was 24.7 weeks, and 8 (31%) patients continued treatment without progression for 60 or more weeks (1). Methods: This international (29 countries; 356 proposed sites), phase 3, open-label, randomized, parallel-group clinical trial will evaluate whether PF-07220060 plus fulvestrant improves clinical outcomes compared with the investigator-chosen therapies in adult female and male patients with HR+/HER2− advanced/metastatic BC with progression after prior therapy of CDK4/6 inhibitor plus a nonsteroidal aromatase inhibitor.Key eligibility criteria include advanced/metastatic BC with measurable disease or non-measurable bone-only disease, documented HR+/HER2− status, and progressive disease/recurrence during or within 12 months after the last dose of prior CDK4/6 inhibitor given in the advanced or adjuvant setting, respectively. One additional prior line of approved treatment in the advanced setting targeting ESR1, PIK3CA, AKT1, PTEN, or BRCA is allowed. Approximately 500 patients will be randomly assigned (1:1) to receive PF-07220060 (orally and continuously in a 28-day cycle) plus fulvestrant (intramuscular injection on days 1 and 15 of cycle 1 and then on day 1 of each cycle thereafter) or investigator’s choice of fulvestrant alone or everolimus plus exemestane, which must be declared before randomization. The primary endpoint is PFS by blinded independent central review, which is defined as the time from the date of randomization to the date of first documented disease progression, as determined per RECIST v1.1, or death due to any cause, whichever occurs first. Secondary objectives include overall survival, OR, duration of response, CBR, safety, patient-reported outcomes, and pharmacokinetics. 1. Yap. JCO. 2023;41:3009. Clinical trial information: NCT06105632 .
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