trastuzumab (BP 02 / BP02)

A Phase I/II Study of Ibrutinib Plus Trastuzumab in HER2-Positive Metastatic Breast Cancer.

O'Shaughnessy Joyce J, Glidden Andrea A, Locke Tracy T, Scales Amy A et al.

Ibrutinib has demonstrated inhibition of ErbB/HER tyrosine kinases in preclinical models. This Phase I/II study investigated the safety, efficacy, and immunomodulatory effects of ibrutinib in combination with trastuzumab in patients with HER2-positive metastatic breast cancer (MBC) whose disease had progressed on ado-trastuzumab emtansine therapy. In Phase I, cohorts of three patients received ibrutinib 560 mg or 420 mg by mouth once daily combined with standard dosing of trastuzumab. Phase II enrolled additional patients to assess the primary endpoint of clinical benefit rate (CBR) at 420 mg ibrutinib plus trastuzumab. Flow cytometry and NanoString analyses were performed on peripheral blood mononuclear cells. Overall, 26 patients were enrolled. Patients received a median of three prior regimens containing a HER2-targeted therapy in any setting. The most common treatment-related adverse events were bruising, rash, fatigue, and thrombocytopenia. Four patients (15%) experienced cardiac adverse events, including decreased left ventricular ejection fraction in two patients. The CBR of ibrutinib plus trastuzumab was 19.2% (95% confidence interval: 6.6-39.4). Flow cytometry of T- and natural killer (NK)-cell and myeloid-cell panels showed that treatment statistically significantly decreased T helper 17 (TH17) and myeloid-derived suppressor cells (MDSC) with no decrease in T helper 2 (TH2) cells. Ibrutinib plus trastuzumab was well-tolerated but had limited anti-tumor activity in patients with heavily pretreated, HER2-positive MBC (NCT03379428). Trial Registration: Clinicaltrials.gov, NCT03379428.

When precision medicine meets rigid vaccination: bridging the policy gap for patients on biologics.

He Dingxian D, Zhang Yunlu Y, Luo Sushan S, Feng Tianxing T

Evaluating the feasibility of health care databases for assessing the safety of switching between originator biologics and biosimilars.

Mendelsohn Aaron B AB, DeFor Terese A TA, Audrey Djibo Djeneba D, Myers Scott M SM et al.

Real-world data (RWD) have received considerable attention recently, namely, with regard to their value in providing further evidence about the benefit-risk profile for medicinal products beyond clinical trial data. RWD may be particularly useful for establishing interchangeability and supporting switching decisions between originator biologics and their biosimilars. To evaluate the fitness of 3 US health care databases-a national, commercial health plan, a regional integrated delivery network (IDN), and a multipayer, national claims-based database (henceforth, multipayer database)-for capturing data from clinical trials assessing interchangeability between originator biologics and biosimilars across multiple therapeutic areas. We identified 8 clinical trials examining switching between originator biologics and biosimilars from the published literature and ClinicalTrials.gov. All variables representing inclusion/exclusion criteria, interventions, and outcomes from these trials were recorded and grouped into 8 categories: assessment, behavior, demographic, diagnostic, laboratory, procedure, treatment, and vital signs. The 3 databases were then individually evaluated based on the availability of variables identified from the clinical trials and by calculating the percentage of observed data in each database for all relevant variables across the clinical trials, overall and within the above categories. The population size varied across the databases (4 million for the regional IDN through 170 million patient-lives in the multipayer database). All databases had complete (100%) capture for procedure, treatment, and vital signs data and performed well for capturing diagnostic information (78%-100%). Most demographic information (eg, age, sex) was captured; however, race and ethnicity was not available for all databases. Seventy-one percent of the behavior data (eg, whether the patient was sexually active) was captured by the commercial health plan and the regional IDN, but only 29% by the multipayer database. Assessment data (eg, survival, functional status) varied across the databases, with the regional IDN having 93% data capture vs 37% and 16% in the commercial health plan and multipayer database, respectively. Notable differences among the databases were also observed for laboratory data; the regional IDN had complete capture vs only 6% in the multipayer database. Health care databases provide information such as diagnoses, treatments, and some outcomes that may be useful for generating real-world evidence relevant to biosimilar regulatory assessment. However, details on treatment effectiveness may be limited. Specific databases should be evaluated according to their unique attributes to select the most appropriate source(s) of information for a given research need. Further studies are warranted to evaluate data accuracy and timeliness in health care databases.

Cycloastragenol overcomes trastuzumab resistance in HER2-positive breast cancer by regulating cell cycle and epithelial-mesenchymal transition through EZH2/PTEN/AKT pathway.

Wu Mingyuan M, Hou Fenggang F, Yang Zhaoshuo Z, Zhu Zhenfeng Z et al.

The resistance of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients to trastuzumab (Tmab) severely restricts its efficacy. As a natural metabolite with antitumor activity, whether cycloastragenol (CAG) can overcome Tmab resistance and its related mechanism are not clear. This study aims to verify if CAG reverses Tmab resistance in HER2-positive breast cancer cells, clarify its regulatory effects on resistant cell behaviors, and explore the role of the EZH2/PTEN/AKT axis. The study design is combined in vivo and in vitro study. The BT474-TR cells were constructed, and HER2 expression was detected by Western blot and immunofluorescence. Cell Counting Kit-8 assay served to screen the optimal CAG concentration and Tmab dosage. Cell proliferation, migration, and invasion capabilities were evaluated via CFSE staining, colony formation assay, and Transwell and scratch assays. Flow cytometry was employed to examine apoptosis and cell cycle arrest. A xenograft tumor model was established in nude mice. Pathological changes were observed via HE staining, apoptosis was detected using TUNEL staining, microvascular density and VEGF levels were assessed by immunohistochemistry, and protein expression was validated by Western blot. Tmab reduced BT474-TS cell viability and downregulated HER2, while exhibiting minimal effects on HER2-high expression BT474-TR and JIMT-1 cells. CAG treatment enhanced the efficacy of Tmab against drug-resistant cells, reducing cell viability and proliferation, promoting apoptosis, and inducing G0/G1 phase cycle arrest. CAG suppressed migration and invasion capabilities while reversing the EMT phenotype. Additionally, CAG downregulated EZH2 and p-AKT while upregulating PTEN; overexpression EZH2 diminished CAG's antitumor activity. Following CAG combined with Tmab treatment, tumor volume and weight in nude mice were smaller, and tumor tissue exhibited increased pathological damage, elevated apoptotic cells, and reduced microvascular density and VEGF levels. CAG modulates the cell cycle and EMT through the EZH2/PTEN/AKT pathway, effectively overcoming Tmab resistance in HER2-positive BC cells. Clinical trial number: Not applicable.