A Comparative Pharmacokinetic Study to Evaluate the Bioequivalence and Safety of A Humanized Recombinant Monoclonal Antibody Targeting Human Epidermal Growth Factor Receptor 2 (HER2) with the Reference Herceptin in Healthy Chinese Subjects

Purpose:This study aimed to evaluate the safety, tolerability, pharmacokinetics and bioequivalence of a test humanized recombinant monoclonal antibody targeting Human Epidermal Growth Factor receptor 2 (HER-2) with the reference Herceptin®.Materials and methods:The trial consists of two parts (part I and part II). Part I was an open-label, sequential-cohort dose-escalation study, QLHER2 (test) was intravenous infusion at single doses escalating from 0.2 to 6 mg/kg (0.2, 1, 2, 4 and 6mg/kg) and Herceptin(reference) 4 mg/kg in 16 healthy subjects, to evaluated the safety, tolerability and pharmacokinetics of QLHER2. Part II was a randomized, double-blind, parallel-group study to evaluate the bioequivalence of QLHER2 and Herceptin in 60 subjects.Results:Following a 1.5-h intravenous infusion of single ascending doses of QLHER2 (1, 2, 4, or 6 mg/kg) In part I, Cmax and Tmax were 19.43-120.01 μg/mL and 68.91-157.87 h, respectively. AUC0-t and CL were 1.91-34.21 h*μg/mL and 0.54-0.12 ml/h/kg, indicating decreased clearance at higher doses, with a greater than proportional increase in the AUC0-t , and the t1/2 was 68.91-157.87 h. In part II, Plasma concentrations appeared to be comparable between QLHER2 and Herceptin over the 70-day sampling period and the QLHER2/Herceptin ratio of the Cmax and AUC0-t was 105.90% (90% CI: 95.69-117.26) and 95.79% (90% CI: 87.74-106.40%), respectively.Conclusion:The 90% CIs of the Cmax and AUC0-t for QLHER2/Herceptin ratio were within the range of 80.0-125.00% indicated that QLHER2 was bioequivalent to Herceptin. The results supported for further evaluation of QLHER2.Trial registration number: ChiCTR2000041577 and ChiCTR2100041802Date of registration: December 30,2020 and January 5, 2021

Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib With Adjuvant Endocrine Therapy for Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03)

PURPOSE The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS Patients with stage II-III HR+, HER2– disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non–protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.

FTY720 in resistant human epidermal growth factor receptor 2-positive breast cancer

The prognosis of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer has considerably improved. However, no reliable treatment besides anti-HER2 strategies has been available. FTY720, a small-molecule compound used for treating refractory multiple sclerosis, has been reported to have beneficial effects against cancers. We therefore evaluated the efficacy of FTY720 in trastuzumab-resistant breast cancer cells and investigated the possible mechanism involved. This study evaluated morphological changes after FTY720 treatment. Antiproliferative WST-1 assays and LDH Cytotoxicity Assay Kits were used to determine the treatment effects of drugs, whereas Western blot analysis was used to evaluate protein expression. Apoptotic events were investigated through annexin V staining and TUNEL assays using flow cytometry. FTY720 was effective in trastuzumab-resistant breast cancer cell lines despite the presence of PIK3CA mutation. Studied on a xenograft mouse model, FTY720-treated groups had statistically significantly poorer HCC1954 xenograft growth in vivo compared with the control group. Our findings suggest that FTY720 can overcome resistance to trastuzumab therapy in patients with HER2-positive breast cancer, with FTY720 plus trastuzumab might offer even better efficacy in vitro and in vivo.

Expression, Microencapsulation of Recombinant Human Epidermal Growth Factor, and Release Study in Gastric Ulcer Representing Condition

Recombinant human epidermal growth factor (rhEGF) has been studied and expressed in various expression systems. It has been also commercialized and clinically used, yet limited to topical diseases. However, being naturally expressed in different tissues, the rhEGF is potential to be applied not only for external wound and skin disorders, but also to regenerates internal damaged epidermal cells such found in gastric ulcer. In the recent study, chitosan microparticles were developed to facilitate delivery of the rhEGF and to overcome gastric degradation that majorly interfere protein, particularly rhEGF oral administration. The rhEGF was expressed in E. coli BL21(DE3) and purified using Ni-NTA chromatography. The refolded rhEGF showed proliferation activity on MC7 cells. rhEGF loaded chitosan microparticles were stable in the gastric and specifically released the loaded rhEGF in the high oxidative environment in acidic pH representing gastric ulcer condition.

Cardiotoxicity among Patients Using Pertuzumab, Trastuzumab and Taxane with HER2-Positive Early-Stage Breast Cancer: A Single-Centre Experience

Aim: In this study, we aimed to investigate the incidence rate, risk factors, and mortality rates in patients with early-stage breast cancer using anti-HER2 (Human epidermal growth factor receptor-2) treatment. Patients and Methods: A total of 106 patients diagnosed with human epidermal growth factor 2 (HER2)-positive early-stage breast cancer and receiving anti-HER2 treatment at King Abdulaziz Medical City (KAMC) from 2015 to 2019 were included in the analysis to assess the incidence of cardiotoxicity was collected as a retrospective study. Univariate and multivariate analyses as well as multiple exact logistic regression analysis were conducted to understand the relationships between the left ventricular ejection fraction (LVEF) and treatment combinations and comorbidities Results: The LVEF measurements using an echocardiography method at the baseline (before any treatment) and during the anti-HER2 therapy were assessed. The results suggest that the higher the drug combination, the higher the odds ratio for the declined ejection fraction (EF) patient group. Further, patients treated with the pertuzumab and trastuzumab combination were four times more likely to have a decline in their EF than those who did not use the pertuzumab and trastuzumab drug combination (OR 4.28, 95% CI [1.68–10.91]). Conclusion: This study demonstrated that the drug combination considered here is associated with reduced LVEF and, similarly, comorbidities were also related to EF. However, a larger study in a global patient population will confirm the present observations.

Case Report: Significant Efficacy of Pyrotinib in the Treatment of Extensive Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Cutaneous Metastases: A Report of Five Cases

BackgroundBreast cancer (BC) is the most common tumor to develop cutaneous metastases. Most BCs with cutaneous metastasis are human epidermal growth factor receptor 2 (HER2)-positive subtypes. Although the molecular mechanisms of breast cancer metastasis to different sites and the corresponding treatment methods are areas of in-depth research, there are few studies on cutaneous metastasis.Case PresentationFive HER2-positive BC patients with extensive cutaneous metastases were treated with a regimen containing pyrotinib, a novel small-molecule tyrosine kinase inhibitor that irreversibly blocks epidermal growth factor receptor (EGFR), HER2, and human epidermal growth factor receptor 4 (HER4), then their cutaneous metastases quickly resolved at an astonishing speed and their condition was well controlled during the follow-up period.ConclusionsThis case series reports the significant therapeutic effect of pyrotinib on cutaneous metastases of HER2-positive BC for the first time. Based on this, we recommend that pyrotinib can be used as a supplement to trastuzumab for HER2-positive BC patients with cutaneous metastases. In addition, we should consider that the pan-inhibitory effect of pyrotinib on EGFR, HER2, and HER4 may provide a dual therapeutic effect against HER2 and mucin 1.