Immunogenic Cell Death ; Prognosis ; Immunotherapy ; Neoplasms

Background and purpose:For patients with human epidermal growth factor receptor 2(HER2)-positive metastatic breast cancer,trastuzumab treatment can prolong the overall survival and significantly improve the prognosis of patients.However,the reference original research trastuzumab(Herceptin?)is more expensive.Biosimilars have comparable efficacy and safety profiles while increasing patient access to treatment.This clinical trial aimed to evaluate the efficacy,pharmacokinetics,safety and immunogenicity of the trastuzumab biosimilar AK-HER2 compared to trastuzumab(Herceptin?)in patients with HER2-positive metastatic breast cancer.Methods:This multi-center,randomised,double-blind phase Ⅲ clinical trial was conducted in 43 subcenters in China.This study complied with the research protocol,the ethical principles stated in the Declaration of Helsinki and the quality management standards for drug clinical trials.It was approved by the hospital's medical ethics committee.The clinical trial registration agency is the State Food and Drug Administration(clinical trial approval number:2015L04224;clinical trial registration number:CTR20170516).Written informed consent was obtained from subjects before enrollment.Enrolled patients were randomly assigned to the AK-HER2 group and the control group,respectively receiving AK-HER2 or trastuzumab(initial loading dose 8 mg/kg,maintenance dose 6 mg/kg,every 3 weeks as a treatment cycle,total treatment time is 16 cycles)in combination with docetaxel(75 mg/m2,treatment duration is at least 9 cycles).The primary endpoint of this clinical trial was the objective response rate(ORR9)between the AK-HER2 group and the control group in the 9th cycle.Secondary efficacy endpoints included ORR16,disease control rate(DCR),clinical benefit rate(CBR),progression-free survival(PFS)and 1-year survival rate.In this study,100 subjects(AK-HER2 group to control group=1:1)were randomly selected for blood sample collection after the 6th cycle of medication,The collection time points were 45 minutes after infusion(the end of administration),4,8,24,72,120,168,336,and 504 hours after the end of administration.After collection,blood samples were analyzed by PK parameter set(PKPS).Other evaluation parameters included safety and immunogenicity assessment.Results:A total of 550 patients with HER2-positive metastatic breast cancer were enrolled in this clinical trial between Sep.2017 and Mar.2021.In the AK-HER2 group(n=237),129 subjects in the experimental group achieved complete response(CR)or partial response(PR),and the ORR9 was 54.4%.There were 134 subjects in the control group(n=241)who achieved CR or PR,and the ORR9 was 55.6%.The ORR9 ratio between the AK-HER2 group and the control group was 97.9%[90%confidence interval(CI):85.4%-112.2%,P=0.784],which was not statistically significant.In all secondary efficacy endpoints,no statistically significant differences were observed between the two groups.We conducted a mean ratio analysis of pharmacokinetics(PK)parameters between the AK-HER2 group and the control group,and the results suggested that the pharmacokinetic characteristics of the two drugs are similar.The incidence of treatment emergent adverse event(TEAE)leading to drug reduction or suspension during trastuzumab treatment was 3.6%(10 cases)in the AK-HER2 group and 8.1%(22 cases)in the control group.There was statistically significant difference between the two groups(P=0.027).The incidence rate was significantly lower in the AK-HER2 group than in the control group,and there was no statistically significant difference among the other groups.The differences in the positive rates of anti-drug antibodies(ADA)and neutralizing antibodies(NAB)between groups were of no statistical significance(P=0.385 and P=0.752).Conclusion:In patients with HER2-positive metastatic breast cancer,AK-HER2 was comparable to the trastuzumab(Herceptin?)in terms of drug efficacy,pharmacokinetics,safety and immunogenicity.

Entinostat plus exemestane in hormone receptor-positive (HR+) advanced breast cancer (ABC) previously showed encouraging outcomes. This multicenter phase 3 trial evaluated the efficacy and safety of entinostat plus exemestane in Chinese patients with HR + ABC that relapsed/progressed after ≥1 endocrine therapy. Patients were randomized (2:1) to oral exemestane 25 mg/day plus entinostat (n = 235) or placebo (n = 119) 5 mg/week in 28-day cycles. The primary endpoint was the independent radiographic committee (IRC)-assessed progression-free survival (PFS). The median age was 52 (range, 28-75) years and 222 (62.7%) patients were postmenopausal. CDK4/6 inhibitors and fulvestrant were previously used in 23 (6.5%) and 92 (26.0%) patients, respectively. The baseline characteristics were comparable between the entinostat and placebo groups. The median PFS was 6.32 (95% CI, 5.30-9.11) and 3.72 (95% CI, 1.91-5.49) months in the entinostat and placebo groups (HR, 0.76; 95% CI, 0.58-0.98; P = 0.046), respectively. Grade ≥3 adverse events (AEs) occurred in 154 (65.5%) patients in the entinostat group versus 23 (19.3%) in the placebo group, and the most common grade ≥3 treatment-related AEs were neutropenia [103 (43.8%)], thrombocytopenia [20 (8.5%)], and leucopenia [15 (6.4%)]. Entinostat plus exemestane significantly improved PFS compared with exemestane, with generally manageable toxicities in HR + ABC (ClinicalTrials.gov #NCT03538171).

Background::This study aimed to reveal the treatment patterns and clinical outcomes of diverse palbociclib-based regimens in Han patients with estrogen receptor-positive (ER+) metastatic breast cancer in routine clinical practice.Methods::The clinical data of patients with ER+ metastatic breast cancer treated with palbociclib were collected from the National Cancer Center database. The efficacy profile of palbociclib in this Han population was evaluated, especially for various combination regimens. The efficacy of palbociclib-based therapy in patients with prior everolimus treatment was also assessed.Results::A total of 186 patients from 89 cities in 18 provinces in China were enrolled. The median progression-free survival (PFS) was similar among different palbociclib-combined groups ( P = 0.566): 10.0 months (95% confidence interval [CI] 3.8–16.1) in the +exemestane group, 9.7 months (95% CI 6.3–13.1) in the +letrozole group, 7.8 months (95% CI 5.5–10.2) in the +fulvestrant group, 7.2 months (95% CI 3.2–11.3) in the +toremifene group, and 6.1 months (95% CI 1.2–11.0) in the +anastrozole group. Thirty-four patients (18.3%) had received everolimus for their metastatic disease before the prescription of palbociclib. The disease control rate was significantly lower in patients who had received previous everolimus than in the everolimus-na?ve group (50.0% vs. 82.2%, P < 0.001). Patients pre-treated with everolimus had significantly worse PFS than those in the everolimus-na?ve group (3.4 months vs. 8.8 months, P = 0.001). After propensity score matching, patients pre-treated with everolimus had similar PFS (4.4 months, 95% CI 0.5–8.2) compared with everolimus-na?ve patients (6.1 months, 95% CI 4.7–7.5, P = 0.439). Conclusions::Various palbociclib-based regimens have promising efficacy in ER+ metastatic breast cancer in real-world settings, even in patients who had been pre-treated with everolimus.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a heterogeneous genetic profile. Chemotherapy exhibits substantial activity in a small subset of these patients. Drug resistance is inevitable. Major progress has been made in the genetic analysis of TNBC to identify novel targets and increase the precision of therapeutic intervention. Such progress has translated into major advances in treatment strategies, including modified chemotherapy approaches, immune checkpoint inhibitors, and targeted therapeutic drugs. All of these strategies have been evaluated in clinical trials. Nevertheless, patient selection remains a considerable challenge in clinical practice.
Humans ; Immunotherapy ; Molecular Targeted Therapy ; Triple Negative Breast Neoplasms/genetics*

New targeted therapies have been developed to overcome resistance to endocrine therapy (ET) and improve the outcome of HR
Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Breast Neoplasms/drug therapy* ; Hormones ; Humans ; Randomized Controlled Trials as Topic ; Receptor, ErbB-2 ; Receptors, Estrogen

Objective:To explore the latest progress of oncology drug clinical trials in China under COVID-19, as well as to provide decision-making evidence for related stakeholders. Research progress of oncology drug trials and approved cancer drugs in China in 2020 were systematically summarized and compared with 2019.Methods:Information Disclosure Platform for Drug Clinical Studies and China Food and Drug Administration Query System for Domestic and Imported Drug were searched for registered clinical trials and approved oncology drugs, respectively. The trial scope, stage, drug type, effect and mechanism of domestic and global pharmaceutical enterprises were compared between 2019 and 2020.Results:A total of 722 cancer drug trials registered in China in 2020, with an annual growth rate of 52.3%, accounting for 28.3% of all registered trials. Among them, 603 (83.5%) trials were initiated by domestic pharmaceutical enterprises, and 105 (14.5%) were international multicenter trials, phase I trials accounted for 44.5%. For all those trials, there were 458 cancer drug varieties, with an annual growth rate of 36.7%, and 361 (85.8%) were developed by domestic enterprises. Most of the investigational products were therapeutic innovative drugs (77.1%), major in tumor treatment (92.8%). In terms of mechanism, targeted drugs were the most popular, accounting for 76.6%, and programmed cell death-1 (PD-1) and epithelial growth factor receptor (EGFR) were the most common targets. In addition, there were 19 anticancer drugs from 17 companies approved in China in 2019, with 10 drugs from domestic companies. Lung cancer and breast cancer are the most common indications for both registered trials and marketed drugs. No statistically significant differences were found between 2020 and 2019 in terms of the distribution of trial sponsor, scope and stage, as well as the distribution of drug type, effect and mechanism ( P>0.05). Conclusions:During the Covid-19 epidemic period, clinical trials of oncology drugs in China progress smoothly and maintain a high growth rate. Series of innovative products obtained by domestic enterprises in 2020 is the main driving force of development of oncology drug clinical trials in China.

With the progress of tumor molecular biology research, the clinical treatment concept of advanced breast cancer gradually tends to be accurate. Hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER-2) negative breast cancer accounts for more than 70% of all breast cancers, and it is of great significance to explore new treatment strategies to break through the bottleneck of traditional treatment faced by the patient population. Targeted therapy for this type of breast cancer started relatively late. After the first cyclin-dependent kinase (CDK) 4/6 inhibitor Palbociclib entered the clinical application for HR positive and HER-2 negative advanced breast cancer patients in 2015, the clinical treatment pattern of HR positive and HER-2 negative advanced breast cancer has been changed significantly, with a consequent breakthrough improvement in patients′ survival prognosis. Based on the basic pharmacological mechanism, the author analyzes the existing research data and puts forward opinions on how to achieve precise medication in clinical practice and wider application prospects in the future.

Breast cancer is one of the common malignant tumors of women. In recent years, the incidence of breast cancer is high. Human epidermal growth factor receptor-2 (HER-2) is a tyrosine kinase receptor. Breast cancer with abnormal amplification or overexpression of HER-2 have the characteristics of strong tumor invasiveness and poor prognosis. With the advent of anti-HER-2 drugs, the survival period of patients with HER-2 positive breast cancer is gradually prolonged, and the prognosis of patients with HER-2 positive breast cancer is improved. However, the efficacy of traditional HER-2 targeted drugs on patients with low expression of HER-2 is very limited, and the treatment of breast cancer with low expression of HER-2 is still facing challenges. This article reviews the standardization process of the American Society of Clinical Oncology and the American Society of Pathologists guidelines for HER-2 detection, and puts forward the data basis and possibility of defining a new subtype of breast cancer with low expression of HER-2. The birth of a new generation of HER-2 targeting drugs makes it possible to treat patients with low expression of HER-2, which will redefine breast cancer with low expression of HER-2 and provide a new opportunity for the prognosis of patients with low expression of HER-2.

Objective:The 6th edition American Joint Committee on Cancer (AJCC) staging system for breast cancer classifies ipsilateral supraclavicular lymph node metastasis (ISLM) downing stage from M1 to N3, suggesting more patients might receive radical treatment. The aim of this study was to analyze the effect of ISLM on the prognosis of N3 breast cancer and verify the rationality of modified staging.Methods:A total of 321 breast cancer patients with N3 according to the 6th edition AJCC staging system were retrospectively analyzed. Propensity Score Matching (PSM) was used to pair the different subgroups of N3. The primary end point was disease-free survival (DFS), the secondary end point was overall survival (OS). Kaplan-Meier method was used to calculate the DFS and OS. The differences between two groups were analyzed by the Log-rank test.Results:After PSM pairing twice, 78 patients with none-ISLM and 78 patients with ISLM were enrolled in the first group; 51 patients with none-ISLM was compared patients with isolated ISLM in the second group. The results of the two groups showed that patients with none-ISLM have a prolonged DFS (the first group: 58.9 months vs 32.1 months, P=0.101; the second group: 59.0 months vs 44.0 months, P=0.533), while the OS was opposite (the first group: 87.4 months vs 140.4 months, P=0.289; the second group: 87.4 months vs 137.1 months, P=0.289). Conclusions:The prognosis of breast cancer patients with ISLM is similar to that of patients with none-ISLM in stage N3. It is reasonable to include ISLM in N3 in the 6th edition AJCC staging system. Yet, prospective studies with larger sample size are needed to further confirmation.