Efficacy of CT-P6 (trastuzumab biosimilar) versus reference trastuzumab in combination with pertuzumab in HER2-positive early-stage breast cancer: Preclinical and real-life clinical data

After the expiration of trastuzumab data exclusivity, biosimilar drugs were approved by regulatory agencies; among them, CT-P6 which was approved for the treatment of HER2-positive early- and advanced-breast cancer (BC) in 2018. Yet, reference trastuzumab (RTZ) is often combined with pertuzumab in early BC (EBC) patients treated with chemotherapy as it significantly improves the pathological complete response rate. Unfortunately, scarce preclinical and clinical data exists about the combination of CT-P6, pertuzumab and chemotherapy. Therefore, our aim was to study in vitro and in a retrospective cohort of EBC patients, whether CT-P6 was equivalent to RTZ when combined with pertuzumab with or without taxanes. In BT-474 and SKBR3 HER2+ cells we found that CT-P6 alone or in combination with pertuzumab had the same negative effect on cell proliferation, colony formation and HER2 downregulation as well as downstream activation, as RTZ. Adding paclitaxel to these treatments increased their effectivity to a similar extent. In HER2 1+ neuregulin-secreting MB-MDA-175 cells, combinations of CT-P6 or RTZ with pertuzumab were also effective, and mainly dependent on HER3:HER2 heterodimerization. In a retrospective cohort of 44 EBC HER2+ patients treated with neoadjuvant RTZ or CT-P6 in combination with pertuzumab and chemotherapy, we found no differences in efficacy or in adverse events. Moreover, the costs of CT-P6-based treatments were reduced by 1474.07 €/patient. All together we provide pre-clinical and clinical evidence of the equivalence of CT-P6 in combination with pertuzumab and chemotherapy and suggest studying these combinations also in HER2 low/negative BC patients.     

A multicenter REtrospective observational study of first-line treatment with PERtuzumab,trastuzumab and taxanes for advanced HER2 positive breast cancer patients. RePer Study

We carried out a retrospective observational study of 264 HER2-positive advanced breast cancer (ABC) patients to explore the efficacy of first-line treatment with pertuzumab/trastuzumab/taxane in real-world setting. Survival data were analyzed by Kaplan Meier curves and log rank test.

Median follow-up, length of pertuzumab/trastuzumab/taxane treatment and of pertuzumab, trastuzumab maintenance were 21, 4 and 15 months, respectively. The response rate was 77.3%, and the clinical benefit rate 93.6%. Median progression-free survival (mPFS) was 21 months, and median overall survival (mOS) was not reached.

When comparing patients by trastuzumab-pretreatment, similar PFS were observed, although a longer OS was reached in trastuzumab-naïve patients (p = 0.02). Brain metastases at baseline and their development in course of therapy were associated with significantly shorter PFS (p = 0.0006) and shorter OS, although at a not fully statistically relevant extent (p = 0.06).

The addition of maintenance endocrine therapy (ET) to pertuzumab/trastuzumab maintenance was associated with longer PFS (p = 0.0001), although no significant differences were detected in OS (p = 0.31). Results were confirmed by propensity score analysis (p = 0.003 and p = 0.46, respectively).

In multivariate models, longer PFS was related to lower Performance Status (PS) (p = 0.07), metastatic stage at diagnosis (p = 0.006) and single metastatic site (p < 0.0001). An OS advantage was observed with lower PS (p < 0.0001), single metastatic site (p = 0.004), no prior exposure to trastuzumab (p = 0.004) and response to pertuzumab-based treatment (p = 0.003). Our results confirm that trastuzumab/pertuzumab/taxane is the standard of care as first-line treatment of patients with HER2-positive ABC even in the real-world setting. Moreover, the double-maintenance therapy (HER2 block and ET) is strongly recommended when feasible.     

Targeted therapy in gastric cancer

Gastric cancer is often diagnosed at an advanced stage. Although chemotherapy prolongs survival and improves quality of life, the survival of gastric cancer patients with advanced disease is short. Thanks to recent insights into the molecular pathways involved in gastric carcinogenesis, new targeted treatment options have become available for gastric cancer patients. Trastuzumab, an antibody targeted to HER‐2, was shown to improve survival of advanced gastric cancer patients harboring HER‐2 overexpression due to gene amplification in their tumor cells, and is currently also explored in adjuvant and neoadjuvant settings. Another agent with promising results in clinical trials is ramucirumab, an antibody targeting VEGFR‐2. No clear survival benefit, however, were experienced with agents targeting EGFR (cetuximab, panitumumab), VEGF‐A (bevacizumab), or mTOR (everolimus). Drugs targeting c‐MET/HGF are currently under investigation in biomarker‐selected cohorts, with promising results in early clinical trials. This review will summarize the current status of targeted treatment options in gastric cancer.     

曲妥珠单抗并紫杉醇新辅助化疗HER2阳性晚期局部乳腺癌的疗效评估

目的 评估应用曲妥珠单抗与紫杉醇新辅助化疗人表皮生长因子受体2(HER2)阳性局部乳腺癌晚期患者的疗效。方法 选择2017年2月—2018年10月期间入某医院诊治的62例HER2阳性局部乳腺癌晚期患者,按随机数表法进行分组,单一组(31例)单独行曲妥珠单抗治疗,联合组(31例)行曲妥珠单抗与紫杉醇新辅助化疗联合治疗。对比两组患者血清相关指标、临床疗效以及药物毒副反应。结果 治疗后联合组患者的糖类抗原125(CAI125)、肿瘤特异性生长因子(TSGF)、癌胚抗原(CEA)肿瘤标志物表达水平均低于单一组;联合组治疗有效率(64.52%)高于单一组(38.71%),差异有统计学意义(P<0.05)。结论 对HER2阳性局部乳腺癌晚期患者应用曲妥珠单抗与紫杉醇新辅助化疗的疗效较好,可抑制肿瘤细胞增殖,有效控制病情进展,值得推广。     

Whole exome sequencing to identify genetic markers for trastuzumab‐induced cardiotoxicity

Although trastuzumab‐induced cardiotoxicity is an important determinant to limit the use of this drug, the molecular mechanism of risk for this toxicity is not well understood. To identify genetic variants determining the risk of trastuzumab‐induced cardiotoxicity, we carried out whole exome sequencing of germline DNA samples from 9 patients with trastuzumab‐induced cardiotoxicity, and conducted a case‐control association study of 2258 genetic variants between 9 cases (with trastuzumab‐induced cardiotoxicity) and general Japanese population controls registered in the Human Genetic Variation Database (HGVD). The top variant which showed the lowest P‐value in the screening study was rs139503277 in PHD Finger Protein 3 (P_min = .00012, odds ratio [OR] = 51.23). To further validate the result of screening study, we carried out a replication study of 10 variants showing P_min < .001 in the screening study using 234 independent patients treated with trastuzumab, including 10 cases and 224 controls (without trastuzumab‐induced cardiotoxicity). In the replication study, we observed that three variants had an effect in the same direction as in the screening study (rs78272919 in exon 2 of Keratin 15, rs5762940 in exon 2 of zinc and ring finger 3, and rs139944387 in exon 44 of Eyes shut homologs [EYS]). A combined result of the screening and the replication studies suggested an association of a locus on chromosome 6q12 with trastuzumab‐induced cardiotoxicity (rs139944387 in EYS, combined P_min = .00056, OR = 13.73). This finding provides new insights into personalized trastuzumab therapy for patients with human epidermal growth factor receptor 2 (HER2)‐positive cancer.     

曲妥珠单抗治疗后进展的转移性乳腺癌继续曲妥珠单抗治疗的疗效及安全性分析

目的：评价曲妥珠单抗治疗后进展的转移性乳腺癌患者继续行曲妥珠单抗治疗的疗效及安全性。方法回顾性分析曲妥珠单抗治疗过程中出现疾病进展,继续行曲妥珠单抗治疗,仅更换化疗方案的30例HER2阳性转移性乳腺癌患者的临床资料,并评价疗效及不良反应。结果30例HER2阳性转移性乳腺癌患者,均在复发转移阶段接受过曲妥珠单抗治疗,中位治疗时间6.0个月（95%CI为1.7~10.3个月）;30例患者在出现疾病进展后,均继续进行曲妥珠单抗治疗,仅更换联合的化疗方案。30例患者均可评价疗效,其中部分缓解（PR）7例（23.3%）,疾病稳定（SD）12例（40.0%）,疾病进展（PD）11例（36.7%）,无完全缓解（CR）患者。客观缓解率为23.3%,临床获益率为43.3%。总无进展生存期（PFS）为5.0个月（95%CI为3.0~7.0个月）。有临床获益的13例患者的PFS明显长于17例无临床获益者（9.0个月vs 3.0个月,P﹤0.001）。最常见的不良反应为血液学不良反应,考虑主要与化疗药物相关。结论对于曲妥珠单抗治疗过程中出现疾病进展的患者,继续使用曲妥珠单抗,更换化疗方案有较好的临床获益。     

The efficiency and safety of trastuzumab for advanced gastric and gastroesophageal cancer: a meta-analysis of five randomized controlled trials

A meta-analysis was performed to examine the efficiency and safety of trastuzumab in patients with advanced gastric and gastroesophageal cancer (AGC). By searching multiple databases from 1990 to March 2016, all randomized controlled trials (RCTs) which compared the effect of trastuzumab-combined chemotherapy (TC) versus chemotherapy alone (CT) in gastric cancer would be included. Five RCTs with a total of 875 patients were included. Trastuzumab can improve the overall survival (OS) rate, progression-free survival (PFS), one-year survival rate, two-year survival rate and overall response rate (ORR) of patients with AGC. There were no difference between the two arms in terms of grade 3/4 adverse effects, such as vomiting, nausea, neutropenia, thrombocytopaenia and anemia. Diarrhea increased in TC group. Trastuzumab can significantly improve the survival rate, PFS, ORR of patients with AGC. It is safe and feasible and can be tolerated. It needs further prospective multinational multicenter RCTs with large samples to define the clinical benefits of trastuzumab.