SAN ANTONIO (EGMN) – Adding the HER2-directed monoclonal antibody pertuzumab to trastuzumab and docetaxel therapy improves pathologic complete response in the neoadjuvant setting and appears to eradicate some HER2-positive tumors in patients with early breast cancer, investigators have reported.

Pathologic complete response (pCR) at the time of surgery, the primary end point of the study, was 46% with the pertuzumab (Herceptin)/trastuzumab/docetaxel combination, compared with 29% for trastuzumab/docetaxel alone among women with early human epidermal growth factor receptor 2–positive (HER2-positive) disease.

 “What we have observed is a higher pCR rate with trastuzumab and pertuzumab when combined with docetaxel,” Dr. Luca Gianni said during a Dec. 10 press briefing. The results were presented at the San Antonio Breast Cancer Symposium.

Pathologic complete response for neoadjuvant pertuzumab and trastuzumab without chemotherapy was 17%. “Efficacy of the trastuzumab/pertuzumab doublet most importantly shows that a proportion of HER2-positive tumors can be eradicated without the need for chemotherapy,” said Dr. Gianni, director of medical oncology at the National Cancer Institute in Milan.

 “The results of ... these patients having eradication of the tumor indicates that there is a subset of women who can do without chemotherapy. We don’t know, as of yet, how to identify those women, but if we were able to do so, we would spare [them] the unnecessary toxicity,” he said.

The monoclonal antibody pertuzumab is a novel targeted medicine called a HER2 dimerization inhibitor. HER dimerization, or pairing, is thought to play an important role in the growth and formation of several different cancer types. Pertuzumab is the first investigational agent designed to specifically prevent the HER2 receptor from pairing with other HER receptors and may ultimately inhibit cancer cell growth or lead to cancer cell death.

The NEOSPHERE study (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) is a randomized multicenter phase II study that was conducted in 78 centers and involved 417 women with newly diagnosed HER2-positive early, inflammatory, or locally advanced breast cancer who had never received Herceptin.

Patients with operable or locally-advanced/inflammatory HER2-positive breast cancer were included in the study if they had not previously undergone chemotherapy and if their primary tumors were smaller than 2 cm.

The women were randomized to one of four treatments: docetaxel plus trastuzumab (n = 107), docetaxel plus trastuzumab and pertuzumab (n = 107), trastuzumab plus pertuzumab (n = 107), and docetaxel plus pertuzumab (n = 96).

Each group received four cycles of treatment before surgery. Treatment cycles were administered intravenously every 3 weeks. Pertuzumab was administered at an 840-mg loading dose and a 420-mg maintenance dose. Trastuzumab was given at an 8-mg/kg loading dose and a 6-mg/kg maintenance dose. Docetaxel was given at a 75-mg/m² dose with escalation to a 100-mg/m² dose if the starting dose was well tolerated.

After surgery all patients received trastuzumab for up to 1 year and three cycles (every 3 weeks) of standard therapy with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC).

Patients in the neoadjuvant trastuzumab/pertuzumab group also received docetaxel before receiving FEC.

Pathologic complete response in the intent-to-treat population was 29% for the trastuzumab/docetaxel group, 46% for trastuzumab/pertuzumab/docetaxel group, 17% for the trastuzumab/pertuzumab group, and 24% for the pertuzumab/docetaxel group.

The difference between pCR for the docetaxel/trastuzumab group and the trastuzumab/pertuzumab group was significant (P = .0198), as were the differences between the docetaxel/trastuzumab group and the docetaxel/trastuzumab/pertuzumab group (P = .0141), and between the docetaxel /trastuzumab/ pertuzumab group and the docetaxel/pertuzumab group (P = .003).

 “The tolerability of all combinations was very good,” said Dr. Gianni. “When we used the doublet of tumor antibodies, we basically did not observe any grade 3 or higher adverse events.”

He noted that there was no clinically meaningful incidence of diarrhea or skin rash with the addition of pertuzumab. There was also a “lack of any meaningful increase in cardiac risk with the addition of pertuzumab over a short course of four cycles of neoadjuvant therapy.”

Trastuzumab is approved for the treatment of early-stage breast cancer that is HER2 positive and has spread into the lymph nodes, or is HER2 positive and has not spread into the lymph nodes, but has one high-risk feature. The drug is also indicated for use in metastatic HER2-positive breast cancer and is approved, in combination with chemotherapy, for the treatment of HER2-positive metastatic cancer of the stomach or gastroesophageal junction.

The study was sponsored by F. Hoffmann-La Roche Ltd.

Dr. Gianni reported that he is on the advisory boards for F. Hoffmann-La Roche Ltd., Genentech Inc., GlaxoSmithKline, Boehringer Ingelheim GmbH, and Pfizer Inc.

圣安东尼奥(EGMN)——米兰国家癌症研究所医学肿瘤学主任Luca Gianni博士在圣安东尼奥乳腺癌大会上报告称，对早期乳腺癌患者采用曲妥珠单抗与多烯紫杉醇联合治疗加用HER2靶向性单克隆抗体帕妥珠单抗的新辅助治疗方案可提高病理学完全缓解(pCR)率，同时还可能根治某些HER2阳性的肿瘤。

 

单克隆抗体帕妥珠单抗(赫赛汀)是一种被称为HER2(人类表皮生长因子受体2)二聚化抑制剂的新型靶向治疗药，在多种不同类型癌症的生长和形成中均发挥着重要作用，是首个用于特异性阻断HER2受体与其他HER受体发生二聚化的试验药，最终可能会抑制癌细胞生长或导致其死亡。曲妥珠单抗现已获准用于治疗HER2阳性、淋巴结受累的或HER2阳性、尚未侵及淋巴结的早期乳腺癌，还适用于治疗转移性HER2阳性的乳腺癌。

 

本研究为NEOSPHER研究(早期帕妥珠单抗与赫赛汀新辅助治疗方案评估研究)，是一项随机、多中心的II期试验，在78个医疗中心开展，受试者为417例从未接受赫赛汀治疗、初诊为HER2阳性的早期炎性或局部晚期乳腺癌女患者，对于可行手术的或局部晚期/炎性HER2阳性乳腺癌患者，若其之前未行化疗且原发肿瘤<2 cm，亦可纳入本研究。研究者将受试者随机分配接受以下4种治疗方案之一：多烯紫杉醇+曲妥珠单抗(n = 107)，多烯紫杉醇+曲妥珠单抗+帕妥珠单抗(n=107)，曲妥珠单抗+帕妥珠单抗(n = 107)，以及多烯紫杉醇+帕妥珠单抗(n=96)。各组患者均在术前接受4个周期的治疗，治疗周期为每3周静脉用药一次。帕妥珠单抗的负荷剂量为840 mg，维持剂量为420 mg；曲妥珠单抗的负荷剂量为8 mg/kg，维持剂量为6 mg/kg；多烯紫杉醇的初始剂量为75 mg/m²，若能很好地耐受此剂量，则可将剂量递增至100 mg/m²。术后，所有患者均接受1年的曲妥珠单抗治疗和3个周期的标准治疗(由5-氟尿嘧啶、表阿霉素和环磷酰胺构成，即FEC)。在接受FEC治疗前，曲妥珠单抗/帕妥珠单抗新辅助治疗组的患者还接受多烯紫杉醇治疗。主要终点为病理学完全缓解。

 

在意向性治疗群体中，曲妥珠单抗/多烯紫杉醇治疗组到手术时的病理学完全缓解率为29%，而曲妥珠单抗/帕妥珠单抗/多烯紫杉醇治疗组为46%，帕妥珠单抗/多烯紫杉醇治疗组为24%，帕妥珠单抗+曲妥珠单抗但未联用化疗药物的新辅助治疗组为17%。多烯紫杉醇/曲妥珠单抗治疗组与曲妥珠单抗/帕妥珠单抗治疗组之间的pCR具有显著差异(P = 0.0198)，多烯紫杉醇/曲妥珠单抗与多烯紫杉醇/曲妥珠单抗/帕妥珠单抗治疗组之间、多烯紫杉醇/曲妥珠单抗/帕妥珠单抗治疗组与多烯紫杉醇/帕妥珠单抗治疗组之间(P =0.003)的pCR比较情况亦如此。曲妥珠单抗/帕妥珠单抗二联疗法的疗效非常突出地表现在HER2阳性肿瘤的根治比例上。

 

所有联合疗法的耐受性均非常好，采用肿瘤抗体二联治疗时，基本上未观察到任何3级或3级以上的不良事件，腹泻或皮疹的发生率均不具有临床意义，同时，加用帕妥珠单抗后的心脏风险相对于由4个周期的新辅助治疗构成的短程治疗的增加幅度不具有任何意义。

 

该研究由罗氏公司资助。Gianni博士称其是罗氏公司、基因泰克公司、葛兰素史克公司、勃林格殷格翰公司以及辉瑞公司的顾问委员会成员。

 

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