Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autonoma de Barcelona, Centro de Investigación Biomédica en Red Cáncer, Barcelona, Spain.
Instituto do Cancer de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Lancet Oncol. 2018 Oct;19(10):1372-1384. doi: 10.1016/S1470-2045(18)30481-9. Epub 2018 Sep 11.
Adding pertuzumab to trastuzumab and chemotherapy improves survival in HER2-positive early breast cancer and metastatic breast cancer. We assessed the efficacy and safety of pertuzumab versus placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic gastric or gastro-oesophageal junction cancer.
JACOB was a double-blind, placebo-controlled, randomised, multicentre, phase 3 trial in patients aged 18 years or older with HER2-positive metastatic gastric or gastro-oesophageal junction cancer. Eligible patients had measurable or evaluable non-measurable disease at baseline, Eastern Cooperative Oncology Group performance status of 0 or 1, and baseline left ventricular ejection fraction of 55% or more. Patients at 197 oncology clinics (in 30 countries) were randomly assigned (1:1) to receive either pertuzumab (840 mg intravenously) or placebo every 3 weeks, with trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks intravenously), plus chemotherapy (cisplatin 80 mg/m every 3 weeks intravenously, oral capecitabine 1000 mg/m twice a day [2000 mg/m every 24 h] for 28 doses every 3 weeks, or 5-fluorouracil 800 mg/m every 24 h intravenously [120 h continuous infusion] every 3 weeks). Randomisation was by a central permuted block randomisation scheme (block size of 4) with an interactive voice or web response system, stratified by geographical region, previous gastrectomy, and HER2 positivity. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with Clinicaltrials.gov, number NCT01774786 (ongoing, but closed to enrolment).
Between June 10, 2013, and Jan 12, 2016, of 3287 patients assessed, 780 eligible patients were randomly assigned to receive either pertuzumab plus trastuzumab and chemotherapy (pertuzumab group, n=388) or placebo plus trastuzumab and chemotherapy (control group, n=392). Median duration of follow-up was 24·4 months (95% CI 22·3-26·1) in the pertuzumab group and 25·0 months (22·3-28·9) in the control group. After 242 deaths in the pertuzumab group and 262 deaths in the control group (the study was not stopped at this point), overall survival was not significantly different between treatment groups (median overall survival 17·5 months [95% CI 16·2-19·3] in the pertuzumab group and 14·2 months [12·9-15·5] in the control group; hazard ratio 0·84 [95% CI 0·71-1·00]; p=0·057). Serious adverse events occurred in 175 (45%) of 385 patients in the pertuzumab group and 152 (39%) of 388 patients in the control group. Diarrhoea was the most common serious adverse event in both groups (17 [4%] patients in the pertuzumab group vs 20 [5%] patients in the control group). The most common grade 3-5 adverse events were neutropenia (116 [30%] patients in the pertuzumab group vs 108 [28%] patients in the control group), anaemia (56 [15%] vs 65 [17%]), and diarrhoea (51 [13%] vs 25 [6%]). Treatment-related deaths occurred in seven (2%) patients in the control group; no treatment-related deaths occurred in the pertuzumab group.
Adding pertuzumab to trastuzumab and chemotherapy did not significantly improve overall survival in patients with HER2-positive metastatic gastric or gastro-oesophageal junction cancer compared with placebo. Further studies are needed to identify improved first-line treatment options in these types of cancer and to identify patients with HER2-driven tumours who might benefit from dual HER2-targeted therapy.
F. Hoffmann-La Roche Ltd.
在 HER2 阳性早期乳腺癌和转移性乳腺癌中，加入曲妥珠单抗和化疗可提高生存率。我们评估了在 HER2 阳性转移性胃或胃食管交界处癌的一线治疗中，与安慰剂相比，曲妥珠单抗联合化疗与 pertuzumab 的疗效和安全性。
JACOB 是一项双盲、安慰剂对照、随机、多中心、三期临床试验，纳入年龄在 18 岁及以上的 HER2 阳性转移性胃或胃食管交界处癌患者。合格患者在基线时有可测量或可评估的不可测量疾病，东部合作肿瘤学组体能状态为 0 或 1，且左心室射血分数在基线时为 55%或更高。来自 30 个国家的 197 家肿瘤诊所的患者被随机分配（1:1），分别接受 pertuzumab（840 mg 静脉注射）或安慰剂，每 3 周一次，同时给予曲妥珠单抗（8 mg/kg 负荷剂量，然后每 3 周静脉注射 6 mg/kg）和化疗（顺铂 80 mg/m 每 3 周静脉注射一次，卡培他滨 1000 mg/m 每天两次口服[每 24 小时 2000 mg/m]，每 3 周 28 剂，或氟尿嘧啶 800 mg/m 每 24 小时静脉注射[120 小时连续输注]，每 3 周一次）。随机分组采用中央区组随机化方案（区组大小为 4），并通过交互式语音或网络应答系统进行分层，按地理位置、胃切除术和 HER2 阳性进行分层。主要终点是在意向治疗人群中的总生存期。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT01774786（正在进行，但已关闭入组）。
在 2013 年 6 月 10 日至 2016 年 1 月 12 日期间，对 3287 例患者进行了评估，有 780 例合格患者被随机分配接受 pertuzumab 加曲妥珠单抗和化疗（pertuzumab 组，n=388）或安慰剂加曲妥珠单抗和化疗（对照组，n=392）。在 pertuzumab 组和对照组中，中位随访时间分别为 24.4 个月（95%CI 22.3-26.1）和 25.0 个月（22.3-28.9）。在 pertuzumab 组中有 242 例死亡，对照组中有 262 例死亡（此时未停止研究），两组之间的总生存期没有显著差异（pertuzumab 组的中位总生存期为 17.5 个月[95%CI 16.2-19.3]，对照组为 14.2 个月[12.9-15.5]；风险比 0.84[95%CI 0.71-1.00]；p=0.057）。在 pertuzumab 组中有 175（45%）例患者和对照组中有 152（39%）例患者发生严重不良事件。腹泻是两组中最常见的严重不良事件（pertuzumab 组 17 例[4%]，对照组 20 例[5%]）。最常见的 3-5 级不良事件是中性粒细胞减少症（pertuzumab 组 116 例[30%]，对照组 108 例[28%]）、贫血（pertuzumab 组 56 例[15%]，对照组 65 例[17%]）和腹泻（pertuzumab 组 51 例[13%]，对照组 25 例[6%]）。对照组中有 7（2%）例患者发生与治疗相关的死亡；pertuzumab 组无治疗相关死亡。
与安慰剂相比，在 HER2 阳性转移性胃或胃食管交界处癌患者中，加入 pertuzumab 与曲妥珠单抗和化疗并没有显著提高总生存率。需要进一步的研究来确定这些类型癌症的一线治疗的改进方案，并确定可能从双 HER2 靶向治疗中获益的 HER2 驱动肿瘤患者。
罗氏制药有限公司。
