First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial.
First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial.
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DOI：
10.1016/s1470-2045(20)30169-8
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发表时间：
2020-06
期刊：
影响因子：
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通讯作者：
Hechtman JF
中科院分区：
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作者：
Janjigian YY;Maron SB;Chatila WK;Millang B;Chavan SS;Alterman C;Chou JF;Segal MF;Simmons MZ;Momtaz P;Shcherba M;Ku GY;Zervoudakis A;Won ES;Kelsen DP;Ilson DH;Nagy RJ;Lanman RB;Ptashkin RN;Donoghue MTA;Capanu M;Taylor BS;Solit DB;Schultz N;Hechtman JF
将曲妥珠单抗加入一线化疗可改善HER2阳性转移性胃癌患者的总体生存率。我们评估了培溴利珠单抗联合曲妥珠单抗和化疗治疗一线HER2阳性转移性食管胃(EG)癌的安全性和有效性。这是一项开放标签、非随机、单臂、由研究人员发起的单中心2期试验，研究对象为18岁或18岁以上的HER2阳性MEG癌症患者。符合条件的患者在基线时有可测量或可评估的不可测量的疾病，东部合作肿瘤组的表现状态为0、1或2，基线左心室射血分数为≥的53%。患者可接受静脉注射培溴利珠单抗(200 mg平坦剂量)和曲妥珠单抗8 mg/kg负荷量的初始诱导周期。奥沙利铂130 mg/m2或顺铂80 mg/m2静脉滴注，第1天；卡培他滨850 mg/m2，每日2次，停药1周；5-FU 800 mg/m2，静脉滴注，第1~5天；培溴利珠单抗200 mg，曲妥珠单抗6 mg/kg，静脉滴注，均为3周周期的第1天。主要终点是6个月无进展生存期(PFS)。收集治疗前肿瘤和血浆样本，以确定HER2状态，并通过靶向和整个外显子组测序进行探索性生物标志物分析。这项试验在ClinicalTrials.gov注册，编号NCT02954536(正在进行，注册截止)。在2016年11月11日至2019年1月23日期间，共有37名患者入选。在2019年8月6日数据截止时，幸存者的中位随访时间为13个月(范围6-31)。达到了主要终点；37名患者中有26名(70%，95%可信区间54-83%)在6个月内没有进展。35例可测疾病患者总有效率为91%(32例，95%可信区间78~97%)，其中完全缓解6例(17%)，部分缓解26例(74%)，稳定3例(8%)。中位生存期13.0个月(95%可信区间8.6-NA)，中位总生存期27.2个月(95%可信区间18.8-NA)，12个月生存率80%(95%可信区间68~95%)。最常见的与治疗相关的不良事件是神经病变，37名患者中有36名(97%)受到影响。21例(67%)患者发生与治疗相关的3级或4级不良事件，2例发生严重不良事件。2例患者因治疗相关不良事件而停止治疗，4例患者因免疫相关不良事件而停用培布罗珠单抗。32例肿瘤测序患者中有21例(66%)检测到ERBB2扩增或病灶扩大，33例循环肿瘤DNA(CtDNA)测序患者中有18例(54%)检测到ERBB2扩增或病灶扩大。组织和ctDNA测序在29例患者中有27例(93%)有或没有ERBB2扩增。在16例肿瘤匹配的治疗前ctDNA患者中，有13例在第一剂培溴利珠单抗和曲妥珠单抗治疗后肿瘤匹配的ctDNA下降。同时存在肿瘤和ctDNA扩增的患者有较长的无瘤生存期；中位数16.4(n=14，95%可信区间13.0-NA)高于未扩增的患者6.2个月(n=12，95%可信区间5.9-NA)(p=0.013)。Pembrolizumab可以安全地与曲妥珠单抗和化疗联合使用，无论PD-L1状态如何，对HER2阳性的Meg癌都有很好的疗效。基于血浆的ctDNA应该在未来的随机研究中作为一种预测性生物标志物进行探索。目前正在进行一项随机的3期临床试验，评估培溴利珠单抗与安慰剂联合曲妥珠单抗和化疗治疗一线HER2阳性Meg癌的有效性和安全性。
Adding trastuzumab to first-line chemotherapy improves overall survival in patients with HER2-positive metastatic gastric cancer. We assessed the safety and efficacy of pembrolizumab in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic esophagogastric (EG) cancer. This was an open-label, non-randomized, single-arm, investigator-initiated single center phase 2 trial in patients aged 18 years or older with HER2-positive mEG cancer. Eligible patients had measurable or evaluable non-measurable disease at baseline, Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and baseline left ventricular ejection fraction of ≥ 53%. Patients were eligible to receive an initial induction cycle of intravenous (IV) pembrolizumab (200 mg flat dose) and IV trastuzumab 8 mg/kg loading dose. For subsequent cycles, patients received IV oxaliplatin 130 mg/m2 or cisplatin 80 mg/m2 on day 1, oral capecitabine 850 mg/m2 twice a day for 2 weeks followed by 1 week off, or IV 5-FU 800 mg/m2/day on day 1 to 5, and IV pembrolizumab 200 mg flat dose and trastuzumab 6 mg/kg, both administered on day 1 of each 3-week cycle. The primary endpoint was 6-month progression-free survival (PFS). Pre-treatment tumor and plasma samples were collected for confirmation of HER2 status and exploratory biomarker analysis by targeted and whole exome sequencing. This trial is registered with Clinicaltrials.gov, number NCT02954536 (ongoing, closed to enrollment). Between Nov 11, 2016, and Jan 23, 2019, 37 patients were enrolled. At the time of data cutoff on Aug 6, 2019, the median follow-up among survivors was 13 months (range 6–31). The primary endpoint was achieved; 26 of 37 (70%, 95% CI 54–83%) patients were progression-free at 6 months. The overall response rate among 35 patients with measurable disease was 91% (32 patients, 95% CI 78–97%), including 6 (17%) complete responses, 26 (74%) partial responses, and 3 (8%) stable disease. The median PFS was 13.0 months (95% CI 8.6–NA), median overall survival (OS) was 27.2 months (95% CI 18.8–NA), and the 12-month OS rate was 80% (95% CI 68–95%). The most common treatment-related adverse event of any grade was neuropathy, which affected 36 (97%) of the 37 patients. Treatment-related grade 3 or 4 adverse events occurred in 21 (67%) patients, and serious adverse events occurred in 2. Two patients discontinued treatment due to treatment-related adverse events, and 4 discontinued pembrolizumab due to immune-related adverse events. ERBB2 amplification or focal gain was detected in 21 of 32 patients (66%) patients who had tumor sequencing and in 18 of 33 patients (54%) whose circulating tumor DNA (ctDNA) was sequenced. Tissue and ctDNA sequencing were concordant for presence or absence of ERBB2 amplification in 27 of 29 patients (93%). A decline in tumor-matched ctDNA was observed after the first dose of pembrolizumab and trastuzumab in 13 of the 16 patients with tumor-matched pre-treatment ctDNA. Patients with ERBB2 amplification in both tumor and ctDNA had longer PFS; median 16.4 (n = 14, 95% CI 13.0–NA) versus 6.2 months (n = 12, 95% CI 5.9–NA) in those who did not (p = 0.013). Pembrolizumab can be safely combined with trastuzumab and chemotherapy and has promising activity in HER2-positive mEG cancer irrespective of PD-L1 status. Plasma-based ctDNA should be explored in future randomized studies as a predictive biomarker. A randomized phase 3 clinical trial assessing the efficacy and safety of pembrolizumab versus placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive mEG cancer is currently underway.