小柯机器人

日本国立癌症中心医院Kohei Shitara团队比较了一线纳武单抗联合化疗与单纯化疗治疗晚期胃、胃食管交界处和食管腺癌的疗效。相关成果于2021年6月5日发表于《柳叶刀》杂志上。

晚期或转移性人表皮生长因子受体2（HER2） 阴性的胃或胃食管交界腺癌的一线化疗中位总生存期（OS）小于1年。为了评估基于程序性细胞死亡（PD）-1抑制剂的一线治疗对胃、胃-食管交界处和食管腺癌中的疗效，研究组比较了纳武单抗联合化疗与单独化疗的初步结果。

在这项多中心、随机、开放标签、临床3期试验中，研究人员从29个国家的175家医院和癌症中心招募了既往未经治疗、不可切除、非HER2阳性的胃、胃-食管交界处或食道腺癌的成年人（≥18岁），无论其PD配体1 (PD-L1)表达如何。将患者按1：1：1随机分配，分别接受纳武单抗+化疗，纳武单抗+伊匹单抗，或单独化疗。主要终点为，在PD-L1联合阳性评分（CPS）≥5的患者中，纳武单抗联合化疗与单独化疗的OS或无进展生存期（PFS）。

2017年3月27日至2019年4月24日，在评估合格的2687名患者中，研究组随机分配1581名患者，其中789名接受纳武单抗联合化疗，792例接受单独化疗。纳武单抗联合化疗组的中位OS随访时间为13.1个月，单独化疗组为11.1个月。对于PD-L1 CPS≥5的患者，与单独化疗组相比，纳武单抗联合化疗组显著改善了OS和PFS。

其他研究结果显示，在PD-L1 CPS≥1的患者和所有随机分配的患者中，OS显著改善，PFS获益。在所有接受治疗的患者中，纳武单抗联合化疗组782例患者中有462例（59%）发生了3-4级治疗相关的不良事件，单独化疗组767例患者中有341例（44%）。两组中最常见的任何级别治疗相关不良事件（≥25%）是恶心、腹泻和周围神经病变。纳武单抗联合化疗组中有16例（2%）患者死亡，单独化疗组中有4例（1%），均被认为与治疗相关。未发现新的安全事件。

研究结果表明，对于既往未治疗的晚期胃、胃-食管交界或食管腺癌患者，与单独化疗相比，纳武单抗联合化疗显示出优越的OS、PFS和可接受的安全性。

附：英文原文

Title: First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial

Author: Yelena Y Janjigian, Kohei Shitara, Markus Moehler, Marcelo Garrido, Pamela Salman, Lin Shen, Lucjan Wyrwicz, Kensei Yamaguchi, Tomasz Skoczylas, Arinilda Campos Bragagnoli, Tianshu Liu, Michael Schenker, Patricio Yanez, Mustapha Tehfe, Ruben Kowalyszyn, Michalis V Karamouzis, Ricardo Bruges, Thomas Zander, Roberto Pazo-Cid, Erika Hitre, Kynan Feeney, James M Cleary, Valerie Poulart, Dana Cullen, Ming Lei, Hong Xiao, Kaoru Kondo, Mingshun Li, Jaffer A Ajani

Issue&Volume: 2021-06-05

Abstract:

Background

First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone.

Methods

In this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116.

Findings

From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7–19·1) for nivolumab plus chemotherapy and 11·1 months (5·8–16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59–0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56–0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3–4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified.

Interpretation

Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients.

DOI: 10.1016/S0140-6736(21)00797-2

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00797-2/fulltext

LANCET：《柳叶刀》，创刊于1823年。隶属于爱思唯尔出版社，最新IF：202.731
官方网址：http://www.thelancet.com/
投稿链接：http://ees.elsevier.com/thelancet