编者按：胃/胃食管交界部（G/GEJ）腺癌作为全球范围内常见且致死率较高的恶行肿瘤之一，其治疗方案的优化一直备受关注。2024年9月13日至17日，欧洲肿瘤内科学会（ESMO）年会在西班牙巴塞罗那召开，会议中公布了多项关于HER2阳性G/GEJ腺癌治疗的最新研究。本文梳理了出其中两项备受瞩目的研究，分别是KEYNOTE-811研究和DESTINY-Gastric03研究，为胃癌治疗领域带来了新启示。

KEYNOTE-811研究：帕博利珠单抗联合曲妥珠单抗及化疗的最终OS数据更新  

题目：帕博利珠单抗联合曲妥珠单抗和化疗治疗HER2+晚期不可切除或转移性胃/胃食管交界腺癌：Ⅲ期KEYNOTE-811研究的最终总生存结果

研究背景

研究方法

研究结果

研究结论

根据最终OS数据分析，帕博利珠单抗联合曲妥珠单抗和化疗相较于安慰剂组，显著延长了HER2阳性mG/GEJ腺癌患者的一线治疗总生存期。本次研究的数据为该方案作为HER2阳性胃癌患者的一线标准治疗方案提供了有力支持，特别是在PD-L1 CPS≥1的亚组中，疗效更为突出。

DESTINY-Gastric03研究：德曲妥珠单抗（T-DXd）联合治疗在HER2阳性晚期胃癌中的潜在优势  

题目：DESTINY-Gastric03研究：德曲妥珠单抗(T-DXd)单药联合治疗用于晚期/转移性HER2阳性食管、胃或胃食管交界腺癌患者

研究背景

研究方法

研究结果

研究结论

总结

KEYNOTE-811研究为HER2阳性不可切除胃癌的一线治疗奠定了新的标准，而DESTINY-Gastric03研究中的T-DXd联合治疗展现了新的抗肿瘤潜力，但仍需进一步研究以评估其长期安全性和有效性。这两项研究标志着HER2靶向治疗在胃癌领域的又一重大进展，未来将为更多患者带来希望。  

摘要原文

1400O - Final overall survival for the phase III, KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for HER2+ advanced, unresectable or metastatic G/GEJ adenocarcinoma

Presentation Number：1400O

Speakers：Sara Lonardi (Padova, Italy)

Lecture Time：09:15 - 09:25

Abstract

Background

In a prior analysis of the phase 3 KEYNOTE-811 study (NCT03615326), first-line pembrolizumab (pembro)/trastuzumab and chemotherapy (chemo) provided superior PFS, and improved ORR with durable responses vs placebo (pbo)/trastuzumab and chemo in unresectable, HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) cancer, notably in PD-L1 CPS ≥1 tumors; overall survival (OS) was immature. These data supported approval of pembro/trastuzumab and chemo for first-line HER2+ mG/GEJ cancer with PD-L1 CPS ≥1. We present results of the final analysis of OS for KEYNOTE-811.

Methods

Eligible patients (pts) aged ≥18 years with treatment-naive unresectable, HER2+ mG/GEJ adenocarcinoma irrespective of PD-L1 status were randomized 1:1 to pembro 200 mg IV Q3W or pbo IV Q3W plus chemo (5-FU and cisplatin [FP] or capecitabine and oxaliplatin [CAPOX] and trastuzumab [SOC]). Randomization was stratified by region, PD-L1 status, and chemo choice. Dual primary end points were PFS (RECIST v1.1, BICR) and OS. Data cut-off at final analysis was 20 Mar 2024.

Results

A total of 698 pts were randomized (350 to pembro + SOC; 348 to pbo + SOC). Median follow-up was 50.2 mo. In all pts, PFS continued to be longer with pembro + SOC vs pbo + SOC (median 10.0 vs 8.1 mo; HR 0.73; 95% CI, 0.61-0.87). In pts with PD-L1 CPS ≥1, median PFS was 10.9 vs 7.3 mo (HR 0.72; 95% CI, 0.60-0.87). At final analysis, OS was significantly improved with pembro + SOC (median 20.0 vs 16.8 mo; HR 0.80; 95% CI, 0.67-0.94; p=0.0040 [less than prespecified boundary 0.0201) vs pbo + SOC. In pts with PD-L1 CPS ≥1, median OS was 20.1 vs 15.7 mo (HR 0.79; 95% CI, 0.66-0.95). ORR was 72.6% vs 60.1% with pembro + SOC vs pbo + SOC. Grade ≥3 drug-related AE rates were 59% vs 51%.

Conclusions

First-line pembro plus trastuzumab and chemo provided a statistically significant and clinically meaningful improvement in OS vs pbo plus trastuzumab and chemo in all pts with unresectable, HER2+ mG/GEJ cancer. OS was longer in pts with PD-L1 CPS ≥1. These data support the approval of pembro plus trastuzumab and chemo in pts with HER2+ mG/GEJ cancer and confirm this regimen as SOC in the first-line setting.

Clinical trial identification

NCT03615326.

1401O - Trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with advanced/metastatic HER2-positive (HER2+) esophageal, gastric or gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03 (DG-03)

1401O - 曲妥珠单抗 deruxtecan （T-DXd） 单药和联合治疗晚期/转移性 HER2 阳性 （HER2+） 食管、胃或胃食管交界处腺癌 （GEJA） 患者 （pts）：DESTINY-Gastric03 （DG-03）

Presentation Number 

1401O

Speakers：Yelena Y. Janjigian (New York, United States of America, NY)

Lecture Time：09:25 - 09:35

Abstract

Background

T-DXd is a HER2-directed antibody-drug conjugate; T-DXd 6.4 mg/kg is approved for pts with metastatic HER2+ gastric/GEJA who have received a prior trastuzumab-based regimen. Dual PD-1 and HER2 blockade together with fluoropyrimidine (FP; 5-fluorouracil or capecitabine)/platinum has improved outcomes vs chemotherapy/trastuzumab in the first-line (1L) setting. We explored T-DXd in combination with FP and an anti-PD-1 in 1L esophageal/gastric/GEJA.

Methods

DG-03 Part 2 (dose expansion; NCT04379596) enrolled pts with 1L HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization-positive by local testing) esophageal/gastric/GEJA globally, irrespective of PD-L1 status. Pts were randomized (except to arm F), as feasible, to standard of care (SOC), T-DXd monotherapy or T-DXd-based combinations, and stratified by HER2 status (Table). Primary endpoint was investigator-assessed (INV) confirmed objective response rate (ORR) per RECIST 1.1. Safety and tolerability were assessed.

Results

At data cutoff (Jan 31, 2024), 307 pts were enrolled; 229 pts received treatment. Baseline/disease characteristics were not balanced across arms. Combining T-DXd with FP/pembrolizumab (pembro) 200 mg showed durable clinical benefit in pts with HER2+ central PD-L1 CPS ≥1 esophageal/gastric/GEJA. Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 21 (11%) T-DXd-treated pts (arm B [6.4 mg/kg], n=4; arm C [6.4 mg/kg + FP], n=4; arm D [6.4 mg/kg + FP + pembro], n=8; arm E [6.4 mg/kg + pembro], n=5), with 3 deaths (arm D, n=2; arm E, n=1). Summary efficacy and safety are in the table. Table: 1401O

*1 pt allocated to B received FP in error (summarized in C for safety) CPS, combined positive score; NA, not applicable

Conclusions

Combination of T-DXd + FP + pembro showed promising antitumor activity warranting further study in esophageal/gastric/GEJA. Tolerability was lower with T-DXd 6.4 mg/kg + FP + pembro; however, the overall safety profile was manageable.

Clinical trial identification

NCT04379596.