Repositorio
Institucional

Rha, Sun Young

Oh, Do-Youn

Yanez, Patricio

Bai, Yuxian

Ryu, Min-Hee

Lee, Jeeyun

Rivera, Fernando

Alves, Gustavo Vasconcelos

Garrido, Marcelo

Shiu, Kai-Keen

Fernandez, Manuel Gonzalez

Li, Jin

Lowery, Maeve A.

Cil, Timucin

Cruz, Felipe Melo

Qin, Shukui

Luo, Suxia

Pan, Hongming

Wainberg, Zev A.

Yin, Lina

Bordia, Sonal

Bhagia, Pooja

Wyrwicz, Lucjan S.

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial

ELSEVIER SCIENCE INC

LANCET ONCOLOGY

en

Background:<bold> </bold>PD-1 inhibitors combined with chemotherapy have shown efficacy in gastric or gastro-esophageal junction cancer. We compared the efficacy and safety of pembrolizumab plus chemotherapy with placebo plus chemotherapy in participants with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma.Methods:<bold> </bold>KEYNOTE-859 is a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial, done at 207 medical centres across 33 countries. Eligible participants were aged 18 years and older with previously untreated histologically or cytologically confirmed locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to receive pembrolizumab or placebo 200 mg, administered intravenously every 3 weeks for up to 35 cycles. All participants received investigator's choice of fluorouracil (intravenous, 800 mg/m(2) per day) administered continuously on days 1-5 of each 3-week cycle plus cisplatin (intravenous, 80 mg/m(2)) administered on day 1 of each 3-week cycle or capecitabine (oral, 1000 mg/m(2)) administered twice daily on days 1-14 of each 3-week cycle plus oxaliplatin (intravenous, 130 mg/m(2)) administered on day 1 of each 3-week cycle. Randomisation was done using a central interactive voice-response system and stratified by geographical region, PD-L1 status, and chemotherapy in permuted block sizes of four. The primary endpoint was overall survival, assessed in the intention-to-treat (ITT) population, and the populations with a PD-L1 combined positive score (CPS) of 1 or higher, and PD-L1 CPS of 10 or higher. Safety was assessed in the as-treated population, which included all randomly assigned participants who received at least one dose of study intervention. Here, we report the results of the interim analysis. This study is registered with ClinicalTrials.gov, NCT03675737, and recruitment is complete.Findings:<bold> </bold>Between Nov 8, 2018, and June 11, 2021, 1579 (66%) of 2409 screened participants were randomly assigned to receive pembrolizumab plus chemotherapy (pembrolizumab group, n=790) or placebo plus chemotherapy (placebo group, n=789). Most participants were male (527 [67%] of 790 participants in the pembrolizumab plus chemotherapy group, 544 [69%] of 789 participants in the placebo plus chemotherapy group) and White (426 [54%], 435 [55%]). Median follow-up at the data cutoff was 31<middle dot>0 months (IQR 23<middle dot>0-38<middle dot>3). Median overall survival was longer in the pembrolizumab group than in the placebo group in the ITT population (12<middle dot>9 months [95% CI 11<middle dot>9-14<middle dot>0] vs 11<middle dot>5 months [10<middle dot>6-12<middle dot>1], hazard ratio [HR] 0<middle dot>78 [95% CI 0<middle dot>70-0<middle dot>87], p<0<middle dot>0001), in participants with a PD-L1 CPS of 1 or higher (13<middle dot>0 months [11<middle dot>6-14<middle dot>2] vs 11<middle dot>4 months [10<middle dot>5-12<middle dot>0], 0<middle dot>74 [0<middle dot>65-0<middle dot>84], p<0<middle dot>0001), and in participants with a PD-L1 CPS of 10 or higher (15<middle dot>7 months [13<middle dot>8-19<middle dot>3] vs 11<middle dot>8 months [10<middle dot>3-12<middle dot>7], 0<middle dot>65 [0<middle dot>53-0<middle dot>79], p<0<middle dot>0001). The most common grade 3-5 adverse events of any cause were anaemia (95 [12%] of 785 participants in the pembrolizumab group vs 76 [10%] of 787 participants in the placebo group) and decreased neutrophil count (77 [10%] vs 64 [8%]). Serious treatment-related adverse events occurred in 184 (23%) participants in the pembrolizumab group and 146 (19%) participants in the placebo group. Treatment-related deaths occurred in eight (1%) participants in the pembrolizumab group and 16 (2%) participants in the placebo group. No new safety signals were identified.Interpretation: Participants in the pembrolizumab plus chemotherapy group had a significant and clinically meaningful improvement in overall survival with manageable toxicity compared with participants in the placebo plus chemotherapy group. Therefore, pembrolizumab with chemotherapy might be a first-line treatment option for patients with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma.

2023

artículo original

10.1016/S1470-2045(23)00515-6

PDF

Adenocarcinoma* / drug therapy

Antibodies, Monoclonal, Humanized

Antineoplastic Combined Chemotherapy Protocols / adverse effects

B7-H1 Antigen

Double-Blind Method

Female

Humans

Male

Stomach

Neoplasms* / pathology

Oncología

Adenocarcinoma / terapia farmacológica

Anticuerpos Monoclonales Humanizados

Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos

Antígeno B7-H1

método doble ciego

Femenino

Humanos

Masculino

Estómago

Neoplasias / patología

versión publicada

hibrida

metadata

metadata

WOS:001108567100001

1181.0

1195

artículo original

1470-2045

Oncología

MERCK