Long-term results from the phase 3 KEYNOTE-859 trial report outcomes with pembrolizumab plus chemotherapy as first-line treatment for patients with previously untreated locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. The updated analysis, published in the October 2026 issue of ESMO Open, reports efficacy and safety outcomes after a median study follow-up of approximately 4.5 years.
The original article was titled “Pembrolizumab plus chemotherapy as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction adenocarcinoma: 4.5-year follow-up from the randomized phase III KEYNOTE-859 study.”
Authors: S.Y. Rha, L.S. Wyrwicz, P. Yañez, Y. Bai, M.-H. Ryu, J. Lee, F. Rivera, G. Vasconcelos Alves, M. Garrido, K.-K. Shiu, M. González Fernández, J. Li, M.A. Lowery, T. Çil, F. Melo Cruz, D.-Y. Oh, A. Wang, P. Leconte, and S. Qin.
About the KEYNOTE-859 Trial
KEYNOTE-859 was a randomized, double-blind, phase 3 study evaluating pembrolizumab in combination with chemotherapy versus placebo plus chemotherapy in the first-line treatment of HER2-negative gastric or GEJ adenocarcinoma. Eligible participants were aged 18 years or older and had previously untreated locally advanced unresectable or metastatic disease, measurable disease according to RECIST v1.1, known PD-L1 expression status, and an Eastern Cooperative Oncology Group performance status of 0 or 1.
Overall, 1,579 patients were randomly assigned 1:1 to treatment, including 790 patients in the pembrolizumab plus chemotherapy group and 789 in the placebo plus chemotherapy group. Pembrolizumab was administered at 200 mg intravenously every 3 weeks for up to 35 cycles. Chemotherapy was selected by the investigator and consisted of either cisplatin plus fluorouracil or capecitabine plus oxaliplatin. Randomization was stratified by geographic region, PD-L1 tumor expression status with a combined positive score (CPS) <1 versus ≥1, and chemotherapy regimen.
The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety. PFS, ORR, and DOR were assessed according to RECIST v1.1 by blinded independent central review. At the September 27, 2024 data cutoff, the median time from randomization was 54.8 months.
Overall Survival in the Intention-to-Treat Population
At the time of the analysis, 1,417 of the 1,579 participants had died. Median OS was 12.9 months with pembrolizumab plus chemotherapy compared with 11.5 months with placebo plus chemotherapy, corresponding to a hazard ratio of 0.78 (95% CI, 0.70–0.86). Long-term survival rates also remained higher in the pembrolizumab-containing group. Estimated OS rates with pembrolizumab plus chemotherapy versus placebo plus chemotherapy were 28% versus 19% at 24 months, 19% versus 10% at 36 months, and 14% versus 8% at 48 months. These findings showed sustained separation of the OS curves during long-term follow-up.
Outcomes According to PD-L1 Expression
Among 1,235 patients with PD-L1 CPS ≥1, median OS was 13.0 months with pembrolizumab plus chemotherapy compared with 11.4 months with placebo plus chemotherapy (HR 0.74; 95% CI, 0.66–0.84). Estimated OS rates at 48 months were 16% and 8%, respectively. In the PD-L1 CPS ≥10 population, which included 553 patients, median OS was 15.8 months with pembrolizumab plus chemotherapy versus 11.8 months with placebo plus chemotherapy (HR 0.64; 95% CI, 0.53–0.77).
Estimated 24-month OS rates were 38% versus 22%, 36-month OS rates were 30% versus 13%, and 48-month OS rates were 26% versus 10%. The authors noted that the greatest magnitude of OS improvement was observed in patients with PD-L1 CPS ≥10 tumors.
Progression-Free Survival
In the intention-to-treat population, median PFS was 6.9 months with pembrolizumab plus chemotherapy compared with 5.6 months with placebo plus chemotherapy (HR 0.76; 95% CI, 0.68–0.85). The estimated 24-month PFS rates were 17% and 9%, respectively. Among patients with PD-L1 CPS ≥1, median PFS was also 6.9 months with pembrolizumab plus chemotherapy compared with 5.6 months with placebo plus chemotherapy (HR 0.72; 95% CI, 0.64–0.82). Estimated 24-month PFS rates were 19% and 8%.
In patients with PD-L1 CPS ≥10, median PFS was 7.8 months compared with 5.6 months, respectively (HR 0.62; 95% CI, 0.51–0.76). The estimated 24-month PFS rates were 25% and 8%.
Objective Response and Duration of Response
In the overall population, ORR was 51.1% with pembrolizumab plus chemotherapy compared with 42.0% with placebo plus chemotherapy. Median DOR was 8.0 months versus 5.7 months, respectively. Among patients with PD-L1 CPS ≥1, ORR was 51.9% with pembrolizumab plus chemotherapy and 42.6% with placebo plus chemotherapy. Median DOR was 8.3 months versus 5.6 months. In the PD-L1 CPS ≥10 population, ORR was 60.4% with pembrolizumab plus chemotherapy compared with 43.2% with placebo plus chemotherapy, while median DOR was 10.0 months versus 5.7 months.
Safety
A total of 1,572 patients received at least one dose of study treatment and were included in the safety analysis, including 785 patients in the pembrolizumab plus chemotherapy group and 787 in the placebo plus chemotherapy group. All-cause adverse events of any grade occurred in 98.9% of patients receiving pembrolizumab plus chemotherapy and 98.0% receiving placebo plus chemotherapy. Grade 3–5 all-cause adverse events occurred in 75.8% and 69.9%, respectively.
Treatment-related adverse events of any grade were reported in 95.7% of patients receiving pembrolizumab plus chemotherapy compared with 93.5% receiving placebo plus chemotherapy. Grade 3–5 treatment-related adverse events occurred in 59.4% and 51.3% of patients, respectively. Treatment-related adverse events led to treatment discontinuation in 27.0% of patients in the pembrolizumab plus chemotherapy group and 20.3% in the placebo plus chemotherapy group. Treatment-related deaths occurred in 1.0% and 2.0%, respectively.
Immune-mediated adverse events and infusion reactions occurred in 32.0% of patients receiving pembrolizumab plus chemotherapy compared with 13.7% receiving placebo plus chemotherapy. Grade 3–5 immune-mediated adverse events and infusion reactions were reported in 10.1% and 2.0% of patients, respectively. One death related to an immune-mediated adverse event or infusion reaction occurred in each treatment group.
Long-Term Interpretation
After approximately 4.5 years of follow-up, pembrolizumab plus chemotherapy continued to demonstrate longer OS and PFS, a higher ORR, and a longer DOR compared with placebo plus chemotherapy across the study populations evaluated. The magnitude of treatment benefit differed according to PD-L1 expression, with the largest OS improvement observed in the PD-L1 CPS ≥10 population. The authors noted, however, that the study was not powered for formal comparisons between PD-L1 subgroups. PD-L1 expression was therefore described as a potential enrichment factor for treatment benefit rather than a strict selection criterion.
Study Limitations
The authors identified the relatively small number of patients in some subgroups, including those with GEJ adenocarcinoma, as a limitation of the analysis. They also noted that access to postprogression therapy varies between regions and could influence long-term OS outcomes.
Takeaway
With a median follow-up of 54.8 months, pembrolizumab plus chemotherapy continued to show improved OS, PFS, and ORR compared with placebo plus chemotherapy in patients with previously untreated locally advanced or metastatic HER2-negative gastric or GEJ adenocarcinoma.
The survival benefit was observed in the intention-to-treat population as well as in patients with PD-L1 CPS ≥1 and CPS ≥10, with the greatest magnitude of OS improvement reported in the CPS ≥10 population.
The long-term analysis also showed a prolonged duration of response and a manageable safety profile. According to the authors, these findings further support pembrolizumab plus chemotherapy as a first-line treatment option for locally advanced or metastatic HER2-negative gastric or GEJ adenocarcinoma.
The full article is available in ESMO Open.
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