A large phase 3 clinical trial has found that adding pembrolizumab to standard chemotherapy significantly improves survival outcomes in patients with previously untreated HER2-negative advanced gastric or gastroesophageal junction (GEJ) cancer. The KEYNOTE-859 study, published in The Lancet Oncology on October 21, 2023, demonstrated that pembrolizumab plus chemotherapy provided superior overall survival, progression-free survival, and objective response rates compared to placebo plus chemotherapy in this patient population.
This randomized, double-blind, placebo-controlled trial was conducted at 207 medical centers across 33 countries. Funded by Merck Sharp and Dohme, the study aimed to evaluate the efficacy and safety of adding pembrolizumab, an anti-PD-1 immunotherapy, to standard first-line chemotherapy for advanced gastric/GEJ cancer.
The trial enrolled 1579 patients with previously untreated, locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma. Eligible participants were aged 18 years or older, had measurable disease per RECIST v1.1 criteria, adequate organ function, and an ECOG performance status of 0 or 1. Key exclusion criteria included squamous cell or undifferentiated gastric cancer, active autoimmune disease, and known CNS metastases.
Patients were randomized 1:1 to receive either pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 35 cycles, plus investigator's choice of chemotherapy: fluorouracil plus cisplatin or capecitabine plus oxaliplatin. Treatment continued until disease progression, unacceptable toxicity, or completion of 35 cycles.
The study population was predominantly male (68%) and White (55%), with a median age of 62 years. Most patients had metastatic disease (96%) and an ECOG performance status of 1 (63%). The primary tumor location was the stomach in 79% of patients and the GEJ in 21%.
At a median follow-up of 31 months, the pembrolizumab combination demonstrated significant improvements in all primary and key secondary endpoints across the intention-to-treat (ITT) population and PD-L1 subgroups:
In the ITT population, median overall survival was 12.9 months with pembrolizumab plus chemotherapy versus 11.5 months with placebo plus chemotherapy (HR 0.78, 95% CI 0.70-0.87, p<0.0001). The 24-month overall survival rate was 28% versus 19%, respectively.
Median progression-free survival in the ITT population was 6.9 months with pembrolizumab versus 5.6 months with placebo (HR 0.76, 95% CI 0.67-0.85, p<0.0001). The 24-month progression-free survival rate was 18% versus 9%.
The objective response rate was significantly higher with pembrolizumab (51% vs 42%, p<0.0001), including more complete responses (9% vs 6%). Responses were also more durable with pembrolizumab, with a median duration of response of 8.0 months versus 5.7 months.
Importantly, the benefits of pembrolizumab were observed across all PD-L1 expression subgroups, including those with combined positive scores (CPS) ≥1 and ≥10. The magnitude of benefit increased with higher PD-L1 expression:
In patients with PD-L1 CPS ≥1 (78% of population), median overall survival was 13.0 vs 11.4 months (HR 0.74, p<0.0001) and median progression-free survival was 6.9 vs 5.6 months (HR 0.72, p<0.0001).
In the PD-L1 CPS ≥10 subgroup (35% of population), median overall survival was 15.7 vs 11.8 months (HR 0.65, p<0.0001) and median progression-free survival was 8.1 vs 5.6 months (HR 0.62, p<0.0001).
The safety profile of pembrolizumab plus chemotherapy was consistent with the known profiles of the individual agents. Treatment-related adverse events of any grade occurred in 96% of patients in the pembrolizumab group and 94% in the placebo group. Grade 3-5 treatment-related adverse events occurred in 59% and 51% of patients, respectively.
The most common treatment-related adverse events were nausea, diarrhea, and anemia. Immune-mediated adverse events occurred more frequently with pembrolizumab (27% vs 9%), with hypothyroidism being most common. Treatment-related deaths occurred in 1% of patients in the pembrolizumab group and 2% in the placebo group.
This large phase 3 trial provides robust evidence for the addition of pembrolizumab to standard chemotherapy as a new first-line treatment option for patients with HER2-negative advanced gastric or GEJ cancer. The significant and clinically meaningful improvements in overall survival, progression-free survival, and response rates were observed regardless of PD-L1 expression, although the magnitude of benefit increased in patients with higher PD-L1 levels.
The authors concluded that pembrolizumab plus chemotherapy should be considered a new standard first-line treatment for this patient population. They noted that the survival benefit was achieved with a manageable safety profile consistent with previous studies of pembrolizumab.
These results address an important unmet need in advanced gastric cancer, where 5-year survival rates remain low at around 10% with current standard therapies. The KEYNOTE-859 trial builds on previous studies showing efficacy of PD-1 inhibitors in gastric cancer, including the CheckMate 649 trial with nivolumab.
Compared to CheckMate 649, KEYNOTE-859 enrolled a larger population and was placebo-controlled, providing high-quality evidence for the benefit of adding immunotherapy to chemotherapy in the first-line setting. The inclusion of patients regardless of PD-L1 status also allows for broader applicability of the results.
Some limitations of the study should be noted. The trial excluded patients with HER2-positive disease, who comprise about 20% of gastric cancers and have other targeted therapy options. Additionally, the study population was predominantly non-Asian (66%), which may limit generalizability to Asian populations that have a higher incidence of gastric cancer.
The authors also acknowledged that some subgroups, such as those with PD-L1 CPS <1 and those with GEJ tumors, had small sample sizes that limit interpretation of results in these populations. Longer follow-up will also be needed to assess the durability of responses and long-term survival outcomes.
Nevertheless, the KEYNOTE-859 results are likely to have a significant impact on clinical practice. For patients with HER2-negative advanced gastric or GEJ cancer, the addition of pembrolizumab to standard chemotherapy now provides a new first-line treatment option with improved survival outcomes. The benefit across PD-L1 expression levels suggests that all eligible patients could be considered for this combination approach.
The findings also reinforce the role of PD-1 inhibition as an important treatment strategy in gastric cancer. Along with recent positive results for pembrolizumab in HER2-positive disease (KEYNOTE-811), there is now evidence supporting the use of pembrolizumab-based regimens across gastric cancer subtypes.
For clinicians, these results provide a new standard of care to consider for first-line treatment of advanced gastric/GEJ cancer. The safety profile was manageable and consistent with previous pembrolizumab studies, suggesting that most patients should be able to tolerate the combination approach. However, clinicians will need to be vigilant for immune-related adverse events, which were more common with pembrolizumab.
The study also highlights the importance of PD-L1 testing in gastric cancer, as patients with higher expression derived greater benefit. While all patients benefited to some degree, PD-L1 status may help inform discussions with patients about the magnitude of expected benefit.
Looking ahead, several questions remain to be addressed in future research. Longer-term follow-up of KEYNOTE-859 will be important to assess durability of responses and potential for long-term survival in some patients. Studies in Asian populations and in specific subgroups like GEJ tumors will help clarify the generalizability of these results.
Additionally, biomarker analyses beyond PD-L1, such as tumor mutational burden or gene expression profiles, may help further refine patient selection. Combination strategies with other targeted agents or novel immunotherapies could potentially build on these results to achieve even greater improvements in outcomes.
In conclusion, the KEYNOTE-859 trial represents a significant advance in the first-line treatment of HER2-negative advanced gastric and GEJ cancers. By demonstrating improved survival with the addition of pembrolizumab to standard chemotherapy, this study establishes a new treatment paradigm that is likely to benefit many patients with this challenging malignancy. As immunotherapy continues to evolve, ongoing research will be crucial to optimizing and expanding its role in gastric cancer treatment.
References
Rha SY, Oh DY, Yañez P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(11):1181-1195. doi:10.1016/S1470-2045(23)00515-6
