A new meta-analysis published in Clinical Oncology in September 2024 has provided important insights into the efficacy of PD-1/PD-L1 inhibitors for advanced gastroesophageal cancers. The study, conducted by researchers from multiple institutions across the Middle East, North Africa, and the United States, aimed to evaluate the effectiveness of PD-1/PD-L1 inhibitors alone or in combination with chemotherapy compared to chemotherapy alone in patients with advanced, unresectable HER2-negative gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma.
The meta-analysis included data from 10 phase III randomized clinical trials, encompassing a total of 6,782 patients. The researchers conducted a comprehensive search of major medical databases including PubMed, Embase, Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov up to March 28, 2024. The primary endpoints of the study were overall survival and progression-free survival.
To be included in the analysis, studies had to be randomized clinical trials comparing PD-1/PD-L1 inhibitors alone or in combination with chemotherapy versus chemotherapy alone in patients with advanced gastric, GEJ, or esophageal adenocarcinoma. The researchers excluded studies involving HER2-positive patients, resectable cancers, or those using PD-1/PD-L1 inhibitors as neoadjuvant or adjuvant therapy.
The results of the meta-analysis revealed that PD-1/PD-L1 inhibitors significantly improved overall survival compared to chemotherapy alone, with a hazard ratio (HR) of 0.86 (95% CI: 0.80-0.93; p=0.0002). Notably, the combination of PD-1/PD-L1 inhibitors with chemotherapy showed greater efficacy than PD-1/PD-L1 inhibitor monotherapy, with HRs of 0.80 (p<0.00001) and 0.98 (p=0.77), respectively.
Subgroup analyses provided further insights into the effectiveness of PD-1/PD-L1 inhibitors in specific patient populations. Patients with high PD-L1 expression, defined as a combined positive score (CPS) ≥10, showed a more pronounced benefit with an HR of 0.67 (95% CI: 0.59-0.76; p<0.00001). Additionally, patients with microsatellite instability-high (MSI-H) status demonstrated a particularly strong response to PD-1/PD-L1 inhibitors, with an HR of 0.35 (95% CI: 0.24-0.52; p<0.00001).
Interestingly, the study found that the benefit of PD-1/PD-L1 inhibitors was most evident in first-line treatment settings, with an HR of 0.81 (95% CI: 0.76-0.87; p<0.00001) for first-line therapy compared to an HR of 1.00 (95% CI: 0.85-1.18; p=0.98) for second/third-line therapy. This suggests that earlier introduction of immunotherapy may be more beneficial for patients with advanced gastroesophageal cancers.
The meta-analysis also highlighted some limitations in the current evidence base. Notably, there was a lack of significant improvement in overall survival for patients with esophageal adenocarcinoma (HR 0.89; 95% CI: 0.69-1.14; p=0.37), although this finding was based on data from only three trials. Additionally, the authors noted that all trials investigating second and third-line treatments were open-label, which could potentially introduce bias.
The researchers concluded that PD-1/PD-L1 inhibitors, particularly when combined with chemotherapy, offer significant survival benefits for patients with advanced gastroesophageal cancers. They emphasized the importance of incorporating CPS and MSI status into biomarker investigations to help guide treatment decisions.
The potential clinical impact of this meta-analysis is substantial. It provides strong evidence supporting the use of PD-1/PD-L1 inhibitors, especially in combination with chemotherapy, as a first-line treatment option for patients with advanced, HER2-negative gastric and GEJ adenocarcinomas. The findings also underscore the importance of biomarker testing, particularly for PD-L1 expression and MSI status, to identify patients most likely to benefit from immunotherapy.
However, the study also highlights areas where further research is needed. The authors call for more clinical trials investigating the use of PD-1/PD-L1 inhibitors in combination with chemotherapy as second-line treatment, as well as additional studies focusing on esophageal adenocarcinoma. These gaps in the current evidence base present opportunities for future research to further refine and optimize immunotherapy strategies for patients with advanced gastroesophageal cancers.
In conclusion, this comprehensive meta-analysis provides valuable insights into the role of PD-1/PD-L1 inhibitors in the treatment of advanced gastroesophageal cancers. As the field of immunotherapy continues to evolve, these findings will help inform clinical decision-making and guide future research efforts to improve outcomes for patients with these challenging malignancies.
References
Beshr MS, Beshr IA, Al Hayek M, et al. PD-1/PD-L1 Inhibitors in Combination With Chemo or as Monotherapy vs. Chemotherapy Alone in Advanced, Unresectable HER2-Negative Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: A Meta-Analysis. Clin Oncol (R Coll Radiol). 2024;36(12):797-808. doi:10.1016/j.clon.2024.09.007
