Efficacy and safety of PD-1 inhibitors as first- and second- line treatments for advanced gastroesophageal cancers: A network meta-analysis of phase III clinical trials.

Abstract

e16032 Background: Advanced gastroesophageal tumors are among the most prevalent and burdensome cancers worldwide. They have a poor prognosis and limited treatment options. Recent studies show that PD-1/PD-L1 inhibitors can improve outcomes, but the results are inconsistent across trials. Herein, we compare the effectiveness and safety of PD-1/PD-L1 inhibitors with chemotherapy in patients with ERBB2 negative advanced/metastatic gastric and esophageal cancers. Methods: We searched bibliographic databases (PubMed, Embase, Cochrane Central, Web of Science, Medline, Scopus) and ClinicalTrials.gov from January 1, 2010, to November 23, 2020. We included phase III randomized clinical trials comparing anti-PD-1/PD-L1 single-agent or in combination with chemotherapy (chemoimmunotherapy) for advanced gastric or esophageal cancers in the first- or second-line settings. We performed a network meta-analysis with a frequentist approach and a random-effects model using the package ‘netmeta’ for R statistical software. A prospective protocol was uploaded to PROSPERO (CRD42020221822). Results: The final analysis included a total of 8 trials that compared different anti-PD-1 agents; none of them involved anti-PD-L1 agents. The four first-line studies involved 3817 patients. Chemoimmunotherapy improved OS and PFS with no significant safety difference: Nivolumab + chemotherapy, OS (HR, 0.83; 95% CI, 0.75-0.92), PFS (HR, 0.68; 95% CI, 0.57-0.81), SAE (OR 0.54; 0;95% CI, 0.1-2.92); Pembrolizumab + chemotherapy: OS (HR, 0.77; 95% CI, 0.67-0.88), PFS (HR, 0.72; 95% CI, 0.60-0.85), SAE (OR, 1.31; 0;95% CI, 0.23-7.35). Pembrolizumab monotherapy was the safest first-line treatment, SAE (OR, 0.02; 95% CI, 0.00-0.2), but did not improve survival, OS (HR, 0.91; 95% CI, 0.71-1.16), PFS (HR, 1.62; 95% CI, 1.23-2.14). The four second-line studies totalized 2087 individuals. Anti-PD-1 drugs were significantly safer but did not significantly improve survival: camrelizumab, OS (HR 0.71; 95% CI, 0.54-0.93), PFS (HR 0.69; 95% CI, 0.45-1.06), SAE (OR, 0.37; 95% CI, 0.24-0.56); nivolumab, OS (HR 0.77; 95% CI, 0.58-1.02), PFS (HR 1.08; 95% CI, 0.77-1.66), SAE (OR, 0.13; 95% CI, 0.08-0.2) pembrolizumab, OS (HR 0.86; 95% CI, 0.72-1.04), PFS (HR 1.28; 95% CI, 0.96-1.71), SAE (OR, 0.4; 95% CI, 0.30-0.53). Conclusions: the combination of PD-1 inhibitors with chemotherapy improves OS and PFS in previously untreated gastroesophageal cancers. Single-agent anti-PD-1 drugs improve safety in refractory disease, with no significant change in OS and PFS.