Safety and efficacy of pembrolizumab and epacadostat combination therapy in metastatic epithelial-derived cancers: A systematic review and meta-analysis of randomized controlled trials.

Abstract

e15128 Background: In cancer patients, immunotherapy is a progressive treatment that uses the body’s immune system to fight. Pembrolizumab is a programmed cell death protein inhibitor (PD-1 inhibitor) that has demonstrated effectiveness but shows low efficacy in patients with low-level PD-L1 expression. Epacadostat increases the effectiveness of Pembrolizumab in such patients, being an indoleamine 2,3 dioxygenase-1 inhibitor. The objective of our study is to evaluate the efficacy of these two drugs combined in cancer patients undergoing immunotherapy. Methods: We performed an electronic search on PubMed, Embase, and Cochrane, from the inception of these databases until November 24, 2024, to identify all randomized controlled trials (RCTs) and clinical trials that investigated the combination of oral Epacadostat and Pembrolizumab compared with Pembrolizumab plus a matching placebo or comparator in patients of all ages with any type of cancer. Non-cancer populations, preclinical research, and any study not examining the combination of Epacadostat and Pembrolizumab were excluded. The data were extracted and pooled using a random-effects model to calculate the relative risk (RR) with the corresponding 95% confidence interval (CI). Review Manager was used for all statistical analyses. Results: Our search identified seven Randomized Control Trials with a total of 1,398 patients (Intervention group: 707; Control group: 691). We found that the use of Pembrolizumab + Epacadostat showed no statistically significant benefit on the risk of all-cause mortality (RR: 1.20 [0.58, 2.46] I 2 = 0% p = 0.62); Complete Response (RR: 1.04 [0.55, 1.961] I 2 = 0% p = 0.91); Partial Response (RR: 0.98 [0.74, 1.31] I 2 = 52% p = 0.90); Objective Response Rate (RR: 1.00 [0.77, 1.291] I 2 = 47% p = 1.00); Stable disease (RR: 1.03 [0.87, 1.22] I 2 = 0% p = 0.72); Treatment related Serious Adverse Events (SAE) (RR: 1.10 [0.81, 1.491] I 2 = 0% p = 0.54); Grade≥3 Adverse Events(AE) (RR: 0.99 [0.86, 1.14] I 2 = 0% p = 0.91); SAE (RR: 1.04 [0.88, 1.221] I 2 = 0% p = 0.68); Discontinued Study Drug due to TAE (RR: 1.18 [0.87, 1.61] I 2 = 0% p = 0.28); Treatment related AE (RR: 1.00 [0.95, 1.051] I 2 = 4% p = 0.99); Treatment related Grade≥3 AE (RR: 1.09 [0.86, 1.381] I 2 = 51% p = 0.49); Progressive Disease (RR: 0.81 [0.56, 1.17] I 2 = 65% p = 0.26). Conclusions: Our analysis of the seven RCTs showed no statistically significant benefit of Pembrolizumab + Epacadostat in reducing all-cause mortality, complete response rate, partial response, objective response rate, stable disease, treatment related SAE, Grade≥3 AE, SAE, discontinued study drug due to TAE, treatment related AE, Grade≥3 AE treatment related or progressive disease compared to the control. These findings suggest limited therapeutic advantage of this combination, highlighting the need for further research.