Efficacy and safety of PD1/PDL1 inhibitors combined with radiotherapy and anti-angiogenic therapy for solid tumors: A systematic review and meta-analysis

The triple combination of programmed cell death 1 (PD1)/programmed cell death ligand 1 (PDL1) inhibitors, radiotherapy (RT), and anti-angiogenesis agents has been widely used in the treatment of solid tumors and has shown positive efficacy. We conducted a meta-analysis to evaluate the efficacy and safety of PD1/PDL1 inhibitors combined with anti-angiogenic agents and RT for the treatment of solid cancers. METHODS: A systematic search of PubMed, Embase, Cochrane Library, and Web of Science databases was conducted from inception to October 31, 2022. Studies involving patients with solid cancers who received PD1/PDL1 inhibitors combined with RT and anti-angiogenic agents treatment that reported overall response rate, complete remission rate, disease control rate, and adverse events (AEs) were included. A random-effects or fixed-effects model was used for the pooled rates, and 95% confidence intervals (CIs) were determined for all outcomes. The quality of the included literature was assessed using the methodological index for nonrandomized studies critical appraisal checklist. Egger test was used to assess the publication bias in the included studies. RESULTS: Ten studies (4 nonrandomized controlled trials and 6 single-arm trials), including 365 patients, were identified and included in the meta-analysis. The pooled overall response rate after treatment with PD1/PDL1 inhibitors combined with RT and anti-angiogenic agents was 59% (95% CI: 48–70%), whereas the disease control rate and complete remission rate were 92% (95% CI: 81–103%) and 48% (95% CI: 35–61%), respectively. Moreover, the meta-analysis showed that compared with triple-regimen, monotherapy or dual-combination treatment did not improve overall survival (hazard ratio = 0.499, 95% CI: 0.399–0.734) and progression-free survival (hazard ratio = 0.522, 95% CI: 0.352–0.774). The pooled rate of grade 3 to 4 AEs was 26.9% (95% CI: 7.8%–45.9), and the common AEs to triple therapy included leukopenia (25%), thrombocytopenia (23.8%), fatigue (23.2%), gastrointestinal discomfort (22%), increased alanine aminotransferase (22%), and neutropenia (21.4%). CONCLUSION: In the treatment of solid tumors, PD1/PDL1 inhibitors combined with RT and anti-angiogenic drugs achieved a positive response and better survival benefits than monotherapy or dual therapy. In addition, combination therapy is tolerable and safe. REGISTRATION: PROSPERO ID: CRD42022371433.