Efficacy and safety of VEGF/VEGFR inhibitors for platinum-resistant ovarian cancer: a systematic review and meta-analysis of randomized controlled trials

Ovarian cancer (OC) is the seventh most common cancer in women and the eighth leading cause of cancer-related death worldwide [1]. At the time of initial diagnosis, over 70% of patients present with advanced disease due to the presence of atypical early symptoms [2]. Currently, for patients with a new diagnosis, the standard first-liner treatment involves cytoreductive surgery combined with platinum-based systematic chemotherapy, with or without the addition of bevacizumab. However, at first relapse, approximately 25% of patients develop platinum-resistant ovarian cancer (PROC), and nearly all patients will experience relapse and eventually develop platinum-resistant [3]. PROC is associated with a poor prognosis and an overall survival (OS) of less than 12 months, presenting a significant therapeutic challenge [4]. In the platinum-resistant setting, monotherapy with docetaxel, paclitaxel, topotecan or pegylated liposomal doxorubicin (PLD) remains the primary therapeutic option, but it results in a remarkably short survival, highlighting the urgent need for better treatment options. Furthermore, several trials have demonstrated that combining chemotherapy agents leads to increased adverse events without improving clinical benefit for PROC [5‐7].

Tumor angiogenesis has been established as a hallmark of tumor development, growth, and metastasis. This complex process involves multiple signaling pathways. Vascular endothelial growth factor (VEGF), an important driver of angiogenesis in solid tumors, binds to VEGF receptor-1 or -2 (VEGFR-1/VEGFR-2) on target cells [8], thereby activating intracellular tyrosine kinase signaling. VEGF promotes the recruitment of circulating endothelial progenitor cells from the bone marrow and facilitates endothelial cell survival, differentiation, and proliferation during angiogenesis. Angiogenesis also plays a crucial role in the pathogenesis of OC by promoting tumor proliferation and metastasis [9, 10]. The presence of extensive neovascularization is closely associated with a poor prognosis in OC. Anti-VEGF therapy has emerged as a promising therapeutic target with potential clinical benefits for patients with OC, including those with platinum-resistant disease [11‐14]. Recently, various anti-VEGF therapies, such as anti-VEGF monoclonal antibodies (e.g., bevacizumab) and VEGF-R tyrosine kinase inhibitors (e.g., sorafenib, pazopanib, apatinib, cediranib, anlotinib), have been evaluated in OC patients [15].

The AURELIA trial, a randomized phase III trial, demonstrated a significant improvement in progression-free survival (PFS) in PROC patients when treated with a combination of bevacizumab and chemotherapy compared to monochemotherapy (hazard ratio (HR) = 0.48; 95% CI: 0.38–0.60). The median PFS was 6.7 months with the combined regimen versus 3.4 months with monochemotherapy. The objective response rate (ORR) also increased by 15.5% compared to chemotherapy alone. However, there was no statistically significant improvement in OS when bevacizumab was combined with chemotherapy (HR = 0.85; 95% CI: 0.66–1.08, p < 0.17) [16]. Bevacizumab has been approved by the Food and Drug Administration (FDA) for PROC. Other anti-VEGF agents, such as apatinib, have also shown preliminary evidence of efficacy when combined with chemotherapy for PROC. Wang et al. reported that treatment with apatinib plus PLD resulted in a clinically meaningful improvement in PFS (HR = 0.44; 95% CI: 0.28–0.71, p < 0.001). The median PFS was 5.8 months for apatinib plus PLD versus 3.3 months for PLD alone. The median OS was 23.0 months versus 14.4 months for apatinib plus PLD and PLD alone, respectively (HR = 0.66; 95% CI: 0.40–1.09) [17].

Previous meta-analyses have demonstrated that combination therapy offers improved survival benefits compared to chemotherapy alone in ovarian cancer patients [18‐21]. However, there is a lack of specific meta-analysis focusing on platinum-resistant patients. Given the clinical uncertainty and inconsistent efficacy related to VEGF/VEGFR inhibitors in PROC, a systematic review and meta-analysis was conducted to overcome the limitations of individual studies and provide a more accurate estimation of the efficacy and safety of VEGF/VEGFR inhibitors in PROC.

This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study was registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42023402050).

OC is often asymptomatic until it reaches an advanced stage, resulting in delayed diagnosis and poor prognosis. The current screening programs for OC diagnosis are inadequate [31]. PROC remains a significant challenge for clinical diagnosis and treatment due to the extreme cellular heterogeneity and the expression of various resistance and immune evasion mechanisms in this advanced stage of tumor complexity [25]. Combination therapy with VEGF/VEGFR inhibitors has shown a higher likelihood of being the most effective treatment compared to chemotherapy. Recent studies have reported encouraging results, particularly in terms of PFS, for several combination strategies involving VEGF/VEGFR inhibitors in PROC. However, the OS outcomes have been uncertain and inconsistent [16, 17]. To address this, a meta-analysis was conducted, which included eight randomized controlled trials in PROC, and demonstrated better OS, PFS, and ORR outcomes with VEGF/VEGFR inhibitors compared to monochemotherapy. Furthermore, heterogeneity was observed in terms of ORR among the included studies.

Subgroup analyses were performed for OS, PFS, and ORR, considering various stratification factors such as region, combination therapeutic agents, trial phase, ECOG performance status, publication year, and primary tumor site. Regardless of OS, PFS, or ORR, combination therapy with chemotherapy showed greater benefits in the subgroup analysis of combination therapeutic agents. Only one trial included combined PARP inhibitors therapy (cediranib plus olaparib), but it failed to demonstrate any superiority in efficacy compared to the standard treatment for patients with PROC [25]. Some studies have reported that cediranib induces the down-regulation of certain genes in the homologous recombination system, which synergistically enhances the effect of olaparib [32, 33]. Liu et al. demonstrated that the combination of cediranib and olaparib significantly prolonged PFS compared to olaparib alone in platinum-sensitive OC patients (HR = 0.50). Additionally, in the gBRCA/unknown-subset, the combination therapy showed significantly improved OS compared to olaparib alone (37.8 versus 23.0 months, p = 0.047) [34]. However, disappointing results were observed for both OS and PFS in the platinum resistance trials included in our analysis [25]. It should be noted that due to the limited number of trials, the accuracy of subgroup analysis may be insufficient. It is necessary to explore randomized controlled trials of new combinations of PARP inhibitors with various drugs, such as anti-angiogenesis agents, immune checkpoint inhibitors, or other inhibitors of DNA damage response pathways [35].

The analysis of TRAEs revealed that the combination therapy had significantly higher incidences of both any grade TRAEs and grade 3–4 TRAEs compared to monochemotherapy. These findings were consistent with the previously published safety profile of VEGF/VEGFR inhibitors in OC and other solid tumors [36‐41], and no new safety concerns were identified. Most of the TRAEs reported were of grade 1–2, indicating that the adverse events were manageable. Only four trials reported the incidence of grade 3–4 TRAEs. Among them, paclitaxel plus pazopanib treatment had a higher incidence (OR = 3.33, 95% CI: 1.27–8.76), while bevacizumab plus chemotherapy had a lower incidence (OR = 1.68, 95% CI: 0.76–3.69). Combination therapy was associated with a higher incidence of any grade hypertension, mucositis, proteinuria, diarrhea, and hand-foot syndrome. Hypertension is a common adverse effect of VEGF inhibitors, with an incidence of approximately 30% in various clinical trials, and moderate hypertension occurring in 3–16% of cases. Mucositis is another common adverse effect of anti-VEGF therapy, characterized by symptoms such as pain, difficulty swallowing and pronunciation. Mucositis typically manifests 7–10 days after the initiation of treatment, and in the absence of concurrent bacterial, viral, or fungal infections, it is self-limiting and resolves spontaneously within 2–4 weeks. The mechanism underlying proteinuria production involves the regulation of glomerular vascular permeability by the VEGF signaling pathway. Inhibition of VEGF can result in the destruction of glomerular endothelial cells and epithelial cells (podocytes), leading to proteinuria. The use of VEGF-R tyrosine kinase inhibitors can induce hand-foot syndrome, characterized by red spots, swelling, and pain on the extremities, particularly the palms or soles of the feet. This syndrome typically emerges within the first 6 weeks of treatment.

A meta-analysis has demonstrated that combination therapy with VEGF/VEGFR inhibitors yields superior survival benefits compared to chemotherapy for patients with PROC [42]. However, the trials included in the analysis encompassed recurrent OC rather than exclusively focusing on platinum-resistant disease, and they encompassed a subset of patients with platinum-sensitive disease as well. Moreover, the most recent clinical trials were not incorporated. Therefore, our study serves as a supplement to previous meta-analyses, offering more comprehensive content and considering more stratification factors. It also addresses the limitations of previous meta-analyses and provides additional treatment options for patients with PROC. Several limitations were encountered in this meta-analysis. Firstly, the RCTs employed various therapeutic agents and had different baseline characteristics, resulting in a high degree of heterogeneity in the data analysis for ORR. In an attempt to stratify based on baseline characteristics to mitigate heterogeneity, subgroup analyses were conducted. In the future, network meta-analysis can be employed to further investigate the efficacy and safety of combination therapy. Secondly, this study only included eight RCTs comparing VEGF/VEGFR inhibitors in combination therapy with chemotherapy in patients with PROC, and the majority of these trials were phase II trials. Further more reliable data would be provided from phase III clinical trials for analysis, especially when combined with VEGF/VEGFR inhibitors and PARP inhibitors, which are expected to be included in future studies. Additionally, it is important to note that this meta-analysis lacks sufficient subgroup analyses, and the inclusion of more stratification factors would be crucial in demonstrating the efficacy of VEGF/VEGFR inhibitors for PROC.

The combination therapy of VEGF/VEGFR inhibitors for PROC has shown superior OS, PFS, and ORR compared to monochemotherapy, particularly when combined with VEGF/VEGFR inhibitors and chemotherapy. However, it is worth mentioning that combination therapy is associated with a higher incidence of certain adverse events, such as hypertension, mucositis, proteinuria, diarrhea, and hand-foot syndrome. Nevertheless, the safety profile of combination therapy remains manageable. The present study provides more treatment options for PROC patients.