Metronomic chemotherapy combined with immunotherapy in solid tumor: a systematic review

The emergence of immunotherapy, coupled with an enhanced understanding of the distinct mechanisms underlying metronomic chemotherapy (MC), has led to a growing interest in the integration of these two treatment modalities within clinical practice, thereby prompting a multitude of innovative investigations. Advanced solid tumors have a poor prognosis, and patients often struggle with high-intensity chemotherapy during second-line or later treatments. While immune checkpoint inhibitors (ICIs) show limited effectiveness as monotherapy for some solid tumors, MC offers low toxicity and immune modulation benefits. However, the clinical efficacy, safety, and predictive factors of combining MC with ICI remain debated, and there is a lack of comprehensive evidence on its clinical application. This qualitative systematic review aims to assess the efficacy and safety of the MC and ICI combination in solid tumors to inform clinical treatment decisions.

The PubMed, Embase, Cochrane Library, Web of Science, China Wanfang, China CNKI, and China VIP were searched, and the relevant data were extracted, including median progression-free survival (mPFS), median overall survival (mOS), objective response rate (ORR); disease control rate (DCR); and incidences of grade ≥3 adverse events (AEs).

We incorporated a total of six clinical studies. Of these, four studies indicated that patients with non-small cell lung cancer (NSCLC) who underwent oral metronomic vinorelbine chemotherapy in conjunction with immune checkpoint inhibitors, following standard first-line treatment, exhibited improvements in ORR and DCR. Additionally, two of these studies reported enhancements in mPFS and mOS. Treatment efficacy may be influenced by factors such as programmed cell death ligand 1 (PD-L1) expression, epidermal growth factor receptor (EGFR) mutation status, and histological subtype. One study demonstrated that patients with ovarian cancer, who had received multiple lines of therapy, experienced benefits in mPFS, ORR, and DCR when treated with a combination of cyclophosphamide, ICIs, and bevacizumab. Another study demonstrated that patients with breast cancer exhibited improvements in ORR, DCR, mPFS, and mOS when treated with a regimen of MC in conjunction with immunotherapy. Across all six studies, the combination of MC and immunotherapy was found to be well-tolerated, with the majority of adverse reactions classified as grade I or II.

Patients exhibiting suboptimal responses to conventional therapies may potentially derive therapeutic benefit from the combination of MC and immunotherapy. Since current studies are small and lack large-scale phase 3 clinical trials, caution is needed when applying these findings to clinical practice.