Interactions between Bendamustine and Toripalimab

Monitor

Although immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 monoclonal antibodies and inhibitors of programmed cell death-1 (PD-1) and/or programmed death ligand-1 (PD-L1) may be indicated for use in combination with other immunosuppressive agents, their pharmacodynamic effects and efficacy may be affected by systemic corticosteroids and immunosuppressants. The mechanism of this interaction is related to the immunosuppressive effects of systemic corticosteroids and other immunosuppressants, particularly their inhibition of T-cell activation, which may reduce the efficacy of ICIs that rely on a strong immune response to target tumor cells. Additionally, immune-related adverse events (irAEs) from ICIs may indicate a stronger immune response and improved tumor outcomes; therefore, treating those irAEs with immunosuppressive agents could theoretically reduce immune activity and thus the efficacy of the ICI. For instance, data from the Dutch Melanoma Treatment Registry (DTMR) reported that patients with advanced melanoma who experienced severe ICI toxicity had a longer median overall survival (OS) compared to those without severe toxicity (23 months vs. 15 months). Among patients who experienced severe toxicity, those treated with anti-tumor necrosis factor (TNF) therapy with or without steroids for steroid-refractory toxicity had a significantly reduced median OS compared to those managed with steroids alone (17 months vs. 27 months). Likewise, in a study of patients with advanced non-small cell lung cancer (n=640), oral or intravenous corticosteroid use (>/= 10 mg prednisone equivalent per day) at the time of or within 30 days of starting PD-1/PD-L1 blockade with either pembrolizumab, nivolumab, atezolizumab, or durvalumab (n=90) was associated with decreased response and overall poorer outcomes, compared to those who received and discontinued corticosteroid treatment prior to commencing PD-1/PD-L1 therapy. Further, an international multicenter cohort study in melanoma patients who developed irAEs with ICI therapy found that higher peak doses of corticosteroids, but not cumulative doses, were associated with worse survival, though the impact of second-line immunosuppressants remains unclear. A prospective observational study using data from a German multicenter skin cancer registry (ADOREG) evaluated patients with unresectable advanced melanoma who received immunosuppressive therapy (IST) (e.g., methylprednisolone, prednisolone, dexamethasone, infliximab, interferon, methotrexate) within 60 days before or within 30 days after the start of an ICI. The initiation of IST before, but not after the start of ICI, was associated with worse progression free survival in patients without brain metastasis, and worse OS in patients with brain metastasis. However, based on available literature, it is difficult to determine whether these effects are due to corticosteroid and/or immunosuppressant use or if they reflect subgroups of patients in studies with poorer prognoses.

Management

Caution and closer monitoring for reduced efficacy of immune checkpoint inhibitors (ICIs) is advised if corticosteroids and/or other immunosuppressants are used concurrently. Based on available literature, the use of immunosuppressants and/or systemic corticosteroids (>=10 mg prednisone equivalent/day) should be avoided at the time of, or within 30 to 60 days of starting therapy with an ICI if clinically possible. Corticosteroids and/or immunosuppressants can generally be safely used for the treatment of immune-mediated adverse reactions after starting an ICI. Some manufacturers advise that corticosteroids may be used as premedication when the ICI is used in combination with chemotherapy, as antiemetic prophylaxis, and/or to alleviate chemotherapy-related adverse effects. Individual product labeling for the ICI in question should be consulted for more specific recommendations. For example, some ICIs may have recommendations regarding which medication to administer first when the ICI is being administered in combination with chemotherapy.