Dosing Regimens of Immune Checkpoint Inhibitors: Attempts at Lower Dose, Less Frequency, Shorter Course

Abstract

Immune checkpoint inhibitors (ICIs) are a revolutionary breakthrough in the field of cancer by modulating patient’s own immune system to exert anti-tumor effects. The clinical application of ICIs is still in its infancy, and their dosing regimens need to be continuously adjusted. Pharmacokinetic/pharmacodynamic studies showed a significant plateau in the exposure-response curve, with high receptor occupancy and plasma concentrations achieved at low dose levels. Coupled with concerns about drug toxicity and heavy economic costs, there has been an ongoing quest to reevaluate the current ICI dosing regimens while preserving maximum clinical efficacy. Many clinical data showed remarkable anticancer effects with ICIs at the doses far below the approved regimens, indicating the possibility of dose reduction. Our review attempts to summarize the clinical evidence for ICIs regimens with lower-dose, less-frequency, shorter-course, and provide clues for further ICIs regimen optimization.

Immune checkpoint inhibitors as mediators for immunosuppression by cancer-associated fibroblasts: A comprehensive review

“…Also, Nivolumab, Pembrolizumab, and Cemiplimab, are the mAbs that targets PD-1 and approved in order to treat MSI-H or dMMR CRC, HNSCC, hepatocellular carcinoma (HCC). Moreover, NCT00349934 and NCT02614833, are mAbs that target Tim-3 in order to treat breast cancer (BC) was certified as a iICP inhibitor ( 29 , 53 , 60 , 64 , 67 , 68 , 70 ). The restoration of tumor-specific immunity due to the inhibition of iICPs revitalizes malfunctioning T cells and helps tumor cells be eradicated ( 29 , 67 , 68 , 71 ).…”

“…Moreover, NCT00349934 and NCT02614833, are mAbs that target Tim-3 in order to treat breast cancer (BC) was certified as a iICP inhibitor ( 29 , 53 , 60 , 64 , 67 , 68 , 70 ). The restoration of tumor-specific immunity due to the inhibition of iICPs revitalizes malfunctioning T cells and helps tumor cells be eradicated ( 29 , 67 , 68 , 71 ).…”

What is the optimal duration of immune checkpoint inhibitors in malignant tumors?

“…Therefore, there is a premature suggestion for melanoma-early discontinuation of ICIs can be considered in CR patients ready to receive additional treatment for 6 months after achieving CR ( 55 ). However, unlike melanoma, CR as a sign for treatment cessation has not been widely adopted in advanced NSCLC due to the low CR rates (< 5%) ( 56 ).…”

The Financial Toxicity of Advanced Hepatocellular Carcinoma Treatment in Low Middle-Income Countries

“…There is a wealth of evidence suggesting that ICPIs can achieve considerable activity at doses far below those currently approved (33). These evidence are supported by preclinical data suggesting that programmed death-1 (PD-1) receptor occupancy was achieved at very low doses; 90% of PD-1 receptors was saturated at 0.5 mg/kg pembrolizumab, 3 mg/kg avelumab, 4 mg/kg atezolizumab and totally saturated at 0.3 mg/kg durvalumab and 0.3 mg/kg nivolumab (34)(35)(36)(37).…”