Abstract
Immune check-point inhibitors are drugs that are markedly different from other anticancer drugs because of their indirect mechanisms of antitumoral action and their apparently random effect in terms of efficacy and toxicity. This marked pharmacodynamics variability in patients calls for reconsidering to what extent approved dosing used in clinical practice are optimal or whether they should require efforts for customization in outlier patients. To better understand whether or not dosing could be an actionable item in oncology, in this review, preclinical and clinical development of immune checkpoint inhibitors are described, particularly from the angle of dose finding studies. Other issues in connection with dosing issues are developed, such as the flat dosing alternative, the putative role therapeutic drug monitoring could play, the rise of combinatorial strategies, and pharmaco-economic aspects.
Highlights
Immune check-point inhibitors (ICIs), considered as a breakthrough innovation in oncology, are characterized by the fact that their impact in terms of long-term survival remains restricted to a small subset (20–40%) of patients in an even smaller number of cancer diseases such as melanoma, lung, head-and-neck, and kidney cancers
When combining several ICIs, such as the ipilimumab + nivolumab combo in melanoma and non-small cell lung cancer (NSCLC), a limited range of dosing has been tested (i.e., 3mg/kg and 1 mg/kg and vice-versa). Since both drugs were approved as single agents at 3 mg/kg, that no maximum tolerated dose (MTD) was identified in their respective dose-ranging studies, and that ipilimumab was the core component of the combination for melanoma and nivolumab for lung cancer, 3 mg/kg was used as a reference
In order to justify this switch from individual body weight (BW)-dosing to a unique flat dose, population PK analyses of data accumulated during drug development were performed for avelumab [38], durvalumab [39], nivolumab [40] and pembrolizumab [41]
Summary
Immune check-point inhibitors (ICIs), considered as a breakthrough innovation in oncology, are characterized by the fact that their impact in terms of long-term survival remains restricted to a small subset (20–40%) of patients in an even smaller number of cancer diseases such as melanoma, lung, head-and-neck, and kidney cancers. None of them has emerged as a fully consensual predictive tool far [1] This lack of available and validated biomarkers for forecasting clinical outcomes is a major concern, especially with respect to the high cost of ICIs. the Vaccines 2020, 8, 632; doi:10.3390/vaccines8040632 www.mdpi.com/journal/vaccines. There is a rising interest for dose individualization approaches in oncology, especially with the therapeutic drug monitoring of several cytotoxics [2] and oral targeted therapies [3]. To better understand whether dosing could be an actionable item in oncology, here, we review the preclinical and clinical development of ICIs. In addition to dose-finding studies, other related issues such as the trend towards flat dosing, therapeutic drug monitoring (TDM), combinatorial strategies, and pharmaco-economic aspects are developed as well
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