Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

Abstract

Immuno-oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular-targeted therapies. The most notable feature of immuno-oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno-oncology therapies. This review outlines the clinical pharmacology characteristics and development challenges for the 6 approved immunomodulatory monoclonal antibodies that target 2 immune checkpoint pathways: ipilimumab (an anti-cytotoxic T-lymphocyte antigen-4 antibody) and, more recently, nivolumab and pembrolizumab (both anti-programmed death-1 antibodies) and atezolizumab, avelumab, and durvalumab (all anti-programmed death ligand-1 antibodies). These agents have revealed much about the clinical pharmacology features of immune checkpoint inhibitors as a class, as well as the pharmacometric approaches used to support their clinical development and regulatory approval. The development experiences with these pioneering immuno-oncology agents are likely to serve as useful guides in the discovery, progression, and approval of future drugs or combination of drugs in this class. This review includes summaries of the pharmacokinetics and exposure-response of the immune checkpoint inhibitors approved to date, as well as an overview of some quantitative systems pharmacology approaches. The ability of immuno-oncology to meet its full potential will depend on overcoming development challenges, including the need for clear strategies to determine optimal dose and scheduling for monotherapy as well as combination approaches. Keywords immunopharmacology, oncology, clinical pharmacology, clinical trials, pharmacology, immunotherapy, checkpoint inhibitorsIt could be said that if there were a book chronicling the history and progression of cancer treatment, we are now moving on from the chapter describing the time of sole reliance on chemotherapy, the chapter outlining the advent of targeted therapy is partially completed, and a new chapter on immuno-oncology is just beginning. The past few years have seen the regulatory approval of several immuno-oncology agents (Figure 1), including 6 immune checkpoint inhibitors: ipilimumab (Yervoy; Bristol-Myers Squibb), pembrolizumab (Keytruda; Merck), nivolumab (Opdivo; Bristol-Myers Squibb), atezolizumab (Tecentriq; Genentech), avelumab (Bavencio; EMD Serono), and durvalumab (Imfinzi; AstraZeneca). 1,2Immunotherapy in oncology is a switch from the cell-killing modality using relatively nonspecific cytotoxic methods (chemotherapy) or therapies that target cancer-specific pathways to methods that employ the patients' immune system to attack cancer. The immuno-oncology approach calls on the understanding of complex signaling processes of effector and regulatory...

Tolerability and efficacy of durvalumab in Japanese patients with advanced solid tumors

“…As in a previous study, no relationship was observed between drug exposure and safety, with higher drug exposure not associated with an increased risk of AE. Absence of DLT and a MTD of durvalumab is also consistent with other reports . In a population PK analysis, the PK characteristics of durvalumab were best described using a two‐compartment model with nonlinear elimination kinetics at doses <3 mg/kg and linear kinetics at higher doses …”

“…Absence of DLT and a MTD of durvalumab is also consistent with other reports. 25 In a population PK analysis, the PK characteristics of durvalumab were best described using a two-compartment model with nonlinear elimination kinetics at doses <3 mg/kg and linear kinetics at higher doses. 26 The pharmacodynamic effects of durvalumab were also evaluated using sPD-L1 plasma concentration as a potential predictive biomarker.…”

Undo the brake of tumour immune tolerance with antibodies, peptide mimetics and small molecule compounds targeting PD‐1/PD‐L1 checkpoint at different locations for acceleration of cytotoxic immunity to cancer cells

“…The variables intrinsic to tumours, such as tumour burden, hypoxia and Warburg effect may limit the intra‐tumour penetration of antibodies. The levels of antibodies in circulation and tumour are also influenced by such factors as dosage, patient variability, cachexia, and development of anti‐therapeutic antibodies …”

“…The levels of antibodies in circulation and tumour are also influenced by such factors as dosage, patient variability, cachexia, and development of antitherapeutic antibodies. 95 It has been reported that for the antibody BMS-936559 (0.1-10 mg/kg), while 64%-70% of PD-L1 have been detected on the T-cells, the occupancy and accessible levels to PD-L1 in the tumour remained unknown. 96 Radiolabeled antibodies may provide information about tumour accumulation at a given dose but have not been used to calculate the extent of PD-L1-drug engagement in patients, in part due to their prolonged circulation time.…”

Standing in the Shifting Sands of Molecular Targeting and Precision Medicine Is the Oasis of 21st‐Century Oncology Therapeutics

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