Killing a fly with a sledgehammer: Atezolizumab exposure in real-world lung cancer patients

Abstract

Atezolizumab is an anti-PDL1 approved for treating lung cancer. A threshold of 6 μg/mL in plasma has been associated with target engagement. The extent to which patients could be overexposed with the standard 1200 mg q3w dosing remains unknown. Here, we monitored atezolizumab peak and trough levels in 27 real-world patients with lung cancer as part of routine therapeutic drug monitoring. Individual pharmacokinetic (PK) parameters were calculated using a population approach and optimal dosing-intervals were simulated with respect to the target trough levels. No patient had plasma levels below 6 μg/mL. The results showed that the mean trough level after the first treatment was 78.3 ± 17 μg/mL, that is, 13 times above the target concentration. The overall response rate was 55.5%. Low-grade immune-related adverse events was observed in 37% of patients. No relationship was found between exposure metrics of atezolizumab (i.e., minimum plasma concentration, maximum plasma concentration, and area under the curve) and pharmacodynamic end points (i.e., efficacy and toxicity). Further simulations suggest that the dosing interval could be extended from 21 days to 49 up to 136 days (mean: 85.7 days, i.e., q12w), while ensuring plasma levels still above the 6 μg/mL target threshold. This observational, real-world study suggests that the standard 1200 mg q3w fixed-dose regimen of atezolizumab results in significant overexposure in all the patients. This was not associated with increased side effects. As plasma levels largely exceed pharmacologically active concentrations, interindividual variability in PK parameters did not impact efficacy. Our data suggest that dosing intervals could be markedly extended with respect to the target threshold associated with efficacy.

FIGURE 1

Simulation of individual atezolizumab concentrations after the first administration. (a) Individual simulations for the 27 patients. Red line: efficacy threshold (i.e., 6 μg/mL). (b) Distribution of the individual simulations. Black curve: median, light blue shades: 5 to 35th and the 65 to 95th percentiles, dark blue shades: 35 to 65th percentiles.

IGURE 2

Individual atezolizumab concentrations throughout the successive courses. Red line: efficacy threshold (i.e., 6 μg/mL).

FIGURE 3

Comparison of PK profiles between standard dosing (q3w) and model‐guided dosing two representative patients. (a) PK profile for the patient #31 with a recommended q19w schedule. (b) PK profile for the patient #31 with a recommended q7w schedule. Red line: efficacy threshold (i.e., 6 μg/mL). Red line: efficacy threshold (i.e., 6 μg/mL). PK, pharmacokinetic.