Model-based simulation to support the extended dosing regimens of atezolizumab

The currently recommended dosages of atezolizumab for patients with non-small cell lung cancer (NSCLC) and urothelial carcinoma (UC) is 840 mg every 2 weeks, 1200 mg every 3 weeks (q3w), and 1680 mg every 4 weeks (q4w). However, it has been argued that these dosages may not be optimal. This study aimed to explore the feasibility of extended dosing regimens by population pharmacokinetics (PK) simulations and exposure-response (E-R) relationships.

All simulations were conducted based on the established population PK and E-R model for safety (i.e., adverse events of special interest, AESI) and efficacy (i.e., objective response rate, ORR) for patients with NSCLC or UC. The PK, AESI, and ORR profiles of the following dosing regimens were simulated: (i) 840 mg q4w, (ii) 1200 mg every 6 weeks (q6w), and (iii) 1680 mg q8w. These regimens were compared with those of the 1200 mg q3w standard regimen.

The simulation revealed that the ranking of efficacy for different extended dosing regimens were 1680 mg q8w ≅ 1200 mg q3w ≅ 1200 mg q6w > 840 mg q4w based on the predicted probability of ORR in patients with NSCLC and UC, and this ranking order was similar to that of the safety outcome of the AESI. The minimum serum concentration at steady-state (C_min,ss) values for all dosing regimens was all higher than the target effective concentration of 6 μg/mL.

The findings from this simulation suggest that extended dosing regimens are unlikely to significantly impair clinical outcomes and may provide more therapeutic benefits to patients in terms of safety.