Alternative dosing regimens for atezolizumab: an example of model-informed drug development in the postmarketing setting

Abstract

PurposeTo determine the exposure–response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) and to identify alternative dosing regimens.MethodsER analyses were conducted using pooled NSCLC and UC data from phase 1 and 3 studies (PCD4989g, OAK, IMvigor211; ClinicalTrials.gov IDs, NCT01375842, NCT02008227, and NCT02302807, respectively). Objective response rate, overall survival, and adverse events were evaluated vs pharmacokinetic (PK) metrics. Population PK-simulated exposures for regimens of 840 mg every 2 weeks (q2w) and 1680 mg every 4 weeks (q4w) were compared with the approved regimen of 1200 mg every 3 weeks (q3w) and the maximum assessed dose (MAD; 20 mg/kg q3w). Phase 3 IMpassion130 (NCT02425891) data were used to validate the PK simulations for 840 mg q2w. Observed safety data were evaluated by exposure and body weight subgroups.ResultsNo significant ER relationships were observed for safety or efficacy. Predicted exposures for 840 mg q2w and 1680 mg q4w were comparable to 1200 mg q3w and the MAD and consistent with observed PK data from IMpassion130. Observed safety was similar between patients with a Cmax above and below the predicted Cmax for 1680 mg q4w and between patients in the lowest and upper 3 body weight quartiles.ConclusionAtezolizumab regimens of 840 mg q2w and 1680 mg q4w are expected to have comparable efficacy and safety as the approved regimen of 1200 mg q3w, supporting their interchangeable use and offering patients greater flexibility.Electronic supplementary materialThe online version of this article (10.1007/s00280-019-03954-8) contains supplementary material, which is available to authorized users.

Artificial Intelligence and Mechanistic Modeling for Clinical Decision Making in Oncology

“…Baseline clearance was a proxy for unobserved baseline prognostic factors (e.g., disease status). They concluded that the ER relationship for nivolumab was flat (a conclusion shared with others 74,77 ), which further supported the subsequent label change for nivolumab from 3 mg/kg q2w to flat dosing, first 240 mg q2w, and then 480 mg q4w based only on in silico simulations. 78 However, as stated above, the ER relationship for ICI is complex and further mechanistic modeling is warranted to address, e.g., the circular relationship between clearance and disease status/cachexia.…”

“…65 ER modeling has been performed for ipilimumab, 73 nivolumab, 74,75 pembrolizumab, 76 or atezolizumab. 77 For example, Feng et al 75 used several model-derived individual PK parameters (e.g., the average drug concentration during the first cycle, to mitigate for (2)) as measures of exposure and a multivariate Cox model (to adjust for (1)) to relate them to OS. Overall response and adverse events were modeled using logistic regression.…”

Opportunities for using in silico‐based extended dosing regimens for monoclonal antibody immune checkpoint inhibitors

“…Subsequent approval for NSCLC, triple‐negative breast cancer (TNBC) and small‐cell lung cancer (SCLC) was granted based on statistically significant improvements in duration of response, ORR or hazard ratios for OS or progression‐free survival (PFS) 54 . Initially, Genentech only offered one vial size (1200 mg), but later added a second size (840 mg) based on results of population PK modelling and simulation that demonstrated comparable exposure of 840 mg q2wk and 1680 mg q4wk with 1200 mg q3wk 55 . The atezolizumab dosing label was recently modified (May 2019) based on these in silico findings to reflect these two alternative dosing options in order to provide patients with flexibility in their scheduled visits to the clinic.…”

Extended-Interval Dosing Strategy of Immune Checkpoint Inhibitors in Lung Cancer: Will it Outlast the COVID-19 Pandemic?

“…A similar exposure-matching study with atezolizumab employed data from three clinical trials: PCD4989g (NSCLC and urothelial carcinoma cohorts), OAK (NSCLC), and IMvigor211 (urothelial carcinoma) (15). The predicted exposure with extended-interval dosing at 1680 mg Q4W was comparable to the standard 1200 mg Q3W regimen.…”

“…The majority of ICIs were initially approved as either every 2 weeks (Q2W) or every 3 weeks (Q3W) dosing regimens. Extended-interval dosing of nivolumab and atezolizumab have subsequently been approved based on in silico (modeling/simulation) studies (14,15). The extended-interval frequency of treatment with pembrolizumab (the most commonly utilized ICI in the first-line setting for advanced NSCLC) at 400 mg every 6 weeks (Q6W) was recently granted accelerated approval by the U.S. FDA on April 28, 2020, thereby providing an evidence-based option for less frequent treatment of patients with lung and other cancers for which pembrolizumab has previously obtained approval.…”