Pan-cancer population pharmacokinetics and exposure-safety and -efficacy analyses of atezolizumab in patients with high tumor mutational burden

Abstract

We retrospectively investigated the pharmacokinetics and exposure-efficacy/safety relationships of single-agent atezolizumab based on tissue tumor mutational burden (tTMB) status (high vs low [≥16 vs <16 mutations/megabase]) in a pan-tumor population from seven clinical trials. Data sources included the OAK, POPLAR, BIRCH, FIR, IMvigor210, IMvigor211, and PCD4989g studies; 986 of 2894 treated patients (34%) had TMB data. Exposure metrics were obtained using a prior two-compartment intravenous-infusion population-pharmacokinetics model, merged with prognostic, biomarker, efficacy, and safety variables. Baseline demographic/clinical characteristics and prognostic factors were well balanced between patients with high (n = 175) and low (n = 811) tTMB. Exposure was similar in the high- and low-tTMB subgroups, with no difference seen in the evaluable vs total treated populations. The objective response rate (ORR) was 29.7% vs 13.4%, complete response rate was 6.9% vs 3.2%, and median duration of response (95% CI) was 29.0 (18.6-NE) months vs 15.9 (12.5-20.5) months for patients with high-tTMB vs low-tTMB tumors, respectively. A flat exposure-efficacy relationship was seen for ORR in patients with high-tTMB based on the cycle 1 minimum atezolizumab concentration and area under the serum concentration time curve (AUC). A nonsignificant exposure-safety profile was seen for grade 3/4 adverse events and adverse events of special interest based on the AUC of atezolizumab in the high-tTMB population. tTMB is an additional predictive biological factor affecting response to atezolizumab, and quantitative investigations of atezolizumab exposure and relationships of exposure with safety and efficacy support the use of a 1200-mg, every 3-week regimen in a tumor-agnostic high-tTMB population.

Trial registration: ClinicalTrials.gov NCT02008227 NCT01903993 NCT02031458 NCT01846416 NCT02302807 NCT02108652 NCT01375842.

Keywords: atezolizumab; biomarkers; clinical pharmacology; mutation; pharmacokinetics; tumor.

FIGURE 1

Flowchart of the analysis populations. AESI, adverse event of special interest; ER, exposure‐response; mUC, metastatic urothelial carcinoma; NSCLC, non‐small cell lung cancer; popPK, population pharmacokinetics; SLD, sum of longest diameters; TMB, tumor mutational burden

FIGURE 2

Atezolizumab exposure distribution by tTMB status. Post hoc analysis of exposures across 880 patients treated with atezolizumab 1200 mg are shown, including 709 patients with tTMB <16 mut/Mb and 171 patients with tTMB ≥16 mut/Mb. The dotted line indicates the therapeutic target exposure of 6 µg/mL. The height of the bar represents the number of patients within that concentration range, while the width represents binning of patients from 0 to 160 µg/mL by multiples of 10. A cumulative distribution trend (dark and light grey lines) is superimposed over the frequency distribution histogram for each subgroup. tTMB, tissue tumor mutational burden

FIGURE 3

Proportion of tTMB‐high patients who were responders (CR + PR) to atezolizumab by (A) cycle 1 AUC and (B) cycle 1 C _min and the proportion of tTMB‐high patients with grade 3/4 AEs by AUC (C) and (D) any‐grade AESI by AUC. AUC and C _min values for each response event (yes, 1.00; no, 0) are represented by open grey circles. Solid black circles with standard error bars: proportion of response from binned observations by quartiles of the log‐transformed exposure (y value); median exposure value within the bin (x value). Black line: model‐fitted curve of the probability of response across atezolizumab exposure. Dashed lines: binning boundaries. Shaded area: 95% confidence band for the logistic regression curve. Observed data points are based on 171 and 167 patients for efficacy and safety, respectively. AESI, adverse event of special interest; AUC, area under the curve; C _min, minimum concentration; CR, complete response; PR, partial response; tTMB, tissue tumor mutational burden

FIGURE 4

Change in SLD from baseline by TMB status and atezolizumab exposure. (A) Tumor size change across 713 tTMB efficacy‐evaluable patients with available tumor scan data (gray). Mean changes in tumor size from baseline are represented by the solid black line for the tTMB‐high subgroup (≥16 mut/Mb; n = 145) and by the dotted black line for the tTMB‐low subgroup (<16 mut/Mb; n = 568). (B) tTMB efficacy and cycle 1 atezolizumab C _min PK‐evaluable patients (n = 703). Mean tumor size changes from baseline as a function of cycle 1 atezolizumab C _min exposure quartile are shown in red (n = 176), yellow (n = 176), blue (n = 176), and green (n = 175). C _min, minimum concentration; PK, pharmacokinetics; SLD, sum of longest diameter; tTMB, tissue tumor mutational burden