Anti-neoplastic agent, humanized immunoglobulin G1 (IgG1) monoclonal antibody. ATC code:
Pharmacology: Pharmacodynamics: Mechanism of Action:
Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells suppresses cytotoxic T-cell activity through the inhibition of T-cell proliferation and cytokine production. PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells, and can contribute to the inhibition of the antitumor immune response in the microenvironment.
Atezolizumab is an Fc-engineered humanized immunoglobulin G1 (IgG1) monoclonal antibody that directly binds to PD-L1 and blocks interactions with the PD-1 and B7.1 receptors, releasing PD-L1 / PD-1 pathway-mediated inhibition of the immune response, including reactivating the antitumor immune response. Atezolizumab leaves the PD-L2/PD-1 interaction intact. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.
Clinical / Efficacy Studies:
Second Line Non-Small Cell Lung Cancer (2L NSCLC): OAK: A phase III, open-label, multi-center, international, randomized study, GO28915 (OAK), was conducted to evaluate the efficacy and safety of Tecentriq compared with docetaxel in patients with locally advanced or metastatic NSCLC who have progressed during or following a platinum-containing regimen. A total of 1225 patients were enrolled, with the primary analysis population consisting of the first 850 randomized patients. Eligible patients were stratified by PD-L1 expression status in tumor-infiltrating immune cells (IC), by the number of prior chemotherapy regimens, and by histology.
Patients were randomized (1:1) to receive either Tecentriq or docetaxel. This study excluded patients who had a history of autoimmune disease, active or corticosteroid-dependent brain metastases, administration of a live, attenuated vaccine within 28 days prior to enrollment, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to enrollment. Tumor assessments were conducted every 6 weeks for the first 36 weeks, and every 9 weeks thereafter. Tumor specimens were evaluated prospectively for PD-L1 expression on tumor cells (TC) and IC and the results were used to define the PD-L1 expression subgroups for the analyses described as follows.
The demographic and baseline disease characteristics of the primary analysis population were well balanced between the treatment arms. The median age was 64 years (range: 33 to 85), and 61% of patients were male. The majority of patients were white (70%). Approximately three-fourths of patients had non-squamous disease (74%), 10% had known EGFR mutation, 0.2% had known ALK rearrangements, 10% had CNS metastases at baseline, and most patients were current or previous smokers (82%). Baseline ECOG performance status was 0 (37%) or 1 (63%). Seventy five percent of patients received only one prior platinum-based therapeutic regimen.
Tecentriq was administered as a fixed dose of 1200 mg by IV infusion every 3 weeks. No dose reduction was allowed. Patients were treated until loss of clinical benefit as assessed by the investigator. Docetaxel was administered 75 mg/m2
by IV infusion on day 1 of each 21 day cycle until disease progression. For all treated patients, the median duration of treatment was 2.1 months for the docetaxel arm and 3.4 months for the Tecentriq arm.
The primary efficacy endpoint was OS. The key results of this study with a median survival follow-up of 21 months are summarized in Table 1. Kaplan-Meier curves for OS in the ITT population are presented in Figure 1. Figure 2 summarizes the results of OS in the ITT and PD-L1 subgroups, demonstrating OS benefit with Tecentriq in all subgroups, including those with PD-L1 expression <1% in TC and IC. (See Table 1 and Figure 1 and Figure 2.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
An improvement in OS was observed with Tecentriq compared to docetaxel in both non-squamous NSCLC patients (hazard ratio [HR] of 0.73, 95% CI: 0.60, 0.89; median OS of 15.6 vs. 11.2 months for Tecentriq and docetaxel, respectively) and squamous NSCLC patients (HR of 0.73, 95% CI: 0.54, 0.98; median OS of 8.9 vs. 7.7 months for Tecentriq and docetaxel, respectively). The observed OS improvement was consistently demonstrated across subgroups of patients including those with brain metastases at baseline (HR of 0.54, 95% CI: 0.31, 0.94; median OS of 20.1 vs. 11.9 months for Tecentriq and docetaxel respectively) and patients who were never smokers (HR of 0.71, 95% CI: 0.47, 1.08; median OS of 16.3 vs. 12.6 months for Tecentriq and docetaxel, respectively). However, patients with EGFR mutations did not show improved OS with Tecentriq compared to docetaxel (HR of 1.24, 95% CI: 0.71, 2.18; median OS of 10.5 vs. 16.2 months for Tecentriq and docetaxel respectively).
Prolonged time to deterioration of patient-reported pain in chest as measured by the EORTC QLQ-LC13 was observed with Tecentriq compared with docetaxel (HR 0.71, 95% CI: 0.49, 1.05; median not reached in either arm). The time to deterioration in other lung cancer symptoms (i.e. cough, dyspnea, and arm/shoulder pain) as measured by the EORTC QLQ-LC13 was similar between Tecentriq and docetaxel. The average global health status and functioning scores (i.e. physical, role, social, emotional, and cognitive) as measured by the EORTC QLQ-C30 did not show clinically meaningful deterioration over time for both treatment groups, suggesting maintained health-related quality of life and patient-reported functioning for patients remaining on treatment.
POPLAR: A phase II, multi-center, international, randomized, open-label, controlled study GO28753 (POPLAR), was conducted in patients with locally advanced or metastatic NSCLC. The primary efficacy outcome was overall survival. A total of 287 patients were randomized 1:1 to receive either Tecentriq or docetaxel. Randomization was stratified by PD-L1 expression status in IC, by the number of prior chemotherapy regimens and by histology. An updated analysis with a total of 200 deaths observed and a median survival follow-up of 22 months showed a median OS of 12.6 months in patients treated with Tecentriq, vs. 9.7 months in patients treated with docetaxel (HR of 0.69, 95% CI: 0.52, 0.92). ORR was 15.3% vs. 14.7% and median DOR was 18.6 months vs. 7.2 months for Tecentriq vs. docetaxel, respectively.
As with all therapeutic proteins, there is the potential for immune response to atezolizumab. Across multiple phase III studies, 13.1% to 38.5% of patients developed treatment-emergent anti-drug antibodies (ADAs). ADA positivity appeared to have no clinically relevant impact on pharmacokinetics or safety. Although some variability was observed across the studies, overall, ADA positivity appeared to have no clinically relevant impact on efficacy.
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of antibodies to Tecentriq with the incidence of antibodies to other products may be misleading.
The pharmacokinetics of atezolizumab have been characterized in patients in multiple clinical trials at doses 0.01 mg/kg to 20 mg/kg and 1200 mg every 3 weeks, as well as 840 mg every 2 weeks. Exposure to atezolizumab increased dose proportionally over the dose range of 1 mg/kg to 20 mg/kg. A population analysis that included 472 patients described atezolizumab pharmacokinetics for the dose range: 1 - 20 mg/kg with a linear two-compartment disposition model with first-order elimination. Based on pharmacokinetic modeling, the overall exposure of atezolizumab administered at doses of 840 mg administered every 2 weeks, 1200 mg every 3 weeks and 1680 mg every 4 weeks are comparable. A population pharmacokinetic analysis suggests that steady-state is obtained after 6 to 9 weeks after multiple doses. The maximum systemic accumulation ratio across dosing regimen is 3.3.
Based on an analysis of exposure, safety and efficacy data, the following factors have no clinically relevant effect: age (21-89 years), body weight, gender, positive ADA status, albumin levels, tumor burden, region or ethnicity, renal impairment, mild hepatic impairment, level of PD-L1 expression, or ECOG status.
Tecentriq is administered as an IV infusion. There have been no studies performed with other routes of administration.
A population pharmacokinetic analysis indicates that central compartment volume of distribution (V1) is 3.28 L and volume at steady state (Vss) is 6.91 L in the typical patient.
The metabolism of Tecentriq has not been directly studied. Antibodies are cleared principally by catabolism.
A population pharmacokinetic analysis indicates that the clearance of atezolizumab is 0.200 L/day and the typical terminal elimination half-life (t½) is 27 days.
Pharmacokinetics in Special Populations:
Pediatric population: No studies have been conducted to investigate the pharmacokinetics of Tecentriq in children.
Geriatric population: No dedicated studies of Tecentriq have been conducted in geriatric patients. The effect of age on the pharmacokinetics of atezolizumab was assessed in a population pharmacokinetic analysis. Age was not identified as a significant covariate influencing atezolizumab pharmacokinetics based on patients of age range of 21-89 years (n=472), and median of 62 years of age. No clinically important difference was observed in the pharmacokinetics of atezolizumab among patients <65 years (n=274), patients between 65-75 years (n=152) and patients >75 years (n=46) (see Special Dosage Instructions under Dosage & Administration).
Renal impairment: No dedicated studies of Tecentriq have been conducted in patients with renal impairment. In the population pharmacokinetic analysis, no clinically important differences in the clearance of atezolizumab were found in patients with mild (eGFR 60 to 89 mL/min/1.73 m2
; n=208) or moderate (eGFR 30 to 59 mL/min/1.73 m2
; n=116) renal impairment compared to patients with normal (eGFR greater than or equal to 90 mL/min/1.73 m2
; n=140) renal function. Only a few patients had severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2
; n=8) (see Special Dosage Instructions under Dosage & Administration).
Hepatic impairment: No dedicated studies of Tecentriq have been conducted in patients with hepatic impairment. In the population pharmacokinetic analysis, there were no clinically important differences in the clearance of atezolizumab between patients with mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin >1.0 to 1.5 x ULN and any AST, n = 71) and normal hepatic function (bilirubin and AST ≤ ULN, n=401). No data are available in patients with either moderate (bilirubin > 1.5 to 3.0 x ULN and any AST) or severe (bilirubin > 3.0 x ULN and any AST) hepatic impairment. Hepatic impairment was defined by the National Cancer Institute (NCI) criteria of hepatic dysfunction (see Special Dosage Instructions under Dosage & Administration).
Toxicology: Nonclinical Safety:
Carcinogenicity: No carcinogenicity studies have been conducted with Tecentriq.
Genotoxicity No mutagenicity studies have been conducted with Tecentriq.
Impairment of Fertility: No fertility studies have been conducted with Tecentriq; however, assessment of the cynomolgus monkey male and female reproductive organs was included in the chronic toxicity study. Tecentriq had an effect on menstrual cycles in all female monkeys in the 50 mg/kg dose group characterized by an irregular cycle pattern during the dosing phase and correlated with the lack of fresh corpora lutea in the ovaries at the terminal necropsy; this effect was reversible during the dose-free recovery period. There was no effect on the male reproductive organs.
Reproductive Toxicity: No reproductive or teratogenicity studies in animals have been conducted with Tecentriq. The PD-L1/PD-1 signaling pathway is well established as essential in maternal / fetal tolerance and embryo-fetal survival during gestation. Administration of Tecentriq is expected to have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo lethality.
Other: Not applicable.