Tecentriq
atezolizumab
Species
MonkeyMouse
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey (pivotal); mouse pilot study
“The Applicant conducted repeat-dose toxicology studies in mice and Cynomolgus monkeys.”
Why that species
Binds human, murine and cynomolgus monkey PD-L1
“In vitro pharmacology studies demonstrated that atezolizumab binds to human, murine, and Cynomolgus monkey PD-L1”
Surrogate molecule
Yes: mouse IgG2a chimeric antibodies with atezolizumab binding region, used to minimize immunogenicity in mouse studies
“To minimize immunogenicity in mice, the Applicant generated two mouse IgG2a chimeric antibodies (PRO304397 and PRO314483), containing the binding region of atezolizumab.”
Species: general tox
Mouse (2-week) and cynomolgus monkey (up to 26 weeks, pivotal)
“General toxicology studies evaluated atezolizumab in mice for two weeks and in Cynomolgus monkeys for up to 26 weeks.”
Species: DART
Not conducted; reproductive organs assessed in chronic monkey study (irregular cycles, no new corpora lutea)
“Reproductive and developmental toxicity studies have not been conducted with atezolizumab. However, in the chronic toxicity study in sexually mature monkeys, atezolizumab treatment at the high-dose resulted in irregular menstrual cycles and a lack of newly formed corpora lutea in the ovaries.”
Species: carcinogenicity
Not conducted (ICH S6(R1), ICH S9)
“Carcinogenicity studies have not been conducted in accordance with ICH S6(R1) and ICH S9.”
Surrogate used in
Yes: mouse IgG2a chimeric antibodies with atezolizumab binding region (PRO304397, PRO314483) for mouse studies
“To minimize immunogenicity in mice, the Applicant generated two mouse IgG2a chimeric antibodies (PRO304397 and PRO314483), containing the binding region of atezolizumab.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“In GLP-compliant toxicology studies, Cynomolgus monkeys received atezolizumab at doses up to 50 mg/kg/week given SC for 8 weeks or administered IV for up to 26 weeks.”
Pivotal GLP studies
GLP cynomolgus monkey studies: 8-week SC and IV, and 26-week IV, weekly up to 50 mg/kg
“In GLP-compliant toxicology studies, Cynomolgus monkeys received atezolizumab at doses up to 50 mg/kg/week given SC for 8 weeks or administered IV for up to 26 weeks.”
Route in tox
IV and SC
“In GLP-compliant toxicology studies, Cynomolgus monkeys received atezolizumab at doses up to 50 mg/kg/week given SC for 8 weeks or administered IV for up to 26 weeks.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted, which is in accordance with ICH S6(R1).”
Carcinogenicity
Not conducted (ICH S6(R1), ICH S9); no increased carcinogenic risk expected from mechanism
“Carcinogenicity studies have not been conducted in accordance with ICH S6(R1) and ICH S9. Furthermore, due to its mechanism of action, atezolizumab is not expected to be associated with an increased carcinogenic risk.”
Reproductive & developmental
No dedicated studies; chronic monkey study: irregular menstrual cycles and no new corpora lutea at high dose
“Reproductive and developmental toxicity studies have not been conducted with atezolizumab. However, in the chronic toxicity study in sexually mature monkeys, atezolizumab treatment at the high-dose resulted in irregular menstrual cycles and a lack of newly formed corpora lutea in the ovaries.”
Safety pharmacology
Incorporated into 8- and 26-week monkey studies (CNS, cardiovascular telemetry, respiratory)
“Central nervous system, cardiovascular (telemetry and/or surface leads), and respiratory safety pharmacology parameters were evaluated as part of the 8- and 26-week GLP Cynomolgus monkey toxicology studies (Studies 08-1148 and 13-3278).”
Genotox: Ames
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted, which is in accordance with ICH S6(R1).”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted, which is in accordance with ICH S6(R1).”
Genotox: in vivo
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted, which is in accordance with ICH S6(R1).”
Carcinogenicity model
Not conducted (ICH S6(R1), ICH S9); no increased carcinogenic risk expected from mechanism
“Carcinogenicity studies have not been conducted in accordance with ICH S6(R1) and ICH S9. Furthermore, due to its mechanism of action, atezolizumab is not expected to be associated with an increased carcinogenic risk.”
Carcinogenicity timing
Not required (ICH S6(R1) and ICH S9)
“Carcinogenicity studies have not been conducted in accordance with ICH S6(R1) and ICH S9.”
hERG / QT
No hERG assay; no atezolizumab-related ECG findings in monkey toxicology studies
“No atezolizumab-related electrocardiographic findings were observed; all electrocardiograms evaluated in this study were qualitatively and quantitatively within normal limits.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Tecentriq don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for monoclonal antibodies
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: Arteritis/periarteritis in monkeys and sciatic neuropathy in mice, possibly enhanced autoreactive immune response (EMA assessment report, p. 36)
NOAEL / key findings
Arteritis/periarteritis in monkeys and sciatic neuropathy in mice, possibly enhanced autoreactive immune response
“Atezolizumab-related findings in the repeated dose toxicity studies were sciatic neuropathy in C57BL/6 mice and arteritis/periarteritis in Cynomolgus monkeys. Both findings may be due to enhancement of an autoreactive immune-response in pre-disposed animals.”
Risksopen answer page →
Immune & cytokine safety
No cytokine release from human PBMCs up to 250 µg/mL; minimal Fcγ receptor binding, no ADCC up to 10 µg/mL
“Atezolizumab showed minimal binding to human Fcγ receptors and did not stimulate cytokine release from human PBMCs at concentrations up to 250 µg/mL or ADCC activity at concentrations up to 10 µg/mL.”
Biodistribution & persistence
Human TCR staining in placenta (syncytiotrophoblasts), lymph node, tonsil and thymus
“staining was detected in the placenta, lymph node, tonsil, and thymus. Frequent, moderate, apical cytoplasmic and membranous staining was observed in syncytiotrophoblasts of the placenta.”
Modality-specific risk
Immune-mediated tissue damage and multi-organ inflammation from PD-L1 blockade; irregular menstruation
“Toxicological effects of atezolizumab administration in animals were limited to irregular menstruation in female monkeys and immune-mediated effects, including tissue damage and multi-organ inflammation.”
Anti-drug antibodies: animals
ATA in 50/56 treated monkeys (and 7/16 controls); mean exposure maintained during dosing
“ATAs were detected in 50 out of 56 monkeys receiving test article and 7 out of 16 animals in the vehicle control group. Although ATAs were present in the majority of treated animals, mean treatment exposure was maintained during the dosing period.”
Anti-drug antibodies: patients
13% to 36% developed ADA in the first year across 9 studies
“During the first year of treatment with TECENTRIQ across 9 clinical studies, 13% to 36% of patients developed ADA to atezolizumab.”
Label warnings
- Severe and Fatal Immune-Mediated Adverse Reactions
- Infusion-Related Reactions
- Complications of Allogeneic HSCT after PD-1/PD-L1 Inhibitors
- Embryo-Fetal Toxicity
Immune-mediated reactionsHypersensitivity & infusion reactionsEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not stated; first-in-human dose-escalation study in patients with solid tumours (PCD4989g)
“Multicenter, first-in-human, dose-escalation, open-label study”
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Tecentriq don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for monoclonal antibodies
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: Arteritis/periarteritis in monkeys and sciatic neuropathy in mice, possibly enhanced autoreactive immune response (EMA assessment report, p. 36)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week IV cynomolgus monkey study (13-3278) with recovery groups; recovery length not stated
“13-3278 3/sex (main) 2/sex (recovery) IV: 0, 5, 15, 50 26 weeks Q1W”
Pivotal GLP studies
GLP cynomolgus monkey studies: 8-week SC and IV, and 26-week IV, weekly up to 50 mg/kg
“In GLP-compliant toxicology studies, Cynomolgus monkeys received atezolizumab at doses up to 50 mg/kg/week given SC for 8 weeks or administered IV for up to 26 weeks.”
DART package
Species: DART
Not conducted; reproductive organs assessed in chronic monkey study (irregular cycles, no new corpora lutea)
“Reproductive and developmental toxicity studies have not been conducted with atezolizumab. However, in the chronic toxicity study in sexually mature monkeys, atezolizumab treatment at the high-dose resulted in irregular menstrual cycles and a lack of newly formed corpora lutea in the ovaries.”
Reproductive & developmental
No dedicated studies; chronic monkey study: irregular menstrual cycles and no new corpora lutea at high dose
“Reproductive and developmental toxicity studies have not been conducted with atezolizumab. However, in the chronic toxicity study in sexually mature monkeys, atezolizumab treatment at the high-dose resulted in irregular menstrual cycles and a lack of newly formed corpora lutea in the ovaries.”
PPND / ePPND: when
Not conducted; literature-based assessment of reproductive and developmental risk instead (oncology, ICH S9)
“The Applicant did not conduct reproductive and developmental toxicology studies with atezolizumab.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S6(R1), ICH S9)
“Carcinogenicity studies have not been conducted in accordance with ICH S6(R1) and ICH S9.”
Carcinogenicity model
Not conducted (ICH S6(R1), ICH S9); no increased carcinogenic risk expected from mechanism
“Carcinogenicity studies have not been conducted in accordance with ICH S6(R1) and ICH S9. Furthermore, due to its mechanism of action, atezolizumab is not expected to be associated with an increased carcinogenic risk.”
Carcinogenicity timing
Not required (ICH S6(R1) and ICH S9)
“Carcinogenicity studies have not been conducted in accordance with ICH S6(R1) and ICH S9.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: toxicity studies provide no margin to exposure at the proposed clinical dose
“The toxicity studies provide no margin to the exposure at the proposed clinical dose of atezolizumab.”
NOAEL / key findings
Arteritis/periarteritis in monkeys and sciatic neuropathy in mice, possibly enhanced autoreactive immune response
“Atezolizumab-related findings in the repeated dose toxicity studies were sciatic neuropathy in C57BL/6 mice and arteritis/periarteritis in Cynomolgus monkeys. Both findings may be due to enhancement of an autoreactive immune-response in pre-disposed animals.”
Efficacy evidenceopen answer page →
Efficacy evidence
Syngeneic mouse melanoma and colorectal tumour models with murine/human chimeric atezolizumab; tumour growth reduced by at least 80%
“For in vivo pharmacology studies, the Applicant generated murine/human chimeric antibodies of atezolizumab to minimize immunogenicity in mice and evaluated PD-L1 blockade in syngeneic mouse models of melanoma and colorectal cancer. Anti-PD-L1 antibody reduced tumor growth by ≥ 80%.”
Why that model
Chimeric mouse IgG2a versions used to reduce immunogenicity seen in earlier mouse studies
“The Applicant generated mouse IgG2a/human chimeric antibodies for murine in vivo studies in order to reduce immunogenicity, which was observed in prior mouse studies.”
Reviewer's view of the efficacy data
EMA: syngeneic tumour models with chimeric mAbs adequately evaluated PD-L1 blockade and provide sufficient proof-of-concept
“The in vivo effect of blocking PD-L1 was adequately evaluated in murine syngeneic tumour models using chimeric anti-PD-L1 mAbs. These studies demonstrate that treatment with anti-PD-L1 mediates an effective anti-tumour response and provide sufficient proof-of-concept.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No reproductive and developmental toxicity studies; non-product-specific literature-based assessment of pregnancy risk instead
Why: Immunogenicity in mice reduced exposure; ICH S6(R1) weight-of-evidence approach used to describe pregnancy risk · Within the guideline · Weight of evidence · Pharmacology or kinetics
“The Applicant did not conduct reproductive and developmental toxicology studies with atezolizumab. Atezolizumab was immunogenic in mice after three weekly doses, resulting in reduced exposures by Week 3.”
“A weight-of-evidence approach in accordance to ICH S6(R1) was applied to describe the potential risk of atezolizumab to human pregnancy, which is acceptable.”
Safety marginVerdict not stated
Toxicity studies provide no exposure margin over the proposed clinical dose
“The toxicity studies provide no margin to the exposure at the proposed clinical dose of atezolizumab.”
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