Keytruda
pembrolizumab
Species
Monkey
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“consisted of pivotal 1-month and 6-month repeat-dose chronic toxicity studies both with 4-month recovery periods in Cynomolgus monkey”
Why that species
Comparable binding to human and cynomolgus PD-1 (~2X difference); no binding to rodent or dog PD-1
“Its binding affinities to PD-1 derived from human and cynomolgus monkeys were comparable (~2X difference), however, the antibody did not bind to rodent or dog PD-1.”
Surrogate molecule
No surrogate in toxicology studies; hamster anti-murine PD-1 (J43) used as surrogate for in vivo pharmacology only
“Given the lack of cross-reactivity of MK-3475 with murine PD-1, a commercially available hamster anti-murine PD-1 mAb, J43, was used as surrogate for in vivo pharmacology studies.”
Species: general tox
Cynomolgus monkey only (1-month and 6-month studies)
“consisted of pivotal 1-month and 6-month repeat-dose chronic toxicity studies both with 4-month recovery periods in Cynomolgus monkey”
Species: DART
Not conducted: dedicated embryofetal studies not warranted; literature-based assessment accepted
“Dedicated nonclinical studies investigating the effects of pembrolizumab on embryofetal development are not warranted at this time to support its use in the intended patient population.”
Species: carcinogenicity
Not conducted (product for advanced cancer)
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer and are neither planned nor expected as post-marketing requirements at this time.”
Surrogate used in
Yes: hamster anti-mouse PD-1 J43 for in vivo pharmacology only; toxicology used pembrolizumab
“Given the lack of cross-reactivity of MK-3475 with murine PD-1, a commercially available hamster anti-murine PD-1 mAb, J43, was used as surrogate for in vivo pharmacology studies.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“consisted of pivotal 1-month and 6-month repeat-dose chronic toxicity studies both with 4-month recovery periods in Cynomolgus monkey”
Pivotal GLP studies
Pivotal 1-month and 6-month repeat-dose cynomolgus monkey studies, each with 4-month recovery
“consisted of pivotal 1-month and 6-month repeat-dose chronic toxicity studies both with 4-month recovery periods in Cynomolgus monkey”
Route in tox
Intravenous (bolus)
“Route of administration: Bolus IV injection via the saphenous vein”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for pembrolizumab.”
Carcinogenicity
Not conducted; not required for a product to treat advanced cancer; not planned as a post-marketing requirement
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer and are neither planned nor expected as post-marketing requirements at this time.”
Reproductive & developmental
Not conducted; dedicated embryofetal studies not warranted for the intended patient population
“Dedicated nonclinical studies investigating the effects of pembrolizumab on embryofetal development are not warranted at this time to support its use in the intended patient population.”
Safety pharmacology
Evaluated within the 1- and 6-month repeat-dose monkey studies
“safety pharmacology was evaluated as part of the 1-month and 6-months repeat-dose toxicity study in cynomolgus monkeys”
Genotox: Ames
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for pembrolizumab.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for pembrolizumab.”
Genotox: in vivo
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for pembrolizumab.”
Carcinogenicity model
Not conducted (product for advanced cancer)
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer and are neither planned nor expected as post-marketing requirements at this time.”
Carcinogenicity timing
Not required; not planned as a postmarketing requirement
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer and are neither planned nor expected as post-marketing requirements at this time.”
hERG / QT
No hERG assay; no effects on ECG, blood pressure or CV/respiratory/CNS histopathology in monkey repeat-dose studies
“The following parameters were evaluated: electrocardiograms, general veterinary and physical examinations with body temperature and blood pressure, clinical observations (within 1 to 3 hours post-dose), and histopathology of tissues from the cardiovascular, respiratory, renal, and nervous systems. No pembrolizumab-related effects were observed in any parameter evaluated.”
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 Keytruda 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: Well tolerated; NOAEL was the highest dose tested in both studies (EMA assessment report, p. 30)
NOAEL / key findings
Well tolerated; NOAEL was the highest dose tested in both studies
“Overall, pembrolizumab was well tolerated and the NOAEL in both studies was the highest dose tested.”
Risksopen answer page →
Immune & cytokine safety
No cytokine release (IL-2) from hPBMCs cultured on immobilized pembrolizumab
“Pembrolizumab was evaluated in a cytokine release assay there was no evidence of cytokine release, as assessed by IL-2 production following culture of hPBMCs in pembrolizumab-immobilized (air-dried) plates.”
Biodistribution & persistence
Vss 30.9-54.8 mL/kg in monkeys, similar to plasma volume; limited distribution out of plasma
“the Vss mean value (30.9, 36.8, 54.8 ml/kg) was similar to the plasma volume of monkeys suggesting that pembrolizumab has a limited distribution out of the plasma compartment”
Modality-specific risk
Autoimmune adverse events secondary to the drug's pharmacological action
“In patients that receive pembrolizumab, autoimmune diseases are the most common adverse events, and are likely secondary to the pharmacological actions of the drug.”
Anti-drug antibodies: animals
6-month monkey: ADA in 5 animals at 6 mg/kg and 1 at 200 mg/kg, increasing pembrolizumab elimination; drug interference at higher doses
“Anti-pembrolizumab antibodies were detected in 5 animals of the 6 mg/kg group (during the dosing period) and in 1 animal in the 200 mg/kg group (during the recovery period) and were associated with an increase in elimination of pembrolizumab.”
Anti-drug antibodies: patients
1.4% (3/211) developed anti-pembrolizumab antibodies (subcutaneous KEYTRUDA QLEX); one with neutralizing antibodies
“With a median (min, max) duration of treatment on KEYTRUDA QLEX of 6.9 months (1 day, 1 year) in Study MK-3475A-D77, 1.4% (3/211) of patients developed anti-pembrolizumab antibodies, and one ADA-positive patient developed neutralizing antibodies (NAb) against pembrolizumab.”
Label warnings
- Severe and Fatal Immune-Mediated Adverse Reactions
- Hypersensitivity and Administration-Related Reactions
- Complications of Allogeneic HSCT
- Increased Mortality in Patients with Multiple Myeloma when Pembrolizumab is Added to a Thalidomide Analogue and Dexamethasone
- 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
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.
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 Keytruda 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: Well tolerated; NOAEL was the highest dose tested in both studies (EMA assessment report, p. 30)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month (26-week) cynomolgus monkey study with 4-month recovery
“consisted of pivotal 1-month and 6-month repeat-dose chronic toxicity studies both with 4-month recovery periods in Cynomolgus monkey”
Pivotal GLP studies
Pivotal 1-month and 6-month repeat-dose cynomolgus monkey studies, each with 4-month recovery
“consisted of pivotal 1-month and 6-month repeat-dose chronic toxicity studies both with 4-month recovery periods in Cynomolgus monkey”
DART package
Species: DART
Not conducted: dedicated embryofetal studies not warranted; literature-based assessment accepted
“Dedicated nonclinical studies investigating the effects of pembrolizumab on embryofetal development are not warranted at this time to support its use in the intended patient population.”
Reproductive & developmental
Not conducted; dedicated embryofetal studies not warranted for the intended patient population
“Dedicated nonclinical studies investigating the effects of pembrolizumab on embryofetal development are not warranted at this time to support its use in the intended patient population.”
PPND / ePPND: when
Not conducted: dedicated developmental studies not warranted for the intended advanced-cancer population
“Dedicated nonclinical studies investigating the effects of pembrolizumab on embryofetal development are not warranted at this time to support its use in the intended patient population.”
Carcinogenicity
Species: carcinogenicity
Not conducted (product for advanced cancer)
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer and are neither planned nor expected as post-marketing requirements at this time.”
Carcinogenicity model
Not conducted (product for advanced cancer)
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer and are neither planned nor expected as post-marketing requirements at this time.”
Carcinogenicity timing
Not required; not planned as a postmarketing requirement
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer and are neither planned nor expected as post-marketing requirements at this time.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey exposure at all doses tested exceeded human exposure at 2 mg/kg Q3W
“In addition, in both monkey studies, exposure of pembrolizumab at all dose levels tested exceeded that measured in humans at the intended clinical dose and schedule of 2 mg/kg once every 3 weeks.”
NOAEL / key findings
Well tolerated; NOAEL was the highest dose tested in both studies
“Overall, pembrolizumab was well tolerated and the NOAEL in both studies was the highest dose tested.”
Efficacy evidenceopen answer page →
Efficacy evidence
MC38 syngeneic mouse colon tumor model with hamster anti-mouse PD-1 surrogate J43
“The antitumor activity induced by blocking PD-1 was shown in vivo in mice in a syngeneic tumour model where MC38 colon adenocarcinoma was injected subcutaneously and mice were treated using a commercially available homologous anti-mouse PD-1 monoclonal antibody J43 at 2 mg/kg and 10 mg/kg doses every 3-4 weeks.”
Why that model
Pembrolizumab does not cross-react with murine PD-1
“Given the lack of cross-reactivity of MK-3475 with murine PD-1, a commercially available hamster anti-murine PD-1 mAb, J43, was used as surrogate for in vivo pharmacology studies.”
Reviewer's view of the efficacy data
EMA: lack of nonclinical proof-of-concept at the clinical dose acceptable given human clinical data
“Given the availability of clinical data from humans, the lack of a non-clinical proof-of-concept at the 2 mg/kg every 3 weeks dose is acceptable.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No embryo-fetal study in monkey; literature assessment of pregnancy outcomes in PD-1 knockout mice instead
Why: Known link between PD-1 deficiency and abortion; antibody active only in nonhuman primate · Weight of evidence · No relevant species
“On the basis of the known association between PD-1 deficiency and increased rates of abortion, FDA agreed with the Applicant’s request to provide a literature assessment of the scientific data of pregnancy outcomes in PD-1 -/- mice in lieu of conducting an embryofetal study in the monkey with MK-3475.”
“This decision was made in part because MK-3475 is not active in any species other than the nonhuman primate.”
DARTAccepted with a conditionBeyond the letter
Too few sexually mature males dosed for at least 3 months to assess male fertility
“Pembrolizumab is not expected to cause adverse effects in the male and female reproductive system, however as the number of sexually mature male treated with pembrolizumab for a sufficiently long duration (≥ 3 months according to ICH S6(R1) was too low to draw any conclusions about the effect of pembrolizumab on male fertility, a statement has been included in the SmPC section 5.3.”
OtherAccepted with a conditionBeyond the letter
Potential for exaggerated recall response to antigens not investigated; additional pharmacology study requested postmarketing
“The Applicant did not, however, investigate the potential for an exaggerated recall response to an antigen in either the presence or absence of pembrolizumab following a primary response in the presence of anti-PD-1.”
“Understanding this potential may be useful in advising patients on the safety of vaccination during treatment with pembrolizumab, and an additional pharmacology study has been requested as a post-marketing commitment to better define this potential.”
Efficacy modelAcceptedBeyond the letter
In vivo antitumour activity shown only with a surrogate anti-mouse PD-1 antibody; no proof-of-concept at the clinical dose
Why: Clinical data from humans available · Human data
“Given the availability of clinical data from humans, the lack of a non-clinical proof-of-concept at the 2 mg/kg every 3 weeks dose is acceptable.”
Similar precedents
JemperliAntibodies · dostarlimab · PD-1Monkey only · 13 wkLibtayoAntibodies · cemiplimab · PD-1Monkey only · 26 wkLoqtorziAntibodies · toripalimab · PD-1Monkey only · 26 wkOpdivoAntibodies · nivolumab · PD-1Monkey only · 13 wkPenpulimabAntibodies · penpulimab · PD-1Monkey only · 13 wkTevimbraAntibodies · tislelizumab · PD-1Monkey only · 13 wk