NAV

Dostarlimab

Identification

Summary

Dostarlimab is an anti-PD-1 monoclonal antibody used in the treatment of mismatch repair deficient endometrial cancers and solid tumours with no alternative treatment options.

Brand Names
Jemperli
Generic Name
Dostarlimab
DrugBank Accession Number
DB15627
Background

Dostarlimab is an IgG4 humanized monoclonal antibody targeted against the human programmed death receptor-1 (PD-1).6 PD-1 receptors are found on T-cells and, when activated, serve to inhibit immune responses - some cancers leverage this system by overexpressing PD-1 ligands, thereby effectively inhibiting the anti-tumor immune response that would typically attempt to destroy the cancerous cells.3 Agents acting on the PD-1 pathway, such as nivolumab and pembrolizumab, facilitate endogenous immune-mediated anti-tumor activity and may therefore be used to treat a wide variety of cancers, including those of the skin, lung, kidneys, and liver.

In April 2021, dostarlimab was granted accelerated approval by the FDA - as GlaxoSmithKline's dostarlimab-gxly (Jemperli) - for the treatment of adult patients with recurrent or advanced mismatch repair deficient (dMMR) endometrial cancer experiencing disease progression despite treatment with platinum-containing chemotherapy regimens.7 A companion diagnostic device - the VENTANA MMR RxDx Panel - was also approved alongside this indication to select appropriate patients for treatment.7 This indication was granted full FDA approval on February 10, 2023.10 Dostarlimab-gxly was granted second accelerated approval for the treatment of solid tumours in the same month.9

Dostarlimab is currently under investigation for the treatment of rectal cancers with mismatch repair deficiency. A prospective phase II study in patients with mismatch repair-deficient locally advanced rectal cancer resulted in all twelve patients exhibiting a complete clinical response.5

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
C6420H9832N1680O2014S44
Protein Average Weight
144000.0 Da (non-glycosylated)
Sequences
>Heavy Chain
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISGGGSYTYY
QDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTK
GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP
PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS
CSVMHEALHNHYTQKSLSLSLGK
>Light Chain
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTLHTGVPS
RFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]
Download FASTA Format
Synonyms
  • Dostarlimab
  • dostarlimab-gxly
  • Immunoglobulin G4, anti-programmed cell death protein 1 (PDCD1) (humanized clone ABT1 gamma4-chain), disulfide with humanized clone ABT1 kappa-chain, dimer
External IDs
  • GSK-4057190
  • GSK4057190
  • TSR 042
  • TSR-042
  • WBP-285
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Pharmacology

Indication

Dostarlimab is indicated for the treatment of adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer that has progressed despite ongoing or prior treatment with a platinum-containing chemotherapy regimen. It is used as monotherapy or in combination with carboplatin and paclitaxel.6,11,12,13

It is also indicated for the treatment of dMMR recurrent or advanced solid tumors in adults, as determined by an FDA-approved test, that have progressed on or following prior treatment and in patients who have no satisfactory alternative treatment options. This indication is approved under accelerated approval, and continued approval for this indication may be contingent upon verification and description of and description of clinical benefit in confirmatory trials.9

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatAdvanced microsatellite instability high endometrial carcinomaRegimen in combination with: Paclitaxel (DB01229), Carboplatin (DB00958)••••••••••••••••••••••••••
Used in combination to treatAdvanced mismatch repair-deficient (dmmr) endometrial cancerRegimen in combination with: Paclitaxel (DB01229), Carboplatin (DB00958)••••••••••••••••••••••••••
Treatment ofAdvanced mismatch repair-deficient (dmmr) endometrial cancer•••••••••••••••••••••••• ••• •••••••••• •••••• •• ••••••••• ••••••••••••••••••• ••••••••••••• ••• • ••••••••• ••• •••••••• ••••••• •• ••••••••••••••••••
Treatment ofAdvanced mismatch repair deficient (dmmr) solid tumors••••••••••••••••••••••••••• ••••••••••• ••••••••• •••••••• ••••••• ••••••••••• ••••• •••••••• ••••••••••••••••••
Used in combination to treatRecurrent microsatellite instability (msi)-high endometrial cancerRegimen in combination with: Paclitaxel (DB01229), Carboplatin (DB00958)••••••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Dostarlimab is an immunotherapy that facilitates the body's endogenous anti-tumor immune response in the treatment cancer.6 It is administered over a span of 30 minutes via intravenous infusion every three to six weeks depending on the cycle.6

Agents that interfere with the PD-1/PD-L1 pathway, including dostarlimab, remove an important immune system inhibitory response and may therefore induce immune-mediated adverse reactions which can be severe or fatal. These reactions can occur in any organ system and can occur at any time after starting therapy, and while they most often manifest during therapy they may also appear after discontinuing the causative agent. Patients receiving therapy with dostarlimab should be monitored closely for evidence of an underlying immune-mediated reaction and evaluated and treated promptly if an immune-mediated reaction is suspected.6

Mechanism of action

Approximately 13-30% of recurrent endometrial cancers involve microsatellite instability (MSI) or mismatch repair deficiency (dMMR).3,4 The mutations resulting in dMMR endometrial cancers are primarily somatic in nature (~90%), although 5-10% of cases involve germline mutations.4 Cancers that have mutations resulting in dMMR can upregulate the expression of programmed death receptor-1 (PD-1) ligands 1 and 2 (PD-L1 and -L2) - PD-1 is found on T-cells and, when activated, inhibits their proliferation and the production of cytokines.6 The binding of these ligands to PD-1 thereby functions as an immune checkpoint that downregulates the anti-tumor immune response.3

Dostarlimab is a monoclonal antibody targeted against PD-1 - it binds to the receptor and prevents interactions with PD-L1 and PD-L2, thus allowing the anti-tumor immune response to proceed unimpeded.6

TargetActionsOrganism
AProgrammed cell death protein 1
binder
antibody
Humans
Absorption

During the first cycle, and administered at 500mg intravenously every 3 weeks, the mean Cmax and AUC0-tau of dostarlimab-gxly are 171 mcg/mL and 35,730 mcg.h/mL, respectively. When administered at 1000mg every 6 weeks, the mean Cmax and AUC0-tau are 309 mcg/mL and 95,820 mcg.h/mL, respectively.6

Volume of distribution

At steady-state, the mean volume of distribution of dostarlimab is 5.3L.6

Protein binding

Not Available

Metabolism

The metabolism of dostarlimab has not been characterized, but it is expected to be degraded via catabolic pathways into smaller peptides and amino acids.6,2

Route of elimination

Not Available

Half-life

The mean terminal elimination half-life of dostarlimab is 25.4 days.6

Clearance

At steady-state, the mean clearance of dostarlimab is 0.007 L/h.6

Adverse Effects
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Toxicity

There are no data regarding overdose with dostarlimab. Symptoms of overdosage are likely to be consistent with the adverse effect profile of dostarlimab and may therefore involve significant immune-mediated reactions.6

Pathways
Not Available
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
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interactions in your software
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Dostarlimab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Dostarlimab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Dostarlimab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Dostarlimab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Dostarlimab.
Food Interactions
No interactions found.

Products

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International/Other Brands
Jemperli (GlaxoSmithKline)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
JemperliInjection50 mg/1mLIntravenousGlaxoSmithKline LLC2021-04-22Not applicableUS flag
JemperliInjection, solution, concentrate500 mgIntravenousGlaxo Smith Kline (Ireland) Limited2022-06-06Not applicableEU flag
JemperliSolution50 mg / mLIntravenousGlaxosmithkline Inc2022-02-22Not applicableCanada flag

Categories

ATC Codes
L01FF07 — Dostarlimab
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
P0GVQ9A4S5
CAS number
2022215-59-2

References

General References
  1. Kaplon H, Muralidharan M, Schneider Z, Reichert JM: Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. doi: 10.1080/19420862.2019.1703531. [Article]
  2. Temrikar ZH, Suryawanshi S, Meibohm B: Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients. Paediatr Drugs. 2020 Apr;22(2):199-216. doi: 10.1007/s40272-020-00382-7. [Article]
  3. Green AK, Feinberg J, Makker V: A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer. Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-7. doi: 10.1200/EDBK_280503. [Article]
  4. Deshpande M, Romanski PA, Rosenwaks Z, Gerhardt J: Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability. Cancers (Basel). 2020 Nov 10;12(11). pii: cancers12113319. doi: 10.3390/cancers12113319. [Article]
  5. Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, El Dika IH, Segal N, Shcherba M, Sugarman R, Stadler Z, Yaeger R, Smith JJ, Rousseau B, Argiles G, Patel M, Desai A, Saltz LB, Widmar M, Iyer K, Zhang J, Gianino N, Crane C, Romesser PB, Pappou EP, Paty P, Garcia-Aguilar J, Gonen M, Gollub M, Weiser MR, Schalper KA, Diaz LA Jr: PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer. N Engl J Med. 2022 Jun 5. doi: 10.1056/NEJMoa2201445. [Article]
  6. FDA Approved Drug Products: Jemperli (dostarlimab-gxly) for intravenous injection [Link]
  7. FDA News Release: FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer [Link]
  8. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]
  9. FDA Approved Drug Products: JEMPERLI (dostarlimab-gxly) injection, for intravenous use (February 2023) [Link]
  10. BioSpace: US FDA grants regular approval for Jemperli for the treatment of patients with recurrent or advanced mismatch repair-deficient endometrial cancer [Link]
  11. FDA Approved Drug Products: JEMPERLI (dostarlimab-gxly) injection, for intravenous use (July 2023) [Link]
  12. Health Canada Approved Drug Products: JEMPERLI (dostarlimab) Intravenous Solution for Infusion [Link]
  13. EMA Approved Drug Products: JEMPERLI (dostarlimab) Intravenous Infusion [Link]
RxNav
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Wikipedia
Dostarlimab

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentNeoplasm1
3Active Not RecruitingTreatmentOvarian Neoplasms / Ovarian, Fallopian Tube and Primary Peritoneal Carcinoma1
3RecruitingTreatmentColon Neoplasm / Neoplasms, Colon1
3RecruitingTreatmentEndometrial Cancer1
3RecruitingTreatmentOvarian Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous50 mg/1mL
Injection, solutionIntravenous500 MG
Injection, solution, concentrateIntravenous500 mg
SolutionIntravenous50 mg / mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

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Details1. Programmed cell death protein 1
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
Antibody
General Function
Signal transducer activity
Specific Function
Inhibitory cell surface receptor involved in the regulation of T-cell function during immunity and tolerance. Upon ligand binding, inhibits T-cell effector functions in an antigen-specific manner. ...
Gene Name
PDCD1
Uniprot ID
Q15116
Uniprot Name
Programmed cell death protein 1
Molecular Weight
31646.635 Da
References
  1. FDA Approved Drug Products: Jemperli (dostarlimab-gxly) for intravenous injection [Link]

Drug created at March 07, 2020 19:58 / Updated at February 14, 2024 00:55