Adagrasib

Identification

Summary

Adagrasib is a KRAS inhibitor indicated for the treatment of locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer in patients who have received at least one prior systemic therapy.

Brand Names

Krazati

Generic Name

Adagrasib

DrugBank Accession Number

DB15568

Background

Adagrasib (MRTX849) is an oral, small-molecule KRAS inhibitor developed by Mirati Therapeutics. KRAS mutations are highly common in cancer and account for approximately 85% of all RAS family mutations.⁵ However, the development of KRAS inhibitors has been challenging due to their high affinity for guanosine triphosphate (GTP) and guanosine diphosphate (GDP), as well as the lack of a clear binding pocket.¹ Adagrasib targets KRAS^G12C, one of the most common KRAS mutations, at the cysteine 12 residue and inhibits KRAS-dependent signalling.² In a phase I/IB clinical study that included patients with KRAS^G12C-mutated advanced solid tumors (NCT03785249), adagrasib exhibited anti-tumor activity. The phase II of the same study showed that in patients with KRAS^G12C-mutated non-small-cell lung cancer (NSCLC), adagrasib was efficient without new safety signals.^2,3,6

In February 2022, the FDA accepted a new drug application (NDA) for adagrasib for the treatment of patients with previously treated KRAS^G12C–positive NSCLC.⁷ In December 2022, the FDA granted accelerated approval to adagrasib for the treatment of KRAS^G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy.^8,9 Adagrasib joins sotorasib as another KRAS^G12C inhibitor approved by the FDA.⁴

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Adagrasib (DB15568)

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Weight

Average: 604.13
Monoisotopic: 603.2524793

Chemical Formula

C₃₂H₃₅ClFN₇O₂

Synonyms

• ((2s)-4-(7-(8-chloronaphthalen-1-yl)-2-(((2s)-1- methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydropyrido(3,4-d)pyrimidin-4-yl)-1-(2-fluoroprop2-enoyl)piperazin-2-yl)acetonitrile
• 2-piperazineacetonitrile, 4-(7-(8-chloro-1-naphthalenyl)-5,6,7,8-tetrahydro-2-(((2s)-1-methyl-2-pyrrolidinyl)methoxy)pyrido(3,4-d)pyrimidin-4-yl)-1-(2-fluoro-1-oxo-2-propen-1-yl)-, (2s)-
• KRAS G12C inhibitor MRTX849

External IDs

• MRTX-849
• MRTX849

Pharmacology

Indication

Adagrasib is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.⁸

This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).⁸

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Associated Conditions

• Locally Advanced Non-Small Cell Lung Cancer
• Metastatic Non-Small Cell Lung Cancer

Contraindications & Blackbox Warnings

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Pharmacodynamics

The exposure-response relationship and pharmacodynamic response time course of adagrasib have not been elucidated. The use of adagrasib can cause QTc interval prolongation. The increase in QTc is concentration-dependent. In patients given 600 mg of adagrasib twice daily, the mean QTcF change from baseline (ΔQTcF) was 18 ms at the mean steady-state maximum concentration.⁸ The use of adagrasib can also lead to severe gastrointestinal adverse reactions, hepatotoxicity and interstitial lung disease/pneumonitis.⁸

Mechanism of action

In normal cells, KRAS is activated by binding to guanosine triphosphate (GTP), and this promotes the activation of the MAP kinase pathway and intracellular signal transduction. When GTP is hydrolyzed to guanosine diphosphate (GDP), KRAS is inactivated. This mechanism works as an "on"/"off" system that regulates cell growth. The substitution of Gly12 by cysteine in KRAS (KRAS^G12C) impairs GTP hydrolysis, and maintains KRAS in its active form. Therefore, the presence of this mutation leads to uncontrolled cellular proliferation and growth, as well as malignant transformation.¹ Adagrasib is a covalent inhibitor of KRAS^G12C that irreversibly and selectively binds and locks KRAS^G12C in its inactive, guanosine diphosphate–bound state.² Therefore, the use of adagrasib inhibits tumor cell growth and viability in cancers with KRAS^G12C mutations with minimal off-target activity.⁸

Target	Actions	Organism
AGTPase KRas	inhibitor	Humans

Absorption

The AUC and C_max of adagrasib increase in a dose-proportional manner between 400 mg and 600 mg (0.67 to 1 times the approved recommended dose). At the recommended dose, adagrasib reached steady-state within 8 days, with a 6-fold accumulation. The T_max of adagrasib is approximately 6 hours. The administration of a high-fat and high-calorie meal (900-1000 calories, 50% from fat) did not have a clinically significant effect on the pharmacokinetics of adagrasib.⁸ Adagrasib has high oral bioavailability and is able to penetrate the central nervous system.⁵

Volume of distribution

Adagrasib has an apparent volume of distribution of 942 L.⁸

Protein binding

In vitro, adagrasib has a human plasma protein binding of 98%.⁸

Metabolism

Following single-dose administration, adagrasib is mainly metabolized by CYP3A4. However, since adagrasib inhibits CYP3A4 following multiple dosing, other enzymes such as CYP2C8, CYP1A2, CYP2B6, CYP2C9, and CYP2D6 contribute to its metabolism at steady-state.⁸

Route of elimination

Adagrasib is eliminated through feces and urine. In patients given a single dose of radiolabeled adagrasib, 75% of the dose was recovered in feces (14% as unchanged), while 4.5% was recovered in urine (2% as unchanged).⁸

Half-life

Adagrasib has a terminal elimination half-life of 23 hours.⁸

Clearance

Adagrasib has an apparent oral clearance (CL/F) of 37 L/h.⁸

Adverse Effects

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Toxicity

Toxicity information regarding adagrasib is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as hepatotoxicity, gastrointestinal adverse reactions and QTc interval prolongation.⁸ Symptomatic and supportive measures are recommended.

The carcinogenicity of adagrasib has not been evaluated. In an in vitro bacterial reverse mutation (Ames) assay, adagrasib was not mutagenic. An in vitro chromosomal aberration assay and an in vivo micronucleus assay in rats showed that it was not genotoxic. Studies evaluating the effects of adagrasib on fertility have not been performed. The oral administration of adagrasib to rats for up to 13 weeks induced phospholipidosis at doses higher than 150 mg/kg (approximately 2 times the human exposure at the recommended dose based on AUC). The presence of phospholipidosis led to the increased vacuolation of multiple organs.⁸

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Adagrasib can be increased when it is combined with Abametapir.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Adagrasib.
Abrocitinib	The metabolism of Abrocitinib can be decreased when combined with Adagrasib.
Acalabrutinib	The serum concentration of Acalabrutinib can be increased when it is combined with Adagrasib.
Acebutolol	The metabolism of Acebutolol can be decreased when combined with Adagrasib.
Acenocoumarol	The serum concentration of Acenocoumarol can be increased when it is combined with Adagrasib.
Acetaminophen	The metabolism of Acetaminophen can be decreased when combined with Adagrasib.
Acetohexamide	The metabolism of Acetohexamide can be decreased when combined with Adagrasib.
Acetylsalicylic acid	The metabolism of Acetylsalicylic acid can be decreased when combined with Adagrasib.
Afatinib	The serum concentration of Afatinib can be increased when it is combined with Adagrasib.

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Food Interactions

• Take with or without food. High-fat and high-calorie meals do not have a clinically significant effect on adagrasib pharmacokinetics.

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International/Other Brands

Krazati (Mirati Therapeutics)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Krazati	Tablet, coated	200 mg/1	Oral	Mirati Therapeutics, Inc	2022-12-12	Not applicable

Categories

ATC Codes

L01XX77 — Adagrasib

• L01XX — Other antineoplastic agents
• L01X — OTHER ANTINEOPLASTIC AGENTS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Antineoplastic Agents
• Antineoplastic Agents, Immunological
• Antineoplastic and Immunomodulating Agents
• Cytochrome P-450 CYP1A2 Substrates
• Cytochrome P-450 CYP2B6 Substrates
• Cytochrome P-450 CYP2C8 Substrates
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP2D6 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Immune Checkpoint Inhibitors
• Nitriles
• P-glycoprotein inhibitors
• QTc Prolonging Agents
• RAS GTPase Inhibitors

Classification

Not classified

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

8EOO6HQF8Y

CAS number

2326521-71-3

InChI Key

PEMUGDMSUDYLHU-ZEQRLZLVSA-N

InChI

InChI=1S/C32H35ClFN7O2/c1-21(34)31(42)41-17-16-40(18-23(41)11-13-35)30-25-12-15-39(28-10-4-7-22-6-3-9-26(33)29(22)28)19-27(25)36-32(37-30)43-20-24-8-5-14-38(24)2/h3-4,6-7,9-10,23-24H,1,5,8,11-12,14-20H2,2H3/t23-,24-/m0/s1

IUPAC Name

2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

SMILES

[H][C@@]1(COC2=NC3=C(CCN(C3)C3=CC=CC4=C3C(Cl)=CC=C4)C(=N2)N2CCN(C(=O)C(F)=C)[C@@]([H])(CC#N)C2)CCCN1C

References

Synthesis Reference

Fell, Jay B et al. “Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer.” Journal of medicinal chemistry vol. 63,13 (2020): 6679-6693. doi:10.1021/acs.jmedchem.9b02052

General References

1. Christensen JG, Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, Sudhakar N, Bowcut V, Baer BR, Ballard JA, Burkard MR, Fell JB, Fischer JP, Vigers GP, Xue JY, Gatto S, Fernandez-Banet J, Pavlicek A, Velastegui K, Chao RC, Barton J, Pierobon M, Baldelli E, Patricoin EF, Cassidy DP, Marx MA, Rybkin II, Johnson ML, Ou SI, Lito P, Papadopoulos KP, Janne PA, Olson P: The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients. Cancer Discov. 2019 Oct 28. pii: 2159-8290.CD-19-1167. doi: 10.1158/2159-8290.CD-19-1167. [Article]
2. Ou SI, Janne PA, Leal TA, Rybkin II, Sabari JK, Barve MA, Bazhenova L, Johnson ML, Velastegui KL, Cilliers C, Christensen JG, Yan X, Chao RC, Papadopoulos KP: First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRAS(G12C) Solid Tumors (KRYSTAL-1). J Clin Oncol. 2022 Aug 10;40(23):2530-2538. doi: 10.1200/JCO.21.02752. Epub 2022 Feb 15. [Article]
3. Janne PA, Riely GJ, Gadgeel SM, Heist RS, Ou SI, Pacheco JM, Johnson ML, Sabari JK, Leventakos K, Yau E, Bazhenova L, Negrao MV, Pennell NA, Zhang J, Anderes K, Der-Torossian H, Kheoh T, Velastegui K, Yan X, Christensen JG, Chao RC, Spira AI: Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRAS(G12C) Mutation. N Engl J Med. 2022 Jul 14;387(2):120-131. doi: 10.1056/NEJMoa2204619. Epub 2022 Jun 3. [Article]
4. Romero D: Two new agents target KRAS G12C. Nat Rev Clin Oncol. 2020 Jan;17(1):6. doi: 10.1038/s41571-019-0304-3. [Article]
5. Brazel D, Arter Z, Nagasaka M: A Long Overdue Targeted Treatment for KRAS Mutations in NSCLC: Spotlight on Adagrasib. Lung Cancer (Auckl). 2022 Nov 10;13:75-80. doi: 10.2147/LCTT.S383662. eCollection 2022. [Article]
6. Tian H, Yang Z, He J: Adagrasib: A landmark in the KRAS(G12C)-mutated NSCLC. MedComm (2020). 2022 Nov 25;3(4):e190. doi: 10.1002/mco2.190. eCollection 2022 Dec. [Article]
7. Cancer Network: New Drug Application for Adagrasib Accepted by FDA for KRAS G12C+ NSCLC [Link]
8. FDA Approved Drug Products: KRAZATI (adagrasib) tablets for oral use [Link]
9. PR NewsWire: Mirati Therapeutics Announces U.S. FDA Accelerated Approval of KRAZATI (adagrasib) as a Targeted Treatment Option for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) with a KRASG12C Mutation [Link]

External Links

ChemSpider

81409342

BindingDB

50539763

RxNav

2625882

ChEMBL

CHEMBL4594350

Wikipedia

Adagrasib

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Recruiting	Treatment	Advanced Colorectal Cancer / Metastatic Colorectal Cancer (CRC)	1
3	Recruiting	Treatment	Advanced Non-Small Cell Lung Cancer (NSCLC) / Metastatic Non-Small Cell Lung Cancer	1
2	Recruiting	Treatment	Advanced Malignant Neoplasm / Malignant Neoplasm of Lung / Metastatic Cancer	1
2	Recruiting	Treatment	Advanced Non-Small Cell Lung Cancer (NSCLC) / Metastatic Lung Cancer	1
2	Recruiting	Treatment	Brain Metastases / CDK Gene Mutation / KRAS G12C Mutation / Metastatic Malignant Solid Neoplasms / NTRK Family Gene Mutation / PI3K Gene Mutation / ROS1 Gene Mutation	1
2	Recruiting	Treatment	KRAS P.G12C / Stage IV Non-small Cell Lung Cancer (NSCLC)	1
2	Recruiting	Treatment	Resectable Non-small Cell Lung Cancer	1
2, 3	Active Not Recruiting	Treatment	Advanced Non-Small Cell Lung Cancer (NSCLC) / Metastatic Non-Small Cell Lung Cancer	1
1	Active Not Recruiting	Treatment	Advanced or Metastatic Solid Tumor	1
1	Active Not Recruiting	Treatment	Advanced Solid Tumors	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, coated	Oral	200 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US10689377	No	2020-06-23	2037-05-17

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	From > 262 mg/mL to < 0.010 mg/mL	FDA label

Predicted Properties

Property	Value	Source
Water Solubility	0.0115 mg/mL	ALOGPS
logP	5.16	ALOGPS
logP	4.9	Chemaxon
logS	-4.7	ALOGPS
pKa (Strongest Basic)	8.46	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	8	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	88.83 Å2	Chemaxon
Rotatable Bond Count	7	Chemaxon
Refractivity	166.79 m3·mol-1	Chemaxon
Polarizability	62.27 Å3	Chemaxon
Number of Rings	6	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Targets

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Details1. GTPase KRas

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

Curator comments

Adagrasib binds to G12C-mutated KRAS, not its wild-type form.

General Function

Protein complex binding

Specific Function

Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Plays an important role in the regulation of cell proliferation (PubMed:23698361, PubMed:22711838).

Gene Name

KRAS

Uniprot ID

P01116

Uniprot Name

GTPase KRas

Molecular Weight

21655.67 Da

References

1. Christensen JG, Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, Sudhakar N, Bowcut V, Baer BR, Ballard JA, Burkard MR, Fell JB, Fischer JP, Vigers GP, Xue JY, Gatto S, Fernandez-Banet J, Pavlicek A, Velastegui K, Chao RC, Barton J, Pierobon M, Baldelli E, Patricoin EF, Cassidy DP, Marx MA, Rybkin II, Johnson ML, Ou SI, Lito P, Papadopoulos KP, Janne PA, Olson P: The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients. Cancer Discov. 2019 Oct 28. pii: 2159-8290.CD-19-1167. doi: 10.1158/2159-8290.CD-19-1167. [Article]
2. FDA Approved Drug Products: KRAZATI (adagrasib) tablets for oral use [Link]

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Drug created at November 01, 2019 18:31 / Updated at February 15, 2023 07:39