Adagrasib

Adagrasib
Clinical data
Trade names	Krazati
Other names	MRTX-849
AHFS/Drugs.com	Monograph
MedlinePlus	a623003
License data	US DailyMed: Adagrasib;
Routes of; administration	By mouth
Drug class	Antineoplastic agent
ATC code	L01XX77 (WHO) ;
Legal status
Legal status	US: ℞-only; EU: Rx-only;
Identifiers
	IUPAC name {(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1methylpyrrolidin-2-yl]methoxy}-5,6,7,8tetrahydropyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop2-enoyl)piperazin-2-yl}acetonitrile;
CAS Number	2326521-71-3;
PubChem CID	138611145;
DrugBank	DB15568;
UNII	8EOO6HQF8Y;
KEGG	D12301;
CompTox Dashboard (EPA)	DTXSID801336759 ;
ECHA InfoCard	100.329.928
Chemical and physical data
Formula	C32H35ClFN7O2
Molar mass	604.13 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CN1CCC[C@H]1COC2=NC3=C(CCN(C3)C4=CC=CC5=C4C(=CC=C5)Cl)C(=N2)N6CCN([C@H](C6)CC#N)C(=O)C(=C)F;
	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; Key:PEMUGDMSUDYLHU-ZEQRLZLVSA-N;

Adagrasib, sold under the brand name Krazati, is an anticancer medication used to treat non-small cell lung cancer.^[1]^[2] Adagrasib is an inhibitor of G12C mutated KRAS GTPase.^[1] It is taken by mouth.^[1] It is being developed by Mirati Therapeutics.^[1]^[5]

The most common adverse reactions include diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation.^[2] The most common laboratory abnormalities include decreased lymphocytes, increased aspartate aminotransferase, decreased sodium, decreased hemoglobin, increased creatinine, decreased albumin, increased alanine aminotransferase, increased lipase, decreased platelets, decreased magnesium, and decreased potassium.^[2]

It was approved for medical use in the United States in December 2022 for lung cancer^[1]^[2]^[5]^[6] and together with Cetuximab in 2024 for colorectal cancer.^[7]^[8]

Medical uses

Adagrasib is indicated for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer, as determined by an FDA approved test, who have received at least one prior systemic therapy.^[1]^[2]^[9]

In June 2024, the US FDA granted accelerated approval to adagrasib plus cetuximab for adults with KRAS G12C-mutated locally advanced or metastatic colorectal cancer, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.^[10]

History

Approval by the US Food and Drug Administration (FDA) was based on KRYSTAL-1, a multicenter, single-arm, open-label clinical trial (NCT03785249) which included participants with locally advanced or metastatic non-small cell lung cancer with KRAS G12C mutations.^[2] Efficacy was evaluated in 112 participants whose disease has progressed on or after platinum-based chemotherapy and an immune checkpoint inhibitor, given either concurrently or sequentially.^[2]

The FDA granted the application for adagrasib fast-track, breakthrough therapy, and orphan drug designations.^[2]

Society and culture

Legal status

In November 2023, the Committee for Medicinal Products for Human Use of the European Medicines Agency, following a re-examination procedure, adopted a positive opinion recommending the granting of a conditional marketing authorization for the medicinal product Krazati, intended for the treatment of people with KRAS G12C mutation non-small cell lung cancer.^[11] The applicant for this medicinal product is Mirati Therapeutics B.V.^[11]

References

^ ^a ^b ^c ^d ^e ^f ^g "Krazati- adagrasib tablet, coated". DailyMed. U.S. National Library of Medicine. 10 December 2021. Archived from the original on 14 January 2023. Retrieved 21 January 2023.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ "FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC". U.S. Food and Drug Administration (FDA). 12 December 2022. Archived from the original on 14 December 2022. Retrieved 14 December 2022. This article incorporates text from this source, which is in the public domain.
^ "Krazati EPAR". European Medicines Agency. 5 January 2024. Archived from the original on 17 February 2024. Retrieved 18 March 2024.
^ "Krazati Product information". Union Register of medicinal products. 9 January 2024. Archived from the original on 28 April 2024. Retrieved 18 March 2024.
^ ^a ^b "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" (Press release). Mirati Therapeutics Inc. 12 December 2022. Archived from the original on 13 December 2022. Retrieved 13 December 2022 – via MultiVu.
^ "Drug Approval Package: Krazati". U.S. Food and Drug Administration (FDA). 11 January 2023. Retrieved 25 June 2024.
^ Center for Drug Evaluation and Research (21 June 2024). "FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer". FDA.
^ Grisham J (21 June 2024). "FDA Approves First Colorectal Cancer Treatment that Targets KRAS Gene | Memorial Sloan Kettering Cancer Center". www.mskcc.org. Retrieved 19 July 2024.
^ "Accelerated Approval: Krazati (adagrasib) oral tablets" (PDF). U.S. Food and Drug Administration. 12 December 2022. Archived (PDF) from the original on 13 December 2022. Retrieved 13 December 2022. This article incorporates text from this source, which is in the public domain.
^ "FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer". U.S. Food and Drug Administration (FDA). 21 June 2024. Archived from the original on 22 June 2024. Retrieved 25 June 2024. This article incorporates text from this source, which is in the public domain.
^ ^a ^b "Krazati: Pending EC decision". European Medicines Agency (EMA). 10 November 2023. Archived from the original on 13 November 2023. Retrieved 13 November 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

External links

Clinical trial number NCT03785249 for "Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1" at ClinicalTrials.gov