Sotorasib

Last updated

Sotorasib
Sotorasib structure.svg
Clinical data
Pronunciation /ˌsoʊtəˈræsɪb/
SOH-tə-RAS-ib
Trade names Lumakras, Lumykras
Other namesAMG 510
AHFS/Drugs.com Monograph
MedlinePlus a621036
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class Antineoplastic agent
ATC code
Legal status
Legal status
Identifiers
  • 6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2- methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1H)-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
Formula C30H30F2N6O3
Molar mass 560.606 g·mol−1
3D model (JSmol)
  • CC(C)c1nccc(C)c1N2C(=O)N=C(N3CCN(C[C@@H]3C)C(=O)C=C)c4cc(F)c(nc24)c5c(O)cccc5F
  • InChI=1S/C30H30F2N6O3/c1-6-23(40)36-12-13-37(18(5)15-36)28-19-14-21(32)26(24-20(31)8-7-9-22(24)39)34-29(19)38(30(41)35-28)27-17(4)10-11-33-25(27)16(2)3/h6-11,14,16,18,39H,1,12-13,15H2,2-5H3/t18-/m0/s1
  • Key:NXQKSXLFSAEQCZ-SFHVURJKSA-N

Sotorasib, sold under the brand names Lumakras and Lumykras, is an anti-cancer medication used to treat non-small-cell lung cancer. [4] [5] It targets a specific mutation, G12C, in the protein K-Ras encoded by gene KRAS which is responsible for various forms of cancer. [7] [8] Sotorasib is an inhibitor of the RAS GTPase family. [4]

Contents

The most common side effects include diarrhea, musculoskeletal pain, nausea, fatigue, liver damage and cough. [4] [5] The most common adverse reactions for sotorasib used in combination with panitumumab include rash, dry skin, diarrhea, stomatitis, fatigue, and musculoskeletal pain. [4] [9]

Sotorasib is the first approved targeted therapy for people with tumors with any KRAS mutation, which accounts for approximately 25% of mutations in non-small cell lung cancers. [5] KRAS G12C mutations occur in about 13% of people with non-small cell lung cancers. [5] Sotorasib was approved for medical use in the United States in May 2021, [5] [10] and in the European Union in January 2022. [6] The US Food and Drug Administration considers it to be a first-in-class medication. [11]

Medical uses

In the US, sotorasib is indicated for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer, as determined by a Food and Drug Administration (FDA)-approved test, who have received at least one prior systemic therapy. [4] [5] It is also indicated, in combination with panitumumab, for the treatment of adults with KRAS G12C-mutated KRAS G12C-mutated metastatic colorectal cancer as determined by an FDA-approved test, who have received prior fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy. [4] [9]

In the EU, sotorasib, as monotherapy, is indicated for the treatment of adults with advanced non-small cell lung cancer (NSCLC) with KRAS G12C mutation and who have progressed after at least one prior line of systemic therapy. [6]

Chemistry and pharmacology

Sotorasib can exist in either of two atropisomeric forms, and one is more active than the other. [12] [ unreliable medical source? ] It selectively forms an irreversible covalent bond to the sulfur atom in the cysteine residue that is present in the mutated form of KRAS, but not in the normal form. [12] [ unreliable medical source? ]

History

Sotorasib is being developed by Amgen. [12] Phase I clinical trials were completed in 2020. [13] [14] [15] In December 2019, it was approved to begin phase II clinical trials. [16]

Researchers evaluated the efficacy of sotorasib in a study of 124 participants with locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer with disease progression after receiving an immune checkpoint inhibitor and/or platinum-based chemotherapy. [5] The major outcomes measured were objective response rate (proportion of participants whose tumor is destroyed or reduced) and duration of response. [5] The objective response rate was 36% and 58% of those participants had a duration of response of six months or longer. [5] Sotorasib was evaluated in one non-randomized, dose escalation and dose expansion clinical trial (CodeBreaK 100) in participants with non-small cell lung cancer. [17] There were 124 participants with non-small cell lung cancer included in the primary efficacy population, while 204 participants with non-small cell lung cancer were included in the primary safety population. [17] The primary endpoint of the trial was objective response rate. [17] Approximately 36% of participants (37 of 124 participants) treated with sotorasib in the clinical study CodeBreaK 100 had partial shrinkage of their cancer, including two participants with complete shrinkage. [17] Shrinkage lasted more than six months for 58% of participants who had a response to sotorasib. [17] The trial was conducted at 46 sites in 10 countries (Australia, Austria, Belgium, Canada, France, Germany, Japan, Korea, Switzerland, and the United States). [17]

The US Food and Drug Administration (FDA) granted the application for sotorasib orphan drug, fast track, priority review, and breakthrough therapy designations. [5] [11] The FDA granted approval of Lumakras to Amgen Inc. [5] Sotorasib was approved under the FDA's accelerated approval program. [17]

The efficacy of using sotorasib, in combination with panitumumab, was evaluated in CodeBreaK 300 (NCT05198934), a randomized, open-label, controlled trial in participants with KRAS G12C-mutated mutated metastatic colorectal cancer who previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. [9] Mutations were prospectively identified in tumor tissue samples using the QIAGEN therascreen KRAS RGQ PCR kit. [9] A total of 160 participants were randomized (1:1:1) to receive either sotorasib 960 mg orally once daily and panitumumab 6 mg/kg IV every two weeks, sotorasib 240 mg orally once daily and panitumumab 6 mg/kg IV every two weeks, or investigator's choice of standard of care trifluridine/tipiracil or regorafenib. [9]

Society and culture

Economics

At introduction, in the United States, sotorasib costs US$17,900 per month. [10]

In May 2021, sotorasib was approved under the US Food and Drug Administration (FDA) accelerated approval program. [5] In November 2021, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Lumykras, intended for the treatment of people with KRAS G12C mutation non-small cell lung cancer. [18] The applicant for this medicinal product is Amgen Europe B.V. [18] Sotorasib was approved for medical use in the European Union in January 2022. [6] [19]

In January 2025, the FDA approved sotorasib, in combination with panitumumab, for the treatment of adults with KRAS G12C-mutated metastatic colorectal cancer, as determined by an FDA-approved test, who have received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. [9]

Names

Sotorasib is the international nonproprietary name. [20]

Research

In a randomized phase III trial, sotorasib was compared with docetaxel in 345 patients with KRAS G12C-mutated non-small-cell lung cancer (NSCLC) previously treated with previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. The study showed an improvement in the progression-free survival for sotorasib (960 mg daily), compared with docetaxel (median progression-free survival 5.6 months vs 4.5 months; hazard ratio 0·66; p=0·0017). [21] The radiographic response rate for sotorasib was 28.1% compared with 13.2% response rate for docetaxel. Overall survival was not different between sotorasib and docetaxel. At a meeting of FDA Oncologic Drugs Advisory Committee, FDA staff made comments about design and conduct of the trial that raised concerns about the validity of the conclusions of this trial. [22]

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References

  1. 1 2 "Lumakras APMDS". Therapeutic Goods Administration (TGA). 13 April 2022. Archived from the original on 12 April 2022. Retrieved 23 April 2022.
  2. ↑ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 21 December 2022. Archived from the original on 3 April 2022. Retrieved 2 January 2023.
  3. ↑ "Summary Basis of Decision (SBD) for Lumakras". Health Canada. 23 October 2014. Archived from the original on 29 May 2022. Retrieved 29 May 2022.
  4. 1 2 3 4 5 6 7 "Lumakras- sotorasib tablet, coated". DailyMed. Archived from the original on 6 June 2021. Retrieved 6 June 2021.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 "FDA Approves First Targeted Therapy for Lung Cancer Mutation Previously Considered Resistant to Drug Therapy". U.S. Food and Drug Administration (FDA) (Press release). 28 May 2021. Archived from the original on 28 May 2021. Retrieved 28 May 2021.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  6. 1 2 3 4 "Lumykras EPAR". European Medicines Agency. 10 November 2021. Archived from the original on 23 April 2022. Retrieved 23 April 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. ↑ "KRAS mutant-targeting AMG 510". NCI Drug Dictionary. National Cancer Institute. 2 February 2011. Archived from the original on 10 July 2019. Retrieved 16 November 2019.
  8. ↑ Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. (November 2019). "The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity". Nature. 575 (7781): 217–223. Bibcode:2019Natur.575..217C. doi:10.1038/s41586-019-1694-1. PMID   31666701. S2CID   204969251.
  9. 1 2 3 4 5 6 "FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer". U.S. Food and Drug Administration (FDA). 15 January 2025. Retrieved 19 January 2025.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  10. 1 2 "FDA approves Amgen drug for lung cancer with specific mutation". CNBC. 28 May 2021. Archived from the original on 28 May 2021. Retrieved 28 May 2021.
  11. 1 2 Advancing Health Through Innovation: New Drug Therapy Approvals 2021 (PDF). U.S. Food and Drug Administration (FDA) (Report). 13 May 2022. Archived from the original on 6 December 2022. Retrieved 22 January 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  12. 1 2 3 Halford B (3 April 2019). "Amgen unveils its KRas inhibitor in human clinical trials: AMG 510 shuts down a mutant version of the cancer target via covalent interaction". Chemical & Engineering News . Vol. 97, no. 4. Archived from the original on 14 April 2019. Retrieved 16 November 2019.
  13. ↑ Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. (September 2020). "KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors". The New England Journal of Medicine. 383 (13): 1207–1217. doi:10.1056/NEJMoa1917239. PMC   7571518 . PMID   32955176.
  14. ↑ Clinical trial number NCT03600883 for "A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects With Solid Tumors With a Specific KRAS Mutation " at ClinicalTrials.gov
  15. ↑ "The Discovery Of Amgen's Novel Investigational KRAS(G12C) Inhibitor AMG 510 Published In Nature" (Press release). Amgen. 30 October 2019. Archived from the original on 16 November 2019. Retrieved 16 November 2019.
  16. ↑ Irving M (24 December 2019). "Drug targeting common cancer cause enters phase 2 clinical trials". New Atlas. Archived from the original on 24 December 2019. Retrieved 24 December 2019.
  17. 1 2 3 4 5 6 7 "Drug Trials Snapshot: Lumakras". U.S. Food and Drug Administration. 22 August 2023. Archived from the original on 8 September 2023. Retrieved 9 September 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  18. 1 2 "Lumykras: Pending EC decision". European Medicines Agency. 11 November 2021. Archived from the original on 13 November 2021. Retrieved 13 November 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  19. ↑ "Lumykras Product information". Union Register of medicinal products. Archived from the original on 4 March 2023. Retrieved 3 March 2023.
  20. ↑ World Health Organization (2021). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85" (PDF). WHO Drug Information. 35 (1). hdl: 10665/340684 . Archived (PDF) from the original on 19 April 2021. Retrieved 28 May 2021.
  21. ↑ de Langen AJ, Johnson ML, Mazieres J, Dingemans AC, Mountzios G, Pless M, et al. (March 2023). "Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial" (PDF). Lancet. 401 (10378): 733–746. doi:10.1016/S0140-6736(23)00221-0. PMID   36764316. S2CID   256631469.
  22. ↑ "ODAC vote on sotorasib signals FDA intent to confront perceived loss of equipoise in cancer clinical trials". The Cancer Letter. 6 October 2023.

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