Sotorasib

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]

Sotorasib
Clinical data
Pronunciation/ˌsoʊtəˈræsɪb/
SOH-tə-RAS-ib
Trade namesLumakras, Lumykras
Other namesAMG 510
AHFS/Drugs.comMonograph
MedlinePlusa621036
License data
Pregnancy
category
Routes of
administration		By mouth
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
Chemical and physical data
FormulaC30H30F2N6O3
Molar mass560.606 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

The most common side effects include diarrhea, musculoskeletal pain, nausea, fatigue, liver damage and cough.[4][5]

Sotorasib is the first approved targeted therapy for patients 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 patients with non-small cell lung cancers.[5] Sotorasib was approved for medical use in the United States in May 2021,[5][9] and in the European Union in January 2022.[6] The US Food and Drug Administration considers it to be a first-in-class medication.[10]

Medical uses

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-approved test, who have received at least one prior systemic therapy.[4][5]

Clinical development

Sotorasib is being developed by Amgen. Phase I clinical trials were completed in 2020.[11][12][13] In December 2019, it was approved to begin phase II clinical trials.[14]

Because the G12C KRAS mutation is relatively common in some cancer types, 14% of non-small-cell lung cancer adenocarcinoma patients and 5% of colorectal cancer patients,[15] and sotorasib is the first drug candidate to target this mutation, there have been high expectations for the drug.[15][16][17] The Food and Drug Administration has granted a fast track designation to sotorasib for the treatment of metastatic non-small-cell lung carcinoma with the G12C KRAS mutation.[18]

Chemistry and pharmacology

Sotorasib can exist in either of two atropisomeric forms, and one is more active than the other.[15] 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.[15]

History

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.[19] 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.[19] The primary endpoint of the trial was objective response rate.[19] 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.[19] Shrinkage lasted more than six months for 58% of participants who had a response to sotorasib.[19] The trial was conducted at 46 sites in 10 countries (Australia, Austria, Belgium, Canada, France, Germany, Japan, Korea, Switzerland, and the United States).[19]

The U.S. Food and Drug Administration (FDA) granted the application for sotorasib orphan drug, fast track, priority review, and breakthrough therapy designations.[5][10] The FDA granted approval of Lumakras to Amgen Inc.[5] Sotorasib was approved under the FDA's accelerated approval program.[19]

In a randomized phase 3 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).[20] 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.[21]

Society and culture

Economics

At introduction, in the United States, Sotorasib costs US$17,900 per month.[9]

On May 28, 2021, sotorasib was approved under the US FDA's accelerated approval program. 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.[22] The applicant for this medicinal product is Amgen Europe B.V.[22] Sotorasib was approved for medical use in the European Union in January 2022.[6][23]

Names

Sotorasib is the recommended international nonproprietary name.[24]

References
  1. "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. "Lumakras- sotorasib tablet, coated". DailyMed. Archived from the original on 6 June 2021. Retrieved 6 June 2021.
  5. "FDA Approves First Targeted Therapy for Lung Cancer Mutation Previously Considered Resistant to Drug Therapy". U.S. Food and Drug Administration (FDA). 28 May 2021. Archived from the original on 28 May 2021. Retrieved 28 May 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  6. "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.{{cite journal}}: CS1 maint: overridden setting (link)
  9. "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.
  10. 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. Public Domain This article incorporates text from this source, which is in the public domain.
  11. 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.{{cite journal}}: CS1 maint: overridden setting (link)
  12. 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
  13. "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.
  14. 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.
  15. 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. 97 (4). Archived from the original on 14 April 2019. Retrieved 16 November 2019.
  16. Al Idrus A (9 September 2019). "Amgen's KRAS drug continues to deliver but faces 'curse' of high expectations". fiercebiotech.com. Archived from the original on 25 September 2022. Retrieved 16 November 2019.
  17. Kaiser J (October 2019). "Two new drugs finally hit 'undruggable' cancer target, providing hope for treatments". Science. doi:10.1126/science.aba0472.
  18. Astor L (9 September 2019). "FDA Grants AMG 510 Fast Track Designation for KRAS G12C+ NSCLC". targetedonc.com. Archived from the original on 16 November 2019. Retrieved 16 November 2019.
  19. "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. Public Domain This article incorporates text from this source, which is in the public domain.
  20. 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". Lancet. 401 (10378): 733–746. doi:10.1016/S0140-6736(23)00221-0. PMID 36764316.{{cite journal}}: CS1 maint: overridden setting (link)
  21. "ODAC vote on sotorasib signals FDA intent to confront perceived loss of equipoise in cancer clinical trials". The Cancer Letter. 6 October 2023.
  22. "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.
  23. "Lumykras Product information". Union Register of medicinal products. Archived from the original on 4 March 2023. Retrieved 3 March 2023.
  24. World Health Organization (2021). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85" (PDF). WHO Drug Information. 35 (1). Archived (PDF) from the original on 19 April 2021. Retrieved 28 May 2021.

Further reading
  • "Sotorasib". NCI Drug Dictionary. National Cancer Institute.
  • "Sotorasib". National Cancer Institute. 21 June 2021.
  • 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 (CodeBreaK 100)" at ClinicalTrials.gov
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