Sotorasib Explained

Pronounce:
Tradename:Lumakras, Lumykras
Dailymedid:Sotorasib
Pregnancy Au:B3
Pregnancy Au Comment:[1]
Routes Of Administration:By mouth
Atc Prefix:L01
Atc Suffix:XX73
Legal Au:S4
Legal Au Comment:[2]
Legal Ca:Rx-only
Legal Ca Comment:[3]
Legal Us:Rx-only
Legal Us Comment:[4]
Legal Eu:Rx-only
Index2 Label:non-specific
Cas Number:2296729-00-3
Cas Number2:2252403-56-6
Pubchem:137278711
Drugbank:DB15569
Chemspiderid:72380148
Unii:2B2VM6UC8G
Kegg:D12055
Chebi:178199
Synonyms:AMG 510
Iupac Name:6-Fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2''S'')-2- methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-''d'']pyrimidin-2(1H)-one
C:30
H:30
F:2
N:6
O:3
Smiles:CC(C)c1nccc(C)c1N2C(=O)N=C(N3CCN(C[C@@H]3C)C(=O)C=C)c4cc(F)c(nc24)c5c(O)cccc5F
Stdinchi: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
Stdinchikey: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. It targets a specific mutation, G12C, in the protein K-Ras encoded by gene KRAS which is responsible for various forms of cancer.[5] [6] Sotorasib is an inhibitor of the RAS GTPase family.

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

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. KRAS G12C mutations occur in about 13% of patients with non-small cell lung cancers. Sotorasib was approved for medical use in the United States in May 2021,[7] and in the European Union in January 2022. The US Food and Drug Administration considers it to be a first-in-class medication.[8]

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.

Clinical development

Sotorasib is being developed by Amgen. Phase I clinical trials were completed in 2020.[9] [10] In December 2019, it was approved to begin phase II clinical trials.[11]

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,[12] and sotorasib is the first drug candidate to target this mutation, there have been high expectations for the drug.[12] [13] [14] 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.[15]

Chemistry and pharmacology

Sotorasib can exist in either of two atropisomeric forms, and one is more active than the other.[12] 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]

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. The major outcomes measured were objective response rate (proportion of participants whose tumor is destroyed or reduced) and duration of response. The objective response rate was 36% and 58% of those participants had a duration of response of six months or longer. Sotorasib was evaluated in one non-randomized, dose escalation and dose expansion clinical trial (CodeBreaK 100) in participants with non-small cell lung cancer. 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. The primary endpoint of the trial was objective response rate. 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. Shrinkage lasted more than six months for 58% of participants who had a response to sotorasib. The trial was conducted at 46 sites in 10 countries (Australia, Austria, Belgium, Canada, France, Germany, Japan, Korea, Switzerland, and the United States).[16]

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

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).[17] 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.[18]

Society and culture

Economics

At introduction, in the United States, Sotorasib costs per month.[19]

Legal status

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. The applicant for this medicinal product is Amgen Europe B.V.[20] Sotorasib was approved for medical use in the European Union in January 2022.[21] [22]

Names

Sotorasib is the recommended international nonproprietary name.[23]

Further reading

External links

Notes and References

  1. Web site: Updates to the Prescribing Medicines in Pregnancy database . Therapeutic Goods Administration (TGA) . 21 December 2022 . 2 January 2023 . 3 April 2022 . https://web.archive.org/web/20220403064059/https://www.tga.gov.au/updates-prescribing-medicines-pregnancy-database . live .
  2. Web site: Lumakras APMDS . Therapeutic Goods Administration (TGA) . 13 April 2022 . 23 April 2022 . 12 April 2022 . https://web.archive.org/web/20220412232412/https://www.tga.gov.au/apm-summary/lumakras . live .
  3. Web site: Summary Basis of Decision (SBD) for Lumakras . Health Canada . 23 October 2014 . 29 May 2022 . 29 May 2022 . https://web.archive.org/web/20220529195142/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00562&lang=en . live .
  4. Web site: Lumakras- sotorasib tablet, coated . DailyMed . 6 June 2021 . 6 June 2021 . https://web.archive.org/web/20210606182800/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c80a362c-7ac3-4894-a076-0691e68ef8c1 . live .
  5. Web site: KRAS mutant-targeting AMG 510 . NCI Drug Dictionary . National Cancer Institute . 16 November 2019 . 2 February 2011 . 10 July 2019 . https://web.archive.org/web/20190710011837/https://www.cancer.gov/publications/dictionaries/cancer-drug/def/794411 . live .
  6. Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, Gaida K, Holt T, Knutson CG, Koppada N, Lanman BA, Werner J, Rapaport AS, San Miguel T, Ortiz R, Osgood T, Sun JR, Zhu X, McCarter JD, Volak LP, Houk BE, Fakih MG, O'Neil BH, Price TJ, Falchook GS, Desai J, Kuo J, Govindan R, Hong DS, Ouyang W, Henary H, Arvedson T, Cee VJ, Lipford JR . The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity . Nature . 575 . 7781 . 217–223 . November 2019 . 31666701 . 10.1038/s41586-019-1694-1 . 204969251 . 2019Natur.575..217C .
  7. Web site: 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 . 28 May 2021 . 28 May 2021 . https://web.archive.org/web/20210528171655/http://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug . live .
  8. Advancing Health Through Innovation: New Drug Therapy Approvals 2021 . U.S. Food and Drug Administration (FDA) . 13 May 2022 . PDF . 22 January 2023 . 6 December 2022 . https://web.archive.org/web/20221206210020/https://www.fda.gov/media/155227/download . live .
  9. Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, Falchook GS, Price TJ, Sacher A, Denlinger CS, Bang YJ, Dy GK, Krauss JC, Kuboki Y, Kuo JC, Coveler AL, Park K, Kim TW, Barlesi F, Munster PN, Ramalingam SS, Burns TF, Meric-Bernstam F, Henary H, Ngang J, Ngarmchamnanrith G, Kim J, Houk BE, Canon J, Lipford JR, Friberg G, Lito P, Govindan R, Li BT . KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors . The New England Journal of Medicine . 383 . 13 . 1207–1217 . September 2020 . 32955176 . 7571518 . 10.1056/NEJMoa1917239 .
  10. The Discovery Of Amgen's Novel Investigational KRAS(G12C) Inhibitor AMG 510 Published In Nature . 30 October 2019 . Amgen . 16 November 2019 . 16 November 2019 . https://web.archive.org/web/20191116160847/https://www.amgen.com/media/news-releases/2019/10/the-discovery-of-amgens-novel-investigational-krasg12c-inhibitor-amg-510-published-in-nature/ . live .
  11. Web site: Drug targeting common cancer cause enters phase 2 clinical trials . Irving M . 24 December 2019 . New Atlas . 24 December 2019 . 24 December 2019 . https://web.archive.org/web/20191224173651/https://newatlas.com/medical/common-cancer-cause-drug-phase2-clinical-trials/ . live .
  12. . Amgen unveils its KRas inhibitor in human clinical trials: AMG 510 shuts down a mutant version of the cancer target via covalent interaction . Halford B . 3 April 2019 . 97 . 4 . 16 November 2019 . 14 April 2019 . https://web.archive.org/web/20190414132414/https://cen.acs.org/pharmaceuticals/drug-discovery/Amgen-unveils-KRas-inhibitor-human/97/i14 . live .
  13. News: Amgen's KRAS drug continues to deliver but faces 'curse' of high expectations . Al Idrus A . 9 September 2019 . fiercebiotech.com . 16 November 2019 . 25 September 2022 . https://web.archive.org/web/20220925033552/https://www.fiercebiotech.com/biotech/amgen-s-kras-drug-continues-to-deliver-but-faces-curse-high-expectations . live .
  14. Two new drugs finally hit 'undruggable' cancer target, providing hope for treatments. Kaiser J . October 2019 . Science . 10.1126/science.aba0472 . doi . 209242110 .
  15. News: FDA Grants AMG 510 Fast Track Designation for KRAS G12C+ NSCLC . Astor L . 9 September 2019 . targetedonc.com . 16 November 2019 . 16 November 2019 . https://web.archive.org/web/20191116160848/https://www.targetedonc.com/news/fda-grants-amg-510-fast-track-designation-for-kras-g12c-nsclc . live .
  16. Web site: Drug Trials Snapshot: Lumakras . U.S. Food and Drug Administration . 22 August 2023 . 9 September 2023 . 8 September 2023 . https://web.archive.org/web/20230908044416/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshot-lumakras . live .
  17. de Langen AJ, Johnson ML, Mazieres J, Dingemans AC, Mountzios G, Pless M, Wolf J, Schuler M, Lena H, Skoulidis F, Yoneshima Y, Kim SW, Linardou H, Novello S, van der Wekken AJ, Chen Y, Peters S, Felip E, Solomon BJ, Ramalingam SS, Dooms C, Lindsay CR, Ferreira CG, Blais N, Obiozor CC, Wang Y, Mehta B, Varrieur T, Ngarmchamnanrith G, Stollenwerk B, Waterhouse D, Paz-Ares L . 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 . March 2023 . 36764316 . 10.1016/S0140-6736(23)00221-0 . 256631469 .
  18. News: ODAC vote on sotorasib signals FDA intent to confront perceived loss of equipoise in cancer clinical trials . The Cancer Letter . 6 October 2023.
  19. Web site: FDA approves Amgen drug for lung cancer with specific mutation . CNBC . 28 May 2021 . 28 May 2021 . 28 May 2021 . https://web.archive.org/web/20210528171607/https://www.cnbc.com/2021/05/28/fda-approves-amgen-drug-for-lung-cancer-with-specific-mutation-.html . live .
  20. Web site: Lumykras: Pending EC decision . European Medicines Agency . 11 November 2021 . 13 November 2021 . 13 November 2021 . https://web.archive.org/web/20211113051153/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/lumykras . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  21. Web site: Lumykras EPAR . European Medicines Agency . 10 November 2021 . 23 April 2022 . 23 April 2022 . https://web.archive.org/web/20220423222621/https://www.ema.europa.eu/en/medicines/human/EPAR/lumykras . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  22. Web site: Lumykras Product information . Union Register of medicinal products . 3 March 2023 . 4 March 2023 . https://web.archive.org/web/20230304093849/https://ec.europa.eu/health/documents/community-register/html/h1603.htm . live .
  23. ((World Health Organization)) . 2021 . International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85 . WHO Drug Information . 35 . 1 . 28 May 2021 . 19 April 2021 . https://web.archive.org/web/20210419172602/https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-%28inn%29/rl85.pdf . live .

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