OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Adagrasib – Krazati®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Adagrasib	2326521-71-3	C32-H35-Cl-F-N7-O2

ANNOTATED BIBLIOGRAPHY

References updated: 04 October 2023

Abbreviations: KRAS, Kirsten rat sarcoma viral oncogene homolog; NSCLC, non-small cell lung cancer.

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of small molecule enzyme and receptor inhibitors).
• DeLeve LD. Kinase inhibitors. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents, does not discuss adagrasib).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics).
• FDA. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2023/216340Orig1s000MultidisciplineR.pdf

  (FDA website with initial multidiscipline clinical review of the safety and efficacy of adagrasib; states that the overall objective response rate was 43% in adults with NCSLC with KRAS p.G12C mutations and in a pooled safety review [n=366] most patients had at least one adverse event and 48% had a serious adverse event, 32% of patients had an ALT elevation, 5% were above 5 times ULN, and 1 patient [0.3%] developed anicteric drug induced liver injury, with signs of hypersensitivity that resolved on stopping therapy; there were cases of acute liver injury with jaundice or liver failure attributed with adagrasib).
• Awad MM, Liu S, Rybkin II, Arbour KC, Dilly J, Zhu VW, Johnson ML, et al. Acquired resistance to KRASG12C inhibition in cancer. N Engl J Med. 2021;384:2382-2393. [PMC free article: PMC8864540] [PubMed: 34161704]

  (Among 38 patients being treated with adagrasib for advanced solid tumors harboring a KRAS G12C mutation who had an initial response to therapy but subsequent relapse or progression [“acquired resistance”], further mutations in KRAS DNA were found in DNA from tumor tissue and from circulating tumor DNA, mostly secondary mutations or amplifications in KRAS, but also in other genes in the signaling pathways or with histologic transformations).
• Jänne PA, Riely GJ, Gadgeel SM, Heist RS, Ou SI, Pacheco JM, Johnson ML, et al. Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation. N Engl J Med. 2022;387:120-131. [PubMed: 35658005]

  (Among 116 adult with NSCLC harboring a KRAS G12C mutation treated with adagrasib [600 mg twice daily for a median of 13 months], 43% had an objective response, while adverse events occurred in all treated subjects leading to dose interruption or modification in 83% and permanent discontinuation in 16%, and with ALT elevations in 28% which were above 5 times ULN in 5%).
• Ou SI, Jänne PA, Leal TA, Rybkin II, Sabari JK, Barve MA, Bazhenova L, et al. 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;40:2530-2538. [PMC free article: PMC9362872] [PubMed: 35167329]

  (Among 25 patients with advanced KRAS G12C mutant solid tumors treated with adagrasib [600 mg twice daily], the objective response rate was 53% in NSCLC, while the adverse event rate was 92% with nausea in 76%, diarrhea 70%, vomiting 48%, fatigue 40% and ALT elevations in 20% which were above 5 times ULN in 5%).
• Dhillon S. Adagrasib: first approval. Drugs. 2023;83:275-285. [PubMed: 36763320]

  (Review of the mechanism of action, history of development, pharmacodynamics, clinical efficacy, and safety of adagrasib shortly after its initial approval in the US mentions that it has “manageable tolerability” with an overall adverse event rate of 97% with any liver test abnormality in 37% [among 366 treated patients] and ALT elevations in 28%, which were above 5 times the ULN in 4.3% and had a median time to onset of 3 weeks).
• Adagrasib (Krazati) for NSCLC. Med Lett Drugs Ther. 2023;65:e17-e18. [PubMed: 36651795]

  (Concise review of the mechanism of action, clinical efficacy, safety and costs of adagrasib, mentions that its effects were modest and that hepatotoxicity arose in more than 25% of patients, and that patients should be monitored for liver enzyme and bilirubin levels before and monthly for 3 months during therapy).
• Chour A, Denis J, Mascaux C, Zysman M, Bigay-Game L, Swalduz A, Gounant V, et al. Brief report: severe sotorasib-related hepatotoxicity and non-liver adverse events associated with sequential anti-programmed cell death (ligand)1 and sotorasib therapy in KRASG12C-mutant lung cancer. J Thorac Oncol. 2023;18(10):1408-1415. [PubMed: 37217096]

  (Among 102 adults with refractory advanced NSCLC and KRAS G12C mutations treated with sotorasib in France outside of clinical trials, 48 who had received check point inhibitor therapy with anti-PD-L1 immediately before sotorasib had higher rates of severe adverse events [50% vs 13%] and higher rates of ALT elevations above 5 times ULN [33% vs 11%], although no fatal instances of hepatotoxicity occurred).
• Desai A, Rakshit S, Bansal R, Ashara Y, Potter A, Manochakian R, Lou Y, et al. Time from immune checkpoint inhibitor to sotorasib use correlates with risk of hepatotoxicity in non-small cell lung cancer: A brief report. Cancer Treat Res Commun. 2023;36:100743. [PubMed: 37531736]

  (Among 31 patients with advanced, refractory KRAS G12C-mutated NSCLC treated with sotorasib, 10 [32%] developed ALT elevations above 5 times ULN during therapy, all 10 had received previous check point inhibitor therapy [usually anti-PD-L1] and rates of ALT elevations were higher in those receiving checkpoint inhibitors within 30 days [3 of 4: 75%], than 30-90 days [7 of 11:65%], or greater than 90 days [none of 13: 0%], suggesting that sotorasib triggers a delayed immune mediated hepatotoxicity from anti-PD-L1 therapy if given within 3 months of stopping).
• Zhang J, Johnson M, Barve M, Bazhenova L, McCarthy M, Schwartz R, Horvath-Walsh E, Vet al. Practical guidance for the management of adverse events in patients with KRASG12C-mutated non-small cell lung cancer receiving adagrasib. Oncologist. 2023;28:287-296. [PMC free article: PMC10078892] [PubMed: 36892150]

  (Review of the adverse events identified in trials of adagrasib and recommendations regarding monitoring and management based upon FDA labeling, mentions that liver enzymes [ALT, AST, Alk P] should be monitored every month for 3 months and that corticosteroid treatment can be considered for “significant hepatotoxicity”).