Study of the mass balance, biotransformation, and safety of [¹⁴C]IBI351 in healthy Chinese subjects

Abstract

IBI351, a synthetic compound, exerts its anti-tumor effects by specifically, covalently, and irreversibly modifying the 12th cysteine residue of KRAS G12C. However, the pharmacokinetic profile of IBI351 in humans has not yet been reported. The current study aimed to investigate the pharmacokinetics and safety of IBI351 in healthy Chinese male subjects. A single oral dose of 600 mg combined with 150 μCi [¹⁴C]IBI351 was administered to six healthy male volunteers. Blood, urine, and fecal samples were collected at multiple time points to quantify the parent drug and its metabolites. IBI351 showed favorable pharmacokinetic characteristics and was well tolerated by all participants. Seventeen major metabolites were identified in plasma, urine, and feces. The main metabolic pathways included oxidation, hydrogenation, sulfonate conjugation, glucuronide conjugation, and cysteine conjugation. Excretion of IBI351 and its metabolites occurred mainly through feces. Collectively, this first-in-human study provides essential data on the metabolism and safety of IBI351 in Chinese subjects and lays the foundation for its further clinical development as a novel anti-tumor drug.

Keywords

KRAS G12C inhibitor / IBI351 / pharmacokinetics / metabolism / mass balance / radiolabel study

Fundings

The current study was supported by funding from the 13th Five-Year Plan New Drug Creation Program —Isotope Tracer Technology Platform for Clinical Evaluation of Innovative Drugs (Grant No. 2017ZX09304032 with project leaders Jun Zhao and Chen Zhou).

Acknowledgments

None.

References

[1] Lu X, Jin J, Wu Y, et al. Progress in RAS-targeted therapeutic strategies: From small molecule inhibitors to proteolysis targeting chimeras[J]. Med Res Rev, 2024, 44(2): 812-832. doi: 10.1002/med.21993

[2] Moore AR, Rosenberg SC, McCormick F, et al. RAS-targeted therapies: Is the undruggable drugged?[J]. Nat Rev Drug Discov, 2020, 19(8): 533-552. doi: 10.1038/s41573-020-0068-6

[3] Downward J. Targeting RAS signalling pathways in cancer therapy[J]. Nat Rev Cancer, 2003, 3(1): 11-22. doi: 10.1038/nrc969

[4] Waters AM, Der CJ. KRAS: The critical driver and therapeutic target for pancreatic cancer[J]. Cold Spring Harb Perspect Med, 2018, 8(9): a031435. doi: 10.1101/cshperspect.a031435

[5] Chhichholiya Y, Singh HV, Vashistha R, et al. Deciphering the role of KRAS gene in oncogenesis: Focus on signaling pathways, genetic alterations in 3′ UTR, KRAS specific miRNAs and therapeutic interventions[J]. Crit Rev Oncol/Hematol, 2024, 194: 104250. doi: 10.1016/j.critrevonc.2023.104250

[6] Kim D, Xue JY, Lito P. Targeting KRAS(G12C): From inhibitory mechanism to modulation of antitumor effects in patients[J]. Cell, 2020, 183(4): 850-859. doi: 10.1016/j.cell.2020.09.044

[7] Liu SY, Sun H, Zhou JY, et al. Clinical characteristics and prognostic value of the KRAS G12C mutation in Chinese non-small cell lung cancer patients[J]. Biomark Res, 2020, 8: 22. doi: 10.1186/s40364-020-00199-z

[8] Dias Carvalho P, Guimarães CF, Cardoso AP, et al. KRAS oncogenic signaling extends beyond cancer cells to orchestrate the microenvironment[J]. Cancer Res, 2018, 78(1): 7-14. doi: 10.1158/0008-5472.CAN-17-2084

[9] Huang L, Guo Z, Wang F, et al. KRAS mutation: From undruggable to druggable in cancer[J]. Signal Transduct Target Ther, 2021, 6(1): 386. doi: 10.1038/s41392-021-00780-4

[10] Ostrem JM, Peters U, Sos ML, et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions[J]. Nature, 2013, 503(7477): 548-551. doi: 10.1038/nature12796

[11] Dhillon S. Adagrasib: First approval[J]. Drugs, 2023, 83(3): 275-285. doi: 10.1007/s40265-023-01839-y

[12] Nakajima EC, Drezner N, Li X, et al. FDA approval summary: Sotorasib for KRAS G12C-mutated metastatic NSCLC[J]. Clin Cancer Res, 2022, 28(8): 1482-1486. doi: 10.1158/1078-0432.CCR-21-3074

[13] Desai J, Alonso G, Kim SH, et al. Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: A phase 1b trial[J]. Nat Med, 2024, 30(1): 271-278. doi: 10.1038/s41591-023-02696-8

[14] Ma X, Sloman DL, Duggal R, et al. Discovery of MK-1084: An orally bioavailable and low-dose KRAS^G12C inhibitor[J]. J Med Chem, 2024, 67(13): 11024-11052. doi: 10.1021/acs.jmedchem.4c00572

[15] Sacher A, LoRusso P, Patel MR, et al. Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation[J]. N Engl J Med, 2023, 389(8): 710-721. doi: 10.1056/NEJMoa2303810

[16] Zhou Q, Meng X, Sun L, et al. Efficacy and safety of KRAS G12C inhibitor IBI351 monotherapy in patients with advanced NSCLC: Results from a phase 2 pivotal study[J]. J Thorac Oncol, 2024, 19(12): 1630-1639.

[17] Dickinson PA, Cantarini MV, Collier J, et al. Metabolic disposition of osimertinib in rats, dogs, and humans: Insights into a drug designed to bind covalently to a cysteine residue of epidermal growth factor receptor[J]. Drug Metab Dispos, 2016, 44(8): 1201-1212. doi: 10.1124/dmd.115.069203

[18] Vuu I, Dahal UP, Wang Z, et al. Absorption, metabolism and excretion of [¹⁴C]-sotorasib in healthy male subjects: Characterization of metabolites and a minor albumin-sotorasib conjugate[J]. Cancer Chemother Pharmacol, 2022, 90(4): 357-367. doi: 10.1007/s00280-022-04470-y

[19] Blair HA. Sotorasib: First approval[J]. Drugs, 2021, 81(13): 1573-1579. doi: 10.1007/s40265-021-01574-2