2025 / 06

Next Paper
DOI: 10.24075/brsmu.2025.065
Copyright: © 2025 by the authors. Licensee: Pirogov University.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (CC BY).

ORIGINAL RESEARCH

Results of a Phase IIa clinical trial of a RAS-GTPase inhibitor (Ing-Ras) for the treatment of gastrointestinal tumors

Kulinich TM , Kukoleva EA , Goncharov SV , Kudinova EA , Puchkov IA , Goncharova OI , Kaminsky VV , Bozhenko VK
About authors

Russian Scientific Center for Roentgenoradiology, Moscow, Russia

Correspondence should be addressed: Ilya A. Puchkov
Profsoyuznaya, 86, 117997, Moscow, Russia; ur.liam@vokhctuop

About paper

Funding: the study was conducted with financial support from the Ministry of Health of the Russian Federation, the State Task project EGISU No. 1023021500033- 4-3.2.21;3.1.5.

Author contribution: Kulinich TM — research concept and design, material collection and processing, data analysis, manuscript writing; Kukoleva EA — formation of patient groups, a set of clinical material, analysis of results, manuscript writing; Goncharov SV — design of the experimental part of the study, formation of patient groups, a set of clinical material, analysis of results; Kudinova EA, Goncharova OI — analysis of the clinical and experimental research results, manuscript writing and editing; Puchkov IA, Kaminsky VV — formation of patient groups, analysis of results, manuscript writing and editing; Bozhenko VK — research concept and design, manuscript editing and approval.

Compliance with ethical standards: the study was approved by the Ethics Committee of the Russian Scientific Center of Roentgenoradiology (protocol No. 4 dated 28 April 2023). The 2022-1-“Инг-Рас” trial was approved by the Ministry of Health of the Russian Federation (approval No. 177 for the clinical trial dated 30.03.2023). It was conducted in accordance with the ethical principles set out in the World Medical Association Declaration of Helsinki.

Received: 2025-10-23 Accepted: 2025-11-21 Published online: 2025-12-09
|
  1. Coccolini F, Gheza F, Lotti M, Virzì S, Iusco D, Ghermandi C, Melotti R, Baiocchi G, Giulini SM, Ansaloni L, Catena F. Peritoneal carcinomatosis. World J Gastroenterol. 2013; 19 (41): 6979–94. DOI: 10.3748/wjg.v19.i41.6979.
  2. Solass W, Kerb R, Mürdter T, Giger-Pabst U, Strumberg D, Tempfer C, et al. Intraperitoneal chemotherapy of peritoneal carcinomatosis using pressurized aerosol as an alternative to liquid solution: first evidence for efficacy. Ann Surg Oncol. 2014; 21 (2): 553–9. DOI: 10.1245/s10434-013-3213-1.
  3. Wu X, Song W, Cheng C, Liu Z, Li X, Cui Y, et al. Small molecular inhibitors for KRAS-mutant cancers. Front Immunol. 2023; 14: 1223433. DOI: 10.3389/fimmu.2023.1223433. Available from: https://www.frontiersin.org/journals/immunology/ articles/10.3389/fimmu.2023.1223433/full. English.
  4. Wu L, Rao W, Guo L, Zhang F, Li W, Ying J. Pan-cancer analysis to character the clinicopathological and genomic features of KRAS-mutated patients in China. J Cancer Res Clin Oncol. 2025; 151 (2): 94. DOI: 10.1007/s00432-025-06118-9.
  5. Wiechmann S, Maisonneuve P, Grebbin BM, Hoffmeister M, Kaulich M, Clevers H, et al. Conformation-specific inhibitors of activated Ras GTPases reveal limited Ras dependency of patient-derived cancer organoids. J Biol Chem. 2020; 295 (14): 4526–40. DOI: 10.1074/jbc.RA119.011025.
  6. Bozhenko VK, Goncharov SV, Kudinova EA, Kulinich TM, Kukoleva EA, Filippov MS, i dr. Ocenka bezopasnosti s ustanovleniem maksimal'no perenosimoj dozy ingibitora RAS-GTFazy («Ing- Ras») dlya lecheniya opuholej zheludochno-kishchechnogo trakta: predvaritel'nye rezul'taty issledovaniya I fazy. Al'manah klinicheskoj mediciny. 2023; 51 (7): 376–96. DOI: 10.18786/2072-0505-2023-51-045. Russian.
  7. Kulinich TM, SHishkin AM, Ivanov AV, Kaminskij VV, Bozhenko VK. Izuchenie protivoopuholevyh svojstv peptidnoj konstrukcii, vklyuchayushchej internalizuemuyu posledovatel'nost' i ingibitor RAS-GTfazy, v otnoshenii kletok linij raka tolstoj kishki (NT29) i raka yaichnika (OAW-42, OVCAR-3). Vestnik Rossijskogo nauchnogo centra rentgenoradiologii Minzdrava Rossii. 2021; 4 (21). Dostupno po ssylke: https://vestnik.rncrr.ru/vestnik/v21/ docs/kulinich_t4.pdf. Russian.
  8. Yaeger R, Weiss J, Pelster MS, Spira AI, Barve M, Ou SHI, et al. Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. N Engl J Med. 2023; 388 (1): 44–54. DOI: 10.1056/NEJMoa2212419.
  9. Mironov AN, redaktor. Rukovodstvo po provedeniyu klinicheskih issledovanij lekarstvennyh sredstv. M.: Grif i K; 2012. 944 s. Russian.
  10. Goncharov SV, Bozhenko VK, Zaharenko MV, Kiseleva YaYu, Chaptykov AA, Kulinich TM, i dr. Analiz molekulyarnyh fenotipov embrional'no-anatomicheskih otdelov tolstoj kishki v normal'noj slizistoj obolochke i pri kolorektal'nom rake. Al'manah klinicheskoj mediciny. 2023; 51 (8): 441–55. DOI: 10.18786/2072-0505-2023-51-046. Russian.
  11. Farias ST, Weakley A, Harvey D, Chandler J, Huss O, Mungas D. The Measurement of Everyday Cognition (ECog): Revisions and Updates. Alzheimer Dis Assoc Disord. 2021; 35 (3): 258–64. DOI: 10.1097/WAD.0000000000000450.
  12. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45 (2): 228–47. DOI: 10.1016/j.ejca.2008.10.026.
  13. Rubcova NA, Levshakova AV, Peshkov AO, Homyakov VM, Utkina AB, Sidorov DV, i dr. Komp'yuternaya i magnitno-rezonansnaya tomografiya v diagnostike peritoneal'nogo karcinomatoza». Luchevaya diagnostika i terapiya. 2019; 2 (10): 32–41. DOI: 10.22328/2079-5343-2019-10-2-32-41. Russian.
  14. Kaprin AD, Starinskij VV, SHahzadova AO, redaktory. Sostoyanie onkologicheskoj pomoshchi naseleniyu v 2023 godu. M.: MNIOI im. P.A. Gercena, 2024; 262 s. Russian.
  15. O'Neil BH, Wallmark JM, Lorente D, Elez E, Raimbourg J, Gomez-Roca C, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma. PLoS One. 2017; 12 (12): e0189848. DOI: 10.1371/journal.pone.0189848. Available from: https://journals. plos.org/plosone/article?id=10.1371/journal.pone.0189848. English.
  16. Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021; 398 (10294): 27–40. DOI: 10.1016/S0140-6736(21)00797-2.
  17. Sánchez-Hidalgo JM, Rodríguez-Ortiz L, Arjona-Sánchez Á, Rufián-Peña S, Casado-Adam Á, Cosano-Álvarez A, et al. Colorectal peritoneal metastases: Optimal management review. World J Gastroenterol. 2019; 25 (27): 3484–502. DOI: 10.3748/wjg.v25.i27.3484.
  18. Nors J, Iversen LH, Erichsen R, Gotschalck KA, Andersen CL. Incidence of Recurrence and Time to Recurrence in Stage I to III Colorectal Cancer: A Nationwide Danish Cohort Study. JAMA Oncol. 2024; 10 (1): 54–62. DOI: 10.1001/jamaoncol.2023.5098.
  19. Balboa-Barreiro V, Pértega-Díaz S, García-Rodríguez T, González-Martín C, Pardeiro-Pértega R, Yáñez-González- Dopeso L, Seoane-Pillado T. Colorectal cancer recurrence and its impact on survival after curative surgery: An analysis based on multistate models. Dig Liver Dis. 2024; 56 (7): 1229–36. DOI: 10.1016/j.dld.2023.11.041.
  20. Zhang ZT, Xiao WW, Li LR, Wu XJ, Wang QX, Chang H, et al. Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy for initially unresectable locally advanced colon cancer: short-term outcomes of an open-label, single-centre, randomised, controlled, phase 3 trial. EClinicalMedicine. 2024; 76: 102836. DOI: 10.1016/j.eclinm.2024.102836. Available from: https://www. clinicaloncologyonline.net/article/S0936-6555(24)00488-6/fulltext.
  21. Joshi SS, Maron SB, Catenacci DV. Pembrolizumab for treatment of advanced gastric and gastroesophageal junction adenocarcinoma. Future Oncol. 2018; 14 (5): 417–30. DOI: 10.2217/fon-2017-0436.
  22. Fedyanin MYu, Polyanskaya EM, Elsnukaeva HM, Tryakin AA, Pokataev IA, Bulanov AA, i dr. Metaanaliz issledovanij po sravneniyu effektivnosti rezhimov FOLFOXIRI i FOLFOX ili FOLFIRI s targetnoj terapiej pri metastaticheskom rake tolstoj kishki s mutaciej v gene BRAF. Medicinskij Sovet. 2020; (20): 125–32. DOI: 10.21518/2079-701X-2020-20-125-132. Russian.
  23. Ogorodnikova SYu, Konstantinova ED. Metody vizualizacii dannyh v mediko-biologicheskih issledovaniyah. Traektoriya issledovanij — chelovek, priroda, tekhnologii. 2022; 3 (3): 4–18. Dostupno po ssylke: https://restrajectory.ru/3-2.pdf. Russian.
  24. Mahran R, Kapp JN, Valtonen S, Champagne A, Ning J, Gillette W, et al. Beyond KRAS(G12C): Biochemical and Computational Characterization of Sotorasib and Adagrasib Binding Specificity and the Critical Role of H95 and Y96. ACS Chem Biol. 2024; 19 (10): 2152–64. DOI: 10.1021/acschembio.4c00315.
  25. Miyashita H, Kato S, Hong DS. KRAS G12C inhibitor combination therapies: current evidence and challenge. Front Oncol. 2024: 14: 1380584. DOI: 10.3389/fonc.2024.1380584. Available from: https://www.frontiersin.org/journals/oncology/articles/10.3389/ fonc.2024.1380584/full.
  26. Prajapati V, Singh AK, Kumar A, Singh H, Pathak P, Grishina M, et al. Structural insights, regulation, and recent advances of RAS inhibitors in the MAPK signaling cascade: a medicinal chemistry perspective. RSC Med Chem. 2025; 5 (16): 1923–40. DOI: 10.1039/d4md00923a. Available from: https://pubs.rsc.org/en/ content/articlelanding/2025/md/d4md00923a.
  27. Haddad SF, Bouferraa Y, Nair KG. Adagrasib in the treatment of colorectal cancer. Future Oncol. 2025; 21 (18): 2275–85. DOI: 10.1080/14796694.2025.2524311. Epub 2025 Jul 6. PMID: 40619745; PMCID: PMC12323406.
  28. Ding Y, Su H, Shu Y, Chen J. Post-marketing safety concerns of sotorasib: A disproportionality analysis based on FDA adverse event reporting system. Heliyon. 2024; 10 (9): e30437. DOI: 10.1016/j.heliyon.2024.e30437. Availablefrom: https://www.sciencedirect. com/science/article/pii/S2405844024064685?via%3Dihub.
  29. Luo J, Florez N, Donnelly A, Lou Y, Lu K, Ma PC, et al. Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRAS-G12C-Mutated Non-Small Cell Lung Cancer: A Case Series and Literature Review. JCO Precis Oncol. 2024; 8: e2300644. DOI: 10.1200/PO.23.00644. Available from: https:// ascopubs.org/doi/pdf/10.1200/PO.23.00644.
  30. Zhang J, Johnson M, Barve M, Bazhenova L, McCarthy M, Schwartz R, et al. Practical Guidance for the Management of Adverse Events in Patients with KRASG12C-Mutated Non-Small Cell Lung Cancer Receiving Adagrasib. Oncologist. 2023; 28 (4): 287–96. DOI: 10.1093/oncolo/oyad051.
  31. Jänne PA, Riely GJ, Gadgeel SM, Heist RS, Ou SHI, Pacheco JM, et al. Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation. N Engl J Med. 2022; 387 (2): 120–31. DOI: 10.1056/NEJMoa2204619.
  32. Kulinich TM, Shishkin AM, Ivanov AV, Kaminskij VV, Puchkov IA, Bozhenko VK. Razrabotka innovacionnyh protivoopuholevyh preparatov na osnove targetnyh peptidnyh konstrukcij. Vestnik Rossijskogo nauchnogo centra rentgenoradiologii Minzdrava Rossii 2024; (2): 59–68. Dostupno po ssylke: https://vestnik.rncrr. ru/vypusk/vypusk-ub100/?ELEMENT_ID=172. Russian.
  33. Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, et al. Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N Engl J Med. 2021; 384 (25): 2371–81. DOI: 10.1056/NEJMoa2103695.
  34. Parums DV. Editorial: Recent Approval of Sotorasib as the First Targeted Therapy for KRAS G12C-Mutated Advanced Non- Small Cell Lung Cancer (NSCLC). Med Sci Monit. 2022; 28: e938746. DOI: 10.12659/MSM.938746. Available from: https:// medscimonit.com/abstract/full/idArt/938746.
  35. Xia W, Geng Y, Hu W. Peritoneal Metastasis: A Dilemma and Challenge in the Treatment of Metastatic Colorectal Cancer. Cancers (Basel). 2023; 15 (23): 5641. DOI: 10.3390/cancers15235641.