Role of the MDM2-p53 Pathway in BTC

CME

Targeting the MDM2-p53 Pathway in Biliary Tract Cancer: Emerging Data and Implications for Future Clinical Practice

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit

Released: August 29, 2024

Expiration: February 28, 2025

Michael K. Gibson
Michael K. Gibson, MD, PhD, FACP
Patricia LoRusso
Patricia LoRusso, DO, PhD(h)
David N. Neubauer
David N. Neubauer, MD
Steven Christopher Smith
Steven Christopher Smith, MD, PhD
Chetasi Talati
Chetasi Talati, MD

Activity

Progress
1 2
Course Completed

References

  1. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17:557-588.
  2. Valle JW, Lamarca A, Goyal L, et al. New horizons for precision medicine in biliary tract cancers. Cancer Discov. 2017;7:943-962.
  3. American Cancer Society. Cancer Facts & Figures 2024. Atlanta, GA: American Cancer Society; 2024.
  4. Petrick JL, Yang B, Altekruse SF, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based study in SEER-Medicare. PLoS One. 2017;12(10).
  5. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: biliary tract cancers. v.3.2024. nccn.org. Accessed August 28, 2024.
  6. Berchuck JE, Facchinetti F, DiToro DF, et al. The clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer. Ann Oncol. 2022;33:1269-1283.
  7. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273-1281.
  8. Oh DY, Ruth He A, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. 2022;1:EVIDoa2200015.
  9. Durvalumab [prescribing information]. Wilmington, DE: AstraZeneca; 2022.
  10. Kelley RK, Ueno M, Yoo C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;401:1853-1865.
  11. Pembrolizumab [prescribing information]. Rahway, NJ: Merck, 2024.
  12. Pemigatinib [prescribing information]. Wilmington, DE: Incyte; 2023.
  13. Futibatinib [prescribing information]. Princeton, NJ: Taiho; 2024.
  14. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:796-807.
  15. Goyal L, Meric-Bernstam F, Hollebecque A, et al. Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma. N Engl J Med. 2023;388:228-239.
  16. Touat M, Ileana E, Postel-Vinay S, et al. Targeting FGFR signaling in cancer. Clin Cancer Res. 2015;21:2684-2694.
  17. Goyal L, Kongpetch S, Crolley VE, et al. Targeting FGFR inhibition in cholangiocarcinoma. Cancer Treat Rev. 2021;95:102170.
  18. Hollebecque A, Borad M, Goyal L, et al. Efficacy of RLY-4008, a highly selective FGFR2 inhibitor in patients with FGFR2-fusion or rearrangement, FGFR inhibitor-naive cholangiocarcinoma: ReFocus trial. Presented at: European Society for Medical Oncology Congress; September 9-13, 2022. Abstract LBA12.
  19. Dai S, Zhou Z, Chen Z, et al. Fibroblast growth factor receptors (FGFRs): structures and small molecule inhibitors. Cells. 2019;8:614.
  20. Javle MM, Mahipal A, Fonkoua L, et al. Efficacy and safety results of FGFR1-3 inhibitor, tinengotinib, as monotherapy in patients with advanced, metastatic cholangiocarcinoma: results from phase II clinical trial. J Clin Oncol. 2024;42(3_suppl):434.
  21. Heuser M, Araujo Cruz MM, Goparaju R, et al. Enigmas of IDH mutations in hematology/oncology. Exp Hematol. 2015;43:685-697.
  22. Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist. 2012;17:72-79.
  23. Zhu AX, Macarulla T, Javle MM, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: the phase 3 randomized clinical ClarIDHy trial. JAMA Oncol. 2021;7:1669-1677.
  24. Ivosidenib [prescribing information]. Boston, MA: Servier; 2023.
  25. Harding J, Ikeda M, Goyal L, et al. A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH1 and IDH2, as monotherapy and in combination with cisplatin and gemcitabine in advanced IDH-mutant cholangiocarcinoma. Presented at: World Congress on Gastrointestinal Cancers; June 28 - July 1, 2023. Abstract SO-1.
  26. Subbiah V, Lassen U, Élez E, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. 2020;21:1234-1243.
  27. Dabrafenib [prescribing information]. East Hanover, NJ: Novartis; 2024.
  28. Nakada T, Sugihara K, Jikoh T, et al. The latest research and development into the antibody-drug conjugate, [fam-] trastuzumab deruxtecan (DS-8201a), for HER2 cancer therapy. Chem Pharm Bull (Tokyo). 2019;67:173-185.
  29. Ogitani Y, Hagihara K, Oitate M, et al. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016;107:1039-1046.
  30. Ohba A, Morizane C, Kawamoto Y, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing unresectable or recurrent biliary tract cancer (BTC): An investigator-initiated multicenter phase 2 study (HERB trial). J Clin Oncol. 2022;40:4006-4006.
  31. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol. 2024;42:47-58.
  32. Trastuzumab deruxtecan [prescribing information]. Basking Ridge, NJ: Daiichi Sankyo; 2024.
  33. Weisser NE, Sanches M, Escobar-Cabrera E, et al. An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity. Nat Commun. 2023;14:1394.
  34. DiPeri TP, Evans KW, Wang B, et al. Co-clinical trial of novel bispecific anti-HER2 antibody zanidatamab in patient-derived xenografts. Cancer Discov. 2024;14:828-845.
  35. Harding JJ, Fan J, Oh DY, et al. Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol. 2023;24:772-782.
  36. Nakamura Y, Mizuno N, Sunakawa Y, et al. Tucatinib and trastuzumab for previously treated human epidermal growth factor receptor 2-positive metastatic biliary tract cancer (SGNTUC-019): a phase II basket study. J Clin Oncol. 2023;41:5569-5578.
  37. Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47:1003-1010.
  38. Pant S, Yaegar R, Spira Al, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced solid tumors harboring a KRASG12C mutation. J Clin Oncol. 2023;41:425082-425082.
  39. Bekaii-Saab TS, Yaeger R, Spira AI, et al. Adagrasib in advanced solid tumors harboring a KRASG12C mutation. J Clin Oncol. 2023;41:4097-4106.
  40. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21:671-684.
  41. Yamamoto N, Tolcher A, Hafez N, et al. Efficacy and safety of the MDM2-p53 antagonist brigimadlin (BI 907828) in patients with advanced biliary tract cancer: a case series. Onco Targets Ther. 2024;17:267-280.
  42. Kim SJ, Akita M, Sung YN, et al. MDM2 amplification in intrahepatic cholangiocarcinomas: its relationship with large-duct type morphology and uncommon KRAS mutations. Am J Surg Pathol. 2018;42:512-521.
  43. Kato S, Ross JS, Gay L, et al. Analysis of MDM2 amplification: next-generation sequencing of patients with diverse malignancies. JCO Precis Oncol. 2018;2018:PO.17.00235.
  44. Macarulla T, Yamamoto N, Tolcher A, et al. Efficacy and safety of brigimadlin (BI 907828), an MDM2–p53 antagonist, in patients (pts) with advanced biliary tract cancer: data from two phase Ia/Ib dose-escalation/expansion trials. Presented at: ASCO Gastrointestinal Cancers Symposium; January 18-20, 2024. Abstract 487.