Table Info

Table 4.

Not published trials, both recruiting and not recruiting, targeting MAPK pathway

NCT	Phase	Status	Tumors	Line of treatment	Target	Experimental treatment	Standard treatment	Primary endpoints	Sponsor
NCT00397384	1	Completed	eCCA	Non specified	KRAS wild type	Erlotinib + Cetuximab	N.A.	MTD	No-profit
NCT04190628	1	Recruiting	CCA	NTA	BRAF V600 mutation	ABM-1310	N.A.	MTD/RP2D	Profit
NCT04566133	1	Not yet recruiting	CCA	NTA	KRAS mutation	Trametinib + HCQ	N.A.	PFS	Profit

HCQ: hydroxychloroquine

Declarations

Author contributions

MDM, DM, ES contributed conception and design of the review; AC, TG, FDV organized the database; GA, CP, CZ wrote the first draft of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

The authors declare the following financial interests/personal relationships that may be considered as potential competing interests: Massimo Di Maio received honoraria and had roles as consultant or advisor for AstraZeneca, Pfizer, Novartis, Roche, Takeda, Eisai, Janssen, Astellas; received institutional research grant by Tesaro e GlaxoSmithKline, outside the submitted work. All remaining authors declared no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Nathan H, Pawlik TM, Wolfgang CL, Choti MA, Cameron JL, Schulick RD. Trends in survival after surgery for cholangiocarcinoma: a 30-year population-based SEER database analysis. J Gastrointest Surg. 2007;11:1488–96; discussion 1496–7. [DOI] [PubMed]

Mavros MN, Economopoulos KP, Alexiou VG, Pawlik TM. Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis. JAMA Surg. 2014;149:565–74. [DOI] [PubMed]

Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al.; ABC-02 trial investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–81. [DOI] [PubMed]

Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, et al.; Advanced biliary cancer working group. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22:690–701. [DOI] [PubMed] [PMC]

Casadio M, Biancaniello F, Overi D, Venere R, Carpino G, Gaudio E, et al. Molecular landscape and therapeutic strategies in cholangiocarcinoma: an integrated translational approach towards precision medicine. Int J Mol Sci. 2021;22:5613. [DOI] [PubMed] [PMC]

Chen JS, Hsu C, Chiang NJ, Tsai CS, Tsou HH, Huang SF, et al.; Taiwan cooperative oncology group. A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer. Ann Oncol. 2015;26:943–9. [DOI] [PubMed]

Vogel A, Kasper S, Bitzer M, Block A, Sinn M, Schulze-Bergkamen H, et al. PICCA study: panitumumab in combination with cisplatin/gemcitabine chemotherapy in KRAS wild-type patients with biliary cancer-a randomised biomarker-driven clinical phase II AIO study. Eur J Cancer. 2018;92:11–9. [DOI] [PubMed]

Leone F, Marino D, Cereda S, Filippi R, Belli C, Spadi R, et al. Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: a randomized phase 2 trial (Vecti-BIL study). Cancer. 2016;122:574–81. [DOI] [PubMed]

Amin NEL, Hansen TF, Fernebro E, Ploen J, Eberhard J, Lindebjerg J, et al. Randomized phase II trial of combination chemotherapy with panitumumab or bevacizumab for patients with inoperable biliary tract cancer without KRAS exon 2 mutations. Int J Cancer. 2021;149:119–26. [DOI] [PubMed]

10.

Babina IS, Turner NC. Advances and challenges in targeting FGFR signalling in cancer. Nat Rev Cancer. 2017;17:318–32. [DOI] [PubMed]

11.

Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2016;22:259–67. [DOI] [PubMed]

12.

Bekaii-Saab TS, Valle JW, Van Cutsem E, Rimassa L, Furuse J, Ioka T, et al. FIGHT-302: first-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements. Future Oncol. 2020;16:2385–99. [DOI] [PubMed]

13.

Krook MA, Reeser JW, Ernst G, Barker H, Wilberding M, Li G, et al. Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance. Br J Cancer. 2021;124:880–92. [DOI] [PubMed] [PMC]

14.

Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21:671–84. [DOI] [PubMed] [PMC]

15.

Javle M, Lowery M, Shroff RT, Weiss KH, Springfeld C, Borad MJ, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2018;36:276–82. [DOI] [PubMed] [PMC]

16.

Park JO, Feng YH, Chen YY, Su WC, Oh DY, Shen L, et al. Updated results of a phase IIa study to evaluate the clinical efficacy and safety of erdafitinib in Asian advanced cholangiocarcinoma (CCA) patients with FGFR alterations. J Clin Oncol. 2019;37:4117. [DOI]

17.

Mazzaferro V, El-Rayes BF, Droz Dit Busset M, Cotsoglou C, Harris WP, Damjanov N, et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br J Cancer. 2019;120:165–71. [DOI] [PubMed] [PMC]

18.

Furuse J, Goyal L, Meric-Bernstam F, Hollebecque, Valle JW, Morizane C, et al. Efficacy, safety, and quality of life (QoL) with futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harbouring FGFR2 fusions/rearrangements: FOENIX-CCA2. Ann Onco. 2020;31:S1287–318. [DOI]

19.

Salati M, Caputo F, Baldessari C, Galassi B, Grossi F, Dominici M, et al. IDH signalling pathway in cholangiocarcinoma: from biological rationale to therapeutic targeting. Cancers (Basel). 2020;12:3310. [DOI]

20.

Crispo F, Pietrafesa M, Condelli V, Maddalena F, Bruno G, Piscazzi A, et al. IDH1 targeting as a new potential option for intrahepatic cholangiocarcinoma treatment-current state and future perspectives. Molecules. 2020;25:3754. [DOI]

21.

Saha SK, Parachoniak CA, Ghanta KS, Fitamant J, Ross KN, Najem MS, et al. Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer. Nature. 2014;513:110–4. [DOI] [PubMed] [PMC]

22.

Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, 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. [DOI] [PubMed] [PMC]

23.

Zhu AX, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. J Clin Oncol. 2021;39:266. [DOI]

24.

Khurshed M, Molenaar RJ, van Noorden C, Wilmink JW. Metabolic vulnerabilities in IDH1/2-mutated solid tumours lead to phase IB/II clinical trial using metformin and chloroquine. FASEB J. 2019;33:496.7. [DOI]

25.

Lin J, Shi J, Guo H, Yang X, Jiang Y, Long J, et al. Alterations in DNA damage repair genes in primary liver cancer. Clin Cancer Res. 2019;25:4701–11. [DOI] [PubMed]

26.

Chakrabarti S, Kamgar M, Mahipal A. Targeted therapies in advanced biliary tract cancer: an evolving paradigm. Cancers (Basel). 2020;12:2039. [DOI]

27.

Wang Y, Wild AT, Turcan S, Wu WH, Sigel C, Klimstra DS, et al. Targeting therapeutic vulnerabilities with PARP inhibition and radiation in IDH-mutant gliomas and cholangiocarcinomas. Sci Adv. 2020;6:eaaz3221. [DOI] [PubMed] [PMC]

28.

Galdy S, Lamarca A, McNamara MG, Hubner RA, Cella CA, Fazio N, et al. HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target? Cancer Metastasis Rev. 2017;36:141–57. [DOI] [PubMed] [PMC]

29.

Jacobi O, Ross JS, Goshen-Lago T, Haddad R, Moore A, Sulkes A, et al. ERBB2 pathway in biliary tract carcinoma: clinical implications of a targetable pathway. Oncol Res Treat. 2021;44:20–7. [DOI] [PubMed]

30.

Jeong H, Jeong JH, Kim KP, Lee SS, Oh DW, Park DH, et al. Feasibility of HER2-targeted therapy in advanced biliary tract cancer: a prospective pilot study of trastuzumab biosimilar in combination with gemcitabine plus cisplatin. Cancers (Basel). 2021;13:161. [DOI]

31.

Javle MM, Hainsworth JD, Swanton C, Burris HA, Kurzrock R, Sweeney C, et al. Pertuzumab + trastuzumab for HER2-positive metastatic biliary cancer: preliminary data from MyPathway. J Clin Oncol. 2017:35:402. [DOI]

32.

Tsurutani J, Iwata H, Krop I, Jänne PA, Doi T, Takahashi S, et al. Targeting HER2 with trastuzumab deruxtecan: a dose-expansion, phase I study in multiple advanced solid tumors. Cancer Discov. 2020;10:688–701. [DOI] [PubMed] [PMC]

33.

Bang YJ, Giaccone G, Im SA, Oh DY, Bauer TM, Nordstrom JL, et al. First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Ann Oncol. 2017;28:855–61. [DOI] [PubMed] [PMC]

34.

Meric-Bernstam F, Hanna DL, El-Khoueiry AB, Kang YK, Oh DY, Chaves JM, et al. Zanidatamab (ZW25) in HER2-positive biliary tract cancers (BTCs): results from a phase I study. J Clin Oncol. 2021;39:299. [DOI]

35.

Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 2010;1802:396–405. [DOI] [PubMed]

36.

Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y, Hu LL. ERK/MAPK signalling pathway and tumorigenesis. Exp Ther Med. 2020;19:1997–2007. [DOI] [PubMed] [PMC]

37.

Chiang NJ, Hsu C, Chen JS, Tsou HH, Shen YY, Chao Y, et al. Expression levels of ROS1/ALK/c-MET and therapeutic efficacy of cetuximab plus chemotherapy in advanced biliary tract cancer. Sci Rep. 2016;6:25369. [DOI] [PubMed] [PMC]

38.

Trombetta D, Parente P, Latiano TP, Fabrizio FP, Muscarella LA. Identification of EML4-ALK fusion in a sporadic case of cholangiocarcinoma. Eur J Intern Med. 2020;71:92–4. [DOI] [PubMed]

39.

Zhou Y, Lizaso A, Mao X, Yang N, Zhang Y. Novel AMBRA1-ALK fusion identified by next-generation sequencing in advanced gallbladder cancer responds to crizotinib: a case report. Ann Transl Med. 2020;8:1099. [DOI] [PubMed] [PMC]

40.

Saborowski A, Saborowski M, Davare MA, Druker BJ, Klimstra DS, Lowe SW. Mouse model of intrahepatic cholangiocarcinoma validates FIG-ROS as a potent fusion oncogene and therapeutic target. Proc Natl Acad Sci U S A. 2013;110:19513–8. [DOI] [PubMed] [PMC]

41.

Gu TL, Deng X, Huang F, Tucker M, Crosby K, Rimkunas V, et al. Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS One. 2011;6:e15640. [DOI] [PubMed] [PMC]

42.

Peraldo Neia C, Cavalloni G, Balsamo A, Venesio T, Napoli F, Sassi F, et al. Screening for the FIG-ROS1 fusion in biliary tract carcinomas by nested PCR. Genes Chromosomes Cancer. 2014;53:1033–40. [DOI] [PubMed]

43.

El-Khoueiry AB, Rankin C, Siegel AB, Iqbal S, Gong IY, Micetich KC, et al. S0941: a phase 2 SWOG study of sorafenib and erlotinib in patients with advanced gallbladder carcinoma or cholangiocarcinoma. Br J Cancer. 2014;110:882–7. [DOI] [PubMed] [PMC]

44.

El-Khoueiry AB, Rankin CJ, Ben-Josef E, Lenz HJ, Gold PJ, Hamilton RD, et al. SWOG 0514: a phase II study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma. Invest New Drugs. 2012;30:1646–51. [DOI] [PubMed] [PMC]

45.

Moehler M, Maderer A, Schimanski C, Kanzler S, Denzer U, Kolligs FT, et al.; Working group of internal oncology. Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme. Eur J Cancer. 2014;50:3125–35. [DOI] [PubMed]

46.

Bengala C, Bertolini F, Malavasi N, Boni C, Aitini E, Dealis C, et al. Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial. Br J Cancer. 2010;102:68–72. [DOI] [PubMed] [PMC]

47.

Lee JK, Capanu M, O’Reilly EM, Ma J, Chou JF, Shia J, et al. A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas. Br J Cancer. 2013;109:915–9. [DOI] [PubMed] [PMC]

48.

Ikeda M, Sasaki T, Morizane C, Mizuno N, Nagashima F, Shimizu S, et al. A phase 2 study of lenvatinib monotherapy as second-line treatment in unresectable biliary tract cancer: primary analysis results. Ann Oncol. 2017;28:V246. [DOI]

49.

Andersen JB. Molecular pathogenesis of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2015;22:101–13. [DOI] [PubMed]

50.

Yoshikawa D, Ojima H, Iwasaki M, Hiraoka N, Kosuge T, Kasai S, et al. Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer. 2008;98:418–25. [DOI] [PubMed] [PMC]

51.

Zhu AX, Meyerhardt JA, Blaszkowsky LS, Kambadakone AR, Muzikansky A, Zheng H, et al. Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study. Lancet Oncol. 2010;11:48–54. [DOI] [PubMed]

52.

Lubner SJ, Mahoney MR, Kolesar JL, Loconte NK, Kim GP, Pitot HC, et al. Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study. J Clin Oncol. 2010;28:3491–7. [DOI] [PubMed] [PMC]

53.

Iyer RV, Groman A, Ma WW, Malhotra U, Iancu D, Grande C, et al. Gemcitabine (G), capecitabine (C) and bevacizumab (BV) in patients with advanced biliary cancers (ABC): final results of a multicenter phase II study. J Clin Oncol. 2015;33:4078. [DOI]