Precision Oncology for Hepatocellular Cancer: Slivering the Liver by FGF19–FGFR4–KLB Pathway Inhibition Vivek Subbiah 1 and Sumanta K

VIEWS

IN THE SPOTLIGHT Precision Oncology for Hepatocellular Cancer: Slivering the Liver by FGF19–FGFR4–KLB Pathway Inhibition Vivek Subbiah 1 and Sumanta K. Pal 2 Summary: This issue reports two studies, one by Hatlen and colleagues and the other by Kim and colleagues, that detail the drug-development journey of the FGF19–FGFR4 inhibitor fi sogatinib (BLU-554), from identifi cation of the drug to preclinical validation studies to fi nally the results of the proof-of-concept fi rst-in-human phase I trial of this potent and selective, type I irreversible inhibitor of FGFR4. Moreover, Hatlen and colleagues also report a resistance mechanism acquired after therapy that targets selective FGFR4 inhibition, which validates FGF as a specifi c target in hepatocellular cancer.

See related article by Hatlen et al., p. 1686 (9). See related article by Kim et al., p. 1696 (8).

O sliver of liver, Get lost! Go away! in HCC. In fact, the four nonselective VEGF-based multikinase You tremble and quiver, O sliver of liver inhibitors (sorafenib, regorafenib, lenvatinib, and cabozan- –“ A Sliver of Liver” tinib) that have been approved by the FDA in HCC are in use Myra Cohn Livingston, 1926–1996 without a biomarker to guide this therapy selection. Further- more, understanding of the response and resistance mecha- The identifi cation of oncogenic activation of tyrosine nisms to these multikinase inhibitors has yet to be elucidated. kinases, such as mutations in the EGFR or BRAF genes, rear- Immune checkpoint inhibitors indicated for HCC confer very rangements of the NTRK genes, and mutations/rearrange- modest activity, and more than ten nonspecifi c, phase III tri- ments of RET, has enabled the development of targeted als in all patients with HCC have failed to meet the primary treatments for such pathway-aberrant cancers. However, such end-point, warranting an urgent biomarker-driven therapy ( 2). advances have had a limited impact on patients with hepatocellular carcinoma (HCC), the cancer with the second high- est mortality in the world, with 700,000 deaths worldwide CHALLENGES OF DRUG DEVELOPMENT recorded every year. Patients with HCC have yet to derive IN THE FGFR PATHWAY meaningful durable benefi t from selective biomarker-driven targeted therapy in this era of precision oncology ( 1 ). One The family of FGFs regulates multiple biological processes, major challenge in HCC has been absence of “druggable” including cell proliferation, migration, differentiation, apop- alterations; that is, genes reported to be frequently mutated tosis, metabolism, and angiogenesis. Consequently, aberrant in HCC such as the TERT promoter, TP53, and CTNNB1 activation of FGFR signaling has been implicated in several (β-catenin), have all remained formidable as targets with no malignancies. The FGFR tyrosine kinase family consists of effective drug (1 ). Additional aberrations identifi ed through four members, FGFR1–4, which are activated through 22 the efforts of The Cancer Genome Atlas include LZTR1, different FGF ligands, highlighting the complexities, both EEF1A1, SF3B1, SMARCA4, ALB, APOB , and CPS1 , in addition known and unknown, of this pathway, as evidenced by the to well-characterized driver oncogenes such as CCND1, FGF19 variable success of more than 20 compounds (Table 1) that (11q13.3 ), MYC (8q24.21), MET (7q31.2), VEGFA (6p21.1), and have been in development to target FGFR ( 3–6 ). Several FGFR MCL1 (1q21.3; ref. 1). This wide variability in aberrations inhibitors that have entered early-phase trials have been lim- combined with the lack of effective drugs targeting them have ited by their nonselectivity and side effects from pan-FGFR resulted in a dearth of biomarker-driven drug therapy options inhibition, mainly from the on-target toxicity of hyperphos- phatemia, leading to frequent treatment interruptions and dose reductions and thereby loss of effi cacy ( 4 ). Indeed, in the 1 Department Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, landmark study of the FGFR inhibitor erdafi tinib (Balversa) Texas. 2 Department of Medical Oncology & Experimental Therapeutics, in FGFR3-mutant bladder cancer, nearly half of the patients City of Hope Comprehensive Cancer Center, Duarte, California. had treatment-related adverse events of grade 3 or higher; Corrected online December 10, 2019. nonetheless, given the confi rmed response rate of 40% with Corresponding Author: Vivek Subbiah, The University of Texas MD Ander- a medial overall survival of 13.8 months, erdafi tinib became son Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: the fi rst-ever biomarker-based drug to be approved in blad- 713-563-0393; Fax: 713-792-0334; E-mail: [email protected] der cancer and the fi rst-in-class FGFR inhibitor to receive Cancer Discov 2019;9:1646–9 approval (7 ). On the basis of observed toxicities, most FGFR doi: 10.1158/2159-8290.CD-19-1156 inhibitor trials recommend mitigation strategies for these ©2019 American Association for Cancer Research. electrolyte imbalances, such as maintaining a low-phosphate

1646 | CANCER DISCOVERY DECEMBER 2019 www.aacrjournals.org

Table 1. Small-molecule FGFR inhibitors in clinical development and their measured in vitro IC50 values compared with BLU-554 (ﬁ sogatinib)

FGF4 measured IC50 Measured IC50 Inhibitor (nmol/L, in vitro ) (nmol/L, in vitro ) Company JNJ-42756493 (erdafi tinib, Balversa)a 5.7 FGFR1: 1.2 Janssen FGFR2: 2.5 FGFR3: 3 BLU-554 (fi sogatinib) 5 FGFR1: 624 Blueprint Medicines FGFR2: 1202 FGFR3: 2203 BLU-9931 3 FGFR1: 591 Blueprint Medicines FGFR2: 493 FGFR3: 150 H3B-6527 <1.2 FGFR1: 320 H3 Biomedicine, Eisai Incorporation FGFR2: 1290 FGFR3: 1060 PRN1371 19.3 FGFR1: 0.6 Principia Biopharma FGFR2: 1.3 FGFR3: 4.1 TAS-120 (futibatinib) 8.3 FGFR1: 3.9 Taiho Oncology FGFR2: 1.3 FGFR3: 1.6 INCB054828 (pemigatinib) 30 FGFR1: 0.4 Incyte Pharmaceuticals FGFR2: 0.5 FGFR3: 1 AP24534 (ponatinib) 7.7 FGFR1: 2.2 Ariad Pharmaceuticals FGFR2: 1.6 FGFR3: 18.2 ARQ 087 (derazantinib) 34 FGFR1: 4.5 ArQule FGFR2: 1.8 FGFR3: 4.5 BIBF 1120 (nintedanib) 610 FGFR1: 69 Boehringer Ingelheim FGFR2: 37 FGFR3: 108 PD166866 N/A FGFR1: 52.4 Pfi zer PD173074 N/A FGFR1: 22–25 Pfi zer FGFR3: 29 NVP-FGF401 1.1 N/A Novartis NVP-BGJ398 (infi gratinib) 60 FGFR1: 0.9 Novartis FGFR2: 1.4 FGFR3: 1 Dovitinib (CHIR258, TKI258) N/A FGFR1: 8 Novartis FGFR3: 9 LYS2874455 6 FGFR1: 2.8 Eli Lilly FGFR2: 2.6 FGFR3: 6.4 AZD4547 165 FGFR1: 0.2 AstraZeneca FGFR2: 2.5 FGFR3: 1.8 Debio-1347 (CH5183284) 290 FGFR1: 9.3 Debiopharm International FGFR2: 7.6 FGFR3: 22 BAY1163877 (rogaratinib) 33 FGFR1: 12–15 Bayer FGFR2: <1 FGFR3: 19 E-3810 (lucitanib) >1,000 FGFR1: 17.5 Clovis Oncology FGFR2: 82.5 FGFR3: 237.5

aBalversa is the ﬁ rst FGFR kinase inhibitor approved by the FDA. Balversa (erdaﬁ tinib) received accelerated approval from the FDA for the treatment of adults with locally advanced or metastatic urothelial carcinoma that has susceptible FGFR3 or FGFR2 genetic alterations, and who have progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum- containing chemotherapy.

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Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. VIEWS diet that excludes products like cheese, ice cream, chocolate, ACQUIRED RESISTANCE PARADIGM IN fast foods, colas, yogurt, and meats, which likely can have FGFR4, AND NEXT STEPS major implications for most patients’ way of life and, one can argue, quality of life in those with advanced cancer. In the The initial clinical benefit seen with select targeted quest for FGFR selectivity, and to limit off-target toxicities therapies in oncology is often diminished by the eventual, such as those associated with concurrent VEGFR2 inhibition, seemingly inevitable development of acquired resistance. several observations were made—drugs that selectively target Therefore, as critical as it is to identify a novel drug to target FGFR without VEGFR2 demonstrated a loss of FGFR4 path- an aberration, so too is the almost immediate effort to iden- way inhibition. This finding presented a new need to develop tify the emerging mechanisms of resistance and to formulate a selective FGFR4 inhibitor so that the lack of VEGFR2 activ- a therapeutic strategy to overcome them in real time. In their ity does not affect the clinical outcomes regarding disease study, Hatlen and colleagues studied patients who devel- control, especially in FGFR4-driven cancers. oped disease progression on fisogatinib, identified muta- This issue of Cancer Discovery presents critical findings on tions in the gatekeeper (V550) and hinge-1 (C552) residues the FGF19–FGFR4 inhibitor fisogatinib (BLU-554), a potent of FGFR4 that confer resistance to fisogatinib in the clinical and selective, type I irreversible inhibitor of FGFR4. First, Kim setting, and validated those mechanisms of resistance in vivo and colleagues (8) report the identification, preclinical valida- and in vitro. Of the 7 patients who had imaging evidence of tion, and complete clinical data from the first-in-human response per RECIST, 2 (29%) showed evidence of on-target phase I trial of fisogatinib. Then, Hatlen and colleagues (9) resistance. Hatlen and colleagues went on to demonstrate report their findings on the novel acquired mechanisms of that LY2874455, a gatekeeper-agnostic FGFR inhibitor, over- resistance identified within the kinase domain of FGFR4 comes this resistance to fisogatinib in bothin vitro and in vivo in two patients on the aforementioned phase I trial who models. This finding further validates the theory that can- progressed on fisogatinib. Furthermore, they go on to dem- cers with acquired resistance to selective FGFR4 inhibitors onstrate in vitro evidence of overcoming this resistance by still maintain the FGF19–FGFR4–KLB pathway dependency. using a pan-FGFR inhibitor that reaffirms continued aber- Now, with this validation of the FGF19–FGFR4–KLB axis rant FGFR4 signaling despite the mutations in the kinase as a target in HCC, biomarker-driven precision oncology has domains. With the background of the developmental thera- arrived for this deadly cancer and undoubtedly become the peutic challenge in both HCC and the FGFR pathway, it is subject of future investigation. What are the next steps? It is commendable that the authors have pursued a tricky target logical to move fisogatinib in the multikinase inhibitor-naïve in a challenging disease with very few therapeutic options and setting in HCC to see if there would be better efficacy and have demonstrated a validated biomarker-based approach for delayed acquired resistance. Next is how to use combina- this target. tion therapies in these patients to maximize the success of treatments in HCC. Given the nonoverlapping side effects of immune checkpoint inhibitors, and given the role of immune FGFR4 AND FGF19 PATHWAY checkpoint inhibitors in HCC, concurrent development of Located in chromosome 5, human FGFR4 is a protein- combination trials is warranted. FGFR4 inhibition may be coding gene containing three immunoglobin-like domains the first step to slivering liver cancer by identifying subsets (D1–D3), a transmembrane domain, and an intracellular within HCC identified and consequently targeted by their kinase domain that binds specific ligands (10). Function- molecular aberrations. Oh! Liver cancer, “Get lost! Go away!” ally, it is involved in normal physiologic processes including Disclosure of Potential Conflicts of Interest bile-acid biosynthesis and is predominantly expressed in liver tissue. FGF19 ligand binds to FGFR4 with high affinity. V. Subbiah is a consultant at Incyte, Novartis, and Helsin; is a sci- entific advisory board member for R-Pharma US, LOXO Oncology/Eli FGF19 amplification is associated with development of cir- Lilly, and Medimmune; reports receiving commercial research grants rhosis and HCC. FGFR4 is regulated using its coreceptor KLB from Blueprint Medicines, LOXO Oncology/Eli Lilly, Pharmamar, (a transmembrane protein). FGF19/FGFR4/KLB activation D3, Pfizer, Multivir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston leads to the formation of FGF receptor substrate 2 (FRS2) Biomedical, Idera Pharmaceuticals, Bayer, Inhibrx, Exelixis, Medim- and GRB2 complex, activating the RAS–RAF–MAPK and mune, Altum, Dragonfly Therapeutics, Takeda, Roche/Genentech, PI3K–AKT pathways. GlaxoSmithKline, Nanocarrier, Vegenics, Northwest Biotherapeutics, The authors here developed a highly potent selective oral Berghealth, Incyte, and Fujifilm; and has received other remuneration FGFR4 inhibitor with companion IHC assay to identify aber- from ASCO and ESMO. S.K. Pal is a consultant at Aveo, Eisai, Novartis, rant FGF19 expression as a surrogate marker of pathway Exelixis, Ipsen, Pfizer, Astellas, BMS, Roche, and Genentech. No other activation. Next, they elegantly translated this to a first-in- potential conflicts of interest were disclosed. human phase I trial in patients with advanced HCC to assess Published online December 2, 2019. safety and preliminary clinical activity of fisogatinib together with the validation of FGF19 IHC as a predictive biomarker REFERENCES of response in advanced HCC. Fisogatinib demonstrates an acceptable toxicity profile with early evidence of antitumor . 1 The Cancer Genome Atlas Research Network. Comprehensive and activity in patients with FGF19–IHC-positive HCC regard- integrative genomic characterization of hepatocellular carcinoma. Cell 2017;169:1327–41. less of the underlying risk factor for HCC (such as hepatitis 2. Llovet JM, Hernandez-Gea V. Hepatocellular carcinoma: reasons for B, hepatitis C, nonalcoholic steatohepatitis, and others) and phase III failure and novel perspectives on trial design. Clin Cancer prognostic factors. Res 2014;20:2072–9.

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3. Turner N, Grose R. Fibroblast growth factor signalling: from develop- 7. Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, ment to cancer. Nat Rev Cancer 2010;10:116–29. et al. Erdafitinib in locally advanced or metastatic urothelial carci- 4. Lewin J, Siu LL. Development of fibroblast growth factor receptor noma. N Engl J Med 2019;381:338–48. inhibitors: kissing frogs to find a prince? J Clin Oncol 2015;33:3372–4. 8. Kim RD, Sarker D, Meyer T, Yau T, Macarulla T, Park J-W, et al. First- 5. Pal SK, Rosenberg JE, Hoffman-Censits JH, Berger R, Quinn DI, in-human phase I study of fisogatinib (BLU-554) validates aberrant Galsky MD, et al. Efficacy of BGJ398, a fibroblast growth factor FGF19 signaling as a driver event in hepatocellular carcinoma. Cancer receptor 1–3 inhibitor, in patients with previously treated advanced Discov 2019;9:1696–707. urothelial carcinoma with FGFR3 alterations. Cancer Discov 2018;8: 9. Hatlen MA, Schmidt-Kittler O, Sherwin CA, Rozsahegyi E, Rubin N, 812–21. Sheets MP, et al. Acquired on-target clinical resistance validates FGFR4 6. Farrell B, Breeze AL. Structure, activation and dysregulation of fibro- as a driver of hepatocellular carcinoma. Cancer Discov 2019;9:1686–95. blast growth factor receptor kinases: perspectives for clinical target- 10. Raja A, Park I, Haq F, Ahn SM. FGF19-FGFR4 signaling in hepatocel- ing. Biochem Soc Trans 2018;46:1753–70. lular carcinoma. Cells 2019;8:pii:E536.

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Correction: Precision Oncology for Hepatocellular Cancer: Slivering the Liver by FGF19–FGFR4–KLB Pathway Inhibition

In the original version of this article (1), “FGFR4” was incorrectly spelled as “FGF4” in the title, and “FGFR4” and “FGF19” were incorrectly spelled as “FGF4” and “FGFR19” in the Summary and the section titled “Acquired Resistance Paradigm in FGFR4, and Next Steps.” The latest online HTML and PDF versions of the article have been corrected. The authors and publisher regret the error.

REFERENCE 1. Subbiah V, Pal SK. Precision oncology for hepatocellular cancer: slivering the liver by FGF19–FGFR4–KLB pathway inhibition. Cancer Discov 2019;9:1646–9.

326 | CANCER DISCOVERY FEBRUARY 2020 AACRJournals.org Precision Oncology for Hepatocellular Cancer: Slivering the Liver by FGF19−FGFR4−KLB Pathway Inhibition

Vivek Subbiah and Sumanta K. Pal

Cancer Discov 2019;9:1646-1649.

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