FormalPara Key Points

In this phase I study of INCB062079 for previously treated advanced solid tumors, INCB062079 demonstrated a manageable safety profile, generally dose-proportional pharmacokinetics, and pharmacodynamics consistent with target inhibition.

Because of slow patient accrual, the study was terminated before a maximum tolerated dose of INCB062079 could be identified, and clinical development was terminated.

Nevertheless, the results validate INCB062079 as a clinical grade fibroblast growth factor receptor-4 inhibitor and support future research into the relevance of the FGF19/FGFR4 signaling axis as a therapeutic target in solid tumors.

1 Introduction

Fibroblast growth factor (FGF)-19 is an endocrine factor produced by the ileum in response to postprandial luminal bile salts [1,2,3]. In the liver, FGF19 binds to FGF receptor (FGFR)-4, and the co-receptor βklotho, thereby regulating both bile salt formation and hepatocyte proliferation [3,4,5]. Under physiologic conditions, FGF19 and its receptors are thought to play a critical role in protecting against cholestatic liver injury [1].

Emerging evidence indicates that dysregulation of the FGF19/FGFR4 signaling axis contributes to oncogenesis in hepatocellular carcinoma (HCC) and several other solid tumors [6,7,8]. In clinical HCC samples, FGF19 is genomically amplified in the context of an 11q13 amplicon in approximately 5% of tumors [4a, b). One of the two patients achieving stable disease had advanced HCC and unknown FGF19 status, and had progressed on sorafenib before study enrollment. This patient, who received INCB062079 10 mg once daily, achieved stable disease without progression for 31.3 months. The other patient achieving stable disease had intrahepatic cholangiocarcinoma with no reported FGF19 status and had been previously treated with surgery, radiation, and five lines of systemic therapy. This patient received INCB062079 10 mg twice daily and achieved stable disease without progression for 4.9 months.

Fig. 4
figure 4

a Waterfall plot of best percentage change in the sum of target lesions for individual patients receiving INCB062079 (efficacy-evaluable population). Data were from investigator review per standard RECIST v1.1 and modified RECIST for hepatocellular carcinoma, and response was unconfirmed. b Duration of treatment and response assessments among individual patients receiving INCB062079. aThis patient had cholangiocarcinoma and FGF3, FGF4, and FGF19 amplifications. bThis patient had esophageal cancer and FGF3, FGF4, FGF10, and FGF19 amplifications, and an FGFR4 p.S551F mutation. cThis patient had ovarian cancer. dPatients were enrolled after a protocol amendment requiring all newly enrolled patients to have a C4 concentration < 40.9 ng/mL and to take a prophylactic bile acid sequestrant for the prevention of diarrhea while receiving INCB062079 treatment. BID twice daily, C4 7α-hydroxy-4-cholesten-3-one, GE gastroesophageal, NE not evaluable, PD progressive disease, PR partial response, QD once daily, RECIST Response Evaluation Criteria in Solid Tumors, SD stable disease

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4 Discussion

Dysregulation of FGF19/FGFR4/βklotho-mediated signal transduction through the MAPK, PI3K/AKT/mTOR, JAK-STAT, NFκB, and Wnt/β-catenin pathways can result in uncontrolled cellular growth in preclinical models of HCC [6, 8, 28]. Whereas this oncogenic mechanism is highly relevant to hepatobiliary cancers, dysregulation of the FGF19/FGFR4/βklotho signaling axis has also been observed in other solid tumors [6,7,8]. We therefore evaluated INCB062079, a potent, oral, irreversible inhibitor of FGFR4, in patients with solid tumors, including hepatobiliary cancers, in the context of a first-in-human clinical trial. Manageable on-target gastrointestinal toxicity was observed in most patients at the initial dosages. However, dose escalation beyond 15 mg twice daily was not possible because two of six patients experienced gastrointestinal/hepatobiliary DLTs. The protocol was subsequently amended to include eligibility criteria that mitigated this toxicity by requiring the prophylactic use of bile acid sequestrants and a pretreatment serum C4 concentration cut-off < 40.9 ng/mL. This amendment resulted in an apparent blunting of toxicity allowing successful dose escalation. Importantly, the generally dose-proportional PK of INCB062079 was associated with an expected increase in plasma C4 and FGF19 concentrations, consistent with target inhibition of FGFR4 in vivo. A partial response was observed at the highest dose levels tested (15 mg twice daily), indicating a signal of antitumor activity. Despite these findings, because of the rarity of FGF19/FGFR4 alterations and the slow accrual of patients who satisfied the eligibility criteria, the study was terminated before the MTD could be identified, and the clinical development of INCB062079 was terminated.

Increasing postprandial luminal bile salt concentrations result in exocrine farnesoid X receptor (FXR)-induced production of FGF19 by enterocytes, which serves to activate FGFR4/βklotho-mediated signaling in hepatocytes and cholangiocytes [27, 29]. Under normal physiologic conditions, FGF19/FGFR4/βklotho signal activation suppresses bile acid biosynthesis in hepatocytes by downregulating the CYP7A1 gene [3, 4, 8] via SHP/liver receptor homolog-1 (LRH-1)-dependent [30, 31] and JNK-dependent [4] feedback mechanisms. Consistent with this, FGFR4 inhibition was associated with increased CYP7A1 RNA expression and bile salt excretion in cynomolgus monkeys [21]. Furthermore, in murine models, knocking out FGFR4 or βklotho leads to elevated bile acid excretion and an increased bile acid pool [5, 32]. Moreover, βklotho–/– mice have been shown to display phenotypic characteristics suggestive of early-stage liver damage, including increased liver size, increased ALT and AST levels, increased proinflammatory cytokine expression, and fibrogenesis [33]. It was further demonstrated that these characteristics were associated with a large increase in microbiota-derived deoxycholic acid [33]. Given the potential toxicity of excessive bile salt accumulation [33], the expected on-target gastrointestinal and hepatobiliary toxicity of selective FGFR4 inhibitors must be scrutinized and mitigated to ensure an adequate therapeutic index of this drug class. The observed safety profile of INCB062079 was consistent with its proposed mechanism of action, with manageable any-grade diarrhea (60.9%), nausea (47.8%), vomiting (26.1%), and AST and ALT increases (17.4 and 13.0%, respectively). Such on-target effects were also observed in 106 patients with advanced HCC receiving the selective FGFR4 inhibitor fisogatinib in a recent phase I study [7], which reported treatment-related adverse events of diarrhea (any-grade 74%; grade 3 or higher, 8%), nausea (42%; 2%), and vomiting (35%; 4%). Treatment-related grade 3 or higher ALT and AST increase adverse events were also observed in 11% and 15%, respectively, of patients treated with fisogatinib [7]. Because this class of drug has greatest applicability in hepatobiliary cancers, the potential liability of on-target FGFR4 toxicity and need for mitigation efforts are of clear importance.

Without mitigation efforts, the INCB062079 dose could not be escalated without intolerable dose-limiting gastrointestinal toxicity in patients, indicative of a narrow therapeutic index. For this reason, efforts were made to select patients with low baseline plasma C4 expression and prophylactically treat with bile acid sequestrants. Preclinical toxicology data indicate that bile acid sequestration is a novel method to prevent FGFR4-induced hepatic and gastrointestinal toxicity [34, 35]. Although the patient sample sizes in the present study are too small to draw conclusions, diarrhea was reported by a smaller percentage of patients who received concurrent prophylactic treatment with a bile acid sequestrant (Cohorts 4 and 5), compared with patients who did not receive such treatment. Bile acid sequestrant treatment may therefore have merit as a clinical strategy to blunt gastrointestinal toxicity associated with FGFR4 inhibition and should be explored in future studies.

Importantly, INCB062079 exhibited linear exposure relative to dose and did not accumulate with repeat dosing. The addition of bile acid sequestrant did not appear to interfere with absorption or reduce INCB062079 exposure. PK/PD modeling did indicate a statistically significant increase in bile salt and C4 concentrations with increasing INCB062079 exposure and a two- to four-fold increase in FGF19 concentrations with repeat dosing. These findings suggest that INCB062079 inhibits its proposed target, further supporting INCB062079 as a clinical grade FGFR4 inhibitor. FGF19/FGFR4/βklotho pathway inhibition by INCB062079 in tumor tissues could not be confirmed because paired pretreatment and on-treatment biopsies were not obtained in this study (per protocol).

Determination of antitumor activity was not a primary objective of this phase I study and could not be satisfactorily assessed given that higher INCB062079 doses were not tested. Interestingly, a partial response was seen in a patient with ovarian cancer with unknown FGF19/FGFR status. In addition, long-term stable disease was observed in a patient with HCC treated with INCB062079 (31.3 months). This observation is in kee** with previous findings with fisogatinib, where eight patients with HCC achieved either partial or complete responses lasting over 6 months [7]. Taken together, these observations are hypothesis-generating and support further investigation of the efficacy and safety of selective FGFR4 inhibitors in patients with advanced HCC and other solid tumors. No correlation was established between potential biomarkers and clinical efficacy; the two patients with known FGF19 amplifications did not respond to study treatment. Other selective FGFR4 inhibitors currently in phase I/II clinical trials for HCC or other advanced solid tumors as monotherapy or in combination with other anticancer agents include roblitinib (FGF401) [22] (NCT02325739), EVER4010001 (NCT04699643), ABSK-011 [36] (NCT04906434), and H3B-6527 [37] (NCT02834780). Together, these studies will help clarify the merit of selective FGFR4 inhibitor treatments in patients with solid tumors.

Limitations of the study include a lack of pretreatment data on the types of FGF19/FGFR4 alterations, including fusions or other rearrangements, mutations, amplifications, as well as FGF19 protein overexpression. In addition, FGFR4/FGF19 genomic testing data were missing in 52.2% of patients in the dose-escalation cohort; however, this reflects the design of Part 1, which enrolled patients regardless of FGFR4/FGF19 alteration status. Expansion cohorts had been planned for these analyses to explore the predictive and prognostic significance of FGF19 and FGFR4 alterations on patient outcome. Importantly, inclusion of other histology/tumor types led to hypothesis-generating clinical observations that would have been explored in the planned expansion cohorts. For example, the only partial responder in the present study had heavily pretreated ovarian cancer. Recent retrospective and translational analyses indicate that FGFR4 overexpression is associated with a worse outcome in advanced ovarian cancer, and that blockade of ligand-dependent FGFR4 activation is deleterious to ovarian cancer cell growth in vitro and in vivo [13]. Finally, although only a minority of patients had C4 concentrations exceeding the C4 concentration cut-off initiated  with the protocol amendment, this additional eligibility criterion served to slow accrual and thus further narrowed a pool of patients with an already infrequent FGF19/FGFR4 variant. Indeed, the C4 threshold was established based on a limited sample size using an assay not certified by the Clinical Laboratory Improvement Amendments (CLIA) while the study was ongoing, without statistical power for robust analysis. In retrospect, C4 levels should be embedded as an integrated biomarker of toxicity. Nevertheless, the data presented herein help to credential INCB062079 as a bona fide clinical grade inhibitor of FGFR4, provide useful information for future drug development of agents blocking FGFR4, and support continued investigation to determine the relevance of the FGF19/FGFR4 axis as a target in solid tumors.