Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study ...evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements.
In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed.
Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6–21·3). 38 (35·5% 95% CI 26·5–45·4) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 60% of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 12%), arthralgia (nine 6%), stomatitis (eight 5%), hyponatraemia (eight 5%), abdominal pain (seven 5%), and fatigue (seven 5%). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven 5%), pyrexia (seven 5%), cholangitis (five 3%), and pleural effusion (five 3%). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 42%); no deaths were deemed to be treatment related.
These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements.
Incyte Corporation.
FGFR2 rearrangements resulting in dysregulated signaling are drivers of cholangiocarcinoma (CCA) tumorigenesis, and occur almost exclusively in intrahepatic CCA. Pemigatinib, a selective, potent, ...oral inhibitor of FGFR1-3, has demonstrated efficacy and safety in a Phase II study of patients with previously treated locally advanced/metastatic CCA harboring
fusions/rearrangements. We describe the study design of FIGHT-302, an open-label, randomized, active-controlled, multicenter, global, Phase III study comparing the efficacy and safety of first-line pemigatinib versus gemcitabine plus cisplatin in patients with advanced CCA with
rearrangements (NCT03656536). The primary end point is progression-free survival; secondary end points are objective response rate, overall survival, duration of response, disease control rate, safety and quality of life. Clinical Trial Registration: NCT03656536 (ClinicalTrials.gov).
Pemigatinib is a fibroblast growth factor receptor-2 (FGFR2) inhibitor approved for use in patients with previously treated cholangiocarcinoma (CCA) and FGFR2 fusions or rearrangements. This ongoing ...global Expanded Access Program (EAP) allows physicians in regions where pemigatinib is not commercially available to request pemigatinib for patients with locally advanced or metastatic CCA who, in the physician's opinion, could benefit from pemigatinib treatment.
Eighty-nine patients from Europe, North America, and Israel were treated from January 2020 through September 2021.
Patients had FGFR gene fusions (68.5%), rearrangements (12.4%), translocations (5.6%), amplifications (2.2%), and other alterations (11.2%). Median duration of treatment in the EAP was 4.0 months (range, 0.1-13.6). The most frequently reported adverse event (AE) was hyperphosphatemia (22.5%); the most common serious AE was cholangitis (3.4%). Treatment discontinuation was associated with reports of AEs for seven patients (7.9%). AEs associated with pemigatinib were consistent with those observed in clinical trials.
Efficacy was not assessed in this EAP. However, some patients remained on treatment for up to a year, suggesting that they observed a benefit from treatment. Patients with CCA should undergo molecular testing to identify those who could benefit from targeted treatments such as pemigatinib.
Oncogenic fibroblast growth factor receptor (FGFR) gene alterations have been described in patients with cholangiocarcinoma (CCA). This post hoc analysis assessed progression-free survival (PFS) in ...patients who had received first- or second-line systemic therapy for advanced/metastatic CCA before enrollment in the phase II FIGHT-202 study (ClinicalTrials.gov identifier: NCT02924376).
Patients with locally advanced or metastatic CCA with
fusions/rearrangements (n = 107), other
alterations (n = 20), or no
alterations (n = 18) and documented disease progression after at least one systemic cancer therapy before enrollment in FIGHT-202 were assessed. Prior therapy and disease response data were collated from electronic case report forms. PFS was calculated for each prior line of systemic cancer therapy.
Among patients with
fusions/rearrangements, other
/
alterations, and no
/
alterations, respectively, the median PFS with prior first-line systemic therapy was 5.5 months (95% CI, 4.0 to 8.0; n = 102), 4.4 months (2.7 to 7.1; n = 19), and 2.8 months (1.6 to 11.3; n = 16); the median PFS with prior second-line systemic therapy was 4.2 months (3.0 to 5.3; n = 39), 3.0 months (1.1 to 9.9; n = 8), and 5.9 months (2.4 to 12.5; n = 6). The median PFS was 7.0 months (4.9 to 11.1) for patients with
fusions/rearrangements (n = 65) with second-line pemigatinib received during the FIGHT-202 trial.
In patients with CCA and
fusions or rearrangements, second-line treatment with pemigatinib may be associated with longer PFS compared with second-line treatment with systemic therapy received before study enrollment; however, a prospective controlled trial is required to confirm this. The results support the therapeutic potential of pemigatinib previously demonstrated in FIGHT-202.
Abstract
Background: Aberrant FGFR signaling results in tumor cell proliferation, migration, and survival, as well as angiogenesis, and is implicated in the development and progression of many ...cancers, including urothelial carcinoma (UC). Ten to 15% of patients with advanced UC have FGFR3 mutations and 6% have an FGFR3 translocation. INCB054828 is a novel, selective, orally administered inhibitor of FGFR1, FGFR2, and FGFR3 tyrosine kinase activities (AACR 2015; Abstract 771).
Methods: This phase 2, open-label trial will evaluate INCB054828 monotherapy for histologically confirmed metastatic or unresectable UC (NCT02872714; Table). Eligible patients will have known FGF/FGFR alterations, will be ≥18 years of age, have Eastern Cooperative Oncology Group performance status ≤2, adequate liver and renal function, and have life expectancy ≥12 wks. Patients will have inadequate response to ≥1 previous treatment in this setting or will be platinum-ineligible, and must not have received any investigational drugs within 21 days of first dose, including selective FGFR inhibitors. Patients will self-administer INCB054828 orally once daily at a starting dose of 13.5 mg on a 21-day 2-weeks-on and 1-week-off cycle. Patients will receive treatment until disease progression or unacceptable toxicity. The primary endpoint will be objective response rate (complete plus partial responses assessed from CT scans or MRI per investigator using Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints will include safety, duration of response, progression-free survival, and overall survival. Exploratory endpoints will include predictive biomarker assessment. The study is currently recruiting; 96 patients are planned for the primary analysis (estimated to occur in March 2018).
Study DesignPrescreen for FGF/FGFR Status• Adults with metastatic/surgically unresectable urothelial carcinoma with inadequate response to ≥1 previous treatment or platinum-ineligible- Positive for FGF/FGFR alterations → continue screening- Negative for FGF/FGFR alterations → discontinue studyScreen for eligibility criteria and patient characteristics• Eastern Cooperative Oncology Group performance status ≤2• Adequate hepatic function (total bilirubin ≤1.5 × upper limit of normal ULN; ≤2.5 × ULN for Gilbert syndrome or liver metastasis; aminotransferases <2.5 × ULN <5 × ULN for liver metastases)• Adequate renal function (creatinine clearance ≥30 mL/min; serum phosphate >institutional ULN; serum calcium >institutional normal range)• Life expectancy ≥12 weeksEnroll and start INCB054828 treatment• Oral once daily dosing: 21-day (2-weeks-on/1-week-off) cycleStart clinical assessment after cycle 3• Stable disease/partial or complete response → continue treatment on 21-day cycle; clinical assessments every 3 cycles• Disease progression → discontinue treatment; safety and survival follow-up
Citation Format: Neal D. Shore, Ekaterine Asatiani, Christine F. Lihou, Huiling Zhen, Sumati Gupta. Phase 2, open-label, multicenter study of the efficacy and safety of INCB054828 for metastatic or surgically unresectable urothelial carcinoma harboring fibroblast growth factor (FGF)/FGF receptor (FGFR) alterations abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT059. doi:10.1158/1538-7445.AM2017-CT059
Abstract
Background: Dysregulation of FGFR signaling is strongly implicated in the establishment and progression of many cancers; rearrangements in chromosome 8p11 leading to activation of FGFR1 have ...been associated with rare but aggressive myeloid and lymphoid neoplasms with eosinophilia. INCB054828 is a novel, selective, orally administered inhibitor of FGFR1, FGFR2, and FGFR3 tyrosine kinase activities (AACR 2015; Abstract 771).
Methods: This open-label, single-arm, phase 2 study will evaluate the efficacy and safety of INCB054828 monotherapy in patients with myeloid/lymphoid neoplasms with FGFR1 rearrangement (Table; NCT03011372). Eligible patients are ≥18 years of age, have documented lymphoid or myeloid neoplasm with 8p11 rearrangement known to lead to FGFR1 activation and have an Eastern Cooperative Oncology Group performance status ≤2. In addition, patients must not be candidates for stem cell transplant (or must have relapsed after transplant and delayed lymphocyte infusion); must have progressed on ≥1 prior anticancer treatment; must not be eligible for other disease-modifying therapies. Patients will self-administer INCB054828 orally, once-daily at a starting dose of 13.5 mg on a 21-day cycle (2 wks on; 1 wk off); treatment will continue until disease progression or unacceptable toxicity occurs. The primary endpoint will be overall clinical benefit rate (proportion of patients with complete or partial response, complete hematologic response, cytogenetic response, marrow response see Table for response criteria, or clinical benefit). Secondary endpoints will include duration of response/clinical benefit, progression-free survival, overall survival, and safety. The study is currently recruiting (planned enrollment, n~46); primary analysis is expected in January 2019.
Study DesignScreen for eligibility criteria and patient characteristics• Documented lymphoid/myeloid neoplasm with 8p11 rearrangement known to lead to FGFR1 activation• Not candidates for stem cell transplantation (or have relapsed after transplantation and delayed lymphocyte infusion); progression on ≥1 prior anticancer treatment; not suitable for other disease-modifying therapies• Eastern Cooperative Oncology Group performance status ≤2• Adequate hepatic function (total bilirubin ≤1.5 × upper limit of normal ULN; ≤2.5 × ULN for Gilbert syndrome or disease involving liver; aminotransferases <2.5 × ULN <5 × ULN with disease involving liver)• Adequate renal function (creatinine clearance ≥30 mL/min; serum phosphate >institutional ULN; serum calcium within institutional normal range)• Life expectancy ≥12 weeksEnroll and initiate INCB054828 treatment• Oral once daily dosing: 21-day (2-weeks-on/1-week-off) cycleStart disease assessment* after cycle 2• Stable disease/partial or complete response → continue treatment on 21-day cycle• Disease progression → discontinue treatment; safety and survival follow-up*Bone marrow (BM) aspirates every 3 cycles starting from cycle 2 day 1 until month 12; then every 12 cycles until month 24 for patients with confirmed complete cytogenetic response; then every 12 months until disease progression or end of treatment. Response criteria are:• Complete response (CR): presence of all the following (1) bone marrow: ≤5% myeloblasts; 0% lymphoblasts; (2) peripheral blood: WBC ≤10x109/L; Hgb ≥11 g/dL; ≥100×109/L platelets ≤450×109/L; neutrophils ≥1.0×109/L; blasts 0%; neutrophil precursors ≤2%; monocytes ≤1×109/L; eosinophils ≤0.5×109/L; (3) prior extramedullary disease completely resolved• Complete cytogenetic response (CCyR): no 8p11 translocations• Complete hematologic response (CHR): see (2) under CR• Complete marrow response (CMR): see (1) under CR
Citation Format: Srdan Verstovsek, Alessandro Rambaldi, Ekaterine Asatiani, Christine F. Lihou, Huiling Zhen, Andreas Hochhaus. Phase 2, open-label, multicenter study to evaluate the efficacy and safety of INCB054828 in patients with myeloid/lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) rearrangement abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT057. doi:10.1158/1538-7445.AM2017-CT057
Abstract only
TPS4145
Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR translocations and activating mutations is implicated in many cancers, including CCA. ...FGFR2 translocation, the most common FGFRalteration, occurs in ~13% of pts with intrahepatic CCA. INCB054828 is a novel, orally available, selective inhibitor of FGFR1, FGFR2, and FGFR3 tyrosine kinase activity (AACR 2015; Abstract 771). Methods: This phase 2, open-label trial will evaluate INCB054828 monotherapy in pts with advanced/metastatic or unresectable CCA (NCT02924376). Pts will be prescreened locally or centrally for FGF/FGFR status prior to enrollment (Table): FGFR2 translocation (Cohort A); other FGF/FGFR alteration (Cohort B); no FGF/FGFR alteration (Cohort C; negative control for effects of FGF/FGFR alteration on objective response rate ORR). Eligibility criteria include: age ≥18 years; ECOG performance status ≤2; adequate liver and renal function; life expectancy ≥12 wks; disease progression after ≥1 prior systemic therapy; no prior use of selective FGFR inhibitors. Pts will self-administer INCB054828 orally at a starting dose of 13.5 mg QD on a 21-day cycle (2 wks on; 1 wk off); treatment will continue until disease progression or unacceptable toxicity. The primary endpoint will be ORR (complete or partial response, independent radiologic review committee, RECIST v1.1) in pts with FGFR2 translocation (Cohort A). Secondary endpoints include ORR in pts positive or negative for any FGF/FGFRalteration and duration of response, PFS, OS, and safety (all cohorts). The study has currently enrolled 2 pts (recruitment ongoing; estimated primary completion, April 2018). Clinical trial information: NCT02924376. Table: see text
Abstract
Background
Dysregulated fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling resulting from oncogenic FGFR alterations is implicated in many cancers. Pemigatinib (INCB054828) is an ...oral, selective FGFR1, 2, and 3 inhibitor. This phase 1, multisite, open-label study evaluated pemigatinib in Japanese patients (pts) with advanced malignancies (NCT03235570).
Methods
Japanese pts (≥20 y) in part 1 (dose escalation) had advanced solid tumors and no standard therapies available. Pts in part 2 (dose expansion) had measurable disease with FGF/FGFR alterations. Part 1 pts were enrolled using a 3 + 3 design to receive pemigatinib starting at 9 mg QD and then at 13.5 mg QD, each on 21-d 2-wk on/1-wk off intermittent dosing cycles. Part 2 pts started at the recommended phase 2 dose (RP2D). Primary endpoint was safety.
Results
As of the data cutoff (January 18, 2019), 25 pts were enrolled (part 1, n = 9; part 2, n = 16). Median age was 63 (range, 32-79) y; 16 pts were men; 24 pts discontinued therapy, mainly due to disease progression (n = 21). Most common tumors were esophageal (n = 5) and cholangiocarcinoma (n = 3). No dose-limiting toxicities occurred; the RP2D was 13.5 mg QD (intermittent dosing). Most common adverse events (AEs) were hyperphosphatemia (n = 19), dysgeusia (n = 9), alopecia (n = 8), constipation, diarrhea, nausea, and decreased appetite (each, n = 7); most frequent grade ≥3 AEs were anemia, cholangitis, and decreased appetite (each, n = 2). One pt with metastatic adenocarcinoma and FGFR2 amplification had a partial response (ongoing at cutoff); 9 pts had stable disease. At 13.5 mg, steady-state geometric mean (%CV) maximum concentration was 159 nmol/L (88.5%), area under the curve was 2300 h·nmol/L (58.5%), and terminal half-life was 14.0 h (42.1%).
Conclusions
In these Japanese pts with advanced malignancies, the pemigatinib tolerability profile is consistent with previous reports; pharmacokinetics are similar to Western populations. Recruitment is ongoing.
Abstract only
4080
Background: Genomic studies of cholangiocarcinoma (CCA) have identified actionable alterations in multiple genes including IDH1, IDH2, FGFR2 and BRAF, but no targeted therapies ...have been approved for this indication. Pemigatinib (formerly INCB054828) is a selective FGFR1-3 inhibitor currently being evaluated in multiple tumor types, including advanced CCA harboring FGFR2 rearrangements. Comprehensive genomic profiling (CGP) was used to identify and enroll advanced CCA patients with FGFR2 rearrangements into FIGHT-202 (NCT02924376). Here we provide an overview of the genomic landscape of advanced CCA and identify actionable alterations. Methods: CGP was performed on tumor samples from 1104 patients with advanced CCA using FoundationOne, a broad-based genomic panel which identifies mutations, rearrangements, and amplifications in 315 cancer genes. Results: The most frequently altered genes in advanced CCA were TP53 (38.1%), CDKN2A/B (28.8%), KRAS (21.9%), ARID1A (15.7%), SMAD4 (11.3%), BAP1 (10.6%), IDH1 (10.5%), PBRM1 (10.0%), FGFR2 (9.4%), ERBB2 (7.6%), PIK3CA (7.0%), MDM2/ FRS2 (5.8%), and BRAF (4.7%). FGFR2: BAP1 was the most significantly co-occurring alteration pair (odds ratio = 8.5; q-value = 1.08 x 10
-13
, Fisher’s exact test). 42.9% of patients had at least one alteration for which a targeted agent has been either approved or is under investigation. 91 (8.2%) patients had FGFR2 rearrangements, involving 44 unique partner genes, 37 (84.1%) of which were observed only once. The most prevalent FGFR2 rearrangement partner, BICC1, occurred in only 28 (30.7%) FGFR2 rearrangement positive patients. FGFR2 activating point mutations were found in 13 (1.2%) patients. Of 1,091 evaluable patients for microsatellite instability (MSI) or tumor mutational burden (TMB), only 10 (0.9%) were MSI-H and 13 (1.2%) had high TMB (≥ 20 mutations/megabase). None of the MSI-H or TMB-High patients had FGFR2, IDH1 or IDH2 activating alterations. Conclusions: The high frequency (42.9%) of patients with actionable alterations and myriad FGFR2 rearrangement partners strongly support the use of fusion partner-agnostic CGP in advanced CCA.
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