Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study
Milind Javle, Sameek Roychowdhury, Robin Kate Kelley, Saeed Sadeghi, Teresa Macarulla, Karl Heinz Weiss, Dirk-Thomas Waldschmidt,
Lipika Goyal, Ivan Borbath, Anthony El-Khoueiry, Mitesh J Borad, Wei Peng Yong, Philip A Philip, Michael Bitzer, Surbpong Tanasanvimon, Ai Li, Amit Pande, Harris S Soifer, Stacie PeacockShepherd, Susan Moran, Andrew X Zhu, Tanios S Bekaii-Saab, Ghassan K Abou-Alfa
Summary
Background Treatment options are sparse for patients with advanced cholangiocarcinoma after progression on first- line gemcitabine-based therapy. FGFR2 fusions or rearrangements occur in 10–16% of patients with intrahepatic cholangiocarcinoma. Infigratinib is a selective, ATP-competitive inhibitor of fibroblast growth factor receptors. We aimed to evaluate the antitumour activity of infigratinib in patients with locally advanced or metastatic cholangiocarcinoma, FGFR2 alterations, and previous gemcitabine-based treatment.
Methods This multicentre, open-label, single-arm, phase 2 study recruited patients from 18 academic centres and hospitals in the USA, Belgium, Spain, Germany, Singapore, Taiwan, and Thailand. Eligible participants were aged 18 years or older, had histologically or cytologically confirmed, locally advanced or metastatic cholangiocarcinoma and FGFR2 fusions or rearrangements, and were previously treated with at least one gemcitabine-containing regimen. Patients received 125 mg of oral infigratinib once daily for 21 days of 28-day cycles until disease progression, intolerance, withdrawal of consent, or death. Radiological tumour evaluation was done at baseline and every 8 weeks until disease progression via CT or MRI of the chest, abdomen, and pelvis. The primary endpoint was objective response rate, defined as the proportion of patients with a best overall response of a confirmed complete or partial response, as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors, version 1.1. The primary outcome and safety were analysed in the full analysis set, which comprised all patients who received at least one dose of infigratinib. This trial is registered with ClinicalTrials.gov, NCT02150967, and is ongoing.
Findings Between June 23, 2014, and March 31, 2020, 122 patients were enrolled into our study, of whom 108 with FGFR2 fusions or rearrangements received at least one dose of infigratinib and comprised the full analysis set. After a median follow-up of 10·6 months (IQR 6·2–15·6), the BICR-assessed objective response rate was 23·1% (95% CI 15·6–32·2; 25 of 108 patients), with one confirmed complete response in a patient who only had non-target lesions identified at baseline and 24 partial responses. The most common treatment-emergent adverse events of any grade were hyperphosphataemia (n=83), stomatitis (n=59), fatigue (n=43), and alopecia (n=41). The most common ocular toxicity was dry eyes (n=37). Central serous retinopathy-like and retinal pigment epithelial detachment-like events occurred in 18 (17%) patients, of which ten (9%) were grade 1, seven (6%) were grade 2, and one (1%) was grade 3. There were no treatment-related deaths.
Interpretation Infigratinib has promising clinical activity and a manageable adverse event profile in previously treated patients with locally advanced or metastatic cholangiocarcinoma harbouring FGFR2 gene fusions or rearrangements, and so represents a potential new therapeutic option in this setting.
Funding QED Therapeutics and Novartis.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Lancet Gastroenterol Hepatol
2021; 6: 803–15
Published Online August 3, 2021 https://doi.org/10.1016/
S2468-1253(21)00196-5
See Comment page 773
Department of Gastrointestinal Medical Oncology,
MD Anderson Cancer Center,
Houston, TX, USA
(Prof M Javle MD); James Cancer Hospital (S Roychowdhury MD) and Department of Internal Medicine (S Roychowdhury), Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; Department of Medicine, Division of Hematology/ Oncology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA (R K Kelley MD); Division of Hematology and Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA (S Sadeghi MD); Department of Medical Oncology, Hospital Vall d’Hebron, Barcelona, Spain
(T Macarulla MD); Internal Medicine, Salem Medical Center, Heidelberg, Germany (Prof K H Weiss MD); Internal Medicine IV, University Hospital Heidelberg,
Heidelberg, Germany (Prof K H Weiss); Clinic for Gastroenterologie and
Hepatologie, Klinikum der Universität zu Köln, Cologne,
Germany
(D-T Waldschmidt MD);
Introduction
Cholangiocarcinoma is a rare and aggressive malignancy that typically presents at diagnosis as locally advanced or metastatic disease.1 The per-capita incidence of cholangiocarcinoma is highest in northeastern Thailand and lowest in Canada.2 In the USA, the incidence of intrahepatic cholangiocarcinoma increased between 2000 and 2015, with an annual percentage change of
5·06%,3 and an estimated 8000 new cases of cholangio- carcinoma are diagnosed annually.4 Patients with metastatic disease survive for an estimated median of 11·7 months (95% CI 9·5–14·3) from the time of diagnosis5 and the 5-year relative survival rate for patients with metastatic intrahepatic cholangiocarcinoma is 2%.4
First-line treatment options for patients with locally advanced or metastatic cholangiocarcinoma include
Hematology/Oncology
(L Goyal MD) and Medicine (Prof A X Zhu MD), Massachusetts General Hospital Cancer Center, Boston, MA, USA; Department of Hepato-gastroenterology, Cliniques Universitaires St Luc,
Brussels, Belgium
(Prof I Borbath MD); Division of
Research in context
Evidence before this study progressed on one or more previous treatment lines. Accrual Treatment options for patients with cholangiocarcinoma after into cohort 1, which includes 108 patients with FGFR2 fusions progression on first-line gemcitabine-based therapy are sparse or other rearrangements, is now complete. We observed
and prognosis is poor. Identification of molecular drivers objective, confirmed responses in 25 patients (objective implicated in the development of specific cholangiocarcinoma response rate 23·1%, 95% CI 15·6–32·2), with responses in all subtypes is changing the standard of care in this disease. subgroups studied, including in patients who had two or more These drivers include genomic alterations in the fibroblast previous treatment lines. The adverse event profile of
growth factor receptor (FGFR), particularly FGFR2 fusions or infigratinib was consistent with previous reports and in line rearrangements, which have been shown to drive with reported class effects of these agents. Cohorts 2 and 3 are tumourigenesis in cholangiocarcinoma and other cancers. ongoing and will provide further insight into the activity of
We searched PubMed for articles published in English between infigratinib in patients with other FGFR alterations and in those Jan 1, 2010, and Jan 6, 2021, using the search terms “advanced previously exposed to FGFR inhibitors other than infigratinib.
OR metastatic, cholangiocarcinoma OR biliary tract cancer”, Implications of all the available evidence “treatment”, and “FGFR OR fibroblast growth factor receptor”. Infigratinib, administered as a second-line or later-line We identified six reports describing clinical trials of FGFR
inhibitors in patients with cholangiocarcinoma harbouring treatment, showed meaningful clinical activity against
alterations in the genes coding for fibroblast growth factors chemotherapy-refractory cholangiocarcinoma with FGFR2 and FGFRs, reflecting the relative novelty of this approach. fusions or rearrangements. Adverse events were largely Only two completed phase 2 studies, involving infigratinib and reversible and manageable, and consistent with previous pemigatinib, have been reported to date. observations in this patient population. The encouraging
findings from this study have resulted in the initiation of a
Added value of this study phase 3 study of infigratinib versus gemcitabine–cisplatin in the Our study is an ongoing, open-label, multicohort, phase 2 study first-line setting (NCT03773302). Infigratinib represents a evaluating the safety and activity of infigratinib in patients with potential new therapeutic option for patients with
locally advanced or metastatic cholangiocarcinoma that has cholangiocarcinoma and FGFR fusions or rearrangements.
Medical Oncology, USC Norris Comprehensive Cancer Center, Keck School of Medicine,
Los Angeles, CA, USA (A El-Khoueiry MD); Department of Medical Oncology and Hematology (T S Bekaii-Saab MD) and Department of Internal
Medicine (M J Borad MD), Mayo Clinic, Scottsdale, AZ, USA; National University Cancer Institute Singapore, National University Health System, Singapore (W P Yong MBChB); Cancer Science Institute of Singapore, National University of Singapore, Singapore
(W P Yong MBChB); Karmanos Cancer Institute, Detroit, MI,
USA (P A Philip MD); Department of Internal Medicine I (M Bitzer MD) and Center for Personalized Medicine (M Bitzer), Eberhard- Karls University, Tübingen, Germany; Internal Medicine, Chulalongkorn University,
Bangkok, Thailand (S Tanasanvimon MD); Biostatistics and Data Management (A Li PhD),
Clinical Development (A Pande MD, S P Shepherd MD, S Moran MD), and Translational Medicine (H S Soifer PhD), QED Therapeutics, San Francisco, CA, USA; Jiahui International Cancer Center, Jiahui Health, Shanghai, China (Prof A X Zhu); Memorial Sloan Kettering Cancer Center, New York, NY, USA (Prof G K Abou-Alfa MD); Weill Medical College at Cornell University, New York, NY, USA
(Prof G K Abou-Alfa)
Correspondence to: Prof Milind Javle, Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA [email protected]
gemcitabine plus cisplatin, which is the only regimen for which National Comprehensive Cancer Network level 1 evidence is available (based on the results of the ABC-02 study).5,6 Second-line options include fluorouracil–folinic acid–oxaliplatin (FOLFOX),7 gemcitabine-based combi- nations, or fluorouracil-based combinations, although there is insufficient evidence to recommend specific regimens in this setting.8
Molecular drivers implicated in the development of specific cholangiocarcinoma subtypes have been identified,9,10 including genomic alterations in the fibroblast growth factor receptor (FGFR) genes that result in constitutively active FGFR signalling. These FGFR alterations have been implicated in cholangiocarcinoma11 and urothelial cancer.12 FGFR2 fusions or rearrangements (fusion events) have been identified in 10–16% of patients with intrahepatic cholangiocarcinoma.13,14 Second-line or later-line chemotherapy has limited efficacy in FGFR- altered cholangiocarcinoma. Among 37 patients with advanced cholangiocarcinoma and FGFR2 fusions who were undergoing third-line treatment with an FGFR inhibitor, retrospective analysis of outcomes associated with the second-line regimen identified a median progression-free survival of 4·6 months (95% CI 2·7–7·2) and an objective response rate of 5·4%.15 Available literature does not show a clear advantage for second-line chemotherapy in patients with FGFR2 fusion-positive versus FGFR2 wild-type cholangiocarcinoma and this
topic is an intense area of investigation because of the small, retrospective nature of existing studies.16
Phase 1 and 2 trials with FGFR inhibitors, including infigratinib, have shown single-agent complete and partial responses, per Response Evaluation Criteria in Solid Tumours (RECIST), in patients with cholan- giocarcinoma harbouring FGFR2 fusions and the development of treatment resistance through mutations in FGFR2,17 further supporting FGFR2 fusions as a therapeutic target for molecularly selected patients with cholangiocarcinoma.17,18 Currently, only two FGFR inhibitors have received accelerated approval by the US Food and Drug Administration (FDA) for the targeted treatment of advanced solid malignancies: erdafitinib for patients with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 or FGFR2 alterations and progression following at least one line of previous platinum-containing chemotherapy,19 and pemigatinib for patients with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion.20 Futibatinib has also received break- through therapy designation by the FDA for the treatment of patients with previously treated, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions and other rearrangements.21 Given the hetero- geneous nature of FGFR alterations and the emergence of resistance mechanisms, more agents able to effectively inhibit FGFR alterations are needed.
Infigratinib (BGJ398) is an orally bioavailable, potent, selective ATP-competitive inhibitor of FGFRs.22,23 Infigratinib selectively inhibits the kinase activity of FGFR-1, FGFR-2, and FGFR-3, with single-digit nano- molar inhibitory concentration values.23 Infigratinib has shown single-agent activity and a manageable safety profile against tumours with FGFR alterations in early clinical studies.24
We aimed to evaluate the antitumour activity of infigratinib in patients with locally advanced or metastatic cholangiocarcinoma, FGFR2 alterations, and previous gemcitabine-based treatment.25 Interim results, which included safety and activity data from 71 patients in cohort 1, have previously been reported.26 We now report a mature analysis after completing accrual in cohort 1.
Methods
Study design and participants
This multicentre, open-label, single-arm, phase 2 study was done in patients with unresectable, locally advanced or metastatic cholangiocarcinoma with FGFR alterations who had previously received gemcitabine, with or without cisplatin or carboplatin, in the advanced or metastatic setting. Patients were recruited from 18 academic centres and hospitals in the USA, Belgium, Spain, Germany, Singapore, Taiwan, and Thailand. The study design comprised three cohorts. Cohort 1, which has completed enrolment, comprises patients with FGFR2 fusions or rearrangements who had not received previous selective FGFR inhibitors and is the focus of this Article. Cohort 2, which is still ongoing, comprises patients with FGFR1 mutations and fusions or rearrangements, FGFR3 mutations and fusions or rearrangements, or FGFR2 mutations, who have not previously received an FGFR inhibitor. Cohort 3 is recruiting patients with FGFR2 fusions or rearrangements who had received previous treatment with an FGFR inhibitor other than infigratinib. Eligible patients in cohort 1 were aged 18 years or older and had histologically or cytologically confirmed cholangiocarcinoma. Patients with cancer of the gall- bladder or ampulla of Vater were not eligible. Patients were required to have local or central laboratory determination of FGFR2 fusions or rearrangements by a validated test done by an accredited laboratory, previous treatment with at least one regimen containing gemcitabine for advanced or metastatic disease, documented progression following that previous regimen or discontinuation from the previous regimen because of toxicity, an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less (with an ECOG performance status of 2 considered on a case-by- case basis), and evidence of measurable disease according to RECIST, version 1.1. Patients were not eligible if they had been previously treated, or were currently being treated, with a mitogen-activated protein kinase kinase inhibitor, infigratinib, or another selective FGFR inhibitor. Patients were also excluded if they
had neurological symptoms related to an underlying disease that required increasing doses of corticosteroids, current evidence of corneal or retinal disorders (con- firmed by ophthalmic examination), or a history or current evidence of extensive tissue calcification. Patients with an absolute neutrophil count of less than 1000 cells per μL, a platelet count of less than 75 000 platelets per μL, a haemoglobin concentration of less than 9·0 g/dL, a total bilirubin concentration of more than 1·5-times the upper limit of normal (ULN), aspartate aminotransferase and alanine aminotrans- ferase concentrations of more than 2·5 × the ULN (>5 ×the ULN in the presence of liver metastases), a serum creatinine concentration of more than 1·5-times the ULN, and a calculated or measured creatinine clearance of less than 45 mL/min, were excluded. The full eligibility criteria can be found in the appendix (pp 1–3). The study protocol was approved by national or institutional ethics committees at participating sites. The study was done in accordance with the Declaration of Helsinki. All patients provided written informed consent
(including for FGFR pre-screening).
Procedures
FGFR2 fusion status was determined from tumour tissue by local or institutional laboratory tests via next-generation sequencing, fluorescence in situ hybridisation, or quantitative RT-PCR (qRT-PCR), or by a central laboratory via a next-generation sequencing assay (FoundationOne; Foundation Medicine, Cambridge, MA, USA). Local or central laboratory tests reporting FGFR2 fusion status were reviewed by the study personnel for compliance with the study protocol. Patients were treated with 125 mg of oral infigratinib once daily, taken in the morning 1 h or more before, or 2 h or more after, a meal, for 21 consecutive days of 28-day cycles, as previously described.24 Patients took the first dose of infigratinib at their study centre. On the days when pharamacokinetics sampling was done, patients also took their dose of infigratinib at their study centre. Treatment continued until disease progression, intolerance, withdrawal of consent, or death. Infigratinib treatment interruptions (of up to 14 days) and dose modifications were allowed for the management of adverse events. Dose modification criteria are shown in the appendix (pp 4–9).
Laboratory assessments (haematology and clinical chemistry) were done at baseline, on days 1, 8, 15, and 21
of cycle 1, days 1 and 15 of cycle 2, and day 1 of each cycle thereafter.
Hyperphosphataemia is a known side-effect of treatment with infigratinib and other selective FGFR inhibitors. Use of a phosphate-binding agent, such as oral sevelamer, was recommended for patients with hyperphosphataemia (serum phosphate concentration
>5·5 mg/dL). Patients took sevelamer on days when infigratinib was administered, according to the prescribing information (appendix p 3) and institutional
See Online for appendix
guidelines. Patients with hyperphosphataemia were instructed to remain on a low-phosphate diet.
Radiological tumour evaluation was done at baseline and every 8 weeks until disease progression via CT or MRI of the chest, abdomen, and pelvis. Tumour response was assessed by investigators and by blinded independent central review (BICR) according to RECIST, version 1.1. All objective responses required confirmation by repeat scan done at least 4 weeks after the criteria for response were first met.
Eye disorders, including central serous retinopathy-like and retinal pigment epithelial detachment-like events, were also adverse events of special interest because, like hyperphosphataemia, ocular disorders are a known side- effect of treatment with infigratinib and other selective FGFR inhibitors. Patients had visual field testing and optical coherence tomography at the screening visit, on day 15 of cycle 1, day 1 of cycles 2 and 3, every 4 months thereafter, and at the end of study treatment for early detection of asymptomatic central serous retinopathy or retinal pigment epithelial detachment.
Outcomes
The primary endpoint was objective response rate, defined as the proportion of patients with a best overall response of a confirmed complete or partial response, as assessed by BICR according to RECIST, version 1.1. Independent review of radiological assessments was introduced in protocol amendment 2 to allow for independent confirmation of the objective response rate. The primary endpoint was changed from investigator- confirmed objective response rate to BICR-assessed objective response rate, supported by BICR-assessed and investigator-assessed duration of response (defined as the time from the date of initial response to the date of disease progression or death due to any cause), in protocol
Figure 1: Trial profile
amendment 4. Secondary endpoints were investigator- assessed objective response rate, BICR-assessed and investigator-assessed best overall response, BICR- assessed and investigator-assessed disease control rate (the proportion of patients with a best overall response of a complete response, partial response, or stable disease [defined as neither sufficient shrinkage to be classified as a complete or partial response, nor an increase in lesions that would be classified as progressive disease]), time to response, BICR-assessed and investigator-assessed progression-free survival (the time from the start of treatment to the event, defined as the first documented progression or death due to any cause) per RECIST (version 1.1), overall survival (defined as the time from the start of treatment to death due to any cause), safety, and tolerability. Results on the biomarker-based secondary endpoints will be published separately. Adverse events were assessed by the investigator according to the Common Terminology Criteria for Adverse Events, version 4.03. Treatment-emergent adverse events were those that started or worsened during the on-treatment period. Treatment-related adverse events were those that were attributed to the study treatment, infigratinib, by either the investigator, the study sponsor, or both.
Statistical analysis
The sample size was calculated to provide a sufficient precision for the estimate of objective response rate. With at least 106 patients with FGFR2 fusions or rearrange- ments in cohort 1, the half-width of the exact 95% CI width of objective response rate was expected not to exceed 10%. Data are summarised by demographic and baseline characteristics, and activity and safety observations and measurements. Categorical data are presented as frequencies and percentages. For continuous data, mean, SD, median, and IQR are presented.
At the time of the first formal interim analysis, which was pre-planned, the interim activity analysis set 1 was intended to include 72 patients with FGFR2 fusions or rearrangements; the half-width of the exact 95% CI for objective response rate was not expected to exceed 12%.
The BICR-assessed objective response rate and the investigator-assessed objective response rate were analysed by use of Clopper–Pearson 95% CIs, accompanied by an analysis of the duration of response to allow for a more complete characterisation of the effect of infigratinib. The Brookmeyer–Crowley method was used to construct 95% CIs for duration of response. The discordance rate between BICR-assessed and investigator-assessed responses was calculated as 1 minus the concordance rate. The concordance rate is the sum of the numbers of participants who were responders in both BICR and investigator assessments and the number of participants who were responders in neither the BICR assessment nor the investigator assessment divided by the total number of participants in the full analysis set. Progression-free survival and overall survival were described by use of the
Race
White
78 (72%)
Asian 11 (10%)
Black 4 (4%)
Other 15 (14%)
Previous chemoembolisation or intra-arterial 3 (3%) therapy
Previous gemcitabine‡ 107 (99%)
Previous cisplatin 84 (78%)
Previous oxaliplatin 27 (25%)
Previous fluorouracil 26 (24%)
Previous treatment with gemcitabine and 83 (77%)
cisplatin in the same regimen
Kaplan−Meier method. All outcomes were analysed in the full analysis set, which comprised all patients who received at least one dose of infigratinib. Outcomes were analysed in pre-specified subgroups stratified by age, lines of previous treatment, sex, and geographical region, and in post-hoc subgroups stratified by baseline ECOG performance status, disease stage, and reason for discontinuing last gemcitabine treatment (due to intolerance vs due to disease progression). Analyses were done by use of SAS, version 9.4. This study is registered with ClinicalTrials.gov, NCT02150967. There was no data monitoring committee.
Role of the funding source
The study was designed by the funders (Novartis and QED Therapeutics, an affiliate of BridgeBio Pharma), with input from the investigators (MJ, MB, and GKA-A). QED Therapeutics compiled and analysed the study data
in collaboration with the corresponding author (MJ), and interpreted data in collaboration with all authors. The corresponding author wrote the first draft of the report with QED Therapeutics and with the help of Miller Medical Communications (funded by QED Therapeutics), which provided medical writing services and supported subsequent drafts developed under the direction of all authors.
0 45 (42%)
1 62 (57%)
2 1 (1%)
Disease stage*
II 1 (1%)
III 0
IV 107 (99%)
Laboratory values
Serum albumin concentration, g/L 37·7 (8·1)
Serum bilirubin concentration, μmol/L 11·4 (6·3)
Extra-hepatic metastasis
Lung 74 (69%)
Lymph nodes 62 (57%)
Bone 28 (26%)
Peritoneum or ascites 16 (15%)
Other 36 (33%)
Results
Between June 23, 2014, and March 31, 2020, (the data cutoff date for this analysis), 122 patients were enrolled into our study, of whom 108 with FGFR2 fusions or rearrangements were included in cohort 1, received at least one dose of infigratinib, and comprised the full analysis set (figure 1). FGFR2 fusion status was determined by local or institutional laboratory tests in 96 (89%) of 108 patients by use of next-generation sequencing (84 [78%] patients), fluorescence in situ hybridisation (nine [8%] patients), or qRT-PCR (three [3%] patients), and by a central laboratory next-generation sequencing assay in 12 (11%) patients.
Patient demographics and clinical characteristics at baseline are shown in table 1. Most patients were female
Overall (n=108) Previous lines of therapy
1 (n=50) 2 (n=32) 3 (n=14) ≥4 (n=12)
BICR-assessed objective response rate 25 (23·1%, 15·6–32·2) 17 (34·0%, 21·2–48·8) 5 (15·6%, 5·3–32·8) 2 (14·3%, 1·8–42·8) 1 (8·3%, 0·2–38·5)
BICR-assessed best overall response
Complete response
1 (1%)
0 0
1 (7%)
0
Partial response 24 (22%) 17 (34%) 5 (16%) 1 (7%) 1 (8%)
Stable disease 66 (61%) 27 (54%) 22 (69%) 10 (71%) 7 (58%)
Unconfirmed complete response or partial response 12 (11%) 4 (8%) 7 (22%) 0 1 (8%)
Progressive disease 11 (10%) 4 (8%) 3 (9%) 1 (7%) 3 (25%)
Unknown 6 (6%) 2 (4%) 2 (6%) 1 (7%) 1 (8%)
BICR-assessed confirmed or unconfirmed response 37 (34·3%, 25·4–44·0) 21 (42·0%, 28·2–56·8) 12 (37·5%, 21·1–56·3) 2 (14·3%, 1·8–42·8) 2 (16·7%, 2·1–48·4)
BICR-assessed disease control rate 91 (84·3%, 76·0–90·6) 44 (88·0%, 75·7–95·5) 27 (84·4%, 67·2–94·7) 12 (85·7%, 57·2–98·2) 8 (66·7%, 34·9–90·1)
BICR-assessed median duration of response (IQR), months 5·0 (3·7–9·3) 5·6 (3·7–9·5) 4·0 (3·7–5·0) NE (4·9–NE) 7·4 (7·4–7·4)
BICR-assessed median progression-free survival (95% CI), months 7·3 (5·6–7·6) 7·3 (5·6–9·3) 7·4 (5·4–7·7) 5·6 (2·8–8·3) 7·6 (1·9–8·8)
Median overall survival (95% CI), months 12·2 (10·7–14·9) 14·5 (10·4–18·6) 10·9 (9·9–14·3) 8·7 (3·5–17·5) 14·4 (6·4–41·1)
Data are n (%, 95% CI) or n (%), unless otherwise indicated. BICR=blinded independent central review. NE=not estimable.
Table 2: Activity endpoints in the full analysis set
and most were White, and the median age was 53 years (table 1). 102 (94%) patients had extra-hepatic metastatic disease, including lung metastases in 74 (69%) patients and bone metastases in 28 (26%) patients. Three patients received previous therapy in the neoadjuvant or adjuvant setting for advanced disease. More than half the patients had received two or more previous lines of therapy (table 1). 107 (99%) of 108 patients had previously received gemcitabine-based regimens, with or without cisplatin, for metastatic disease. The remaining patient had received carboplatin plus paclitaxel, which was reported to the study sponsor and the institution’s review board and inclusion of the patient was approved. Overall, 95 patients progressed on their previous regimen (94 who were on gemcitabine and one who was on carboplatin–paclitaxel). The remaining 13 patients discontinued gemcitabine because of toxicity, nine of whom had progressed on a subsequent anticancer therapy before starting the study treatment. Nine patients had a medical history of hepatitis B or C. At baseline, 51 (47%) patients had mild hepatic dysfunction (total bilirubin concentration >ULN to 1·5 × ULN or aspartate aminotransferase concentration
> ULN) and five (5%) had moderate hepatic dysfunction (total bilirubin concentration >1·5 to 3·0 × ULN, with any aspartate aminotransferase concentration) per National Cancer Institute Organ Dysfunction Working Group hepatic dysfunction categories.
88 (81%) patients had FGFR2 fusions and 20 (19%) had other FGFR2 rearrangements, based on local and central laboratory testing (figure 1; appendix pp 10–11). As reported by others,20 BICC1 was the most frequently reported FGFR2 fusion partner (27 patients [25%]); intron 17 FGFR2 rearrangements were observed in nine (8%) patients, and 44 (41%) patients had fusion partners that were not identified in another patient in cohort 1 (appendix pp 10–11).
At a median follow-up of 10·6 months (IQR 6·2−15·6), the BICR-assessed objective response rate was 23·1% (95% CI 15·6–32·2; 25 of 108 patients), with one confirmed complete response in a patient who only had non-target lesions identified at baseline and 24 partial responses (table 2; figure 2A). 88 (88%) of 100 patients with post-baseline measurements of target lesions had a reduction in BICR-assessed tumour burden (figure 2B).
The median time to response was 3·6 months (IQR 1·8−3·8), the median duration of response was 5·0 months (IQR 3·7–9·3), and the disease control rate was 84·3% (95% CI 76·0–90·6). Investigator-assessed outcomes are shown in the appendix (p 12). The investigator-assessed objective response rate was 30·6% (95% CI 22·1−40·2%; 33 of 108 patients) and the median investigator-assessed duration of response was 6·0 months (IQR 4·9−9·2). The discordance rate (BICR- assessed vs investigator-assessed) for confirmed response was 20·4%, similar to previously reported values.28 The BICR-assessed objective response rate was numerically higher in patients who had one previous line of therapy than in those who had two or more lines (table 2); the median duration of response was 5·6 months (95% CI 3·7–9·5) for those who had one previous line of therapy and 4·9 months (3·7–not estimable [NE]) for those who had two or more lines. At the time of data cutoff, the median progression-free survival was 7·3 months (95% CI 5·6−7·6; 73 [68%] events overall; 63 [58%] with disease progression; ten [9%] deaths; figure 3A) and the median overall survival was 12·2 months (95% CI 10·7−14·9;
70 [65%] events; figure 3B). Median BICR-assessed progression-free survival and overall survival were similar between patients who had one line of previous therapy and those who had two or more lines of previous therapy (median progression-free survival 7·4 months [95% CI 5·6–7·7]; median overall survival 11·8 months [95% CI
Percentage change in tumour burden (%)
Figure 2: Tumour responses
Swimmer plot of treatment duration and best overall tumour response in the full analysis set. (B) Waterfall plot of maximum percentage change in BICR-assessed tumour burden in patients with measurable disease at baseline and at least one post-baseline scan (n=100). One patient with a complete response had only
non-target lesions identified at baseline and is not included in this plot. The dotted line represents a partial response (30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters). BICR=blinded independent central review.
Patients (n=108)
9·9–14·4]). Objective response rates were generally similar in subgroups stratified by age, lines of previous treatment, sex, baseline ECOG performance status, disease stage, the reason for discontinuing the last gemcitabine treatment, and geographical region, as shown in figure 4.
Hyperphosphataemia, stomatitis, fatigue, and alopecia were the most common all-grade treatment-emergent adverse events (table 3). Grade 3 treatment-emergent adverse events occurred in 61 (56%) patients and grade 4 treatment-emergent adverse events occurred in nine (8%)
Overall survival (%)
Figure 3: Survival in the full analysis set
Progression-free survival. (B) Overall survival.
Progression-free survival (%)
patients; six of the grade 4 adverse events were laboratory abnormalities. 34 (31%) patients had a serious adverse event, the most frequently reported being anaemia (n=4), pyrexia (n=4), hypercalcaemia (n=3), and sepsis (n=3). The most common treatment-related adverse events of any grade were hyperphosphataemia and stomatitis (table 3).
The median time to first onset of hyperphosphataemia (an adverse event of special interest, including multiple related preferred terms) was 8 days (IQR 8–15); no patients discontinued treatment because of hyperphos- phataemia. Most patients (87 [81%]) took a concomitant phosphate-binding medication during the study either prophylactically (52 [48%]), or after the first dose of infigratinib (35 [32%]). Of the 35 patients who took a phosphate-binding medication after the first dose of infigratinib, 21 did so during the course of study treatment within 2 weeks after having a phosphate concentration of more than 5·5 mg/dL.
Central serous retinopathy-like and retinal pigment epithelial detachment-like events occurred in 18 (17%) patients, of which ten (9%) were grade 1, seven (6%) were
grade 2, one (1%) was grade 3, none were grade 4, and none were serious. The most common central serous retinopathy-like and retinal pigment epithelial detachment-like events were the appearance of chorio- retinopathy (n=10), subretinal fluid (n=6), and serous retinal detachment (n=3). The median time to first onset of central serous retinopathy-like or retinal pigment epithelial detachment-like events was 39 days (IQR 15–93) and two patients discontinued treatment because of central serous retinopathy or retinal pigment epithelial detachment. Central serous retinopathy-like and retinal pigment epithelial detachment-like events are part of the adverse event of special interest of eye disorder. The median time to first onset of an eye disorder was 25 days (IQR 15–65).
The median duration of treatment with infigratinib was 5·5 months (IQR 3·5−8·7). Overall, 69 (64%) patients had adverse events leading to dose interruption and 65 (60%) had adverse events leading to dose reduction. Treatment-emergent adverse events leading to dose adjustment in 10% or more of patients were
hyperphosphataemia (n=28) and stomatitis (n=13).
16 (15%) patients discontinued infigratinib treatment because of adverse events, and, most commonly, because of subretinal fluid (n=2), fatigue (n=2), and increased blood creatinine concentration (n=2). Five (5%) patients died during the on-study period, all as a result of cholangiocarcinoma. A sixth patient had an adverse event of grade 4 sepsis that was not treatment-related and died 36 days after the last study treatment. Subsequent anticancer treatments administered after the discon- tinuation of infigratinib are shown in the appendix (p 13).
Discussion
These mature results from our study show that infigratinib had meaningful clinical activity in patients with previously treated cholangiocarcinoma harbouring FGFR2 fusions or rearrangements, half of whom were being treated in the third or later line. The confirmed BICR-assessed objective response rate was 23·1% (95% CI 15·6–32·2) and the objective response rate in the second-line setting was 34·0% (21·2–48·8). The median time to response was 3·6 months, the median duration of response was 5·0 months, the median progression-free survival was 7·3 months, and the median overall survival was 12·2 months.
Infigratinib was one of the first FGFR inhibitors to enter early-phase clinical trials and this investigation was done at a time when very few patients with gastrointestinal cancer underwent routine next-generation sequencing. Furthermore, there were no life expectancy requirements in the eligibility criteria, with the result that patients with advanced disease were included after receiving multiple lines of previous therapy. Heavily pre-treated patients might have more toxicities and lesser benefit from anti- cancer therapy. The magnitude of the objective response rate benefit was clinically meaningful and was numerically higher in patients who had one previous line of therapy than in those who had two or more lines. These clinical activity data support earlier evidence of a benefit from infigratinib for previously treated patients with cholangiocarcinoma, patients for whom outcomes have traditionally been very poor.5,7
In our study, patients treated in the second-line setting had a median overall survival of 14·5 months and those treated in the third or later lines had a median overall survival of 8·7–14·4 months. Before the introduction of FGFR inhibition, the standard of care for patients with advanced cholangiocarcinoma after gemcitabine-based therapy was modified FOLFOX. The ABC-06 study,7 in which patients with locally advanced or metastatic biliary tract cancers were recruited, reported a median overall survival of 6·2 months (95% CI 5·4–7·6) for patients treated with modified FOLFOX plus active symptom control and a median overall survival of 5·3 months (4·1–5·8) for patients treated with active symptom control only (hazard ratio 0·69, 95% CI 0·50−0·97; p=0·031), with the recognised caveat that efficacy estimates in
Figure 4: Forest plot of BICR-assessed objective response rate in the subgroup-stratified full analysis set N represents the number of patients who received at least one study treatment. n represents the number of patients with baseline, at least one post-baseline assessment, and a complete response or partial response. The dots represent the objective response rates and the error bars represent the 95% CIs. BICR=blinded independent central review. ECOG=Eastern Cooperative Group.
FGFR2 fusion-positive tumours are unknown in patients treated with FOLFOX. Results of a previous analysis suggest that second-line chemotherapy has little efficacy in patients with cholangiocarcinoma with FGFR2 fusions or rearrangements.15 In the FIGHT-202 study,20 146 previously treated patients with locally advanced or metastatic cholangiocarcinoma and FGFR2 fusions or rearrangements received pemigatinib. Patients had an objective response rate of 35·5% (95% CI 26·5–45·4), a duration of response of 7·5 months (5·7–14·5), a progression-free survival of 6·9 months (6·2–9·6), and an overall survival of 21·1 months (14·8–NE). The FOENIX-CCA2 study29 reported an objective response rate of 37·3% (95% CI 25·8–50·0) and a duration of response of 8·3 months (6·2–NE) in 67 patients with locally advanced or metastatic cholangiocarcinoma and FGFR2 fusions or rearrangements following treatment with futibatinib. Together with the results of our study, these data support the activity of FGFR inhibitors for patients with previously treated cholangiocarcinoma with FGFR2 fusions or rearrangements.
To the best of our knowledge, infigratinib has the largest safety database, along with the longest follow-up data, for an FGFR inhibitor in clinical development. Adverse events were typically reversible, transient, and manageable
Treatment-emergent adverse events Treatment-related adverse events of any grade
Grade 1 Grade 2 Grade 3 Grade 4 Any grade
Any adverse event 8 (7%) 29 (27%) 61 (56%) 9 (8%) 107 (99%) 104 (96%)
Hyperphosphataemia 37 (34%) 35 (32%) 11 (10%) 0 83 (77%) 80 (74%)
Stomatitis 29 (27%) 14 (13%) 16 (15%) 0 59 (55%) 55 (51%)
Fatigue 21 (19%) 18 (17%) 4 (4%) 0 43 (40%) 31 (29%)
Alopecia 34 (31%) 7 (6%) 0 0 41 (38%) 35 (32%)
Dry eye 25 (23%) 11 (10%) 1 (1%) 0 37 (34%) 34 (31%)
Palmar-plantar erythrodysaesthesia syndrome 11 (10%) 18 (17%) 7 (6%) 0 36 (33%) 35 (32%)
Arthralgia 22 (20%) 12 (11%) 0 0 34 (31%) 31 (29%)
Dysgeusia 27 (25%) 7 (6%) 0 0 34 (31%) 28 (26%)
Constipation 22 (20%) 9 (8%) 1 (1%) 0 32 (30%) 10 (9%)
Dry mouth 24 (22%) 3 (3%) 0 0 27 (25%) 23 (21%)
Hypercalcaemia 13 (12%) 8 (7%) 5 (5%) 1 (1%) 27 (25%) 17 (16%)
Blood creatinine concentration increased 19 (18%) 7 (6%) 0 0 26 (24%) 17 (16%)
Diarrhoea 17 (16%) 6 (6%) 3 (3%) 0 26 (24%) 19 (18%)
Dry skin 23 (21%) 2 (2%) 0 0 25 (23%) 22 (20%)
Decreased appetite 16 (15%) 7 (6%) 1 (1%) 0 24 (22%) 16 (15%)
Hypophosphataemia 6 (6%) 4 (4%) 13 (12%) 1 (1%) 24 (22%) 10 (9%)
Blurred vision 13 (12%) 10 (9%) 0 0 23 (21%) 20 (19%)
AST concentration increased 18 (17%) 3 (3%) 2 (2%) 0 23 (21%) 10 (9%)
Vomiting 16 (15%) 6 (6%) 1 (1%) 0 23 (21%) 14 (13%)
Anaemia 8 (7%) 8 (7%) 4 (4%) 0 20 (19%) 6 (6%)
Nausea 11 (10%) 8 (7%) 1 (1%) 0 20 (19%) 11 (10%)
Epistaxis 18 (17%) 1 (1%) 0 0 19 (18%) 10 (9%)
Nail discolouration 17 (16%) 2 (2%) 0 0 19 (18%) 19 (18%)
Abdominal pain 9 (8%) 5 (5%) 4 (4%) 0 18 (17%) 8 (7%)
Dyspepsia 15 (14%) 3 (3%) 0 0 18 (17%) 7 (6%)
Headache 13 (12%) 4 (4%) 1 (1%) 0 18 (17%) 10 (9%)
Pain in extremity 12 (11%) 4 (4%) 2 (2%) 0 18 (17%) 10 (9%)
Onychomadesis 8 (7%) 9 (8%) 0 0 17 (16%) 17 (16%)
ALT concentration increased 10 (9%) 4 (4%) 2 (2%) 0 16 (15%) 9 (8%)
Blood alkaline phosphatase concentration increased 7 (6%) 5 (5%) 4 (4%) 0 16 (15%) 5 (5%)
Nail disorder 9 (8%) 7 (6%) 0 0 16 (15%) 15 (14%)
Pyrexia 12 (11%) 3 (3%) 1 (1%) 0 16 (15%) 1 (1%)
Weight decreased 7 (6%) 7 (6%) 2 (2%) 0 16 (15%) 6 (6%)
Back pain 9 (8%) 5 (5%) 1 (1%) 0 15 (14%) 1 (1%)
Upper abdominal pain 7 (6%) 6 (6%) 1 (1%) 0 14 (13%) 2 (2%)
Hyponatraemia 0 0 14 (13%) 0 14 (13%) 5 (5%)
Insomnia 11 (10%) 3 (3%) 0 0 14 (13%) 1 (1%)
Myalgia 11 (10%) 3 (3%) 0 0 14 (13%) 10 (9%)
Peripheral oedema 13 (12%) 1 (1%) 0 0 14 (13%) 5 (5%)
Onychalgia 7 (6%) 5 (5%) 2 (2%) 0 14 (13%) 13 (12%)
Cough 12 (11%) 1 (1%) 0 0 13 (12%) 2 (2%)
Lacrimation increased 13 (12%) 0 0 0 13 (12%) 11 (10%)
Onycholysis 6 (6%) 7 (6%) 0 0 13 (12%) 13 (12%)
Blepharitis 9 (8%) 3 (3%) 0 0 12 (11%) 10 (9%)
Lipase concentration increased 2 (2%) 3 (3%) 5 (5%) 2 (2%) 12 (11%) 8 (7%)
Trichiasis
Data are n (%). ALT=alanine aminotransferase. AST=aspartate am
Table 3: Treatment-emergent and treatment-related adv 10 (9%)
inotransferase
erse events in 2 (2%)
.
the full analys 0
is set (n=108 0
) 12 (11%) 11 (10%)
class effects of the FGFR inhibitors, as previously observed.25,26,30 On-target toxicities of FGFR inhibitors, including changes in calcium−phosphate homoeostasis, ocular toxicity (eg, central serous retinopathy and retinal pigment epithelial detachment), and changes in the skin and nails, can be managed with close monitoring, dose interruption, reduction, or both, supportive care (eg, eye drops), dietary modification, and concomitant medications, thereby avoiding premature treatment discontinuation.31,32 Hyperphosphataemia, a pharmacodynamic, mechanism- based marker of activity33 and a class effect seen with FGFR inhibitors,34 was reported in 77% of patients, only 10% of whom had grade 3 events. This toxicity was manageable with dietary modification and chelating agents. As experience with infigratinib and other FGFR inhibitors increases, management guidelines for asymptomatic hyperphosphataemia are expected to be further refined. Gastrointestinal side-effects, such as those reported for FGFR-4 inhibitors,35 were relatively uncommon, consistent with the low affinity of infigratinib for FGFR-4.22 The single-arm, open-label design might be a study limitation, but was considered appropriate given the paucity of available treatments in this setting. Randomised studies are ongoing in the first-line setting to assess the benefit of FGFR inhibitors versus standard chemotherapy, including the phase 3 PROOF study (NCT03773302), which will compare infigratinib to standard-of-care gemcitabine plus cisplatin in patients with cholangio- carcinoma. In our study, BICR mitigated the potential for bias in this open-label design. The median BICR-assessed progression-free survival of 7·3 months and the median overall survival of 12·2 months are consistent with the primary endpoint; they further support that infigratinib provides a clinically relevant duration of benefit of more than historical outcomes of 3−4 months’ median progression-free survival and 5−8 months’ median overall
survival.34
Infigratinib, administered as a second-line or later-line treatment, represents a potential new therapeutic option for patients with cholangiocarcinoma and FGFR2 fusions or rearrangements. Results from cohorts 2 and 3 of this study will provide further clarification regarding the role of infigratinib in patients with cholangiocarcinoma and FGFR1 and FGFR3 fusions and rearrangements, FGFR1, FGFR2, and FGFR3 mutations, and in patients previously treated with FGFR inhibitors other than infigratinib.
Contributors
MJ, SR, RKK, SS, TM, KHW, D-TW, LG, IB, AE-K, MJB, WPY, PAP, MB,
ST, AXZ, and TSB-S contributed to clinical investigation, MJ and GKA-A contributed to study design, MJ, SR, RKK, SS, TM, KHW, D-TW, LG, IB, AE-K, MJB, WPY, PAP, MB, ST, AXZ, TSB-S, and GKA-A contributed to
data collection, MJ, AP, HSS, SPS, and SM contributed to data analysis, MJ, AP, HSS, SPS, SM, and GKA-A contributed to data interpretation. AL, AP, and HSS accessed and verified the data. MJ created the figures and was responsible for data presentation. AL supervised the statistical analyses reported in this Article. AP supervised the clinical study.
AP and HSS contributed to data curation (review and cleaning).
HSS supervised translational research. All authors provided input on
additional analyses before writing the manuscript. MJ, AL, AP, HSS, SPS, and SM wrote the original draft of the manuscript. All authors reviewed and edited the manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Declaration of interests
MJ reports medical writing support from QED Therapeutics; grants from QED Therapeutics, Incyte, Taiho, Basilea, OncoSil, Meclun, Agios, AstraZeneca, and Merck; consulting fees from QED Therapeutics, Incyte, Taiho, Basilea, Oncosil, Meclun, Agios, and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from QED Therapeutics, Incyte, Taiho, Basilea, Oncosil, Meclun, Agios, AstraZeneca, and EMD Serono; and participation on a data safety monitoring board or advisory board for NuCana, QED Therapeutics, Incyte, Taiho, Basilea, Oncosil, Meclun, Agios, and AstraZeneca. SR reports clinical trial financial support to their institution from QED Therapeutics; consulting fees from QED Therapeutics and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from IDT Integrated DNA Technologies and Illumina; financial support for attending meetings or travel from Incyte; and participation on a data safety monitoring board or advisory board for Incyte, AbbVie, QED Therapeutics, and Bayer. RKK reports funding (to their institution), supply of the study drug, medical writing support, and payment of article processing charges from QED Therapeutics; research financial support for conduct of clinical trials (to their institution) from Agios, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, EMD Serono, Exelixis, Genentech, Merck, Novartis, Partner Therapeutics, QED Therapeutics, and Taiho; support for travel to a 2019 presentation at a satellite symposium from Ipsen; membership of independent data safety monitoring committees or data and safety monitoring boards for Genentech/Roche and Merck (compensation to self from Genentech/ Roche in 2018–19; other independent data safety monitoring committee roles uncompensated); advisory board payments to self from Gilead, Exact Sciences, and Genentech; and advisory board payments to institution from Agios, AstraZeneca, Bristol Myers Squibb, and Merck. SS reports research funding to their institution from QED Therapeutics, Boehringer Ingelheim, and Zymeworks; consulting fees from QED Therapeutics, Eisai, and Exelixis; and honoraria for lectures, presentations, or speaker bureau from QED Therapeutics, Lilly, Eisai, and Exelexis. KHW reports consulting fees from Alexion, Bayer, Eisai, Novartis, Orphalan, Pfizer, Vivit therapeutics, Ultragenyx, and Univar, and travel support from Gilead. D-TW works for the speaker bureau of or gives expert testimony for AstraZeneca, Eisai, Bristol Myers Squibb, Celgene, Incyte, Ipsen, Falk, Novartis, Roche Pharma AG, Servier, Shire Baxalta, and Sirtex; reports financial support with travel, accommodation, and expenses from Bayer Health Pharma, Celgene, Novartis, and Sirtex; and has submitted a research grant application to Servier (to institution). LG reports research funding to their institution from Agios, Adaptimmune, Bayer, Eisai, Merck, MacroGenics, Genentech, Novartis, Incyte, Loxo Oncology, Relay Therapeutics,
QED Therapeutics, Taiho Oncology, Leap Therapeutics, Bristol Myers Squibb, and NuCana; scientific advisory board fees (to self) from Agios Pharmaceuticals, Alentis Therapeutics AG, H3 Biomedicine, Incyte, QED Therapeutics, Sirtex Medical, and Taiho Oncology; consulting fees (to self) from Agios Pharmaceuticals, Alentis Therapeutics, Genentech, Exelixis, Incyte Corporation, QED Therapeutics, Sirtex Medical, and Taiho Oncology; and participation in an independent data safety monitoring committee for AstraZeneca. IB reports research scientific advisory board fees (to self) from QED Therapeutics, Servier, and Taiho Oncology; consulting fees (to self) from Roche and QED Therapeutics; and financial support for conduct of clinical trials (to their institution) from Servier. AE-K reports medical writing support from QED Therapeutics; grants to their institution from AstraZeneca, Astex, and Fulgent; and consulting fees from Agenus, Bristol Myers Squibb, Merck, Roche-Genentech, EISAI, Exelixis, QED Therapeutics, Gilead, AstraZeneca, ABL Bio, CytomX, and Pieris; MJB reports financial support (to their institution) from QED Therapeutics; grants to their institution from Senhwa Pharmaceuticals, Adaptimmune, Agios Pharmaceuticals, Halozyme Pharmaceuticals, Celgene Pharmaceuticals, EMD Merck Serono, Toray, Dicerna, Taiho Pharmaceuticals, Sun
Biopharma, Isis Pharmaceuticals, RedHill Pharmaceuticals, Boston Biomed, Basilea, Incyte Pharmaceuticals, Mirna Pharmaceuticals, Medimmune, Bioline, SillaJen, ARIAD Pharmaceuticals, Puma Biotechnology, and Novartis Pharmaceuticals; and consulting fees from ADC Therapeutics, Exelexis, Inspyr Therapeutics, G1 Therapeutics, Immunovative Therapies, OncBioMune Pharma, Western Oncolytics, Lynx Group, Genentech, Merck, and Huya. WPY reports receiving an honorarium fee (to self) from Taiho; fees (to self) for consulting or advisory roles from Bristol Myers Squibb, Eisai, Ipsen, MSD, and Novartis; and royalties (to self) from miRXES. PAP reports grants and consulting fees from QED Therapeutics. MB reports a one-time advisory board payment from Incyte Biosciences Germany. AL has been employed at QED Therapeutics since August, 2018, and has stock or stock options in BridgeBio. AP has been a full-time employee of QED Therapeutics since Oct 15, 2019, and has stock in BridgeBio. HSS has been a full-time employee of QED Therapeutics since November, 2018, and has stock and stock options in BridgeBio. SPS is a full-time employee of QED Therapeutics; has a patent planned, issued, or pending for Corcept and AbbVie; and has stock or stock options in BridgeBio, Abbott, AbbVie, Johnson & Johnson, Corcept, and Calithera Biosciences. SM is a full-time employee of QED Therapeutics; has a patent planned, issued, or pending (PCT/US20/34881: methods of treating cholangiocarcinoma); and stock or stock options in BridgeBio. AXZ reports consulting fees from Lilly, Eisai, Bayer, Merck, Sanofi, Roche, and Exelixis. TSB-S reports research funding (to institution) from Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Amgen, Merck, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, and Bristol Myers Squibb; consulting fees (to institution) from Ipsen, Arcus, Array Biopharma, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, and Merck; consulting fees (to self) from AbbVie, Boehringer Ingelheim, Janssen, Eisai, Daichii Sankyo, Natera, TreosBio, Celularity, Exact Science, Sobi, Beigene, Kanaph, Xilis, AstraZeneca, and Foundation Medicine; fees for independent data monitoring committees and drug and safety monitoring boards (to self) from AstraZeneca, Exelixis, Lilly, PanCan, and 1Globe; fees for participating in scientific advisory boards for Imugene, Immuneering, and Sun Biopharma; and inventions or patents WO/2018/183488 and WO/2019/055687. GKA-A reports medical writing support for the present manuscript from QED Therapeutics; grants from Arcus, Agios, AstraZeneca, Bayer, BioNtech, Bristol Myers Squibb, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, SillaJen, and Yiviva; consulting fees from Agios, AstraZeneca, Alnylam, Autem, Bayer, BeiGene, Berry Genomics, Celgene, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Incyte, Ipsen, Legend Biotech, Loxo, Merck, MiNA, QED Therapeutics, RedHill, Rafael, Silenseed, SillaJen, Sobi, Surface Oncology, TheraBionic, twoXAR, Vector, and Yiviva; and patents planned, issued, or pending for articles and methods for preventing and treating dermatological adverse events (identified by the International Patent Application number PCT/US2014/031545, filed on
March 24, 2014, and with the priority application serial number 61/804,907, filed on March 25, 2013). All other authors declare no competing interests.
Data sharing
The deidentified individual participant data that underlie the results reported in this Article, the research protocol, data dictionaries, and additional supporting documents might be made available on written request from qualified researchers for scientifically valid research proposals submitted to the authors of this publication ([email protected]). Data requests shall be considered beginning 6 months and ending
2 years after publication of the study, provided that any investigational drug discussed has been approved for at least 6 months. The scope and format of data provided to third parties will be determined by any legal, regulatory, contractual, or consent provisions or other practical considerations applicable to these data.
Acknowledgments
This study was funded by Novartis and QED Therapeutics, an affiliate of BridgeBio, and was presented, in part, at the 2020 Cholangiocarcinoma Foundation Annual Conference (July 22–24, 2020) and at the 2021 Gastrointestinal Cancers Symposium (Jan 15–17, 2021). We thank all
patients who participated in this study, the patients’ families, the clinical investigators, the clinical research nurses, the clinical research monitors, the data management team, and all other members of the 2204 clinical study team. We also thank Roo Vold at QED Therapeutics for helping with data verification and editorial review, and Lee Miller and
Deirdre Carman at Miller Medical Communications for their medical editing and writing assistance, which was funded by QED Therapeutics.
References
Patel N, Benipal B. Incidence of cholangiocarcinoma in the USA from 2001 to 2015: a US cancer statistics analysis of 50 states. Cureus 2019; 11: e3962.
Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management.
Nat Rev Gastroenterol Hepatol 2020; 17: 557–88.
Gad MM, Saad AM, Faisaluddin M, et al. Epidemiology of cholangiocarcinoma; United States incidence and mortality trends. Clin Res Hepatol Gastroenterol 2020; 44: 885–93.
American Cancer Society. Key statistics for bile duct cancer. 2020. https://www.cancer.org/cancer/bile-duct-cancer/about/key- statistics.html (accessed Oct 20, 2020).
Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362: 1273–81.
National Comprehensive Cancer Network. NCCN guidelines version 3.2021. Hepatobiliary cancers. 2021. https://www.nccn.org/ professionals/physician_gls/pdf/hepatobiliary.pdf (accessed
July 13, 2021).
Lamarca A, Palmer DH, Wasan HS, et al. 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.
Lowery MA, Goff LW, Keenan BP, et al. Second-line chemotherapy in advanced biliary cancers: a retrospective, multicenter analysis of outcomes. Cancer 2019; 125: 4426–34.
Javle M, Bekaii-Saab T, Jain A, et al. Biliary cancer: utility of next- generation sequencing for clinical management. Cancer 2016; 122: 3838–47.
Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet 2015; 47: 1003–10.
Borad MJ, Champion MD, Egan JB, et al. Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma. PLoS Genet 2014; 10: e1004135.
Ross JS, Wang K, Khaira D, et al. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. Cancer 2016; 122: 702–11.
Farshidfar F, Zheng S, Gingras MC, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep 2017; 18: 2780–94.
Kongpetch S, Jusakul A, Lim JQ, et al. Lack of targetable FGFR2 fusions in endemic fluke-associated cholangiocarcinoma.
JCO Glob Oncol 2020; 6: 628–38.
Javle M, Sadeghi S, Roychowdhury S, et al. SO-5 Efficacy of second- line chemotherapy in patients with advanced or metastatic cholangiocarcinoma and FGFR2 fusions: a retrospective analysis. Ann Oncol 2020; 31: S219.
Abou-Alfa GK, Bibeau K, Schultz N, et al. Effect of FGFR2 alterations on survival in patients receiving systemic chemotherapy for intrahepatic cholangiocarcinoma. Proc Am Soc Clin Oncol 2021; 39 (suppl 3): 303.
Goyal L, Saha SK, Liu LY, et al. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma. Cancer Discov 2017; 7: 252–63.
Lamarca A, Kapacee Z, Breeze M, et al. Molecular profiling in daily clinical practice: practicalities in advanced cholangiocarcinoma and other biliary tract cancers. J Clin Med 2020; 9: 2854.
Loriot Y, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med 2019; 381: 338–48.
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: 671–84.
Taiho Oncology. FDA grants breakthrough therapy designation for Taiho Oncology’s futibatinib for treatment of advanced cholangiocarcinoma. April 1, 2021. https://www.taihooncology.com/ us/news/2021-04-01_toi_tpc_futibatinib_btd/ (accessed July 13, 2021).
Guagnano V, Furet P, Spanka C, et al. Discovery of 3-(2,6-dichloro-3,5- dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]- pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem 2011; 54: 7066–83.
Guagnano V, Kauffmann A, Wöhrle S, et al. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov 2012; 2: 1118–33.
Nogova L, Sequist LV, Perez Garcia JM, et al. Evaluation of BGJ398, a fibroblast growth factor receptor 1–3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study. J Clin Oncol 2017; 35: 157–65.
Javle M, Lowery M, Shroff RT, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma.
J Clin Oncol 2018; 36: 276–82.
Javle M, Kelley RK, Roychowdhury S, et al. Updated results from a phase II study of infigratinib (BGJ398), a selective pan-FGFR kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions. Ann Oncol 2018;
29 (suppl 8): viii720 (abstr).
Meng Z-W, Pan W, Hong H-J, Chen J-Z, Chen Y-L. Modified staging classification for intrahepatic cholangiocarcinoma based on the sixth and seventh editions of the AJCC/UICC TNM staging systems. Medicine (Baltimore) 2017; 96: e7891.
Amit O, Mannino F, Stone AM, et al. Blinded independent central review of progression in cancer clinical trials: results from a meta- analysis. Eur J Cancer 2011; 47: 1772–78.
Furuse I, Goyal L, Meric-Bernstam F, et al. 116MO Efficacy, safety, and quality of life (QoL) with futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harbouring FGFR2 fusions/rearrangements: FOENIX-CCA2. Ann Oncol 2020;
31 (suppl 6): 1288–89.
Pal SK, Rosenberg JE, Hoffman-Censits JH, et al. Efficacy of BGJ398, a fibroblast growth factor receptor 1–3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations. Cancer Discov 2018; 8: 812–21.
Lacouture ME, Sibaud V, Anadkat MJ, et al. Dermatologic adverse events associated with selective fibroblast growth factor receptor inhibitors: overview, prevention, and management guidelines. Oncologist 2021; 26: e316–26.
Magone MT, Hartley IR, Fitzgibbon E, et al. Ocular adverse effects of infigratinib, a new fibroblast growth factor receptor tyrosine kinase inhibitor. Ophthalmology 2021; 128: 624–26.
Lyou Y, Grivas P, Rosenberg JE, et al. Hyperphosphatemia secondary to the selective fibroblast growth factor receptor 1–3 inhibitor infigratinib (BGJ398) is associated with antitumor efficacy in fibroblast growth factor receptor 3-altered advanced/metastatic urothelial carcinoma. Eur Urol 2020; 78: 916–24.
Lamarca A, Barriuso J, McNamara MG, Valle JW. Molecular targeted therapies: ready for “prime time” in biliary tract cancer. J Hepatol 2020; 73: 170–85.
Kim RD, Sarker D, Meyer T, et al. First-in-human phase I study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma. Cancer Discov 2019;
9: 1696–707.