Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma

Abstract

Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 ( FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study ( ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population.

Fig 1.

(A) Duration of exposure. Swimplot presenting duration of exposure, dosing history, and efficacy assessments. (B) Best percentage change in sum of longest tumor diameters from baseline. Only patients with baseline and at least one postbaseline assessment are included. N, number of patients who received at least one study treatment; n, number of patients with baseline and at least one postbaseline assessment.

Fig 2.

Progression-free survival (full analysis set). Kaplan-Meier plot of progression-free survival as per investigator assessment according to Response Evaluation Criteria in Solid Tumors v1.1.

Fig A1.

Study design. (*) Safety follow-up was conducted for all patients. (†) Disease progression follow-up was conducted for patients who discontinued treatment for any reason other than disease progression. Follow-up continued until the first incidence of disease progression, initiation of a subsequent cancer therapy, or death. (‡) Survival follow-up will continue until all patients have discontinued study drug treatment and at least 80% of patients have died, withdrawn consent, or been lost to follow-up. CT, computed tomography; MRI, magnetic resonance imaging; PO, orally; RECIST, Response Evaluation Criteria in Solid Tumors.

Fig A2.

Genetic alterations in cholangiocarcinoma. (A) Clustered alteration profiles. (B) Most frequent gene alterations in cholangiocarcinoma.

Fig A3.

CA19-9 data: postbaseline data versus tumor regression. Best percentage change from baseline in sum of longest diameters and CA19-9 concentration (full analysis set). Analysis excluded any patient with no postbaseline assessment.