Safety and efficacy of the selective FGFR inhibitor debio 1347 in phase I study patients with FGFR genomically activated advanced biliary tract cancer (BTC).

Abstract

447 Background: BTC are aggressive tumors with limited treatment options and poor overall survival. Aberrant FGFR signaling has been implicated in BTC carcinogenesis. Debio 1347 is an orally available selective FGFRi with potent antitumor effect in preclinical model bearing FGFR alterations. Debio 1347 showed encouraging preliminary clinical activity and manageable treatment-emergent adverse events (TEAE) in its first-in-human (FIH) ph1 study (NCT1948297) dose-escalating part. Here we report only results from the BTC pts of this study. Methods: This FIH study enrolled pts with advanced solid malignancies harboring defined activating alterations of FGFR 1, 2, or 3: amplifications (amp), mutations (mut) and translocations (trans). Pharmacokinetics (PK) and pharmacodynamics were serially evaluated in blood, skin and/or tumor tissue. A confirmatory post-hoc analysis was performed centrally for all available biopsies. Results: Eight pts, six with intrahepatic cholangiocarcinoma (iCCA) and two with gallbladder cancer (GBC), were treated with Debio 1347 at doses between 60 and 150 mg orally daily in 28-day cycles. Among the iCCA pts, one had an FGFR2mut, one had an FGFR2 activating deletion (del), and one had an FGFR3mut; the other three had FGFR2trans. One of the two GBC pts had an FGFR3trans, the other one an FGFR2mut. All pts had prior systemic therapy (mostly 2 or 3 lines). The most common TEAEs were hyperphosphatemia (8/8), nail changes (5/8), nausea (5/8), dry mouth (4/8) and stomatitis (3/8). No grade ≥ 3 related TEAE were reported except grade 3 hyperphosphatemia (4/8). PK was comparable to that in pts with other solid malignancies.A partial response lasting up to 48 weeks was observed in an iCCA pt (FGFR2 del exon 5); three additional iCCA pts (FGFR2trans: ROCK1; KIAA1217; DDX21) and one GBC pt (FGFR3-TACC3 trans) had target lesions regression < 30% and stayed on trial between 24 – 37 weeks. Overall disease control was 62.5%. Conclusions: These results suggest that BTC pts with genomic events leading to activation of FGFR2/3 may benefit from treatment with Debio 1347. Further study is ongoing in the expansion cohort of this trial. Clinical trial information: NCT1948297.

TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion–Positive Intrahepatic Cholangiocarcinoma

“…The efficacy seen across several early-phase clinical trials of FGFR2 inhibitors in patients with advanced refractory ICC (14,(28)(29)(30) represents a breakthrough in a disease with no FDA-approved targeted therapies to date. However, as seen with other tyrosine kinase inhibitors, the rapid emergence of resistance associated with recurrent acquired mutations in the target's kinase domain has limited the durability of benefit to ATP-competitive inhibitors.…”

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

“…129,130,133,142 Many FGFR inhibitors are currently being developed, most of which have already shown adequate safety in phase I trials and early efficacy in phase II studies in patients with refractory iCCA (Table 1). 139,140,[145][146][147][148][149][150][151][152][153][154] Activated FGFR FGF P JAK-STAT…”

“…Data extracted from. 139,140,[145][146][147][148][149][150][151][152][153][154] IC50 data also extracted from. 162 AEs, adverse events; CCA, cholangiocarcinoma; CR, complete response; DCR, disease control rate; FGFR, fibroblast growth factor receptor; GBC, gallbladder cancer; IC50, half maximal inhibitory concentration; iCCA, intrahepatic cholangiocarcinoma; LFTs, liver function tests; mDOR, median duration of response; mPFS, median progression-free survival; PDGFR, platelet-derived growth factor receptor; PR, partial response; ORR, objective response rate; TEAEs, treatment-emergent adverse events; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.…”

“…139,[145][146][147]150,154 For the majority of compounds under development, responses have been homogeneously absent for patients with other FGFR aberrations. 139,140,145,146,151,153,154 Together with the development of FGFR inhibitors and their assessment in the clinic, research is happening in parallel to understand mechanisms of resistance to these compounds and potential ways to overcome them. Goyal and colleagues reported the first evidence of acquired resistance to FGFR inhibition in CCA.…”

Molecular Profiling in Daily Clinical Practice: Practicalities in Advanced Cholangiocarcinoma and Other Biliary Tract Cancers

“…The development of targeted therapies is significantly impacting the care and management of patients with advanced iCCA [ 9 , 10 ], for whom inhibitors of fibroblast growth factor receptor (FGFR) fusions [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ] and isocitrate dehydrogenase (IDH) mutations [ 12 ] are becoming a reality. Alternative potential targets for future “Precision Medicine” strategies in BTC may include chromatin remodeling genes ( ARID1 , BAP1, and PBRM1 ) and other aberrations such as BRAF and RNF43 mutations, HER2 and HER3 amplifications or NTRK fusions [ 10 , 23 , 24 , 25 , 26 , 27 ].…”