GBC are often diagnosed in an advanced stage and carry a dismal prognosis. Overall, 5-year survival rate of all GBCs in USA is around 18% with advanced GBC being with less than 2% survival at 5 years. The median survival of GBC for resectable tumors is 12–14 months and unresectable tumors around 6 months.[2]
First line chemotherapy of advanced biliary tract carcinoma (BTC), including GBC, is gemcitabine combined with a platinum usually cisplatin based on ABC-02 trial. Gemcitabine platinum combination has shown superior overall survival (OS) compared to single agent gemcitabine.[6] Recently, interim results of the TOPAZ-1 clinical trial presented at ASCO GI 2022 showed a significant improvement in OS and progression free survival (PFS) with no significant increase in toxicity in advanced BTC and GBC treated with a combination of durvalumab and standard of care chemotherapy when compared to chemotherapy alone.[7] 5-Florouracil + oxaliplatin + leucovorin is considered second line therapy upon progression with gemcitabine-cisplatin combination based on the ABC-06 trial.[8] Previous studies have shown that common genomic alterations associated with GBC are TP53, CDKN2A/B, ERBB2, PI3KCA, ARID1A, KRAS, EGFR, FGFR1-3, BAP1, BRAF, and MET.[9] Our previous work identified Dickoppf homologue 3 (DKK3), a secreted protein belonging to the Wnt antagonist family, as a potential tumor suppressor in GBC cell lines. Additionally, we performed quantitative proteomics and phospho-proteomics analysis on DKK3 overexpression in GBC which showed phosphorylation alteration in 14 kinases [10–11]
FGFR2 or cluster of differentiation 332 (CD332) is a protein encoded by the FGFR2 gene residing on chromosome 10.[12] A full-length representative protein consists of an extracellular region, composed of three domains, a single hydrophobic that spans the entire length of the membrane and a cytoplasmic tyrosine kinase domain. The interaction between FGFR and FGF leads to mitogenesis and differentiation through signaling cascade. FGFR2 alterations has been implicated in breast, urinary bladder, gastric, colorectal, uterine, skin (including melanoma and squamous cell carcinoma [SCC]), lung SCC, pancreatic, prostate and BTC.[9][13–16] Fig. 3 illustrates the FGFR signaling pathway and site of action of treatments mentioned in the above case.
Pazopanib is a multiple kinase inhibitor targeted towards tumor angiogenesis by inhibition of enzymes including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), c-KIT and FGFR.[17] It has received worldwide approval for renal cell carcinoma and soft tissue sarcoma.[18] Erdafitinib, a selective pan-FGFR kinase inhibitor, has been implemented in patients with FGFR altered tumors, one of which is CCA. A phase II open label, multicenter, clinical trial comprising of Asian patients with FGFR altered advanced CCA who progressed on more than 1 line of therapy received erdafitinib. In 10 FGFR2 + patients, objective response rate (ORR) was 60.0%; disease control rate (DCR) was 100%; median PFS was 12.35 months. [19]
Pemigatinib, a small molecule kinase inhibitor, is the first FDA approved (April 2020) FGFR inhibitor for advanced CCA with FGFR 2 fusion or rearrangement in patients who progressed on 1 or more lines of therapy.[20] This decision was based on the FLIGHT 202 trial, a multicenter open-label single-arm trial, which included 107 patients with advanced CCA. The study demonstrated an ORR of 36% with 3 patients having complete metabolic response and a median duration of response (DOR) of 9.1 months. Those that did develop response, 63% had a >/= 6 months response and 18% had a >/= 12 months response.[21]
The caveat to selective FGFR inhibitor is that only a limited number of patients respond to therapy in the first place suggesting a primary resistance. And those who do respond, the median DOR is around 7–9 months suggesting a secondary resistance. Other mechanisms of resistance include gatekeeper mutations, activation of alternate signaling pathways, polyclonal secondary FGFR mutations, cooccurring tumor suppressor gene alterations such as BAP1, CDKN2A/B, PBRM1, TP53 etc.[22–24] A number of FGFR2-point mutations (N549H, N549K, E565A, K641R, or K659M) and gatekeeper mutation (V565F and V565I) were seen in patients who developed progression on reversible ATP-competitive FGFR inhibitor. King et al. and Goyal et al. suggested combination therapy with mTOR/PI3K targeted therapy, immune checkpoint inhibitor, vascular endothelial growth factor (VEGF) inhibitor, chemotherapy or sequential FGFR targeted therapy as a possible direction towards overcoming resistance. [22–24] Prevention of treatment resistance relies heavily on the understanding of tumor heterogeneity. Goyal et al. suggests tracing genetic alterations that emerge upon disease progression through serial circulating tumor DNA (ctDNA) analysis and, based on those findings, recommends sequential treatment with various FGFR inhibitors depending upon their spectrum of activity. This could potentially extend the efficacy of FGFR inhibitors.[23–24]
In our case, the patient progressed on multiple lines of cytotoxic chemotherapy but later responded to sequential anti-FGFR therapy. Previously published data points towards the potential role of sequential anti-FGFR therapy in CCA.[23–25] As gallbladder cancer shares several clinical and pathological characteristics of CCA, it is reasonable to assume that a similar effect would likely be seen in these patients.
Foundation One CDx performed on tissue sample showed development of FGFR2 alterations apart from S252W resistance through secondary FGFR mutations. Addition of MEK inhibitor to the ongoing pemigatinib in order to overcome resistance mutation would be a viable option to consider in this scenario. A study by Cristianziano et al. demonstrated that dual blockade of FGFR2 fusion proteins and MEK 1/2 with a combination of BGJ398/infigratinib and trametinib was superior to single agent FGFR2 fusion or MEK1/2 inhibitors in vitro and in vivo, thus indicating a promising clinical benefit of dual FGFR2-MEK1/2 blockade in patients with CCA.[5]
Another option to overcome resistance would be to consider irreversible FGFR kinase inhibitors. Futibatinib is an irreversible FGFR 1–4 tyrosine kinase inhibitor which had shown activity in a number of solid tumors CCA and gastric, urothelial, central nervous system, head and neck, and breast cancers, most significantly in FGFR2 fusion/rearrangement-positive intrahepatic CCA.[26] An article by Sootome et. al summarizing the preclinical significance of TAS120 strongly suggests the use of futibatinib in patients who have developed resistance to prior tyrosine kinase inhibitors.[27] In contrast to reversible FGFR inhibitors, very few resistant clones were observed with prolonged futibatinib treatment, and in the FGFR2 kinase domain, no mutations were observed. Futibatinib was found to be effective in tumors with FGFR mutations known to be resistant to reversible inhibitors. Goyal et al. reported 4 advanced CCA cases which initially progressed on selective FGFR2 inhibitor showing efficacy to pan-FGFR inhibitor futibatinib.[4] A recent update from the FOENIX-CCA2 trial reported a median PFS and OS of 8.9 and 20 months, respectively with a good safety profile suggesting durable efficacy and sustained tolerability of futibatinib in advanced CCA with FGFR alterations.[28] Other irreversible FGFR tyrosine kinase inhibitor under investigation include PRN1371, FINN-2, FINN-3, BLU9931 and fisogatinib/BLU554. [29–32] Table 1 describes all the studies referenced in this article along with ongoing clinical trials involving CCA with FGFR alteration.[33–46]
Table 1A:
Clinical trials included in this article
Study name
|
Patient demographic
|
Therapy
|
Response (median)
|
Toxicity
|
Phase 1 clinical trial [4]
|
Advanced FGFR2 fusion-positive CCA
|
TAS-120/futabatinib
|
ORR – 4/4 (100%)
PFS – 5.1–17.4 months
|
-
|
ABC-02 trial [6]
|
Locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer
|
Cisplatin 25 mg/m2 of body-surface area) followed by gemcitabine 1000 mg/m2, each administered on days 1 and 8, every 3 weeks for eight cycles vs. gemcitabine alone 1000 mg/m2 on days 1, 8, and 15, every 4 weeks for six cycles
|
OS − 11.7 vs 8.1 months
HR − 0.68
PFS − 8 vs 5 months
DCR − 81.4 vs 71.8%
|
No statistical difference between the two groups - Neutropenia, transaminitis, alopecia, fatigue, anorexia, etc.
|
TOPAZ-1[7]
|
Chemotherapy naïve unresectable locally advanced, recurrent, or metastatic BTC
|
Durvalumab (1500 mg every 3 weeks) or placebo + gemcitabine cisplatin (gemcitabine 1000 mg/m2 and Cisplatin 25 mg/m2 on Days 1 and 8) for up to 8 cycles, followed by durvalumab (1500 mg) vs. placebo + gemcitabine cisplatin (gemcitabine 1000 mg/m2 and Cisplatin 25 mg/m2 on Days 1 and 8) for up to 8 cycles
|
OS – 12.8 vs 11.5 months
HR – 0.8
PFS – 7.2 vs 5.7 months
ORR − 26.7% vs 18.7%
|
No statistical difference between the two groups
Grade 3–4 adverse events − 62.7% vs 64.9%
|
ABC-06 trial [8]
|
Advanced BTC that progressed after first line therapy
|
FOLFOX - oxaliplatin 85 mg/m2, L-folinic acid 175 mg [or folinic acid 350 mg], fluorouracil 400 mg/m2 [bolus], and fluorouracil 2400 mg/m2 as a 46-h continuous intravenous infusion) vs. active symptom control (ASC)
|
6 month OSR − 50.6 vs 35.5%
12 month OSR – 25.9 vs 11.4%
|
Grade 3–5 FOLFOX-related adverse events - neutropenia 12%, fatigue or lethargy 11%, and infection 10%
|
LUC2001 [19]
|
Asian patients with FGFR altered advanced CCA who progressed after ≥ 1 prior treatment
|
Erdafitinib 8 mg once daily
|
ORR – 60%
DCR – 100%
PFS – 12.35 months
|
The most common adverse events (> 30%) - hyperphosphatemia, dry mouth, stomatitis, and dry skin.
Grade 3 or higher − 57.1%
|
FIGHT-202 [21]
|
Locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements with disease progression after ≥ 1 prior treatment and an ECOG performance status of 0–2
|
Pemigatinib 13.5 mg once daily 21-day cycle; 2 weeks on, 1 week off
|
ORR − 35.5%
DOR – 9.1 months
|
Grade 3 or higher – 64%
|
Phase I Dose-Expansion Study [26]
|
CCA was the most common tumor type represented (37.6%), followed by primary CNS tumors (21.2%), urothelial cancer (11.2%), breast cancer (6.5%), and gastric cancer (5.3%); 18.2% of patients had other tumors with FGFR alterations.
|
Futibatinib 20 mg once daily
|
ORR – 13.7%
FGFR2 fusion/rearrangement–positive intrahepatic cholangiocarcinoma ORR − 25.4%
|
Overall Adverse Events – 58.2%
Grade 3 or higher – 6.5%
Hyperphosphatemia (81.2%), diarrhea (33.5%), and nausea (30.4%)
|
FOENIX-CCA2 trial
|
Advanced/metastatic CCA with FGFR2 fusion/rearrangement and progressive disease after ≥ 1 prior treatment (including gemcitabine plus platinum-based chemotherapy)
|
Futibatinib 20 mg once daily
|
ORR − 41.7%
DCR – 82.5%
DOR – 9.5 months
PFS – 8.9 months
OS- 20.0 months
|
TRAE related treatment discontinuation – 4%
NO treatment related deaths.
Hyperphosphatemia (85%), alopecia (33%), dry mouth (30%), diarrhea (28%), dry skin (27%), and fatigue (25%)
|
Table 1B:
Ongoing clinical trials involving advanced CCA with FGFR2 alteration.
Study Name
|
Patient Demographic
|
Therapy
|
The PROOF trial (NCT03773302) [33]
|
Advanced/Metastatic or inoperable cholangiocarcinoma with FGFR2 gene fusions/translocations
|
Infigratinib (BGJ398) 125 mg orally once daily, 3 weeks on, 1 week off vs. Gemcitabine 1000 mg/m2 D1 and D8 + Cisplatin 25 mg/m2 D1 and D8 for a 21-day cycle.
|
A Multicenter, Open-Label, Phase II Trial (NCT04238715) [34]
|
Unresectable advanced or metastatic cholangiocarcinoma with FGFR 2 gene fusion
|
E7090 140 mg orally once daily
|
Phase 1 clinical trial (NCT04526106) [35]
|
Unresectable or metastatic cholangiocarcinoma and other unresectable or metastatic solid tumors with FGFR2 alteration
|
Multiple doses of RLY-4008 for oral administration
|
FIGHT 302 (NCT03656536) [36]
|
Chemotherapy naïve unresectable/metastatic cholangiocarcinoma with FGFR2 rearrangements
|
Pemigatinib 13.5 mg once daily for a 21 day cycle vs. Gemcitabine 1000 mg/m2 D1 and D8 + Cisplatin 25 mg/m2 D1 and D8 for a 21-day cycle.
|
Phase II, Open Label, Multicenter Study (NCT04919642) [37]
|
Advanced/metastatic and surgically unresectable cholangiocarcinoma with 1) FGFR 2 fusions who failed prior FGFR inhibitor treatment, 2) FGFR2 fusions who responded on prior FGFR inhibitor treatment, 3) with other FGFR alterations, or 4) whose tumors do not contain a detectable FGFR alteration
|
TT-00420 orally once daily
|
Phase II Study (NCT04233567) [38]
|
Advanced or Metastatic solid tumors (including cholangiocarcinoma) with FGFR1-3 gene fusions or other FGFR Genetic alterations
|
Infigratinib (BGJ398) 125 mg orally daily, 3 weeks on, 1 week off
|
FOENIX-CCA3 (NCT04093362) [39]
|
Chemotherapy naïve advanced cholangiocarcinoma harboring FGFR2 gene rearrangements
|
TAS-120 orally once daily for a 21-day cycle vs. Gemcitabine 1000 mg/m2 D1 and D8 + Cisplatin 25 mg/m2 D1 and D8 for a 21-day cycle.
|
FIDES-01 (NCT03230318) [40]
|
FGFR2 gene fusion-, mutation- or amplification- positive inoperable or advanced intrahepatic cholangiocarcinoma
|
Derazantinib 300 mg orally once daily
|
Single-arm, Multicenter, Open-label Phase II Study (NCT04353375) [41]
|
Metastatic or local advanced intrahepatic cholangiocarcinoma with FGFR2 fusion, who have failed at least one systemic therapy
|
HMPL-453 150mg orally once daily
|
Phase II Single-arm, Open-label Study (NCT05174650) [42]
|
Advanced intrahepatic cholangiocarcinoma
|
Atezolizumab 1200 mg IV for a 21 day cycle + Derazantinib 300 mg orally once daily
|
Open-label, Single Arm, Multicenter Phase 2 Study (NCT05039892) [43]
|
Advanced/metastatic cholangiocarcinoma with FGFR2 Gene Alterations who have failed at least 1 previous treatment.
|
3D185
|
Phase 1/1b, Open-label, Multicenter Study (NCT05242822) [44]
|
Advanced tumors (includes cholangiocarcinoma) harboring FGFR2 and/or FGFR3 gene alterations
|
KIN-3248 orally once daily for a 28-day cycles
|
Phase IIa Study (NCT02699606) [45]
|
Asian patients with advanced tumors (includes cholangiocarcinoma)
|
Erdafitinib 8 mg starting dose orally once daily with option to up-titrate to 9 mg for a 28-day cycle
|
Multi-center Open-label, Phase I/II Clinical Trial (NCT04565275) [46]
|
Advanced solid tumors (includes cholangiocarcinoma) with FGFR gene alterations
|
ICP-192
|
BTC – biliary tract cancer; CCA – cholangiocarcinoma; CNS – central nervous system; DCR – disease control rate; DFS – disease free survival; DOR – duration of response; HR – hazard ration; ORR – overall response rate; OS – overall survival; OSR – overall survival rate; PFS – progression free survival. |
Options of switching to futibatinib or adding trametinib to pemigatinib to target downstream pathways were explored but the patient could not travel to be enrolled in clinical trials and eventually developed progression of disease and worsening liver failure. Metastatic GBC with FGFR alterations can be maintained on sequential anti-FGFR therapy for durable periods of time, which is truly remarkable in this case. GBC is an aggressive disease and there is no consensus on treatment options beyond first line chemotherapy. Our study further underpins the value of CGP and the need to further study the role of sequential FGFR inhibitors as a viable treatment option in FGFR altered advanced GBC that failed multiple lines of therapy.