Emerging FGR Inhibitors Play Key Role in Biliary Tract Cancer

Arndt Vogel, MD

Although chemotheray remains a standard in the first- and second-line setting of biliary tract cancer in the locally advanced and metastatic setting, further treatments are emerging rapidly. Specifically, the advances in targeted therapies based on genetic alterations have energized the field. In a presentation during the 2021 Digital Liver Cancer Summit, Arndt Vogel, MD, a hepatologist at Hannover Medical School, Germany, summarized the current systemic treatments with an emphasis on diagnostic advances and greater molecular profiling.¹

“We see druggable alterations in up to 40% of cases of biliary tract cancer,” Vogel said. “But I think we need to be more granular because some of these alterations, such as IDH1 mutation and FGFR2 fusion, are only detected in intrahepatic cholangiocarcinoma.”

The ClarIDHy phase 3 trial (NCT02989857) evaluatedpatients with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had received up to 2 previous treatment regimens for advanced disease.² At the cutoff date, 185 patients were randomly assigned to ivosidenib (n = 124) or placebo (n = 61).

Median follow-up for progression-free survival was 6.9 months (interquartile range, 2.8-10.9). Investi-gators reported that progression-free survival was significantly improved with ivosidenib compared with placebo (median 2.7 months vs 1.4 months; hazard ratio [HR], 0.37; 95% CI, 0.25-0.54; 1-sided P < .0001).

“The hazard ratio is impressive, suggesting that a subgroup of patients with an IDH1 mutation clearly derived benefit from treatment with ivosidenib,” Vogel said

FGFR2 Fusions

FGFR2 fusions are detectable in not only biliary tract cancers, but also in other tumor types, Vogel explained. A majority of FGFR2 fusion partners contain a dimerization domain, which allows the FGFR2 fusions to activate FGFR signaling.

"A number of drugs have been tested in the second- and third-line setting in biliary tract cancer with remarkable reproducible efficacy,” Vogel said (TABLE).^3-6 Vogel noted that the phase 2 studies revealed very high disease control rates of greater than 80% with a median overall survival (OS) in the range of 6 to 7 months. “Clearly, there is efficacy for these FGFR2 inhibitors in patients with biliary tract cancer whose tumor harbors FGFR2 fusions,” Vogel said.

Vogel warned, however, that there were challenges associated with FGFR2 fusions that affect diagnosis.

“It’s important to understand that there are multiple fusion partners identified in biliary tract cancer, which makes diagnosis quite challenging,” Vogel said. “The optimal way to identify these partners is through RNA sequencing, however, not all laboratories offer it.” Vogel recommended consulting with a molecular pathologist to determine the best gene panel to order for the diagnosis of these FGFR2 fusions in the specific cancer setting.

Co-occurring Alterations

The effect of co-occurring alterations, especially in cholangiocarcinoma, has a unique impact on gene partners that rearrange with FGFR2, Vogel said. He cited the FIGHT-202 trial (NCT02924376), a phase 2, multicenter, open-label study of pemigatinib (Pemazyre) monotherapy in previously treated patients with locally advanced, metastatic, or surgically unresectable cholangiocarcinoma, including patients with FGFR2 fusions or rearrangements.⁵ Patients were stratified to 1 of 3 cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations.

What was interesting was that “responses were remarkably lower in patients who had co-occurring [TP53] mutations, along with the FGFR2 fusion,” said Vogel. “This means that when we look at the genetic report, we should pay attention to the co-occurring alterations that are detected,” he said. Vogel is looking forward to the phase 3 data where these observations need to be confirmed.

A challenge that Vogel brought up was related to the use of targeted therapies and secondary resistance. When acquired resistance develops it is often associated with the emergence of secondary FGFR2 kinase domain mutations. He noted findings from a study⁷ that evaluated the irreversible pan-FGFR inhibitor, TAS-120, which demonstrated efficacy in 4 patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma (ICC). These patients developed resistance to BGJ398 or Debio 1347. The investigators reviewed serial biopsies, circulating tumor DNA, and patient-derived ICC cells. They found that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio 1347.

“Clinicians need to be aware that resistance mutations occur and that some mutations can confer resistance to [some] FGFR inhibitors, but not all of them,” Vogel said. “Liquid biopsy may help us monitor the occurrence of resistance mutations and help to guide treatment,” he added.

Immunotherapy

Immunotherapies have shown early promising efficacy in some patients with biliary tract cancers, said Vogel. In advanced biliary tract cancer, results of a tolerability and efficacy study (NCT03046862) evaluating durvalumab (Imfinzi) and tremelimumab in chemotherapy-naïve patients with advanced biliary tract cancer were reported during the 2020 American Society of Clinical Oncology Annual Meeting.⁸

Patients were initially enrolled in the biomarker cohort (BMC) to receive 1 cycle of gemcitabine plus cisplatin on days 1 and 8, followed by gemcitabine plus cisplatin plus durvalumab and tremelimumab every 3 weeks until disease progression. Patients were then allocated to receive gemcitabine plus cisplatin and durvalumab (3C) or gemcitabine plus cisplatin and durvalumab and tremelimumab (4C) until disease progression.

Investigators reported that the disease control rate was 96.7% (95% CI, 90.3%-100%) for the BMC arm, 100% (95% CI, 100%-100%) for the 3C arm, and 97.8% (95% CI, 93.5%-100%) for the 4C arm.⁸ “These were remarkably high disease control rates and very promising median OS of almost 20 months, indicating that immuno-therapy might indeed play a role in biliary tract cancer,” Vogel said. However, Vogel noted that the study was primarily conducted in patients who were Asian and he acknowledged the need for further results from phase 3 trials, which are currently ongoing.

Although chemotherapy remains the standard of care in first- and second-line biliary tract cancer, the emergence of molecular testing has expanded the clinician’s armamentarium with targeted therapies playing a larger role in the treatment landscape.

_REFERENCES

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_{2. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet On-col. 2020;21(6):796-807. doi:10.1016/S1470-2045(20)30157-1}

_{3. Javle MM, Roychowdhury S, Kelley RK, et al. Final results from a phase II study of infigratinib (BGJ398), a FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harbor-ing an FGFR2 gene fusion or rearrangement. J Clin Oncol. 2021;39(suppl 3):265. http://bit.ly/3oX1njs.}

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_{6. Bridgewater J. Efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/other rearrangements: Subgroup analyses of a phase II study (FOENIX-CCA2). Ann Oncol. 2020;31(suppl 4):S260-S273. doi:10.1016/annonc/annonc259}

_{7. Goyal L, Shi L, Liu LY, et al. TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma. Cancer Discov. 2019;9(8):1064-1079. doi:10.1158/2159-8290.CD-19-0182}

_{8. Oh D-Y, Lee K-H, Lee D-W, et al. Phase II study assessing tolerability, efficacy, and biomarkers for durvalumab (D) ± tremelimumab (T) and gemcitabine/cisplatin (GemCis) in chemo-naïve advanced biliary tract cancer (aBTC). J Clin Oncol. 2020;38(suppl 15):4520-4520. doi:10.1200/JCO.2020.38.15_suppl.4520}