THE BETTER PROGNOSIS for cluster 4 may be partly due to its enriched presence of FGFR2 fusion, as they have been associated with improved outcomes. FGFR fusions, which are present in about 15% of intrahepatic tumors, are driver events that result in ligand-independent activation of the FGFR pathway.
An orally available, selective, ATP-competitive pan-FGFR inhibitor has shown activity in tumor models with FGFR alterations. This led to a phase II trial of BGJ398 in 61 heavily pretreated patients with FGFR alterations (79% had FGFR fusions).3 The response rate was 19% overall, rising to 23% in patients with fusions (those with other FGFR alterations did not benefit). Some degree of tumor regression was seen in the majority of patients, Dr. Kelley reported.
Median progression-free survival was 6.7 months, which “compares very favorably to second-line cytotoxic fluorouracil-based therapy, which is generally about 3 months in retrospective studies,” she noted. “We (at UCSF) had, for example, a patient with multifocal intrahepatic tumors and nodal metastases who showed a dramatic partial response, which was sustained for almost 9 months, along with other patients with even longer responses in the trial.”
In an impressive case series, Goyal et al reported that polyclonal secondary FGFR2 kinase domain point mutations arise in the setting of acquired resistance to BGJ398.4 Some of these mutated tumors may be susceptible to structurally different FGFR2 inhibitors in preclinical studies, she said.
One of these agents is TAS-120, a highly selective, covalent pan-FGFR inhibitor that has shown activity against FGFR2 resistance mutations. In a phase I/II basket trial of 23 patients with FGFR2 fusion and other FGFR-altered cholangiocarcinomas, 4 of 9 patients with FGFR2 fusions achieved at least an unconfirmed partial response, and 8 patients had tumor regression.4 Other alterations were generally not as responsive. TAS-120 is currently being evaluated in a large basket trial with planned enrollment of over 800 patients.
“Multiple FGFR2-targeted agents are poised for pivotal trials in the first line and beyond, for advanced cholangiocarcinoma,” she said.
“Early results of FGFR2 inhibitors in cholangiocarcinoma are very promising, with durable partial responses seen and prolonged progression-free survival in target-positive populations.”
— Robin Kate Kelley, MD
“Early results of FGFR2 inhibitors in cholangiocarcinoma are very promising, with durable partial responses seen and prolonged progression-free survival in target-positive populations,” Dr. Kelley said. “They rightly have prompted single-arm pivotal phase II and III trials that could achieve future accelerated or fast track regulatory status for the drugs. If larger studies bear out the current durable overall response rates, these data may warrant their study in an earlier context, including as first-line and possibility adjuvant therapy.”
Although tolerability varies among the agents, there are class toxicities, especially hyperphosphatemia stemming from the FGFR1 inhibition component. Mechanisms of resistance require further study to guide the sequencing of ATP-competitive vs covalent inhibitors and combinations, she added.
ANOTHER PROMISING target is the isocitrate dehydrogenase-1 (IDH1) mutation, which occurs in about 20% of intrahepatic tumors. This mutation results from the accumulation of oncometabolite 2-hydroxyglutarate, which blocks differentiation and leads to uncontrolled proliferation of de-differentiated tumor cells.
Ivosidenib (AG-120), a first-in-class oral, selective, reversible inhibitor of mutant IDH1, is currently in phase III trials of cholangiocarcinoma and acute myelogenous leukemia. In a phase I study of 73 heavily pretreated patients with cholangiocarcinoma, ivosidenib was well tolerated and produced responses in 5% of patients as well as stable disease in 56%; median progression-free survival was 3.8 months, and 12-month progression-free survival was 20.7%.5 Treatment with ivosidenib seems to restore cholangiolar differentiation of cells that are undifferentiated at baseline, based upon paired biopsy findings in a subset of patients enrolled in this study.
The phase III ClarIDHy trial is currently assessing ivosidenib as second- or third-line treatment in 186 patients; this is the first integral biomarker-selected phase III trial in this tumor type. “The results of ClarIDHy will determine the efficacy of ivosidenib as monotherapy in this population. Its favorable safety profile suggests we can use it in combination,” she said.
BAY1436032 is another mutant IDH1-targeted small molecule now in a phase I basket trial of 100 patients. In addition, olaparib (Lynparza) is being evaluated in a phase II trial of 75 patients based on the provocative finding that the mutant IDH1 oncometabolite may suppress homologous recombination in preclinical models.
“There are many other candidate drivers in cholangiocarcinoma, but their incidence is low,” Dr. Kelley continued. Basket trials such as the National Cancer Institute (NCI)-MATCH and TAPUR trials may reveal signals of activity for agents targeting BRAF and BRCA1/2 mutations, other homologous recombination deficiencies, rare fusions such as ROS1 and anaplastic lymphoma kinase (ALK), and other aberrations in rare subsets including HER2 amplification.