Erdafitinib Shows Promise in FGFR-Aberrant Cholangiocarcinoma

Erdafitinib, an oral pan-FGFR inhibitor, demonstrated encouraging clinical activity and a manageable safety profile in Asian patients with FGFR-aberrant advanced cholangiocarcinoma (CCA), according to preliminary results from a phase IIa trial presented at the 2018 ESMO Congress.

In the open-label, multicenter, phase IIa trial (NCT02699606), results showed that the overall response rate (ORR) was 45.5% and the 9-month progression-free survival (PFS) rate was 38%.

The overall prognosis for patients with CCA is poor, and although potentially curative surgical options are available for a small number of patients with early, localized disease, options for those with advanced or metastatic disease have been limited to traditional systemic chemotherapy with gemcitabine and cisplatin.

For some time, investigators have known that FGFR plays a crucial role in tumor cell growth, survival, and migration, as well as in maintaining tumor angiogenesis. However, there has been increasing evidence suggesting that aberrant FGFR signaling drives pathogenesis of CCA.

Investigators sought to evaluate the clinical efficacy and safety of erdafitinib in select patients with advanced CCA with FGFR gene translocations or FGFR gene mutations. To be eligible for enrollment, patients had to be 18 years of age or older, histologically or cytologically confirmed advanced CAA, an ECOG performance status of 0 or 1, and must have failed at least 1 prior line of therapy.

Those who had been treated with chemotherapy, targeted therapies, immunotherapy, or any investigational anticancer agent within the 2 weeks prior to the trial starting were ineligible to enroll, as were those with uncontrolled or history of cardiovascular disease, and those with persistent phosphate greater than the upper limit of normal.

Of the 193 patients who were molecularly screened, 29 patients had FGFR alterations. Of those with alterations, 7 patients had FGFR2 fusions, 3 had FGFR2 mutations, and 2 had FGFR3 mutation; these 12 were given erdafitinib at a continuous dose of 8 mg once daily, with 1 patient uptitrated to receive a 9-mg dose. Eleven of the 12 patients were deemed evaluable for response. The median number of treatment cycles was 7.0 (range, 2-19), while the median treatment duration was 6.34 months (1.6-17.5).

All patients received prior systemic therapy; 4 patients (36.4%) were previously exposed to radiotherapy, while 6 (54.5%) underwent prior cancer-associated surgery. Four of the 11 patients received 1 prior chemotherapy, 4 underwent 2 chemotherapies and 3 patients received 3 or more lines of chemotherapy. Eight patients were treated with standard gemcitabine/cisplatin, while 11 patients received a regimen of cisplatin/oxaliplatin/carboplatin-based chemotherapy.

Of these 11 patients, there were 5 confirmed partial responses (PRs) in those with FGFR2 alterations (1 FGFR2 mutation and 4 FGFR2 fusions). Three patients with FGFR2 fusions had stable disease. Two patients had progressive disease, both of whom had FGFR3 mutations and concurrent KRAS mutations. The disease control rate (DCR) was 72.7%; it was 81.8% when including unconfirmed complete responses and PRs.

The median duration of response with erdafitinib was 3.94 months (95% CI, 3.65-12.16). The median PFS was 5.59 months (95% CI, 1.87 to not evaluable).

The overall response rate was observed in 5 of 11 patients, as well as a 9-month PFS rate of 38%. Of the 9 patients with FGFR2 alteration, the 9-month PFS rate was 49%, while the ORR and DCR were 66.7% and 100%, respectively.

Investigators monitored serum phosphate concentration as a pharmacodynamic endpoint to facilitate dose adjustment per protocol specification. On cycle 1 day 14, they measured serum phosphate for pharmacodynamic uptitration. Results showed that serum phosphate concentrations from patients with CCA were within the 90% model prediction interval. Serum phosphate concentration fell within the targeted range for most of the patients, supporting the current dosing regimen in this population.

One patient with a confirmed PR to treatment with a FGFR2-KIAA1598 fusion confirmed in tumor and cell-free DNA (cfDNA) analysis, was observed to have experienced maximum tumor shrinkage (-46.2%). Further analysis revealed V564L, a secondary FGFR2 kinase domain mutation. Because this gatekeeper mutation had not been observed in the baseline plasma or tumor tissue, investigators postulate that this mutation represents a mechanism of acquired resistance to erdafitinib.

The most common, any grade adverse events (AEs) associated with the treatment were the following: hyperphosphatemia (n = 10), dry mouth (n = 8), stomatitis (n = 8), dry skin (n = 5), nail disorder (n = 4), and hand-foot syndrome (n = 4). AEs that resulted in dose reduction were noted in 5 patients (45.5%), while events that led to dose interruption were observed in all patients (100%).

Three patients (27.3%) experienced serious AEs but were not deemed to be drug-related; these included gastrointestinal hemorrhage (n = 1), pyelonephritis acute (n = 1) and pathological failure (n = 1). Grade 3 or higher AEs were experienced in 6 patients (54.5%), but none of these AEs resulted in treatment discontinuation or death.

Investigators concluded that a larger sample size is needed to further explore safety and effectiveness of erdafitinib in this patient population. Further research is also needed to evaluate the molecular underpinnings of CCA to inform the development of new treatment options.

Chen YY, Park JO, Su WC, et al. Preliminary results of a ph2a study to evaluate the clinical efficacy and safety of erdafitinib in Asian patients with biomarker-selected advanced cholangiocarcinoma (CCA). Ann Oncol. 2018;29(8). doi: 10.1093/annonc/mdy282.008.