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A fourth of previously treated cholangiocarcinomas (CCA) responded to a tyrosine kinase inhibitor (TKI) targeting the fibroblast growth factor receptor (FGFR) family, a phase II open-label study showed.

Confirmed objective responses occurred in 25 of 108 patients treated with infigratinib. Including unconfirmed responses increased the response rate to 34.2%. More than 80% of patients obtained disease control with FGFR inhibitor. Patients who had received no more than one prior systemic therapy responded better, but median progression-free survival (PFS, 7.3-7.4 months) was similar across prior lines of treatment.

Mechanism-based adverse events (AEs) predominated in the safety profile, notably hypophosphatemia and eye disorders, reported Milind Javle, MD, of the MD Anderson Cancer Center in Houston, at the Gastrointestinal Cancers Symposium virtual meeting.

"Infigratinib had meaningful clinical activity against chemotherapy-refractory CCA with FGFR fusions with a confirmed overall response rate (ORR) of 23% and median duration of response (DOR) of 5 months," said Javle. "Infigratinib was generally well tolerated in patients with advanced CCA. AEs were generally reversible and manageable and in line with previous observations in this patient population."

Arising in the bile duct, CCAs have an and typically are locally advanced or metastatic at diagnosis. About 70% of patients have late-stage disease at diagnosis and have few treatment options, Javle noted. First- and second-line options consist of that offer limited benefits.

Identification of molecular drivers of CCA offer the potential to change the standard of care for CCA, Javle continued. Genomic alterations in FGFR, particularly FGFR2 fusions and rearrangements, occur in about 15% of intrahepatic CCAs and predict sensitivity to FGFR inhibitors. for CCAs associated with FGFR2 fusions produces responses in 5% of patients and a median PFS of less than 5 months.

Infigratinib is a competitive inhibitor of FGFR1-3 and demonstrated in tumors with FGFR alterations. The results supported continued investigation in CCA and other malignancies associated with FGFR alterations.

Javle reported findings from the first of three planned cohorts treated with infigratinib. The cohort was limited to patients with FGFR2 gene fusions or alterations. Two smaller cohorts will evaluate the TKI in patients with FGFR1-3 alterations and patients with FGFR2 fusions and progression on a different FGFR inhibitor.

Enrollment in the first cohort was limited to patients with unresectable locally advanced or metastatic CCA associated with FGFR fusions or rearrangements and progression or intolerance to gemcitabine-based chemotherapy. Treatment consisted of single-agent oral infigratinib, continued daily until disease progression. The primary endpoints were ORR and DOR.

Baseline characteristics showed that 88 patients had FGFR fusions and 20 had other FGFR rearrangements. The patients had a median age of 53, women accounted for 62% of the cohort, and 50 (46.3%) had received no more than one prior line of therapy.

Efficacy data showed that one patient achieved a confirmed complete response, 24 had partial responses, and 66 patients had stable disease during treatment, resulting in a disease control rate (DCR) of 84.3%. Twelve patients had unconfirmed responses, making the best ORR 34.3%. Median time to response was 3.6 months and median DOR was 5.0 months. Median PFS was 7.3 months, and median overall survival (OS) was 12.2 months. Three-fourths of the patients were progression free at 4 months.

Patients who had received no more than one prior line of therapy fared better, including a ORR of 34.0%, DOR of 5.6 months, DCR of 88%, and best ORR of 42.0%. That compared with an ORR of 27.6%, DOR of 4.9 months, DCR of 81.0%, and best ORR of 27.6% for the 58 patients with two or more prior lines of therapy. All but a dozen or so patients had some degree of tumor shrinkage.

Biliary cancer is not a single disease, anatomically or molecularly, and oncologists must stop treating it as such, said invited discussant Rachna Shroff, MD, of the University of Arizona Cancer Center in Tucson.

"Cholangiocarcinoma is the poster child for precision medicine, and we need to be doing biomarker testing for all of our patients," she said. "It is absolutely therapeutically relevant."

"Infigratinib hits the target for FGFR2 fusion-positive cholangiocarcinoma and I strongly feel that it mostly hits the mark," Shroff added. "There is a comparable overall response rate to the other FGFR inhibitors, especially when you look at the patient population that received it earlier. There's an impressive median progression-free survival, and over time we're learning how to manage adverse events so that patients can continue on these drugs without significant toxicity."

Questions related to sequencing of FGFR inhibitors and use of combination therapy must be addressed in future studies, she concluded.

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