Infigratinib Approved in Canada for FGFR2+ Cholangiocarcinoma

Riccardo Braglia

Health Canada has approved infigratinib (Truseltiq) for the treatment of adult patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma harboring a FGFR2 fusion or other rearrangement.¹

The FGFR inhibitor has been given the green light under the Notice of Compliance with Conditions policy, which is a form of market approval granted to a product based on promising evidence of clinical effectiveness following submission review.

In the 108 patients who received treatment with the agent, infigratinib elicited an objective response rate (ORR) of 23.1% (95% CI, 15.6%-32.2%) with a median duration of response (DOR) of 5.0 months (95% CI, 0.9-19.1).²

Among those who had received at least 1 prior treatment (n = 50) for advanced cholangiocarcinoma, infigratinib was found to induce a confirmed ORR of 23% (95% CI, 16%-32%), with a median DOR of 5.0 months (95% CI, 3.7-9.3), according to data from a phase 2 trial (NCT02150967).2 In patients who received 2 or more prior lines of therapy (n = 58), the ORR was 13.8% (95% CI, 6.1%-25.4%), with a median DOR of 4.9 months (95% CI, 3.7–not evaluable).

“This is an important next step in growing [infigratinib’s] global reach. We are pleased to have achieved this milestone for patients with previously-treated locally advanced or metastatic cholangiocarcinoma harboring an FGFR2 fusion or other rearrangement,” Riccardo Braglia, vice chairman and chief executive officer of Helsinn Group, stated in a press release. “The conditional approvals from the US FDA and Health Canada mark the beginning of our journey delivering this medicine to patients in need. We look forward to working to enter further markets in the months and years ahead and working closely with BridgeBio as we make strides to reach patients.”

The open-label phase 2 study enrolled patients with unresectable locally advanced or metastatic cholangiocarcinoma who progressed on, or were intolerant to, gemcitabine-based chemotherapy. To be eligible for enrollment, patients needed to have tumors that harbored FGFR gene fusions or rearrangements.

The trial was comprised of 3 cohorts: those with FGFR2 gene fusions or rearrangements (cohort 1; n = 120), those with FGFR1&3 gene fusions or rearrangements and/or FGFR mutations (cohort 2; n = 20), and those with FGFR2 gene fusions who have progressed after previous treatment with a selective FGFR inhibitor other than infigratinib (cohort 3; n = 20). Those in cohorts 1 and 2 were not allowed to have previously received selective FGFR inhibitors.

Study participants received single-agent infigratinib until disease progression. In adult patients with advanced malignancy, the agent was given at a daily dose of 125 mg for 21 days every 28 days.

The primary end points of the trial were ORR and DOR, and key secondary end points included progression-free survival (PFS), disease control rate (DCR), best overall response (BOR), overall survival (OS), safety, and pharmacokinetics.

A total of 122 patients were enrolled to the trial; 14 patients were excluded from the analysis, and 108 with FGFR2 fusion or rearrangements comprised the protocol-defined analysis population, or cohort 1.

Among the 108 patients in cohort 1, 107 had previously received gemcitabine-based treatment, 88 had fusions, and 20 had other rearrangements. A total of 96 patients discontinued treatment with infigratinib because of disease progression (n = 67), toxicity (n = 15), clinical progression (n = 9), patient decision (n = 3), death (n = 1), and loss to follow-up (n = 1).

Among the 108 patients, 81% had a FGFR2 fusion and 19% had a rearrangement. The median age of patients was 53 years (range, 23-81), 62.0% were female, 72.2% were White, 57.4% have an ECOG performance status of 1, and 99.1% had stage IV disease at the time of study entry. Moreover, 68.5% of patients had metastasis in the lung, 57.4% had it in the nodes, 25.9% had it in the bone, and 38.0% had another non-liver site of metastasis.

The median number of prior lines of therapy was 2 (range, 0-8), with 46.3% of patients having received 1 or more prior lines of treatment. Additionally, 29.6% of patients received 2 prior lines, 13.0% received 3 prior lines, and 11.1% received 4 or more lines.

Additional data from the trial showed that the BOR rate with infigratinib was 34.3% (95% CI, 25.4%-44.0%), with a median time to response of 3.6 months (range, 1.4-7.4). The disease control rate with the agent was 84.3% (95% CI, 76.0%-90.6%). Moreover, the median PFS with infigratinib was 7.3 months (95% CI, 5.6-7.6), with a 4-month PFS rate of 75.2% (95% CI, 65.2%-82.7%). The median OS was 12.2 months (95% CI, 10.7-14.9).

Treatment with the agent was determined to be generally well tolerated in patients with advanced cholangiocarcinoma. Toxicities included hyperphosphatemia, stomatitis, fatigue, alopecia, dry eye, Palmar-Plantar Erythrodysesthesia syndrome, arthralgia, dysgeusia, constipation, dry mouth, hypercalcemia, blood creatinine increased, diarrhea, dry skin, decreased appetite, hypophosphatemia, vision blurred, aspartate aminotransferase increased, and vomiting.

Adverse effects were found to be generally reversible and manageable. On-target toxicities were managed with dose interruptions and/or reductions, supportive care, dietary modification, and concomitant medications.

Specifically, those who experienced hyperphosphatemia were managed with dietary modifications and the utilization of phosphate binders. Notably, no patients discontinued treatment because of this toxicity. Eye drops were used in those who experienced eye disorders. Gastrointestinal toxicities were relatively uncommon.

In May 2021, the FDA approved infigratinib for the treatment of patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring an FGFR2 fusion or rearrangement based on data from the phase 2 trial.³

References

1. Helsinn Group and BridgeBio Pharma’s affiliate QED Therapeutics announce Health Canada conditional approval of Truseltiq (infigratinib) for patients with cholangiocarcinoma. News release. Helsinn Group and BridgeBio Pharma, Inc. September 27, 2021. Accessed September 29, 2021. https://bit.ly/3mdIWXg
2. Javle M, Roychowdhury S, Kelley RK, et al. Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement. J Clin Oncol. 2021;39(suppl 3):265. doi:10.1200/JCO.2021.39.3_suppl.265
3. BridgeBio Pharma’s affiliate QED Therapeutics and partner Helsinn Group announce FDA approval of truseltiq (infigratinib) for patients with cholangiocarcinoma. News release. BridgeBio Pharma, Inc. May 28, 2021. Accessed September 29, 2021. https://bit.ly/3wE320C