FDA Withdraws Accelerated Approval of Infigratinib for Advanced FGFR2+ Cholangiocarcinoma

The FDA has withdrawn the approval of infigratinib (Truseltiq) for the treatment of patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma harboring an FGFR2 fusion or other rearrangement.¹

The indication was withdrawn following a voluntary request from the agents’ sponsor, QED Therapeutics, citing difficulties enrolling patients to the required confirmatory study following infigratinib’s accelerated approval. The phase 3 PROOF trial (NCT03773302) was evaluating the efficacy and safety of infigratinib vs standard-of-care gemcitabine plus cisplatin as frontline therapy in patients with unresectable, recurrent, or metastatic cholangiocarcinoma harboring FGFR2 gene fusions and translocations. The study has been terminated; notably, the study was not closed for safety reasons.²

According to the FDA, QED Therapeutics determined the continued distribution of infigratinib for use in the second-line treatment of this patient population was not commercially reasonable.¹

In May 2021, the FDA granted accelerated approval to infigratinib for the treatment of adult patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma harboring an FGFR2 fusion or other rearrangement, as detected by an FDA-approved test.

That regulatory decision was supported by data from a multicenter, open-label, single-arm, phase 2 trial (NCT02150967), which demonstrated that patients treated with the pan-FGFR kinase inhibitor (n = 108) experienced an overall response rate (ORR) of 23% (95% CI, 16%-32%) per blinded independent central review (BICR), including 1 patient who had a complete response and 24 patients who achieved a partial response.

The median duration of response (DOR) was 5 months (95% CI, 3.7-9.3), and 8 of 23 evaluable responders maintained a response for at least 6 months.

The most common adverse effects reported in at least 20% of patients included hyperphosphatemia, increased creatinine, nail toxicity, stomatitis, dry eye, fatigue, alopecia, palmar-plantar erythrodysesthesia syndrome, arthralgia, dysgeusia, constipation, abdominal pain, dry mouth, eyelash changes, diarrhea, dry skin, decreased appetite, vision blurred and vomiting.

The study enrolled patients at least 18 years of age with histologically or cytologically confirmed cholangiocarcinoma who received at least 1 prior gemcitabine-containing regimen with or without cisplatin for advanced or metastatic disease. Other key inclusion criteria consisted of evidence of progressive disease following the prior regimen. If patients discontinued prior treatment due to toxicity, they were required to have continued evidence of measurable or evaluable disease.³

Patients with cancers of the gallbladder or ampulla of Vater were not allowed to enroll. Other key exclusion criteria included prior treatment with a MEK inhibitor or infigratinib (all cohorts), or a selective FGFR inhibitor (cohorts 1 and 2); and insufficient organ function.

Enrolled patients were treated with 125 mg of oral infigratinib once per day for 3 weeks on and 1 week off during 28-day cycles. Treatment continued until disease progression or unacceptable toxicity.

BICR-assessed ORR per RECIST 1.1 criteria served as the trial’s primary end point. Secondary end points included investigator-assessed ORR, best overall response (BOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), DOR, and safety.

PROOF was a multicenter, open-label, randomized, phase 3 study that enrolled patients at least 18 years of age with histologically or cytologically confirmed, unresectable locally advanced or metastatic cholangiocarcinoma. Those with gallbladder cancer or ampulla of Vater carcinoma were not permitted to enroll. Other key inclusion criteria comprised a documented FGFR2 fusion or rearrangement; and an ECOG performance status of 0 or 1.²

Prior systemic therapy for unresectable locally advanced or metastatic cholangiocarcinoma was not allowed, except for prior neoadjuvant or adjuvant therapy completed more than 6 months prior to enrollment; or 1 cycle of gemcitabine-based chemotherapy for locally advanced or metastatic cholangiocarcinoma prior to randomization. Patients were also excluded if they had a history of a liver transplant; underwent prior treatment with a MEK or selective FGFR inhibitor; or had gastrointestinal (GI) impairment or GI disease that could significantly alter the absorption of oral infigratinib.

Patients were randomly assigned 2:1 to receive 125 mg of infigratinib per day for 3 weeks on and 1 week off; or gemcitabine at 1000 mg/m² plus cisplatin at 25 mg/m² on days 1 and 8 of each 21-day cycle. Notably, patients treated with gemcitabine plus cisplatin who experienced disease progression were allowed to cross over to receive infigratinib.

PFS served as the trial’s primary end point. Secondary end points included OS, ORR, BOR, DOR, DCR, and safety.

References

1. Withdrawn: FDA grants accelerated approval to infigratinib for metastatic cholangiocarcinoma. FDA. May 16, 2024. Accessed May 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/withdrawn-fda-grants-accelerated-approval-infigratinib-metastatic-cholangiocarcinoma
2. Phase 3 study of BGJ398 (oral infigratinib) in first line cholangiocarcinoma with FGFR2 gene fusions/​translocations. ClinicalTrials.gov. Updated May 8, 2024. Accessed May 20, 2024. https://clinicaltrials.gov/study/NCT03773302
3. A phase II, single arm study of BGJ398 in patients with advanced cholangiocarcinoma. ClinicalTrials.gov. Updated July 3, 2023. Accessed May 20, 2024. https://www.clinicaltrials.gov/study/NCT02150967