FDA Grants Accelerated Approval to LYTGOBI® for Cholangiocarcinoma

SUMMARY: The FDA on September 30, 2022, granted accelerated approval to LYTGOBI® (Futibatinib) for adult patients with previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring Fibroblast Growth Factor Receptor 2 (FGFR2) gene fusions or other rearrangements. Bile Tract cancer (Cholangiocarcinoma) is a rare, heterogenous cancer, and comprises about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. The 5-year survival among those with advanced stage disease is less than 10%, with limited progress made over the past two decades.

Approximately 75% of patients are diagnosed with late-stage disease, and are often treated with Gemcitabine plus Cisplatin, based on the findings of the ABC-02 study. Second line treatment options include FOLFOX regimen, which is associated with a Response Rate of about 5%, median Progression Free Survival (PFS) of about 4 months, and median Overall Survival (OS) of about 6 months. There is therefore an unmet need for new effective therapies.

FGFRs (Fibroblast Growth Factor Receptors) play an important role in tumor cell proliferation and survival, migration, and angiogenesis. Activating fusions, rearrangements, translocations, and gene amplifications in FGFRs result in dysregulation of FGFR signaling, and may contribute to the pathogenesis of various cancers, including Cholangiocarcinoma. FGFR2 fusions or rearrangements occur almost exclusively in intrahepatic Cholangiocarcinoma, where they are observed in 10-20% of patients, and have been identified as oncogenic drivers. Futibatinib is a highly selective, irreversible FGFR1-4 inhibitor, and demonstrated tolerability and preliminary evidence of clinical efficacy in patients with intrahepatic cholangiocarcinoma.

The present FDA approval was based on the results from the pivotal FOENIX-CCA2 trial (NCT02052778), which is a global, multicenter, open-label, single-arm study that enrolled 103 patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma, harboring a FGFR2 gene fusion or other rearrangement. The presence of FGFR2 fusions or other rearrangements was determined using Next Generation Sequencing testing. Patients received Futibatinib 20 mg orally once daily until disease progression or unacceptable toxicity. The median age was 58 years, 53% had an ECOG Performance Status of 1, all patients had prior anticancer therapy, with 27% receiving prior radiotherapy. FGFR2 fusions were observed in 78% of patients and 22% had a rearrangement. The median time from prior anticancer therapy to the first Futibatinib dose was 1.5 months. The Primary endpoint was Objective Response Rate (ORR) by Independent Central Review. Secondary endpoints were Duration of Response (DOR), Disease Control Rate (DCR), Progression Free Survival (PFS), Overall Survival (OS), Safety, and Patient-Reported Outcomes. At the primary analysis of this trial, an Objective Response Rate of 41.7% was observed, with a median Duration of Response of 9.7 months. The researchers herein reported updated efficacy, including mature Overall Survival, and safety data from the final analysis, with an additional 8 months of follow up.

At a median follow up of 25 months, the median number of treatment cycles was 13.0 and the median treatment duration was 9.1 months. The confirmed Objective Response Rate was 41.7%, like what was noted at the time of primary analysis, and this benefit was consistent across patient subgroups. The Disease Control Rate of 82.5% and was similar as well. The median Duration of Response was 9.5 months, and 74% of responses lasted 6 months or more. The median PFS was 8.9 months, with a 12-month PFS rate of 35%. The median Overall Survival was 20 months, with a 12-month Overall Survival rate of 73%. The most common treatment-related adverse events included hyperphosphatemia (85%), alopecia (33%), dry mouth (30%), diarrhea (28%), dry skin (27%), and fatigue (25%). Approximately 4% of patients discontinued treatment due to adverse events.

The authors concluded that the final analysis of FOENIX-CCA2 study confirmed the results of the primary analysis and reinforced the durable efficacy and continued tolerability of Futibatinib in previously treated patients with advanced/metastatic intrahepatic cholangiocarcinoma harboring FGFR2 fusion/rearrangements. They added that the mature Overall Survival far exceeded historical data in this patient population.

Updated results of the FOENIX-CCA2 trial: Efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/rearrangements. Goyal L, Meric-Bernstam F, Hollebecque A, et al. J ClinOncol. 2022;40(suppl 16):4009. doi:10.1200/JCO.2022.40.16_suppl.4009