Tasurgratinib for Patients With FGFR2 Gene Fusion–Positive CCA: A Phase 2 Study

Intrahepatic cholangiocarcinoma (iCCA) is a biliary tract cancer that represents an estimated 5% to 30% of primary liver cancers. Patients with CCA are often diagnosed at late stages of the disease and, therefore, generally have a poor prognosis.^1,2

There are few treatment options available for patients with surgically unresectable CCA, but the suggested first-line treatment is the combination of gemcitabine plus cisplatin with durvalumab.

Genetic alterations in the fibroblast growth factor receptor 2 (FGFR2) gene can occur in patients with CCA, and FGFR inhibitors are recommended in patients with CCA and FGFR fusions.^3,4

Tasurgratinib (E7090) is an oral selective inhibitor of FGFR1, FGFR2, and FGFR3, with the recommended dose being 140 mg daily, as described in the dose-escalation part of a first-in-human phase 1 study.^5,6

In a single-arm phase 2 study (NCT04238715) reported at ASCO GI by Junji Furuse, MD, PhD, tasurgratinib was evaluated in patients with FGFR2 fusion–positive CCA after gene fusion status had been confirmed by fluorescence in situ hybridization.

Oral tasurgratinib (140 mg) was administered daily in 28-day cycles to Japanese and Chinese patients with surgically unresectable, advanced, or metastatic CCA until disease progression, drug intolerance, or death.

Patients were included if they had ≥1 prior chemotherapies, including a gemcitabine-based combination, no prior FGFR inhibitor, and an Eastern Cooperative Oncology Group performance status of 0 or 1.

Tumor responses were measured every 8 weeks, and complete and partial responses required radiologic confirmation that occurred at least 28 days later. The primary endpoint was the overall response rate (ORR), and secondary endpoints included disease control rate, clinical benefit rate, duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and safety.

There were 63 patients enrolled in this study (28 Japanese, 35 Chinese) with a median age of 55 years. Of these patients, 23 received 1 prior line of therapy, while all others received ≥2 prior lines of therapy. By March 15, 2023 (data cutoff), 55 patients had discontinued treatment: disease progression, 48; adverse events, 4; patient choice, 2; loss of clinical benefit, 1.

There were 19 (30.2%) patients with a partial response and 31 (49.2%) patients with stable disease. The ORR was 30.2% (2-sided 90% confidence interval [CI], 20.7-41.0; 95% CI, 19.2-43.0) and met the prespecified success criteria. The median TTR and DOR were 1.87 months and 5.6 months, respectively.

Tasurgratinib demonstrated encouraging efficacy in individuals diagnosed with CCA and possessing FGFR2 gene fusion who had previously undergone at least 1 round of chemotherapy treatment.

The median PFS was 5.4 months (95% CI, 3.7-5.6), and the median OS was 13.1 months (95% CI, 10.8-17.4). A total of 61 (96.8%) patients had ≥1 treatment-related adverse events (TRAEs); the most common was hyperphosphatemia (51 patients; 81.0%).

The most common grade 3 TRAEs included increased lipase (4 patients; 6.3%), hyperphosphatemia (3 patients; 4.8%), and palmar-plantar erythrodysesthesia syndrome (2 patients; 3.2%).

Thirty-four (53.9%) patients had a dose reduction, and 18 (28.6%) had a treatment interruption due to a treatment-emergent adverse event.⁷

Tasurgratinib demonstrated encouraging efficacy in individuals diagnosed with CCA and possessing FGFR2 gene fusion who had previously undergone at least 1 round of chemotherapy treatment.

Tasurgratinib demonstrated an overall manageable safety profile, which remained consistent with prior studies and the expected pharmacologic behavior of FGFR inhibitors.^4,8-10

References

1. Ronnekleiv-Kelly SM, Pawlik TM. Staging of intrahepatic cholangiocarcinoma. Hepatobiliary Surg Nutr. 2017;6(1):35-43.
2. Patel T. Cholangiocarcinoma—controversies and challenges. Nat Rev Gastroenterol Hepatol. 2011;8(4):189-200.
3. National Institutes of Health. National Cancer Institute. Bile duct Cancer (cholangiocarcinoma) treatment (PDQ)–health professional version. Updated December 12, 2023. Accessed February 27, 2024. www.cancer.gov/types/liver/hp/bile-duct-treatment-pdq
4. Maruki Y, Morizane C, Arai Y, et al. Molecular detection and clinicopathological characteristics of advanced/recurrent biliary tract carcinomas harboring the FGFR2 rearrangements: a prospective observational study (PRELUDE study) [published correction appears in J Gastroenterol. December 30, 2020]. J Gastroenterol. 2021;56(3):250-260.
5. Watanabe SM, Yamamoto Y, Kodama K, et al. E7090, a novel selective inhibitor of fibroblast growth factor receptors, displays potent antitumor activity and prolongs survival in preclinical models. Mol Cancer Ther. 2016;15(11):2630-2639.
6. Koyama T, Shimizu T, Iwasa S, et al. First-in-human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors. Cancer Sci. 2020;111(2):571-579.
7. Furuse J, Jiang B, Kuwahara T, et al. Pivotal single-arm, phase 2 trial of tasurgratinib for patients with fibroblast growth factor receptor (FGFR)-2 gene fusion-positive cholangiocarcinoma (CCA). San Francisco, CA, & online: presented at ASCO Gastrointestinal Cancers Symposium; January 18-20, 2024: poster B16.
8. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study [published correction appears in Lancet Oncol. 2024 Jan;25(1):e3]. Lancet Oncol. 2020;21(5):671-684.
9. Goyal L, Meric-Bernstam F, Hollebecque A, et al. Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma. N Engl J Med. 2023;388(3):228-239.
10. Javle MM, 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):265-265.