Later-Line Infigratinib Outperforms Standard Chemotherapy in Cholangiocarcinoma

Milind M. Javle, MD

Infigratinib conferred a clinically meaningful progression-free survival (PFS) and overall response rate (ORR) benefit when administered as a third- and later-line treatment for patients with FGFR2 fusion–positive cholangiocarcinoma, according to results from a retrospective analysis presented at the 2020 ESMO World Congress on Gastrointestinal Cancer.¹

Lead author, Milind M. Javle, MD, and fellow investigators analyzed data from a subset of patients (n = 37) with FGFR-mutant advanced or metastatic cholangiocarcinoma who received infigratinib, a selective FGFR inhibitor, in the third- or later-line setting in a phase 2 single-arm trial (NCT02150967).

Findings from the retrospective analysis showed that third- and later-line infigratinib therapy led to a superior improvement in median PFS compared with pre-infigratinib, second-line chemotherapy at 6.77 months (95% CI, 3.94-7.79) versus 4.63 months (95% CI, 2.69-7.16). Of note, chemotherapy is the predominant second-line treatment intervention for patients with cholangiocarcinoma, which is the most common biliary tract cancer, with an estimated incidence of 1.67 per 100,000 in the United States.²

The ORR data also favored infigratinib. The ORR was 21.6% (95% CI, 9.8-38.2) with the FGFR inhibitor and 5.4% (95% CI, 0.7-18.2) with second-line chemotherapy. Overall, outcomes seen with second-line chemotherapy in the subset analysis were consistent with what has been previously reported for patients with cholangiocarcinoma, regardless of genomic status, and continue to be insufficient, signaling a need for more effective therapies.²

Building on Existing Data

The retrospective analysis by Javle et al included 37 patients who received standard second-line chemotherapy and subsequent third-line or later infigratinib. Investigators compared the efficacy of each intervention in the 37 patients in an effort to define outcomes for second-line, standard chemotherapy–receiving patients with FGFR2-mutant cholangiocarcinoma, which, prior to this evaluation, were unknown.2 Standard second-line chemotherapy for this patient population has traditionally included gemcitabine- or capecitabine-based combinations, and leucovorin calcium, fluorouracil, oxaliplatin (FOLFOX), Javle explained.

The single-arm study from which these patients were extracted for the retrospective analysis enrolled 71 patients with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease progressed on prior therapy. Patients received 125 mg of infigratinib once daily for 21 days, followed by 7 days off therapy, for 28-day cycles that were repeated until unacceptable toxicity, disease progression, cessation per investigator discretion, or withdrawal of patient consent. The primary end point was investigator-assessed ORR.³

Updated data from the phase 2 study presented at the 2019 ESMO World Congress on Gastrointestinal Cancer demonstrated a 31.0% ORR (95% CI, 20.5-43.1). There were no complete responses, 18 partial responses (25.4%), and 41 patients (57.7%) had stable disease. Among patients with potential for confirmation, defined as patients who either completed 6 cycles of therapy or discontinued treatment prior to the sixth cycle, the median PFS was 6.8 months (95% CI, 5.3-7.6) and the median OS was 12.5 months (95% CI, 9.9-16.6). The median duration of response was 5.4 months (95% CI, 3.7-7.4).³

Investigators of the phase 2 trial concluded that the first-in-class FGFR kinase inhibitor showed meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma with FGFR2 fusions with manageable toxicities, supporting further study and development of infigratinib in and for this highly specific patient population.^3,4

FGFR2 Fusions and Cholangiocarcinoma

FGFR2 fusions present in 13% to 17% of cholangiocarcinoma cases and represent an emerging genomic target across various tumor types.² Although FGFRs are known to play a role in tumor cell production and survival, as well as migration and angiogenesis, the specific prognostic impact of FGFR2 fusions is currently unknown.⁵

Second-line and later therapies are limited for patients with locally advanced or metastatic cholangiocarcinoma beyond frontline combination chemotherapy, but advancements in drug development are slowly broadening available treatment options.⁵ On April 20, 2020, pemigatinib (Pemazyre) received an accelerated approval for adults with locally advanced or metastatic disease that harbors an FGFR2 fusion or other rearrangement, as detected by an FDA-approved test.⁶

Earlier, in January 2020, the FDA awarded infigratinib a fast track designation for adults with first-line advanced or metastatic cholangiocarcinoma and an orphan drug designation for cholangiocarcinoma, according to infigratinib’s developer, QED Therapeutics, a subsidiary of BridgeBio Pharma, Inc.⁷

References

1. Javle M, Sadeghi , Roychowdhury S, et al. Efficacy of second-line chemotherapy in patients with advanced or metastatic cholangiocarcinoma and FGFR2 fusions: a retrospective analysis. Presented at: ESMO World Congress on Gastrointestinal Cancer 2020. July 1-4, 2020; Virtual. ASO-5.
2. Outcomes from second-line chemotherapy in patients with cholangiocarcinoma and FGFR2 fusions. News release. European Society for Medical Oncology. July 1, 2020. Accessed July 2, 2020. https://bit.ly/38pnl6U
3. Javle M, Kelley RK, Roychowdhoury S, et al. A phase II study of infigratinib (BGJ398) in previously-treated advanced cholangiocarcinoma containing FGFR2 fusions. Presented at: Cholangiocarcinoma Foundation Annual Conference 2019. January 30-February 2, 2019. https://bit.ly/2NRezpa
4. Javle M, Lowery M, Shroff RT, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2018;36(3):276-282. doi:10.1200/JCO.2017.75.5009
5. Borad MJ, Gores GJ, Roberts LR. Fibroblast growth factor receptor 2 fusions as a target for treating cholangiocarcinoma. Curr Opin Gastroenterol. 2015;31(3):264-268. doi:10.1097/MOG.0000000000000171
6. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. News release. FDA. April 17, 2020. Accessed July 2, 2020. https://bit.ly/3gmcBJk
7. BridgeBio Pharma’s QED Therapeutics receives Fast Track designation for infigratinib in adults with first-line advanced or metastatic cholangiocarcinoma and Orphan Drug designation for infigratinib in treatment of cholangiocarcinoma. News release. BridgeBio Pharma, Inc. January 6, 2020. Accessed July 2, 2020. https://bit.ly/31I7xLl