Lytgobi (futibatinib)

On this basis, the present review aims at providing an overview of recently explored connections between the FGF/FGFR system and c-Myc oncoprotein, sustaining the therapeutic potential of targeting the FGF/FGFR/c-Myc axis in MM by using inhibitors targeting FGF ligands or FGF receptors. Importantly, the provided findings may represent the rationale for using FDA approved FGFR TK inhibitors (i.e. Pemigatinib, Futibatinib, Erdafitinib) for the treatment of MM patients presenting with an aberrant activation of this axis.

P2, N=43, Active, not recruiting, Taiho Oncology, Inc. | Trial primary completion date: Aug 2025 --> Mar 2024

The side effects from taking futibatinib were manageable and similar in people with different types of cancer. To fully understand the safety of futibatinib, researchers will need to look at what side effects are reported in people taking futibatinib over a longer time in the real-world setting (outside of clinical trials).

Although some typical FGFR inhibitor-related side effects were observed, they were manageable and futibatinib had a good safety profile. Futibatinib is an important drug for biliary tract cancer, which has limited treatment options; its development is underway for other types of cancer, and it is expected to benefit more patients.

P2, N=3791, Recruiting, American Society of Clinical Oncology | Trial completion date: Dec 2025 --> Jun 2027 | Trial primary completion date: Dec 2024 --> Jun 2026

In part 1, 20 participants received digoxin (P-gp substrate) and rosuvastatin (BCRP substrate). The most common treatment-emergent adverse events were diarrhea (80%) and increased blood phosphorous (75%) in part 1 and prolonged electrocardiogram QT interval (38%) in part 2. The data show that futibatinib has no clinically meaningful effects on the PK of P-gp or BCRP substrates and that the effect of P-gp inhibition on futibatinib PK is not clinically relevant.

The method assessed FTB and BTB interaction potential in combination therapy at 5 mg/kg. The findings provide essential pharmacokinetics insights for future clinical trials.

P2/3, N=15, Enrolling by invitation, Taiho Oncology, Inc. | Not yet recruiting --> Enrolling by invitation

At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and inter-patient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly-oriented treatment strategies across FGFR2-driven tumors.

P2, N=168, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Jul 2024 --> Oct 2024

P3, N=10, Terminated, Taiho Oncology, Inc. | N=216 --> 10 | Active, not recruiting --> Terminated; Due to Poor Recruitment

This report unveils a potential avenue for targeted therapy for the management of metastatic disease: a patient with ACC who harbored a specific fibroblast growth factor receptor 2 (FGFR-2) mutation and responded significantly to a novel FGFR-2 inhibitor. This finding could pave the way for personalized treatment options for ACC patients with similar genetic alterations. Nevertheless, the use of futibatinib requires further investigation to optimize treatment protocols, including exploring combination therapies, identifying predictive biomarkers for treatment response, and developing strategies to overcome potential resistance.

P2/3, N=15, Not yet recruiting, Taiho Oncology, Inc.

P1, N=38, Terminated, Taiho Oncology, Inc. | Phase classification: P1b/2 --> P1

P2, N=46, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Jun 2024 --> Sep 2025 | Trial primary completion date: May 2024 --> Aug 2025

We present a case of prolonged clinical benefit using FGFR inhibitors sequentially, initially an ATP-competitive inhibitor followed by futibatinib upon progression, for a total of 36 months of FGFR-targeting therapy. This case supports sequential FGFR-targeting therapies for FGFR2 fusion-positive cholangiocarcinoma, with futibatinib acting as rescue therapy after failure of ATP-competitive inhibitors.

Based on the results of this study, futibatinib is now approved in the US, Europe, and Japan. Futibatinib is approved for treating adults with advanced bile duct cancer who have received previous treatment for their cancer, and whose tumors have a gene fusion or other change in the FGFR2 gene.Clinical Trial Registration: NCT02052778 (FOENIX-CCA2).

The method provided a low detection limit of 0.120 ng/mL and maintained a linear concentration-dependent relationship across the range of 1-200 ng/mL. High sensitivity, accuracy and precision were demonstrated for futibatinib quantification in pharmaceutical formulation and spiked plasma matrix by the method, which was validated in accordance with ICH requirements.

P3, N=800, Recruiting, UNICANCER | Not yet recruiting --> Recruiting

Indeed, hyperphosphataemia (the most common all grade and grade 3 treatment-related adverse event) was manageable with phosphate-lowering therapy and dose reductions or interruptions. Although further efficacy and tolerability data are expected, current evidence indicates that futibatinib is a valuable targeted therapy option for adults with locally advanced or metastatic CCA harbouring an FGFR2 fusion or rearrangement who have progressed following systemic therapy, a patient population with limited treatment options and poor life expectancy.

"However, limited evidence has been presented to date for the efficacy of futibatinib in patients progressing under treatment with a non-covalent inhibitor. Between January 2021 and April 2023, 14 patients received futibatinib after treatment with the non-covalent FGFR inhibitors pemigatinib (10 patients) or derazantinib (4 patients). Futibatinib was manageable and active in patients with iCCA progressing under a previously non-covalent FGFR2 inhibitor. Randomized controlled trials are needed to determine the optimal therapeutic approach between an upfront treatment with a covalent inhibitor or a sequential strategy starting with a non-covalent inhibitor, followed by a covalent one if disease progresses due to acquired mutations that this could address."

P2, N=46, Active, not recruiting, Taiho Oncology, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Dec 2023 --> May 2024

P2, N=115, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Sep 2024

FDA has approved four anticancer agents such as erdafitinib, pemigatinib, infigratinib, and futibatinib, for clinical use in oncogenic FGFR-driven malignancies. Furthermore, futibatinib is the first-in-class covalent or irreversible pan-FGFR inhibitor that has received FDA approval for locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene aberrations. This review highlights the current clinical progress concerning the safety and efficacy of all the approved FGFR-TKIs (tyrosine kinase inhibitors) and their ongoing investigations in clinical trials for other oncogenic FGFR-driven malignancies.

P2, N=25, Recruiting, Mayo Clinic | Trial primary completion date: Sep 2024 --> May 2025

P1/2, N=407, Completed, Taiho Oncology, Inc. | Active, not recruiting --> Completed

Of these, nine received treatment with a molecular target drug: eight patients with a mutation of the PIK3CA gene were treated with alpelisib and fulvestrant; one patient with FGFR1/2 amplifications received TAS120. The growing number of detectable mutations and increased accessibility of the test may lead to a greater number of potential therapeutic implications for the NGS assay. Perspectives suggest that NGS analysis can be implemented in daily clinical practice, particularly in contexts where a Molecular Tumor Board (MTB) is active.

P2, N=66, Recruiting, Taiho Oncology, Inc. | N=26 --> 66

Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence.

P1, N=150, Recruiting, Boundless Bio | Phase classification: P1/2 --> P1 | N=47 --> 150 | Trial completion date: Jan 2026 --> Sep 2027 | Trial primary completion date: Jan 2025 --> Sep 2026

P1, N=715, Recruiting, Taiho Pharmaceutical Co., Ltd. | N=367 --> 715 | Trial completion date: May 2024 --> May 2026 | Trial primary completion date: May 2024 --> May 2026

Futibatinib showed a consistent and manageable safety profile across patients with various tumor types. AECIs were mostly reversible with appropriate clinical management.

To our knowledge, this is the first case depicting rapidly reversible SRF accumulation with the use of futibatinib in a real-world clinical setting. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

P3, N=216, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Dec 2023 --> Jun 2024 | Trial primary completion date: Dec 2023 --> Jun 2024

P3, N=800, Not yet recruiting, UNICANCER

The average monthly cost for the treatment of neoplastic diseases was $17,900 with a price of $44,000 for futibatinib (used to treat cholangiocarcinomas with FGFR2 fusions) and minimum of $5100 for binimetinib (melanoma). The average monthly cost for the treatment of non-neoplastic diseases was $6800 with a maximum of $17,000 for belumosudil (graft vs. host disease) and a minimum of $200 for netarsudil eye drops (glaucoma). There is a negative correlation of the cost of the drugs and the incidence of the targeted disease. Many of these agents are or were designated as orphan drugs meaning that there are fewer than 200,000 potential patients in the United States.

The first generation FGFR inhibitors (FGFRi) pemigatinib and futibatinib, have been approved for the treatment of advanced CCA with FGFR2 fusions or rearrangements after systemic chemotherapy...The study includes Part A and Part B. The Part A is to select a dose for Part B. Eligible subjects will be randomized in a 2:2:1 ratio to receive tinengotinib 8 mg QD, tinengotinib 10 mg QD or Physician's Choice (FOLFOX or FOLFIRI) in Part A or 2:1 in Part B to receive the recommended Part B dose or Physician's Choice...Study is open for enrollment. Clinical trial information: NCT05948475.

In this global, phase 2, randomized, open-label study (NCT05727176), patients with CCA harboring FGFR2 fusions/rearrangements who have received ≥1 line of gemcitabine/platinum-based therapy for advanced/metastatic disease will be randomized 1:1 to futibatinib at a starting dose of 20 mg or 16 mg QD continuously on a 21-day cycle. 2022;12:402–15. Clinical trial information: NCT05727176.

This resulted in activation of both AKT- and MAPK-signaling pathways shown on mRNA and protein levels, and rendered cancer cells highly sensitive to pan-FGFR-inhibitors (BGJ 398, AZD 4547, and TAS-120). Collectively, our data illustrates that continuous inhibition of KIT signaling in IM-resistant GISTs lacking secondary KIT mutations induced clonal heterogeneity of GISTs and resulted in accumulation of cancer cells with overexpressed FGF-2 and FGFR1/2, thereby leading to activation of FGFR-signaling. This in turn rendered these cells extremely sensitive to the pan-FGFR inhibitors used in combination with IM, or even alone, and suggests a rationale to re-evaluate the effectiveness of FGFR-inhibitors in order to improve the second-line therapeutic strategies for selected subgroups of GIST patients (e.g., IM-resistant GISTs lacking secondary KIT mutations and exhibiting the activation of the FGFR-signaling pathway).

Per institutional and public databases, FGFR2 mutations and amplifications had a population frequency of 1.1%-2.6% and 1.5%-2.5%, respectively, in breast cancer patients. FGFR2 alterations in breast cancer may represent infrequent but highly promising targets for futibatinib.

These findings suggest convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi.

The first-line chemotherapeutic combination for the treatment of CCA are cisplatin and gemcitabine-based chemotherapies. While the side effect profile of infigratinib is minimal, particularly GI side effects, when compared with futibatinib and pemigatinib, the overall response rate (ORR) and median overall survival (mOS) for infigratinib (ORR=23.1%, mOS=3.8 months) was significantly lower than futibatinib (ORR=35.8%, mOS=21.1 months) and pemigatinib (ORR=35.5%, mOS=21.1 months). While there is ample promise for the use of infigratinib as molecular-directed therapy in the treatment of CCA harboring FGFR2 mutations, there is an appropriate concern for patient-acquired resistance. The heterogeneous nature of FGFR mutations and the emergence of different resistance mechanisms emphasize a need for more agents to inhibit FGFR rearrangements effectively.