Lytgobi (futibatinib)

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.

In heavily pretreated patients with metastatic TNBC harboring FGFR2 gene amplification, futibatinib monotherapy demonstrated modest anticancer activity. Futibatinib was tolerable and had an acceptable safety profile, consistent with previous data. Further biomarker work to identify patients who might benefit most from futibatinib is ongoing.

Futibatinib plus fulvestrant showed antitumor activity in patients with advanced HR+/HER2− breast cancer with FGFR1 amplification progressing on prior CDK4/6 inhibitors, with a numerically higher ORR and doubling in PFS relative to historical fulvestrant results in post-CDK4/6 patients. The safety profile was consistent with those of the individual study drugs. Further biomarker work is ongoing.

These data support secondary FGFR2 mutations as the primary mode of acquired resistance to FGFR inhibitors-most commonly N550 and V565 mutations. Thus, development of combination strategies and next-generation FGFR inhibitors targeting the full spectrum of FGFR2 resistance mutations will be critical.

FGF23 and FGFR1 play key roles in phosphate homeostasis and hyperphosphatemia results from FGFR1 inhibition.Case Description: Case series of patients with urothelial bladder cancer and cholangiocarcinoma (CCA) taking FGFR inhibitors (erdafitinib or futibatinib) at AC Camargo from July 2021 - February 2023. The metabolic changes caused by these drugs are a undesirable, but important side effects that might limit their use in many patients affected by cancer with genetic alterations in FGFRs. CCA = cholangiocarcinoma; P = Phosphate; iCa = Ionized Calcium; Creat = creatinine; 1,25 vitD = 1,25-dihydroxyvitamin D; n/a = not available

P1b/2, N=38, Terminated, Taiho Oncology, Inc. | Trial completion date: Dec 2024 --> Sep 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2024 --> Jun 2023; Strategic decision by sponsor.

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

Only first- and second-line treatments are well codified with the combination of cisplatin-gemcitabine chemotherapy and immunotherapy followed by 5-FU and oxaliplatin chemotherapy, respectively...Ivosidenib targeting IDH1 mutations, as well as futibatinib and pemigatinib targeting FGFR2 fusions, are approved for pre-treated advanced CCA. The combination of dabrafenib and trametinib are approved for BRAFV600E mutated advanced tumours, NTRK inhibitors entrectinib and larotrectinib for tumours bearing NTRK fusion and prembrolizumab for MSI-H advanced tumours, involving a small percentage of BTC in these three settings. Several other potentially targetable alterations are found in BTC, such as HER2 mutations or amplifications or KRASG12C mutations and mutations in genes involved in DNA repair mechanisms. This review aims to clarify the specific diagnostic modalities for gene alterations and to summarize the results of the main trials and developments underway for the management of advanced BTC with targetable alterations.

P2, N=25, Recruiting, Mayo Clinic | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: Sep 2023 --> Sep 2024

Futibatinib was well-tolerated, with only four grade 1 treatment-emergent adverse events (mild hepatic impairment = 2 and control = 2). The results demonstrate that futibatinib dose adjustments due to mild/moderate/severe hepatic impairment are not necessary in patients receiving futibatinib 20 mg daily.

Recent clinical studies showed promising data for FGFR-targeted therapy in reducing tumor volume and led to the United States Food and Drug Administration (FDA) approval of, e.g., pemigatinib, infigratinib, futibatinib, and erdafitinib...Pemigatinib (FIGHT-302) and futibatinib (FOENIX-CAA3) are being evaluated in phase III trials that compare these agents to current first-line gemcitabine and cisplatin in FGFR2-rearranged cholangiocarcinoma. However, complexity in targeting the FGFR signaling pathway is observed. Herein, we describe the characteristics of the FDA-approved and other investigational FGFR-targeted therapeutics, evaluate the most recent preclinical and clinical studies focusing on targeting FGFR genomic alterations in the treatment of cholangiocarcinomas and urothelial cancer, and provide insight into factors involved in response and (acquired) resistance to FGFR inhibition.

These data indicate the primary metabolic pathways of futibatinib are O-desmethylation and glutathione conjugation, with cytochrome P450 enzyme-mediated desmethylation as the main oxidation pathway. C-futibatinib was well tolerated in this Phase 1 study.

"Sysmex Corporation...is now covered by health insurance in Japan as a companion diagnostic for futibatinib,1 a treatment for unresectable biliary tract cancer2 harboring FGFR2 gene fusions3 that has progressed after chemotherapy. Futibatinib was developed by Taiho Pharmaceutical Co., Ltd....Riken Genesis Co., Ltd (HQ: Shinagawa-ku, Tokyo, Japan; President: Kenji Iwakabe), a subsidiary of Sysmex, will begin assay services in Japan corresponding to this insurance coverage from September 2023."

Moreover, we provide evidence that the combination of futibatinib with currently used chemotherapies such as irinotecan and vincristine has a synergistic effect against RMS in vitro. Moreover, limited efficacy is only observed in a PAX3-FOXO1 fusion-negative (FN) RMS cell line with mutationally activated FGFR4, whereas little or no efficacy is observed in PAX3-FOXO1 fusion-positive (FP) RMS cell lines with FGFR4 overexpression. Alternative treatment modalities such as combining futibatinib with other kinase inhibitors or targeting FGFR4 with CAR T cells or antibody-drug conjugate may be more effective than the approaches tested in this study.

P2, N=26, Recruiting, Taiho Oncology, Inc. | Not yet recruiting --> Recruiting

No abstract available

This duration extended to 9.66 (3.06 - 14.06) months among futibatinib recipients...Conclusions Our study demonstrated the efficacy of novel therapeutic agents in CCA. Liquid biopsies can reliably provide information on extended molecular profiling to aid pt selection for personalised therapeutics.

No abstract available

P2, N=26, Not yet recruiting, Taiho Oncology, Inc.

P2, N=168, Active, not recruiting, Taiho Oncology, Inc. | Trial completion date: Jun 2023 --> Jul 2024

These data show clinically meaningful benefit with futibatinib in FGFR2-rearrangement-positive cholangiocarcinoma and provide support for further investigation of futibatinib across other indications. Future directions for this agent include elucidating mechanisms of resistance and exploration of combination therapy approaches.

Four targeted small molecule agents have emerged as effective therapies in the second-line setting for CCA, which has immensely changed the treatment landscape and directly led to further investigation of targeted agents and immunotherapy as treatment for CCA.