Pemazyre (pemigatinib)

P2, N=33, Not yet recruiting, Lund University Hospital

P1, N=70, Recruiting, Massachusetts General Hospital | Not yet recruiting --> Recruiting

Currently, 3 targeted therapies are approved for use in CCA; Ivosidenib in patients with IDH1 mutations and Infigratinib/Pemigatinib in those with FGFR2 fusions. This is important, as it is thought up to 40 % of CCA patients harbour a potentially actionable mutation. In this review we provide an overview of the molecular pathogenesis of CCA and highlight currently available and potential future targeted treatments.

P2, N=10, Terminated, Incyte Corporation | Active, not recruiting --> Terminated; A business decision due to availability of commercial drug and other options for accessing study drug treatment.

P1, N=32, Recruiting, OHSU Knight Cancer Institute | Trial completion date: Aug 2024 --> Feb 2026 | Trial primary completion date: Feb 2024 --> Aug 2025

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.

Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Pemigatinib was recently approved for patients with relapsed or refractory FGFR1-rearranged neoplasms...Hydroxyurea and interferon-α have demonstrated efficacy as initial treatment and in steroid-refractory cases of HES. Mepolizumab, an interleukin-5 (IL-5) antagonist monoclonal antibody, is approved by the U.S Food and Drug Administration for patients with idiopathic HES. Cytotoxic chemotherapy agents, and hematopoietic stem cell transplantation have been used for aggressive forms of HES and CEL, with outcomes reported for limited numbers of patients. Targeted therapies such as the IL-5 receptor antibody benralizumab, IL-5 monoclonal antibody depemokimab, and various tyrosine kinase inhibitors for MLN-eo-TK, are under active investigation.

Hence, we now have multiple genomic biomarker-based, tissue-agnostic Food and Drug Administration approvals for both gene- and immune-targeted therapies (larotrectinib/entrectinib, for NTRK fusions; selpercatinib, RET fusions; dabrafenib plus trametinib, BRAFV600E mutations; pembrolizumab/dostarlimab, microsatellite instability; and pembrolizumab for high tumor mutational burden; pemigatinib is also approved for FGFR1-rearranged myeloid/lymphoid neoplasms). Resistance to biomarker-driven therapeutics is often due to secondary mutations or co-driver gene defects; studies are now addressing the need for customized drug combinations matched to the complex molecular alteration portfolio in each tumor. Future investigation should expand tissue-agnostic therapeutics to encompass both hematologic and solid malignancies and include biomarkers beyond those that are DNA-based.

According to the types of ICC by histopathological features, treatment target variants were detected significantly more frequently in sd-ICCs, with sd-ICC 8/9 (88.9%) and ld-ICC 0% (0/6), of which 3 patients were treated (Pemigatinib for 2cases, clinical trial for 1case). A: The success rate of CGP (tissue) examination was 100% (21/21) for resection specimens, 100% (9/9) for liver biopsy, and 3/7 (42.9%) for biopsy. B: The median TMB was 3 (IQR 1-4) and the median number of variants detected was 4 (IQR 2.5-6). The positive rate of therapeutic target variants per disease was 53.3% (8/15) for ICC, 25% (3/12) for BDC, 11.1% (1/9) for GBC, and 0% (0/1) for ampullary carcinoma.

P2, N=20, Recruiting, The Fourth Affiliated Hospital of Zhejiang University School of Medicine | Trial completion date: Sep 2023 --> Sep 2025

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.

P2, N=14, Active, not recruiting, Academic and Community Cancer Research United | N=24 --> 14

However, some patients remained on treatment for up to a year, suggesting that they observed a benefit from treatment. Patients with CCA should undergo molecular testing to identify those who could benefit from targeted treatments such as pemigatinib.

These results confirm the effectiveness and safety of pemigatinib in a real-world setting.

Comparative analyses with FDA-approved FGFR inhibitors, erdafitinib and pemigatinib, revealed certain advantages of CPL304110 in both in vitro and in vivo assessments. Encouraging preclinical results led the way for the initiation of a Phase I clinical trial (01FGFR2018; NCT04149691) to further evaluate CPL304110 as a novel anticancer therapy.

P2, N=83, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting | N=164 --> 83 | Trial completion date: Jan 2026 --> Nov 2024 | Trial primary completion date: Jan 2026 --> Nov 2024

P2, N=10, Active, not recruiting, Incyte Corporation | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024

The most common treatment-related adverse event, hyperphosphataemia, was exclusively grade 1-2 in severity and, similarly, observed ocular and nail toxicities were rarely grade ≥ 3 in severity. Pending confirmation of its clinical benefits in an ongoing cisplatin plus gemcitabine-controlled, phase 3 study (FIGHT-302), pemigatinib provides a valuable targeted therapy for pretreated patients with advanced (i)CCA harbouring a FGFR2 fusion or rearrangement.

It is still possible to achieve durable tumor response in advanced previously treated intrahepatic cholangiocarcinoma through targeted therapies. The prolonged progression free survival means that there could be an increased risk of secondary malignancy in this patient group, which necessitates diagnostic and therapeutic strategies.

Background: Interest in FGFR-targeted (FGFRi) therapies for UC or pan-tumor use is growing (ongoing clinical studies include erdafitinib (NCT05316155; NCT04172675; NCT03390504; NCT04083976), LOXO-435 (NCT05614739), and pemigatinib (NCT03914794) following accelerated approval of erdafitinib in locally advanced/metastatic (m) post-chemotherapy UC patients with FGFR2/3 (i.e., DNA mutations and fusions) alterations (ALT). FGFR-PRS (+) captured most ALT (+) tumors and an additional 2X more with similar FGFR pathway activation. FGFR-PRS (+) tumors were associated with gene enrichments for ontologies linked to FGFR3 signaling. The correlation of FGFR-PRS score with in vitro FGFRi activity provided initial utility of the signature, which is undergoing clinical evaluation in the ALAMANCE retrospective study of UC patients treated with FGFRi or other standard-of-care therapies.

Pemigatinib + cisplatin combination therapy (n = 5) resulted in significant TGI and prolonged survival in one of two p53abn PDXs. Seven-day treatment with BGJ398 revealed a significant reduction in angiogenesis and CD206 + M2 macrophages. These data collectively support the evaluation of FGFR inhibitors in a clinical trial.

FGFR kinase inhibitorshave the potential to be an effective targeted therapy in pancreas cancer. Additionally, telemedicine is a novel tool that can aid in the study of ultra-rare cancers and reduce barriers to patient participation in clinical trials.

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.

This study complements the FIGHT-202 clinical trial by assessing the use of pemigatinib among a diverse population of patients with CCA under RW conditions. Secondarily, the rwORR and rwPFS from this study support the clinical benefit of pemigatinib demonstrated in FIGHT-202.

The diverse population in this RWS is reflective of the heterogeneous CCA pt population in the US. These real-world overall response rates support the clinical benefit of pemi across racial and ethnic groups and complement the results of the clinical trial. >BL, baseline (date of 1st pemi prescription); CI, confidence interval; FGFR2, fibroblast growth factor receptor 2; P25-P75, 25-75th percentile; rwORR, real-world overall response rate; y, years.

Bortezomib and Axitinib exhibited high efficacy on the patient's sample...Other FGFR inhibitors, including Olverematinib, AZD4547, Axitinib, Cediranib, Dovitinib, and Lenvatinib, also demonstrated exquisite sensitivity. Despite extensive screening, no other single agents or drug combinations exhibited increased effectiveness in the ZMYM2: : FGFR1 transformed BaF3 cells except for Trametinib, a MEK inhibitor, and the combination of Belvarafenib (RAF inhibitor) and Gilteritinib (FLT3 inhibitor)... Ex vivo drug sensitivity assays demonstrated the highly selective efficacy of FGFR inhibitors in ZMYM2: : FGFR1 fusion-positive leukemia cells and a fusion-expressing BaF3 cell line. Mutations in the FGFR1 kinase domain (ZMYM2: : FGFR1 F1171L) could contribute to Ponatinib insensitivity. These ex vivo drug screening results provide further support for ongoing clinical trials which are investigating the use of single agent Pemigatinib and other FGFR1 inhibitors for the treatment of patients with FGFR1-fusion positive leukemias.

In addition, Docking analysis revealed that Pemigatinib and ABCB1 have a high affinity for one another. This study concludes that Pemigatinib is capable of reversing the multidrug resistance mediated by ABCB1, offering ideas and references for the clinical application of Pemigatinib.

Pemigatinib exposure was associated with treatment-emergent adverse events, such as decreased appetite, nausea, and stomatitis, although the relationships were shallow. Overall, analyses indicate that 13.5 mg pemigatinib once daily in 21-day cycles (2 weeks on, 1 week off) offers a favorable benefit-risk profile in patients with advanced/metastatic or surgically unresectable CCA and is the optimal dose for clinical development.

Pemigatinib had similar PK/PD characteristics to Western population and demonstrated an acceptable safety profile and potential anti-cancer benefit in Chinese patients with FGF/FGFR1-3 altered, advanced, solid tumor. (ClinicalTrials.gov: NCT04258527 [prospectively registered February 6, 2020]).

P2, N=8, Completed, Incyte Corporation | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Aug 2023

Pemigatinib was generally well tolerated and demonstrated clinical activity in previously treated, unresectable or metastatic UC with FGFR3 mutations or fusions/rearrangements.

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.

Three patients recurred after first-line therapy: 1 with BRAF mutated GBM, 1 with GBM harboring FGFR3-TACC3 fusion, and 1 with NTRK1 fusion positive glioneuronal tumor received specific BRAF/MEK inhibitor (dabrafenib/trametinib), FGFR inhibitor (pemigatinib), and NTRK inhibitor (larotrectinib), respectively. The incidence of actionable molecular alterations in IDH wt gliomas and glioneuronal/neuronal tumors was low. However, the use of targeted therapies may lead to significant impact on the outcome.

Several new FGFR1 fusion partner genes, including C14orf93, CCDC6, and ETV6 were identified with NGS and PCR profiling. Pemigatinib treatment resulted in marked decreases in the percentages of cells with the FGFR1 rearrangement on FISH, as well as 2–3 log reductions in FGFR1 fusion transcripts in patients with MLNFGFR1. Further investigations are ongoing to determine the relationship between pemigatinib dose intensity and the depth and durability of molecular response.

The 110 compounds were analyzed using virtual screening and compared with the FDA-approved drug pemigatinib, which provided the 34 hits with binding affinities >-6.5 kcal mol...Several techniques were employed to build improved inhibitors based on these SAR, and they were then analyzed utilizing ADMET, MD studies, and MM-GBSA analyses. Finally, the results suggested that the identified four compounds and developed inhibitors from this current work can be employed effectively as prospective FGFR inhibitors for treating Cholangiocarcinoma.Communicated by Ramaswamy H. Sarma.

P2, N=300, Recruiting, Incyte Corporation | Trial completion date: Jun 2025 --> May 2026 | Trial primary completion date: Aug 2023 --> Apr 2025

Pemigatinib, a pan-FGFR inhibitor, is approved to treat intrahepatic cholangiocarcinoma (ICC) harboring FGFR2 fusion mutations...Asn restriction with ASNase or ASNS inhibitors reduced the intracellular Asn, thereby reactivating p53 and sensitizing ICC to F-A Cho-HDO. Our findings highlight the application of genetic engineering therapies in ICC harboring FGFR2 fusions and reveal an axis of adaptation to FGFR2 inhibition that presents a rationale for the clinical evaluation of a strategy combining FGFR2 inhibitors with Asn depletion.

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.

OBJECTIVES: To evaluate the cost-effectiveness of pemigatinib compared to oxaliplatin-L-folinic-acid and fluorouracil plus active symptom control (mFOLFOX+ASC) and ASC alone for the treatment of patients with advanced or metastatic cholangiocarcinoma (CCA) with a fibroblast growth factor receptor 2 (FGFR2) rearrangement or fusion who have progressed on at least one line of prior systemic therapy in Greece. Pemigatinib, a therapy covering the unmet medical need of patients with previously treated locally advanced or metastatic CCA with an FGFR2 fusion or rearrangement, was estimated to be cost-effective compared with mFOLFOX+ASC and ASC alone in Greece.

P2; Trial completion date: Aug 2024 --> Jun 2025 | Trial primary completion date: Apr 2024 --> Dec 2024

New treatment options have recently been approved, e.g. the immune checkpoint inhibitor durvalumab (DUR) or the FGFR2 inhibitor pemigatinib (PMG)...First-line cisplatin+gemcitabine (CIS+GEM) was applied in 112/192 (58%) pts, capecitabine (CAP) in 30/192 (16%) and GEM in 18/192 (9%). In second-line, fluoropyrimidine (5-FU) and oxaliplatin (FOLFOX; 15/62 (24%) or 5-FU and irinotecan (FOLFIRI; 13/62 (21%)) were applied most frequently... In routine clinical practice, first-line gemcitabine-based and second-line fluoropyrimidine-based chemotherapy were the standard of care for pts with CCC until approval of immunotherapies (DUR) and targeted therapies (PMG). JADE will provide important real-world data on how these new treatment options will change the treatment landscape and the outcomes for pts with CCC in Germany.