pemigatinib
Regulatory sources consulted
Approved indications
- In adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement detected by an FDA-approved test; accelerated approval is contingent on confirmation of benefit.
- In adults with relapsed or refractory myeloid or lymphoid neoplasms with an FGFR1 rearrangement.
Clinical warnings
- Major warning · It can cause retinal pigment epithelial detachment. Perform an ophthalmic examination with OCT before treatment, every 2 months for the first 6 months, every 3 months thereafter, and urgently for visual symptoms; follow every 3 weeks until resolution. — DailyMed, PEMAZYRE set_id 9e1f2222-1d89-4e63-989c-ccebe2ab1eb4
- Major warning · Hyperphosphatemia can cause soft-tissue mineralization, cutaneous calcification, calcinosis, and non-uremic calciphylaxis. Monitor phosphate, diet, and need for phosphate-lowering treatment throughout therapy. — DailyMed, PEMAZYRE set_id 9e1f2222-1d89-4e63-989c-ccebe2ab1eb4
Drug interactions
- HighStrong or moderate CYP3A inducers
Mechanism: They reduce exposure and may decrease efficacy.
Recommendation: Avoid the combination.
DailyMed, PEMAZYRE set_id 9e1f2222-1d89-4e63-989c-ccebe2ab1eb4https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9e1f2222-1d89-4e63-989c-ccebe2ab1eb4
- HighStrong or moderate CYP3A inhibitors
Mechanism: They increase exposure and may increase toxicity.
Recommendation: Avoid the combination. If unavoidable, reduce 13.5→9 mg or 9→4.5 mg; resume the prior dose after 3 inhibitor half-lives.
DailyMed, PEMAZYRE set_id 9e1f2222-1d89-4e63-989c-ccebe2ab1eb4https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9e1f2222-1d89-4e63-989c-ccebe2ab1eb4
Adverse events
Common (≥1%)
hyperphosphatemia · alopecia · diarrhea · nail toxicity · fatigue · dysgeusia · nausea · constipation · stomatitis · dry eye · dry mouth · decreased appetite · vomiting · arthralgia · abdominal pain
Pregnancy and lactation
It can cause embryo-fetal harm or pregnancy loss. Verify pregnancy before starting. Females and males with partners who can become pregnant must use effective contraception during treatment and for 1 week afterward. Do not breastfeed during treatment or for 1 week afterward.
Recent literature (PubMed)
The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary or clonal) disorders with the potential for end-organ damage. Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1.5 × 109/L, and may be associated with tissue damage. After the exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of various tests. They include morphologic review of the blood and marrow, standard cytogenetics, fluorescence in situ hybridization, molecular testing and flow immunophenotyping to detect histopathologic or clonal evidence for an acute or chronic hematolymphoid neoplasm. Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2022 World Health Organization and International Consensus Classification endorse a semi-molecular classification scheme of disease subtypes. This includes the major category "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions" (MLN-eo-TK), and the MPN subtype, "chronic eosinophilic leukemia" (CEL). Lymphocyte-variant HE is an aberrant T-cell clone-driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion. The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1.5 × 109/L) without symptoms or signs of organ involvement, a watch and wait approach with close follow-up may be undertaken. 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. Corticosteroids are first-line therapy for patients with lymphocyte-variant HE and HES. Hydroxyurea and interferon-α have demonstrated efficacy as initial treatment and in ster
Fibroblast growth factor (FGF) signalling via FGF receptors (FGFR1-4) orchestrates fetal development and contributes to tissue and whole-body homeostasis, but can also promote tumorigenesis. 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. Erdafitinib is approved for patients with urothelial carcinoma harbouring FGFR2/3 alterations, and futibatinib and pemigatinib are approved for patients with cholangiocarcinoma harbouring FGFR2 fusions and/or rearrangements. Clinical benefit from these agents is in part limited by hyperphosphataemia owing to off-target inhibition of FGFR1 as well as the emergence of resistance mutations in FGFR genes, activation of bypass signalling pathways, concurrent TP53 alterations and possibly epithelial-mesenchymal transition-related isoform switching. 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.
DNA mutations in cholangiocarcinoma: targeting IDH1 and other mutations Biliary tract cancers (BTC) are rare cancers with a poor prognosis, particularly at the metastatic stage, with a 5-year survival rate not exceeding 7%. Two lines of chemotherapy are currently recommended in France, with cisplatin-gemcitabine and 5 FU-oxaliplatin as first and second-line treatment respectively, allowing a median survival of approximately one year. However, many studies have shown that BTC, and more particularly intrahepatic cholangiocarcinoma, have a high somatic alteration rate (mutations, fusions, or amplifications). Some of these alterations are potential therapeutic targets. To date, only ivosidenib and pemigatinib, targeting IDH1 mutations and FGFR2 fusions respectively, are approved in France for pre-treated patients with these molecular alterations. Many other potentially targetable alterations are found in BTC, including mutations in genes involved in DNA repair, BRAF, HER2 and the recently exploited KRASG12C mutation. This review will focus on targetable mutations in BTC and develop the main molecules that can be used in BTC with these actionable alterations, offering new therapeutic perspectives for these patients, with the ultimate goal of improving their prognosis.