Treatment of Bile Duct Cancer

Abstract

Disclosed herein is a method of treating cholangiocarcinoma in a patient, comprising: evaluating a biological sample from the patient for the presence of one or more EGER mutants comprising at least a mutation FGFR3 R397C; or one or more EGER mutants comprising at least a mutation FGFR3 L608F; or one or more EGER mutants comprising at least a fusion FGFR2-TACC2; and if one or more EGER mutants comprising at least a mutation FGFR3 R397C; or one or more EGER mutants comprising at least a mutation FGFR3 L608F; or one or more EGER mutants comprising at least a fusion FGFR2-TACC2 are present in the sample, treating the patient with an EGER inhibitor. [Selection diagram] None

Description

[Technical Field]

[0001] Provided herein are methods of treating cholangiocarcinoma in patients with one or more FGFR mutations with a fibroblast growth factor receptor inhibitor. [Background technology]

[0002] Identifying genetic abnormalities can be useful in selecting appropriate treatments for cancer patients. This is also useful for cancer patients who have failed the main treatment options (frontline therapies) for their cancer type, especially when no standard of care exists for second-line or later-line treatments. Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases involved in regulating cell survival, proliferation, migration, and differentiation. FGFR alterations, including FGFR mutations and FGFR fusions or translocations, have been observed in some cancers. To date, there are no approved effective treatments for patients with FGFR alterations. Summary of the Invention

[0003] Disclosed herein is a method of treating cholangiocarcinoma in a patient, comprising: evaluating a biological sample from the patient for the presence of one or more FGFR mutations; and if one or more FGFR mutations are present in the sample, treating the patient with an FGFR inhibitor.

[0004] Disclosed herein is a method of treating cholangiocarcinoma in a patient, comprising: detecting a biological sample from the patient for the presence of one or more FGFR variants comprising at least FGFR2 SNP C383R; or one or more FGFR variants comprising at least the fusion FGFR2-BICC1; or one or more FGFR variants comprising at least the fusion FGFR2-CCAR1; or one or more FGFR variants comprising at least the fusion FGFR2-KIAA1598; or one or more FGFR variants comprising at least the fusion DTWD2-FGFR2; or one or more FGFR variants comprising at least the fusion ESR2-FGFR2; or one or more FGFR variants comprising at least the fusion FGFR2-MGEA5; or one or more FGFR variants comprising at least the fusion FGFR2-SBNO2; or one or more FGFR variants comprising at least the mutation FGFR2 C390>YS; or one or more FGFR variants comprising at least the mutation FGFR2 N549K; in particular at least FGFR2 assessing for the presence of one or more FGFR variants including C383R; and treating the patient with an FGFR inhibitor if one or more of the FGFR variants described above are present in the sample; particularly, treating the patient with an FGFR inhibitor if one or more FGFR variants including at least FGFR2 SNP C383R are present in the sample.

[0005] Disclosed herein is a method of treating cholangiocarcinoma in a patient, comprising: assessing a biological sample from the patient for the presence of one or more FGFR mutants comprising at least the mutation FGFR3 R397C; or one or more FGFR mutants comprising at least the mutation FGFR3 L608F; or one or more FGFR mutants comprising at least the fusion FGFR2-TACC2; and if one or more of the FGFR mutants described above are present in the sample, treating the patient with an FGFR inhibitor.

[0006] Disclosed herein is a method for treating cholangiocarcinoma in patients with FGFR2 SNP C383R, or with fusion FGFR2-BICC1; or with fusion FGFR2-CCAR1; or with fusion FGFR2-KIAA1598; or with fusion DTWD2-FGFR2; or with fusion ESR2-FGFR2; or with fusion FGFR2-MGEA5; or with fusion FGFR2-SBNO2; or with mutation FGFR2 C390>YS; or with mutation FGFR2 N549K, particularly in patients with FGFR2 C383R, comprising administering an FGFR inhibitor to the patient.The patient may also have one or more additional FGFR mutations.

[0007] Disclosed herein is a method of treating cholangiocarcinoma in a patient with a mutation FGFR3 R397C, or a mutation FGFR3 L608F, or a fusion FGFR2-TACC2, comprising administering an FGFR inhibitor to the patient. The patient may also have one or more additional FGFR mutations.

[0008] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in patients with FGFR2 SNP C383R, or with fusion FGFR2-BICC1; or with fusion FGFR2-CCAR1; or with fusion FGFR2-KIAA1598; or with fusion DTWD2-FGFR2; or with fusion ESR2-FGFR2; or with fusion FGFR2-MGEA5; or with fusion FGFR2-SBNO2; or with mutation FGFR2 C390>YS; or with mutation FGFR2 N549K, particularly in patients with FGFR2 C383R. The patient may also have one or more additional FGFR mutations.

[0009] Disclosed herein are FGFR inhibitors for use in treating cholangiocarcinoma in patients with the FGFR3 R397C mutation, or the FGFR3 L608F mutation, or the fusion FGFR2-TACC2. The patient may also contain one or more additional FGFR mutations.

[0010] Disclosed herein is the use of an FGFR inhibitor in the manufacture of a medicament for treating cholangiocarcinoma in patients with FGFR2 SNP C383R, or with fusion FGFR2-BICC1; or with fusion FGFR2-CCAR1; or with fusion FGFR2-KIAA1598; or with fusion DTWD2-FGFR2; or with fusion ESR2-FGFR2; or with fusion FGFR2-MGEA5; or with fusion FGFR2-SBNO2; or with mutation FGFR2 C390>YS; or with mutation FGFR2 N549K, particularly in patients with FGFR2 C383R. The patient may also have one or more additional FGFR mutations.

[0011] Disclosed herein is the use of an FGFR inhibitor in the manufacture of a medicament for the treatment of cholangiocarcinoma in patients with the FGFR3 R397C mutation, or the FGFR3 L608F mutation, or the fusion FGFR2-TACC2. The patient may also contain one or more additional FGFR mutations.

[0012] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is screened for the presence of one or more FGFR variants comprising at least FGFR2 SNP C383R; or one or more FGFR variants comprising at least the fusion FGFR2-BICC1; or one or more FGFR variants comprising at least the fusion FGFR2-CCAR1; or one or more FGFR variants comprising at least the fusion FGFR2-KIAA1598; or one or more FGFR variants comprising at least the fusion DTWD2-FGFR2; or one or more FGFR variants comprising at least the fusion ESR2-FGFR2; or one or more FGFR variants comprising at least the fusion FGFR2-MGEA5; or one or more FGFR variants comprising at least the fusion FGFR2-SBNO2; or one or more FGFR variants comprising at least the mutation FGFR2 C390>YS; or one or more FGFR variants comprising at least the mutation FGFR2 N549K; in particular at least FGFR2 By assessing for the presence of one or more FGFR variants comprising C383R, it is possible to detect the presence of one or more FGFR variants comprising at least FGFR2 SNP C383R; or one or more FGFR variants comprising at least the fusion FGFR2-BICC1; or one or more FGFR variants comprising at least the fusion FGFR2-CCAR1; or one or more FGFR variants comprising at least the fusion FGFR2-KIAA1598; or one or more FGFR variants comprising at least the fusion DTWD2-FGFR2; or one or more FGFR variants comprising at least the fusion ESR2-FGFR2; or one or more FGFR variants comprising at least the fusion FGFR2-MGEA5; or one or more FGFR variants comprising at least the fusion FGFR2-SBNO2; or one or more FGFR variants comprising at least the mutation FGFR2 C390>YS; or one or more FGFR variants comprising at least the mutation FGFR2 N549K; in particular the presence of at least FGFR2 An FGFR inhibitor, wherein detecting the presence of one or more FGFR mutations including C383R identifies a patient as likely to benefit from or benefit from treatment with an FGFR inhibitor.

[0013] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for one or more FGFR mutants comprising at least the FGFR3 R397C mutation; or one or more FGFR mutants comprising at least the FGFR3 L608F mutation; or one or more FGFR mutants comprising at least the fusion FGFR2-TACC2; and detection of the presence of one or more FGFR mutants comprising at least the FGFR3 R397C mutation; or one or more FGFR mutants comprising at least the FGFR3 L608F mutation; or one or more FGFR mutants comprising at least the fusion FGFR2-TACC2 identifies the patient as being likely to respond to or benefit from treatment with the FGFR inhibitor.

[0014] Disclosed herein is the use of an FGFR inhibitor for the manufacture of a medicament for the treatment of cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is screened for the presence of one or more FGFR variants comprising at least FGFR2 SNP C383R; or one or more FGFR variants comprising at least the fusion FGFR2-BICC1; or one or more FGFR variants comprising at least the fusion FGFR2-CCAR1; or one or more FGFR variants comprising at least the fusion FGFR2-KIAA1598; or one or more FGFR variants comprising at least the fusion DTWD2-FGFR2; or one or more FGFR variants comprising at least the fusion ESR2-FGFR2; or one or more FGFR variants comprising at least the fusion FGFR2-MGEA5; or one or more FGFR variants comprising at least the fusion FGFR2-SBNO2; or one or more FGFR variants comprising at least the mutation FGFR2 C390>YS; or one or more FGFR variants comprising at least the mutation FGFR2 N549K; in particular at least FGFR2 By assessing for the presence of one or more FGFR variants comprising C383R, it is possible to detect the presence of one or more FGFR variants comprising at least FGFR2 SNP C383R; or one or more FGFR variants comprising at least the fusion FGFR2-BICC1; or one or more FGFR variants comprising at least the fusion FGFR2-CCAR1; or one or more FGFR variants comprising at least the fusion FGFR2-KIAA1598; or one or more FGFR variants comprising at least the fusion DTWD2-FGFR2; or one or more FGFR variants comprising at least the fusion ESR2-FGFR2; or one or more FGFR variants comprising at least the fusion FGFR2-MGEA5; or one or more FGFR variants comprising at least the fusion FGFR2-SBNO2; or one or more FGFR variants comprising at least the mutation FGFR2 C390>YS; or one or more FGFR variants comprising at least the mutation FGFR2 N549K; in particular the presence of at least FGFR2 The use, wherein detecting the presence of one or more FGFR mutations including C383R identifies a patient as likely to benefit from or respond to treatment with an FGFR inhibitor.

[0015] Disclosed herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutants comprising at least the FGFR3 R397C mutation; or one or more FGFR mutants comprising at least the FGFR3 L608F mutation; or one or more FGFR mutants comprising at least the fusion FGFR2-TACC2, and detection of the presence of one or more FGFR mutants comprising at least the FGFR3 R397C mutation; or one or more FGFR mutants comprising at least the FGFR3 L608F mutation; or one or more FGFR mutants comprising at least the fusion FGFR2-TACC2 identifies the patient as being likely to respond to or benefit from treatment with the FGFR inhibitor. DETAILED DESCRIPTION OF THE INVENTION

[0016] Reference to a specific numerical value includes at least that particular value unless the context clearly dictates otherwise. When a range of values ​​is expressed, another embodiment includes from the one particular value and / or to the other particular value. Further, reference to values ​​stated in a range includes every value within that range. All ranges are inclusive and combinable.

[0017] The following abbreviations are used throughout this specification: FGFR (fibroblast growth factor receptor); FFPET (formalin-fixed paraffin-embedded tissue); SNP (single nucleotide polymorphism).

[0018] As used herein, "treating" and similar terms refer to reducing the severity and / or frequency of cancer symptoms, eliminating cancer symptoms and / or the underlying causes of said symptoms, reducing the frequency or likelihood of cancer symptoms and / or their underlying causes, and ameliorating or repairing damage caused directly or indirectly by cancer.

[0019] "Biological sample" refers to any sample from a patient from which cancer cells can be obtained and from which FGFR mutations can be detected. Suitable biological samples include, but are not limited to, blood, lymph, bone marrow, solid tumor samples, or any combination thereof. In some embodiments, the biological sample can be FFPET.

[0020] FGFR mutations As used herein, the phrase "FGFR mutant" refers to an FGFR fusion gene, an FGFR single nucleotide polymorphism, an FGFR mutation, or all of these. In one embodiment, the phrase "FGFR mutant" refers to an FGFR fusion gene, an FGFR single nucleotide polymorphism, or both. In one embodiment, the phrase "FGFR mutant" refers to an FGFR fusion gene. In one embodiment, the phrase "FGFR mutant" refers to an FGFR mutation.

[0021] "FGFR fusion" or "FGFR fusion gene" refers to a gene or portion thereof encoding an FGFR (e.g., FGRF2 or FGFR3) and a fusion partner or portion thereof resulting from a translocation between the two genes. The presence of one or more FGFR fusion genes in a patient-derived biological sample can be determined using the disclosed methods or suitable methods described in the literature.

[0022] "FGFR single nucleotide polymorphism" (SNP) refers to the FGFR2 or FGFR3 gene that differs by a single nucleotide between individuals. A specific FGFR SNP in the methods of treatment or uses disclosed herein is FGFR2 C383R. The presence of one or more FGFR SNPs in a patient-derived biological sample can be determined using the disclosed methods or using suitable methods described in the literature.

[0023] Whenever used herein, FGFR2 SNP C383R or FGFR2 C383R refers to an FGFR2 mutation in which cysteine ​​at position 383 is substituted with arginine. The terms may be used interchangeably.

[0024] FGFR inhibitors for use in the disclosed methods or uses FGFR inhibitors suitable for use in the disclosed methods are described herein.

[0025] In some embodiments, if one or more FGFR variants, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient can be treated with an FGFR inhibitor disclosed in U.S. Patent Application Publication No. 2013 / 0072457A1, which is incorporated herein by reference, including any tautomeric or stereochemically isomeric form thereof, and an N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof (suitable R groups are also disclosed in U.S. Patent Application Publication No. 2013 / 0072457A1). In some embodiments, for example, patients are treated with N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine (referred to herein as "JNJ-42756493" or "JNJ493" or erdafitinib): [ka] (including its N-oxide, a pharmaceutically acceptable salt, or a solvate thereof). In some embodiments, the pharmaceutically acceptable salt is an HCl salt. In some embodiments, the patient can be treated with JNJ493 base.

[0026] In some embodiments, if one or more FGFR variants, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient can be treated with an FGFR inhibitor, such as N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-dimethylpiperazin-1-yl)benzamide (AZD4547), as described in Gavine, PR, et al., AZD4547: An Orally Bioavailable, Potent, and Selective Inhibitor of the Fibroblast Growth Factor Receptor Tyrosine Kinase Family, Cancer Res. April 15, 2012 72;2045. [ka] (including, if chemically possible, any tautomeric or stereochemically isomeric form thereof, and an N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof).

[0027] In some embodiments, if one or more FGFR variants including at least FGFR2 SNP C383R are present in the sample, the cholangiocarcinoma patient may be treated with an FGFR inhibitor, such as 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea (NVP-BGJ398), described in WO 2006 / 000420: [ka] (including, if chemically possible, any tautomeric or stereochemically isomeric form thereof, and an N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof).

[0028] In some embodiments, if one or more FGFR mutations, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient may be treated with an FGFR inhibitor, such as 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one (dovitinib), described in WO 2006 / 127926: [ka] (including, if chemically possible, any tautomeric or stereochemically isomeric form thereof, and an N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof).

[0029] In some embodiments, if one or more FGFR variants, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient can be treated with an FGFR inhibitor, such as 6-(7-((1-aminocyclopropyl)-methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide (AL3810) (lucitanib; E-3810), described in Bello, E. et al., E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models, Cancer Res February 15, 2011 71(A)1396-1405 and WO 2008 / 112408: [ka] (including, if chemically possible, any tautomeric or stereochemically isomeric form thereof, and an N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof).

[0030] In some embodiments, if one or more FGFR variants, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient can be treated with an FGFR inhibitor, such as an anti-FGFR2 antibody, as described in WO 2013 / 076186.

[0031] Suitable additional FGFR inhibitors include BAY1163877 (Bayer), BAY1179470 (Bayer), TAS-120 (Taiho), ARQ087 (ArQule), ASP5878 (Astellas), FF284 (Chugai), FP-1039 (GSK / FivePrime), Blueprint, LY-2874455 (Lilly), RG-7444 (Roche), or any combination thereof (including, where chemically feasible, any tautomeric or stereochemically isomeric form thereof, its N-oxide, its pharmaceutically acceptable salt, or its solvate).

[0032] In some embodiments, if one or more FGFR variants, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient can be treated with an FGFR inhibitor, wherein the FGFR inhibitor is BAY1163877 (Bayer) (including any tautomeric or stereochemically isomeric form thereof, if chemically feasible, its N-oxide, its pharmaceutically acceptable salt, or its solvate).

[0033] In some embodiments, if one or more FGFR variants, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient can be treated with an FGFR inhibitor, wherein the FGFR inhibitor is BAY1179470 (Bayer) (including any tautomeric or stereochemically isomeric form thereof, if chemically feasible, its N-oxide, its pharmaceutically acceptable salt, or its solvate).

[0034] In some embodiments, if one or more FGFR mutations, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient can be treated with an FGFR inhibitor, wherein the FGFR inhibitor is TAS-120 (Taiho) (including any tautomeric or stereochemically isomeric form thereof, if chemically feasible, its N-oxide, its pharmaceutically acceptable salt, or its solvate).

[0035] In some embodiments, if one or more FGFR variants, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient can be treated with an FGFR inhibitor, wherein the FGFR inhibitor is ARQ087 (ArQule) (including any tautomeric or stereochemically isomeric form thereof, if chemically feasible, its N-oxide, its pharmaceutically acceptable salt, or its solvate).

[0036] In some embodiments, if one or more FGFR variants, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient may be treated with an FGFR inhibitor, wherein the FGFR inhibitor is ASP5878 (Astellas) (including any tautomeric or stereochemically isomeric form thereof, if chemically feasible, its N-oxide, its pharmaceutically acceptable salt, or its solvate).

[0037] In some embodiments, if one or more FGFR mutations, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient can be treated with an FGFR inhibitor, wherein the FGFR inhibitor is FF284 (Chugai Pharmaceutical Co., Ltd.) (including any tautomeric or stereochemically isomeric form thereof, if chemically feasible, its N-oxide, its pharmaceutically acceptable salt, or its solvate).

[0038] In some embodiments, if one or more FGFR variants, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient may be treated with an FGFR inhibitor, wherein the FGFR inhibitor is FP-1039 (GSK / FivePrime) (including any tautomeric or stereochemically isomeric form thereof, if chemically feasible, its N-oxide, its pharmaceutically acceptable salt, or its solvate).

[0039] In some embodiments, if one or more FGFR variants, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient may be treated with an FGFR inhibitor, wherein the FGFR inhibitor is Blueprint (including any tautomeric or stereochemically isomeric form thereof, if chemically feasible, its N-oxide, its pharmaceutically acceptable salt, or its solvate).

[0040] In some embodiments, if one or more FGFR variants, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient can be treated with an FGFR inhibitor, wherein the FGFR inhibitor is LY-2874455 (Lilly) (including any tautomeric or stereochemically isomeric form thereof, if chemically feasible, its N-oxide, its pharmaceutically acceptable salt, or its solvate).

[0041] In some embodiments, if one or more FGFR variants, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient can be treated with an FGFR inhibitor, wherein the FGFR inhibitor is RG-7444 (Roche) (including any tautomeric or stereochemically isomeric form thereof, if chemically feasible, its N-oxide, its pharmaceutically acceptable salt, or its solvate).

[0042] Salts can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods, such as those described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002 (incorporated herein by reference). Generally, such salts can be prepared by reacting the free acid or free base form of the compound with an appropriate base or acid in water or an organic solvent, or a mixture of the two (generally using non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile). The FGFR inhibitors used in the disclosed methods can exist as mono- or di-salts, depending on the pKa of the acid from which the salt is formed.

[0043] Acid addition salts can be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+) camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, and cinnamic acid. , citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, Isethionic acid, lactic acid (e.g., (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalenesulfonic acid (e.g., naphthalene-2-sulfonic acid), naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid Acids include mitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, pyruvic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, toluenesulfonic acid (e.g., p-toluenesulfonic acid), undecylenic acid, and valeric acid, as well as salts formed with acylated amino acids and cation exchange resins.

[0044] One particular group of salts consists of salts formed from acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid (mesylate), ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, propanoic acid, butanoic acid, malonic acid, glucuronic acid, and lactobionic acid. Another group of acid addition salts includes salts formed from acetic acid, adipic acid, ascorbic acid, aspartic acid, citric acid, DL-lactic acid, fumaric acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloric acid, glutamic acid, DL-malic acid, methanesulfonic acid, sebacic acid, stearic acid, succinic acid, and tartaric acid.

[0045] The compound is anionic or has a functional group that can be anionic (e.g., -COOH is replaced by -COO - If the compound has a cation, the salt can be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, Na + and K. + Alkali metal ions such as Ca 2+ and Mg 2+ Alkaline earth metal cations such as Al 3+ Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH + ) and substituted ammonium ions (e.g., NHR + , NH2R2 + , NHR3 + , NR4 + ) are mentioned.

[0046] Some suitable substituted ammonium ions include: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as those derived from amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 + There is.

[0047] If a compound contains an amine functional group, it may form a quaternary ammonium salt, for example, by reaction with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of the compounds disclosed herein. Compounds containing an amine functional group may also form N-oxides. Also, references herein to compounds containing an amine functional group include N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form N-oxides. Specific examples of N-oxides include N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid). See, for example, Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 101-105. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn. Comm. (1977), 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0048] As used herein, the term "solvate" refers to a physical association of a compound with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, a solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The term "solvate" is intended to encompass both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include compounds of the present disclosure in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, and the like. A compound may exert its biological effects in solution.

[0049] Solvates are well known in pharmaceutical chemistry. Solvates can be important for the preparation process of a substance (e.g., in connection with its purification), for the storage of a substance (e.g., its stability), and for ease of handling, and are often formed as part of the isolation or purification steps of chemical synthesis. One of ordinary skill in the art can determine whether hydrates or other solvates are formed by the isolation or purification conditions used to prepare a given compound using standard and well-established techniques. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g., single-crystal X-ray crystallography or X-ray powder diffraction), and solid-state NMR (SS-NMR, also known as magic-angle spinning NMR or MAS-NMR). Such techniques, along with NMR, IR, HPLC, and MS, are part of a skilled artisan's standard analytical toolkit. Alternatively, one skilled in the art can intentionally form solvates using crystallization conditions that include the amount of solvent required for a particular solvate. The standard methods described above can then be used to confirm whether a solvate has formed. Also included are any complexes of FGFR inhibitors (eg, inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals).

[0050] Additionally, the compounds may have one or more polymorphic (crystalline) or amorphous forms.

[0051] Compounds include compounds with one or more isotopic substitutions. A reference to a particular element includes within its scope all isotopes of that element. For example, a reference to hydrogen includes within its scope: 1 H, 2 H(D), and 3 Similarly, references to carbon and oxygen include within their scope, respectively, 12 C. 13 C, and 14 C, and 16 O and 18The compound may contain one or more radioisotopes. The isotope may be radioactive or non-radioactive. In one embodiment, the compound does not contain a radioisotope. Such a compound is preferred for therapeutic use. However, in another embodiment, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in diagnostic terms.

[0052] In some embodiments, if one or more FGFR variants, including at least FGFR2 SNP C383R, are present in the sample, the cholangiocarcinoma patient is treated with an FGFR inhibitor, and the FGFR inhibitor is N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine (referred to herein as "JNJ-42756493"), or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the FGFR inhibitor is JNJ-42756493 base.

[0053] Methods of Treating Cancer in a Patient Disclosed herein is a method for treating cholangiocarcinoma in a patient, comprising: assessing a biological sample from the patient for the presence of one or more FGFR variants, including at least FGFR2 SNP C383R; and if one or more FGFR variants, including at least FGFR2 SNP C383R, are present in the sample, treating the patient with an FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0054] Disclosed herein is a method for treating cholangiocarcinoma in a patient with FGFR2 SNP C383R, comprising administering an FGFR inhibitor to the patient. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0055] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in patients with FGFR2 SNP C383R. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0056] Disclosed herein is the use of an FGFR inhibitor in the manufacture of a medicament for treating cholangiocarcinoma in patients with FGFR2 SNP C383R. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0057] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR variants including at least FGFR2 SNP C383R, and detecting the presence of one or more FGFR variants including at least FGFR2 SNP C383R identifies the patient as likely to respond to or be effective against treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0058] Disclosed herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR variants including at least FGFR2 SNP C383R, and detecting the presence of one or more FGFR variants including at least FGFR2 SNP C383R identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0059] In one embodiment, erdafitinib is administered at a dose of 10 mg.

[0060] In one embodiment, erdafitinib is administered intermittently at a dose of 10 mg.

[0061] In one embodiment, erdafitinib is administered intermittently at a dose of 10 mg 7 days on / 7 days off.

[0062] In one embodiment, erdafitinib is administered at a dose of 8 mg, particularly 8 mg once daily. In one embodiment, erdafitinib is administered at a dose of 8 mg, particularly 8 mg once daily, with the option of escalating to 9 mg depending on the serum phosphate level (e.g., serum phosphate level is <5.5 mg / dL, <7 mg / dL, 7 mg / dL or more but <9 mg / dL, or <9 mg / dL) and depending on observed treatment-related adverse events. In one embodiment, the serum phosphate level for determining whether to escalate is measured on the treatment day during the first cycle of erdafitinib treatment, particularly on day 14±2 of erdafitinib administration, more particularly on day 14.

[0063] In one embodiment of the present invention, the FGFR2 SNP C383R may be replaced by the FGFR fusion FGFR2-BICC1 in the methods of treatment and uses described herein.

[0064] Disclosed herein is a method for treating cholangiocarcinoma in a patient, comprising: assessing a biological sample from the patient for the presence of one or more FGFR variants, including at least FGFR2-BICC1; and if one or more FGFR variants, including at least FGFR2-BICC1, are present in the sample, treating the patient with an FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0065] Disclosed herein is a method for treating cholangiocarcinoma in a patient with FGFR2-BICC1, comprising administering an FGFR inhibitor to the patient. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0066] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in patients with FGFR2-BICC1. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0067] Disclosed herein is the use of an FGFR inhibitor in the manufacture of a medicament for treating cholangiocarcinoma in patients with FGFR2-BICC1. The patient may have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0068] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutants, including at least FGFR2-BICC1, and detection of the presence of one or more FGFR mutants, including at least FGFR2-BICC1, identifies the patient as likely to respond to treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0069] Disclosed herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR variants including at least FGFR2-BICC1, and detecting the presence of one or more FGFR variants including at least FGFR2-BICC1 identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0070] In one embodiment of the present invention, the FGFR2 SNP C383R may be replaced by the FGFR fusion FGFR2-CCAR1 in the methods of treatment and uses described herein.

[0071] Disclosed herein is a method for treating cholangiocarcinoma in a patient, comprising: assessing a biological sample from the patient for the presence of one or more FGFR variants, including at least FGFR2-CCAR1; and if one or more FGFR variants, including at least FGFR2-CCAR1, are present in the sample, treating the patient with an FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0072] Disclosed herein is a method for treating cholangiocarcinoma in a patient with FGFR2-CCAR1, comprising administering an FGFR inhibitor to the patient. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0073] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in patients with FGFR2-CCAR1. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0074] Disclosed herein is the use of an FGFR inhibitor in the manufacture of a medicament for treating cholangiocarcinoma in patients with FGFR2-CCAR1. The patient may have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0075] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutants including at least FGFR2-CCAR1, and detection of the presence of one or more FGFR mutants including at least FGFR2-CCAR1 identifies the patient as likely to respond to treatment with the FGFR inhibitor, or as likely to respond to treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0076] Disclosed herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR variants including at least FGFR2-CCAR1, and detecting the presence of one or more FGFR variants including at least FGFR2-CCAR1 identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0077] In one embodiment of the present invention, the FGFR2 SNP C383R may be replaced by the FGFR fusion FGFR2-KIAA1598 in the methods of treatment and uses described herein.

[0078] Disclosed herein is a method for treating cholangiocarcinoma in a patient, comprising: assessing a biological sample from the patient for the presence of one or more FGFR mutations, including at least FGFR2-KIAA1598; and if one or more FGFR mutations, including at least FGFR2-KIAA1598, are present in the sample, treating the patient with an FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0079] Disclosed herein is a method for treating cholangiocarcinoma in patients with FGFR2-KIAA1598, comprising administering an FGFR inhibitor to the patient. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0080] Disclosed herein is an FGFR inhibitor used to treat cholangiocarcinoma in patients with FGFR2-KIAA1598. The patient may have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0081] Disclosed herein is the use of an FGFR inhibitor in the manufacture of a medicament for treating cholangiocarcinoma in patients with FGFR2-KIAA1598. The patient may have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0082] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutations including at least FGFR2-KIAA1598, and detection of the presence of one or more FGFR mutations including at least FGFR2-KIAA1598 identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0083] Disclosed herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutants including at least FGFR2-KIAA1598, and detection of the presence of one or more FGFR mutants including at least FGFR2-KIAA1598 identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0084] In one embodiment of the present invention, the FGFR2 SNP C383R may be replaced by the FGFR fusion DTWD2-FGFR2 in the methods of treatment and uses described herein.

[0085] Disclosed herein is a method for treating cholangiocarcinoma in a patient, comprising: assessing a biological sample from the patient for the presence of one or more FGFR variants, including at least DTWD2-FGFR2; and if one or more FGFR variants, including at least DTWD2-FGFR2, are present in the sample, treating the patient with an FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0086] Disclosed herein is a method for treating cholangiocarcinoma in a patient with DTWD2-FGFR2, comprising administering an FGFR inhibitor to the patient. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0087] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in patients with DTWD2-FGFR2. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0088] Disclosed herein is the use of an FGFR inhibitor in the manufacture of a medicament for treating cholangiocarcinoma in patients with FGFR2-DTWD2-FGFR2. The patient may have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0089] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutants including at least DTWD2-FGFR2, and detection of the presence of one or more FGFR mutants including at least DTWD2-FGFR2 identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0090] Disclosed herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutants including at least DTWD2-FGFR2, and detecting the presence of one or more FGFR mutants including at least DTWD2-FGFR2 identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0091] In one embodiment of the present invention, the FGFR2 SNP C383R may be replaced by the FGFR fusion ESR2-FGFR2 in the methods of treatment and uses described herein.

[0092] Disclosed herein is a method for treating cholangiocarcinoma in a patient, comprising: assessing a biological sample from the patient for the presence of one or more FGFR variants, including at least ESR2-FGFR2; and if one or more FGFR variants, including at least ESR2-FGFR2, are present in the sample, treating the patient with an FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0093] Disclosed herein is a method for treating cholangiocarcinoma in a patient with ESR2-FGFR2, comprising administering an FGFR inhibitor to the patient. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0094] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in patients with ESR2-FGFR2. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0095] Disclosed herein is the use of an FGFR inhibitor in the manufacture of a medicament for treating cholangiocarcinoma in patients with ESR2-FGFR2. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0096] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutants including at least ESR2-FGFR2, and detection of the presence of one or more FGFR mutants including at least ESR2-FGFR2 identifies the patient as likely to respond to treatment with the FGFR inhibitor, or as likely to respond to treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0097] Disclosed herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutants including at least ESR2-FGFR2, and detecting the presence of one or more FGFR mutants including at least ESR2-FGFR2 identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0098] In one embodiment of the present invention, the FGFR2 SNP C383R may be replaced by the FGFR fusion FGFR2-MGEA5 in the methods of treatment and uses described herein.

[0099] Disclosed herein is a method for treating cholangiocarcinoma in a patient, comprising: assessing a biological sample from the patient for the presence of one or more FGFR variants, including at least FGFR2-MGEA5; and if one or more FGFR variants, including at least FGFR2-MGEA5, are present in the sample, treating the patient with an FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0100] Disclosed herein is a method for treating cholangiocarcinoma in patients with FGFR2-MGEA5, comprising administering an FGFR inhibitor to the patient. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0101] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in patients with FGFR2-MGEA5. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0102] Disclosed herein is the use of an FGFR inhibitor in the manufacture of a medicament for treating cholangiocarcinoma in patients with FGFR2-MGEA5. The patient may have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0103] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutants, including at least FGFR2-MGEA5, and detecting the presence of one or more FGFR mutants, including at least FGFR2-MGEA5, identifies the patient as likely to respond to treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0104] Disclosed herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutants, including at least FGFR2-MGEA5, and detecting the presence of one or more FGFR mutants, including at least FGFR2-MGEA5, identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0105] In one embodiment of the present invention, the FGFR2 SNP C383R may be replaced by the FGFR fusion FGFR2-SBNO2 in the methods of treatment and uses described herein.

[0106] Disclosed herein is a method for treating cholangiocarcinoma in a patient, comprising: assessing a biological sample from the patient for the presence of one or more FGFR variants, including at least FGFR2-SBNO2; and if one or more FGFR variants, including at least FGFR2-SBNO2, are present in the sample, treating the patient with an FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0107] Disclosed herein is a method for treating cholangiocarcinoma in a patient with FGFR2-SBNO2, comprising administering an FGFR inhibitor to the patient. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0108] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in patients with FGFR2-SBNO2. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0109] Disclosed herein is the use of an FGFR inhibitor in the manufacture of a medicament for treating cholangiocarcinoma in patients with FGFR2-SBNO2. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0110] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutants, including at least FGFR2-SBN02, and detecting the presence of one or more FGFR mutants, including at least FGFR2-SBN02, identifies the patient as likely to respond to treatment with the FGFR inhibitor, or as likely to respond to treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0111] Disclosed herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR variants, including at least FGFR2-SBN02, and detecting the presence of one or more FGFR variants, including at least FGFR2-SBN02, identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0112] In one embodiment of the present invention, the FGFR2 SNP C383R may be replaced by the FGFR mutation FGFR2 C390>YS in the methods of treatment and uses described herein.

[0113] Disclosed herein is a method for treating cholangiocarcinoma in a patient, comprising: assessing a biological sample from the patient for the presence of one or more FGFR mutations, including at least FGFR2 C390>YS; and if one or more FGFR mutations, including at least FGFR2 C390>YS, are present in the sample, treating the patient with an FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0114] Disclosed herein is a method for treating cholangiocarcinoma in a patient with FGFR2 C390>YS, comprising administering an FGFR inhibitor to the patient. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0115] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in patients with FGFR2 C390>YS. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0116] Disclosed herein is the use of an FGFR inhibitor in the manufacture of a medicament for treating cholangiocarcinoma in patients with FGFR2 C390>YS. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0117] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutations including at least FGFR2 C390>YS, and detection of the presence of one or more FGFR mutations including at least FGFR2 C390>YS identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0118] Disclosed herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutations including at least FGFR2 C390>YS, and detecting the presence of one or more FGFR mutations including at least FGFR2 C390>YS identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0119] In one embodiment of the present invention, the FGFR2 SNP C383R may be replaced by the FGFR mutation FGFR2 N549K in the methods of treatment and uses described herein.

[0120] Disclosed herein is a method for treating cholangiocarcinoma in a patient, comprising: assessing the presence of one or more FGFR mutations, including at least FGFR2 N549K, in a biological sample from the patient; and if one or more FGFR mutations, including at least FGFR2 N549K, are present in the sample, treating the patient with an FGFR inhibitor.In one embodiment, the FGFR inhibitor is erdafitinib.

[0121] Disclosed herein is a method for treating cholangiocarcinoma in patients with FGFR2 N549K, comprising administering an FGFR inhibitor to the patient. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0122] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in patients with FGFR2 N549K. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0123] Disclosed herein is the use of an FGFR inhibitor in the manufacture of a medicament for treating cholangiocarcinoma in patients with FGFR2 N549K. The patient may have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0124] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutations including at least FGFR2 N549K, and when the presence of one or more FGFR mutations including at least FGFR2 N549K is detected, the patient is identified as being likely to respond to treatment with the FGFR inhibitor or to respond to treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0125] Disclosed herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutations including at least FGFR2 N549K, and detecting the presence of one or more FGFR mutations including at least FGFR2 N549K identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0126] In one embodiment of the present invention, the FGFR2 SNP C383R may be replaced by the FGFR mutation FGFR3 R397C in the methods of treatment and uses described herein.

[0127] Disclosed herein is a method for treating cholangiocarcinoma in a patient, comprising: assessing a biological sample from the patient for the presence of one or more FGFR mutations, including at least FGFR3 R397C; and if one or more FGFR mutations, including at least FGFR3 R397C, are present in the sample, treating the patient with an FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0128] Disclosed herein is a method for treating cholangiocarcinoma in a patient with FGFR3 R397C, comprising administering an FGFR inhibitor to the patient. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0129] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in patients with FGFR3 R397C. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0130] Disclosed herein is the use of an FGFR inhibitor in the manufacture of a medicament for treating cholangiocarcinoma in patients with FGFR3 R397C. The patient may have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0131] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutations including at least FGFR3 R397C, and detection of the presence of one or more FGFR mutations including at least FGFR3 R397C identifies the patient as likely to respond to treatment with the FGFR inhibitor, or as likely to respond to treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0132] Disclosed herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutations including at least FGFR3 R397C, and detecting the presence of one or more FGFR mutations including at least FGFR3 R397C identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0133] In one embodiment of the present invention, the FGFR2 SNP C383R may be replaced by the FGFR mutation FGFR2 L608F in the methods of treatment and uses described herein.

[0134] Disclosed herein is a method for treating cholangiocarcinoma in a patient, comprising: assessing a biological sample from the patient for the presence of one or more FGFR mutations, including at least FGFR3 L608F; and if one or more FGFR mutations, including at least FGFR3 L608F, are present in the sample, treating the patient with an FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0135] Disclosed herein is a method for treating cholangiocarcinoma in a patient with FGFR3 L608F, comprising administering an FGFR inhibitor to the patient. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0136] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in patients with FGFR3 L608F. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0137] Disclosed herein is the use of an FGFR inhibitor in the manufacture of a medicament for treating cholangiocarcinoma in patients with FGFR3 L608F. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0138] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutations including at least FGFR3 L608F, and detection of the presence of one or more FGFR mutations including at least FGFR3 L608F identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0139] Disclosed herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutations including at least FGFR3 L608F, and detecting the presence of one or more FGFR mutations including at least FGFR3 L608F identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0140] In one embodiment of the present invention, the FGFR2 SNP C383R may be replaced by the FGFR fusion FGFR2-TACC2 in the methods of treatment and uses described herein.

[0141] Disclosed herein is a method for treating cholangiocarcinoma in a patient, comprising: assessing a biological sample from the patient for the presence of one or more FGFR variants, including at least FGFR2-TACC2; and if one or more FGFR variants, including at least FGFR2-TACC2, are present in the sample, treating the patient with an FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0142] Disclosed herein is a method for treating cholangiocarcinoma in a patient with FGFR2-TACC2, comprising administering an FGFR inhibitor to the patient. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0143] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in patients with FGFR2-TACC2. The patient may also have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0144] Disclosed herein is the use of an FGFR inhibitor in the manufacture of a medicament for treating cholangiocarcinoma in patients with FGFR2-TACC2. The patient may have one or more additional FGFR mutations. In one embodiment, the FGFR inhibitor is erdafitinib.

[0145] Disclosed herein is an FGFR inhibitor for use in treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutants including at least FGFR2-TACC2, and detection of the presence of one or more FGFR mutants including at least FGFR2-TACC2 identifies the patient as likely to respond to treatment with the FGFR inhibitor, or as likely to respond to treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0146] Disclosed herein is the use of an FGFR inhibitor for the manufacture of a medicament for treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutants including at least FGFR2-TACC2, and detecting the presence of one or more FGFR mutants including at least FGFR2-TACC2 identifies the patient as likely to respond to or benefit from treatment with the FGFR inhibitor. In one embodiment, the FGFR inhibitor is erdafitinib.

[0147] In one embodiment, the proportion of cholangiocarcinoma patients, particularly advanced cholangiocarcinoma patients, with at least one of the FGFR variants described herein who exhibit an objective response rate is at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, or greater than 45%.

[0148] In one embodiment, the proportion of cholangiocarcinoma patients, particularly advanced cholangiocarcinoma patients, with at least one of the FGFR variants described herein who exhibit an objective response rate, particularly ORR (CR+PR+uCR+uPR), is at least 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, or greater than 54%.

[0149] Methods for identifying and analyzing FGFR variants, such as FGFR2 SNP C383R, can be performed using techniques known to those skilled in the art and described herein, such as reverse transcription polymerase chain reaction (RT-PCR) or in situ hybridization, such as fluorescent in situ hybridization (FISH). Diagnostic tests and screening are typically performed on biological samples selected from tumor biopsy samples, blood samples (isolation and enrichment of sloughed tumor cells), or those described above. The screening process will typically involve direct sequencing, oligonucleotide microarray analysis, or variant-specific antibodies.

[0150] In RT-PCR screening, the level of mRNA in tumors is assessed by generating a cDNA copy of the mRNA and then amplifying the cDNA by PCR. Methods for PCR amplification, primer selection, and amplification conditions are known to those skilled in the art. Nucleic acid manipulation and PCR are carried out by standard methods, for example, as described in Ausubel, FM et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc. or Innis, MA et al., eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Reactions and manipulations related to nucleic acid technology are also described in Sambrook et al., (2001), 3 rd Ed., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, commercially available kits for RT-PCR (e.g., Roche Molecular Biochemicals) or the methodologies described in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531; 5,192,659; 5,272,057; 5,882,864; and 6,218,529 (incorporated herein by reference) may be used. An example of an in situ hybridization technique for assessing mRNA expression would be fluorescence in situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152:649).

[0151] Generally, in situ hybridization involves the following major steps: (1) fixation of the tissue to be analyzed; (2) prehybridization treatment of the sample to increase the accessibility of the target nucleic acid and reduce nonspecific binding; (3) hybridization of a mixture of nucleic acids to nucleic acids in a biological structure or tissue; (4) posthybridization washes to remove nucleic acid fragments not bound by hybridization; and (5) detection of the hybridized nucleic acid fragments. Probes used in such applications are typically labeled, for example, with radioisotopes or fluorescent reporters. Preferred probes are sufficiently long to allow specific hybridization with the target nucleic acid under stringent conditions, for example, from about 50, 100, or 200 nucleotides to about 1,000 nucleotides or more. Standard methods for performing FISH are described in Ausubel, F M et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc. and Fluorescence In Situ Hybridization: Technical Overview by John M S Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp. 077-088; Series: Methods in Molecular Medicine.

[0152] Mutations and fusions are described herein with reference to the reference sequence NCBI Reference Sequence: NM_000141.4 and its corresponding amino acid sequence. FGFR2 C383R represents an FGFR2 mutation in which the cysteine ​​at position 383 is replaced by arginine. FGFR2 C390>YS represents an FGFR2 mutation in which the cysteine ​​at position 390 is replaced by a tyrosine and a serine. FGFR2 N549K represents an FGFR2 mutation in which the asparagine at position 549 is replaced by a lysine. FGFR2-KIAA1598 is a 5'-FGFR2(ex1-17)-KIAA1598(ex7-15)-3' fusion with REARR-POS1 chr10:123242270-123242562 and REARR-POS2 chr10:118709031-118709262, or REARR-POS1 chr10:123242809-123243080 and REARR-POS2 chr10:118710247-118710599. DTWD2-FGFR2 is a 5'-DTWD2(ex1)-FGFR2(ex18)-3' fusion with REARR-POS1 chr10:123242450-123242723 and REARR-POS2 chr5:118322151-118322550. ESR2-FGFR2 is a 5'-ESR2(ex1-3)-FGFR2(ex18)-3' fusion with REARR-POS1 chr10:123239893-123240042 and REARR-POS2 chr14:64740210-64740315. FGFR2-MGEA5 is a 5'-FGFR2(ex1-17)-MGEA5(ex11-16)-3' fusion with REARR-POS1 chr10:123241032-123241358 and REARR-POS2 chr10:103557129-103557439. FGFR2-BICC1 is a 5'-FGFR2(ex1-17)-BICC1(ex3-21)-3' fusion with REARR-POS1 chr10:123242218-123242771 and REARR-POS2 chr10:60445416-60445560. FGFR2-SBNO2 is a 5'-FGFR2(x18)-SBNO2(x19-32)-3' fusion with REARR-POS1 chr10:123240725-123240921 and REARR-POS2 chr19:1113573-1113710. FGFR3 R397C represents an FGFR3 mutation in which the asparagine at position 397 is replaced by a cysteine. FGFR3 L608F represents an FGFR3 mutation in which the leucine at position 608 is replaced by phenylalanine. FGFR2-TACC2 is a 5'-FGFR2(ex1-17)-TACC2(ex11-17)-3' fusion with REARR-POS1 chr10:123240606-123240922 and REARR-POS2 chr10:123994680-123994992. [Example]

[0153] 1) Treatment of patients with bile duct cancer A clinical trial was conducted in patients ≥18 years old registered with advanced solid tumors for which standard curative therapy was no longer effective (NCT01703481; 4-part study). Dose escalation (Part 1, all visits) followed a 3+3 design, with patients receiving ascending erdafitinib doses of 0.5, 2, 4, 6, 9, and 12 mg QD (21-day cycles). Additionally, after daily dose escalation (Part 1), two intermittent doses were evaluated: 10 and 12 mg, 7 days on / 7 days off (28-day cycles). Subsequent parts (Parts 2-4) required detailed documentation of FGFR biomarker-positive disease. Part 2 (pharmacodynamic cohort, all visitors) and Part 3 (dose expansion cohort of the recommended Phase 2 dose of 9 mg QD, cholangiocarcinoma in addition to other cancers): Tumors were required to be KRAS wild-type and to have one of the following: FGFR amplification, FGFR activating mutation, FGFR translocation, or other abnormality of FGFR activation. Part 4 (intermittent 10 mg dose expansion cohort, cholangiocarcinoma in addition to other cancers): Tumors were required to have an FGFR activating mutation or an FGFR translocation. Serial blood samples were collected to measure plasma erdafinitib concentrations in Parts 1 and 2. Sparse samples were collected in Parts 3 and 4.

[0154] result Eleven patients with FGFR-abnormal cholangiocarcinoma were treated with 9 mg QD (n=1, Part 3) or intermittent 10 mg (n=10, Part 4). Of the 11 patients: 3 (27.3%) had FGFR mutations and 8 (72.7%) had translocations. The median treatment duration was 5.3 months (range 1-16 months). Patients received a median of 6 cycles (range 2 to 17). Most patients received ≥6 cycles (8 / 11; 72.7%), of which 4 (36.4%) were treated with ≥9 cycles.

[0155] Systemic erdafitinib exposure in patients with cholangiocarcinoma was similar to that in patients with all other cancer indications in this study.

[0156] Of the three partial responders, one patient had an FGFR mutation (FGFR2 C383R) and two had FGFR translocations (FGFR2-BICC1 [n=1] and FGFR2-CCAR1 [n=1] fusions). The overall disease control rate, including stable disease, was 54.5% (6 / 11). At a median follow-up of 5.5 months: The median duration of response was 11.4 months (95% CI, 9.9-12.9 months). Median progression-free survival was 5.1 months (95% CI, 1.6-11.8 months). The 6-month and 9-month progression-free survival rates were 36% and 24%, respectively. As of the cutoff date, one patient remained on study treatment.

[0157] In this heavily pretreated population, the objective response rate was 27.3%, and the median duration of response was 11.4 months with erdafitinib 9 mg QD or intermittent 10 mg, with all responses seen with the latter dosing schedule. The disease control rate was 54.5%.

[0158] Safety and PK data were consistent with previously published results from part 1 of this study (Tabernero J, et al: J Clin Oncol 33:3401-3408, 2015).

[0159] 2) Treatment of patients with bile duct cancer A study evaluating the clinical efficacy of JNJ-42756493 (erdafitinib) in Asian participants with advanced non-small cell lung cancer, urothelial carcinoma, esophageal cancer, or cholangiocarcinoma (NCT02699606; LUC2001).

[0160] LUC2001 is an open-label, multicenter, Phase 2a study based on the FoundationOne trial, including subjects with advanced cholangiocarcinoma (PCC) with FGFR alterations who have failed at least one prior systemic treatment. The primary endpoint is the objective response rate (ORR; Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1). Secondary endpoints are disease control rate (DCR), safety, and pharmacokinetics. Disease will be assessed every 8 weeks until disease progression (PD). Participants will receive a starting dose of 8 mg erdafitinib once daily (with the option to titrate to 9 mg in 28-day cycles). Drug doses may be modified, delayed, or discontinued based on protocol guidelines.

[0161] Inclusion criteria: Pathologically or cytologically confirmed, advanced or refractory tumors (there is no limit on the total number of prior elective treatments, but participants must have received at least one prior anti-cancer treatment [according to local standard of care]): squamous and non-squamous non-small cell lung cancer (NSCLC), esophageal cancer, urothelial carcinoma, and cholangiocarcinoma Participants must meet the following molecular eligibility criteria (central or local laboratory diagnosis using tumor tissue-based assays; must demonstrate at least one of the following): a) fibroblast growth factor receptor (FGFR) gene translocation, b) FGFR gene mutation considered to be activating, c) Participants with evidence of FGFR pathway activation or other potential targets / pathways inhibited by erdafitinib may be considered or allowed for enrollment if supported by emerging biomarker data. Presence of measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) and well-documented disease progression as defined by RECIST (version 1.1) at baseline Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 Female participants (who are sexually active and have child-bearing potential) and male participants (who have partners who have child-bearing potential) must use medically acceptable methods of contraception. Male participants, if sexually active, must use highly effective contraception and must not donate sperm. Adequate bone marrow, liver, and renal function within 14 days prior to Day 1 of Cycle 1 and before Cycle 1 administration

[0162] Exclusion criteria: Chemotherapy, targeted therapy, immunotherapy, or treatment with an investigational anticancer agent within 2 weeks or at least 5 half-lives of the drug, whichever is longer, up to 4 weeks before the first dose of study drug. Local palliative radiation therapy (which does not have to include radiation to target lesions) and ongoing luteinizing hormone-releasing hormone (LHRH) agonists, bisphosphonates, and denosumab are permitted. Participants with persistent phosphate levels above (>) the upper limit of normal (ULN) during screening (within 14 days prior to Day 1 of Cycle 1 through prior to Cycle 1 dosing) and despite medical management of phosphate levels Participant is taking medications known to have a significant risk of causing QTc prolongation and torsades de pointes. Participants who discontinue any of these medications must have a washout period of at least 5 days or at least 5 half-lives (whichever is longer) before the first dose of study medication. Left ventricular ejection fraction (LVEF) less than 50% (<50%) as assessed by echocardiography (or multi-gated acquisition [MUGA]) performed at screening Uncontrolled intercurrent illnesses, including but not limited to poorly controlled hypertension or diabetes, ongoing active infection requiring antibiotics, psychiatric illness, uncontrolled cardiovascular disease, or risk of gastrointestinal perforation as assessed by the investigator. - Prior selective FGFR inhibitor treatment or RET inhibitor treatment, respectively, depending on biomarker pre-screening results or if the participant had a known allergy, hypersensitivity, or intolerance to erdafitinib or its excipients Any corneal or retinal abnormality likely to increase the risk of ocular toxicity All genders are eligible for the study. Participants must be 18 years of age or older.

[0163] Patients with advanced cholangiocarcinoma who progress after first-line chemotherapy have limited treatment options and a poor prognosis.

[0164] Preliminary Results (Snapshot): As of March 20, 2018, 150 patients with advanced cholangiocarcinoma were molecularly screened. 25 patients had FGFR alterations, of which 11 received 8 mg erdafitinib qd. All patients were evaluable for response. The median age was 53.0 years, and the ECOG score was 0 / 1 in 6 and 5 patients, respectively. The median number of treatment cycles was 4.0, and the median treatment duration was 3.5 months. Three patients achieved partial response (PR), two unconfirmed partial response (uPR), four stable disease (SD), and two progressed disease. The ORR (CR + PR + uCR + uPR) was 45.5%. The DCR (CR + PR + uCR + uPR + SD) was 81.8%. Six patients are still undergoing treatment. All subjects experienced AEs, seven experienced grade 3 or higher AEs, three experienced serious AEs (SAEs) (non-drug-related SAEs), all had AEs leading to drug discontinuation, and three had AEs leading to dose reductions, but no AEs led to treatment discontinuation or death. The most common AEs (>30%) were hyperphosphatemia (8 / 11), dry mouth (7 / 11), stomatitis (7 / 11), diarrhea (4 / 11), onychopathies (4 / 11), and palmar-plantar dysesthesia (4 / 11).

[0165] Participants with confirmed or unconfirmed partial responses include those with FGFR2-KIAA1598 and DTWD2-FGFR2 fusions, ESR2-FGFR2 fusions, FGFR2 C390>YS mutations, and FGFR2-MGEA5 fusions.

[0166] Stable participants included those with FGFR2-BICC1 fusion, FGFR2 fusion with SBNO2 partner, FGFR2 N549K mutation, and FGFR2-KIAA1598 fusion.

[0167] Conclusions: The PK characteristics are consistent with data from other erdafitinib studies. Erdafitinib has demonstrated promising clinical activity and a tolerable safety profile in patients with FGFR-abnormal advanced cholangiocarcinoma.

[0168] As of August 20, 2018, 193 patients with advanced CCA (cholangiocarcinoma) had undergone molecular screening; 29 had FGFR alterations, of which 12 (7 FGFR2 fusions, 3 FGFR2 mutations, and 2 FGFR3 mutations) were treated with continuous erdafitinib at 8 mg once daily (one patient was titrated to a 9 mg dose), of which 11 were evaluable for response. The median number of erdafitinib treatment cycles was 7.0 (range: 2; 19), and the median treatment duration was 6.34 (range: 1.6; 17.5) months.

[0169] All 11 patients had received prior systemic treatment, 4 patients (36.4%) had been exposed to prior radiation therapy, and 6 patients (54.5%) had undergone cancer-related surgery before study enrollment.

[0170] At baseline, 4 patients had received 1 prior chemotherapy, 4 patients had received 2 prior chemotherapy, and 3 patients had received ≥3 prior chemotherapy. Eight patients were treated with gemcitabine plus cisplatin regimen, and 11 patients were treated with cisplatin / oxaliplatin / carboplatin-based chemotherapy.

[0171] Research Evaluation Tumor assessments were performed every 8 (±1) weeks until 1 year from the start of study drug, and then every 12 (±1) weeks until the patient died, or consent was withdrawn or the end of the study occurred, whichever occurred first. Treatment-emergent adverse events (TEAEs): TEAEs were collected from the date of signing the full study informed consent form until the end-of-treatment (EOT) visit. TEAEs and serious TEAEs will be collected until 30 (+7) days after the last dose (EOT). Pharmacokinetic Evaluation: Blood samples for determination of erdafitinib plasma concentrations at various time points were collected during cycles 1 through 4. Pharmacodynamics and Safety: Serum phosphate concentrations were continuously monitored as a pharmacodynamic endpoint during the study to facilitate dose adjustments per protocol specifications. Serum phosphate was measured on Day 14 of Cycle 1 for pharmacodynamic titration. During the study, serum phosphate concentrations were set to be less than 7 mg / dL to avoid prolonged hyperphosphatemia. Exploratory biomarker assessment: Tumor tissue and blood were collected for exploratory biomarker assessment.

[0172] statistical analysis ORR (complete response [CR] or partial response [PR]) and disease control rate (DCR) were calculated with 95% CI. PFS was expressed as descriptive summary statistics; the Kaplan-Meier method was used for evaluation. A visual post-hoc predictive performance assessment was performed on an existing population PK model (built with data from 373 patients (the majority of whom were Caucasian) with various tumor types). A visual post-hoc predictive performance assessment was performed on serum phosphate concentration data based on existing population PK / PD models. Biomarker analysis was performed to explore the relationship between predictive markers and clinical response and PFS.

[0173] The objective response rate (ORR) was 45.5% (n=5), and the ORR a The 95% CI of (16.7; 76.6) was (16.7; 76.6). The ORR (CR + PR + uCR + uPR) was 54.5% (n=6), and the ORR a The 95% CI of was (23.4; 83.3). The disease control rate - DCR (CR + PR + SD) was 72.7% (n=8), and the DCR a The 95% CI of (39.0; 94.0) was (39.0; 94.0). The DCR (CR + PR + uCR + uPR + SD) was 81.8% (n=9), and the DCR a The 95% CI of is (48.2; 97.7).

[0174] a95% confidence intervals (CI) were calculated using the Clopper-Pearson method. CR and PR: confirmed by repeated assessment ≥ 4 weeks after first observation. If only one assessment of CR or PR was observed, the patient was classified as uCR or uPR (unconfirmed CR or PR). To be qualified as SD, follow-up measurements had to meet SD criteria at least once with a minimum interval of less than 6 weeks (not ≥ 6 weeks) after the first dose of study drug. CR, complete response; PR, partial response; PD, progressive disease; QD, once daily; SD, stable disease.

[0175] Five patients had confirmed PR (all with FGFR2 alterations [one mutation and four fusions]), one had unconfirmed PR (FGFR2 fusion), three had stable disease (SD; FGFR2 fusion), and two had progressive disease (PD; both with FGFR3 mutations and concurrent KRAS mutations).

[0176] The median duration of response (DOR) was 3.94 months (95% CI: 3.65; 12.16). The median (95% CI) progression-free survival (PFS) was 5.59 months (1.87, NE), and the 9-month PFS rate (95% CI) was 40% (11;68). Among patients with FGFR2 alterations (n=9), the 9-month PFS rate was 49%, and the ORR (CR+PR+uCR+uPR) and DCR were 66.7% and 100%, respectively.

[0177] All patients experienced drug-related TEAEs (treatment-emergent adverse events), with 6 / 11 patients reporting grade 3 or higher TEAEs. The most common TEAEs were hyperphosphatemia, dry mouth, stomatitis, dry skin, onychopathies, and palmar-plantar dysesthesia. Drug-related TEAEs leading to dose reductions were observed in 5 patients (45.5%), and drug-related TEAEs leading to dose discontinuation were reported in 11 patients (100%). Serious TEAEs (non-drug related) were observed in 3 patients (27.3%): upper gastrointestinal bleeding, acute pyelonephritis, and pathologic fracture, n=1 each. Six patients (54.5%) experienced grade 3 or higher drug-related TEAEs, while no AEs led to treatment discontinuation or death.

[0178] [Table 1]

[0179] One PR patient with an FGFR2-KIAA1598 fusion (confirmed in both tumor and cfDNA analysis) experienced a maximum tumor shrinkage (-46.2%); PFS was 5.59 months. The allelic fraction of the FGFR2-KIAA1598 fusion decreased with treatment and was undetectable in C3D1 and C6D1, but increased with disease progression. Analysis of cfDNA after progression revealed a secondary FGFR2 kinase domain mutation (V564L). This gatekeeper mutation was not detected in baseline plasma or tumor tissue, suggesting that this mutation represents a mechanism of acquired resistance to FGFR inhibition.

[0180] [Table 2]

[0181] Conclusion: The results of PK and PK / PD relationships in Asian patients with advanced CCA are comparable to those of other The findings are consistent with those known for patients with solid tumor types and different ethnic backgrounds, and suggest that progression The authors support the dose selected for patients with type 2 CCA. Various embodiments of the present invention are described below. 1. A method of treating cholangiocarcinoma in a patient, comprising: assessing a biological sample from the patient for the presence of one or more FGFR mutants comprising at least the mutation FGFR3 R397C; or one or more FGFR mutants comprising at least the mutation FGFR3 L608F; or one or more FGFR mutants comprising at least the fusion FGFR2-TACC2; and if one or more FGFR mutants comprising at least the mutation FGFR3 R397C; or one or more FGFR mutants comprising at least the mutation FGFR3 L608F; or one or more FGFR mutants comprising at least the fusion FGFR2-TACC2 are present in the sample, treating the patient with an FGFR inhibitor. 2. A method of treating cholangiocarcinoma in a patient with the mutation FGFR3 R397C; or with the mutation FGFR3 L608F; or with the fusion FGFR2-TACC2, comprising administering to said patient an FGFR inhibitor. 3. An FGFR inhibitor for use in the treatment of cholangiocarcinoma in patients with the mutation FGFR3 R397C; or the mutation FGFR3 L608F; or the fusion FGFR2-TACC2. 4. Use of an FGFR inhibitor for the manufacture of a medicament for treating cholangiocarcinoma in a patient, wherein a biological sample obtained from the patient is evaluated for the presence of one or more FGFR mutants comprising at least the FGFR3 R397C mutation; or one or more FGFR mutants comprising at least the FGFR3 L608F mutation; or one or more FGFR mutants comprising at least the fusion FGFR2-TACC2, and the presence of one or more FGFR mutants comprising at least the FGFR3 R397C mutation; or one or more FGFR mutants comprising at least the FGFR3 L608F mutation; or one or more FGFR mutants comprising at least the fusion FGFR2-TACC2 is detected, thereby identifying the patient as one who will benefit from treatment with the FGFR inhibitor. 5. The method or use according to any one of claims 1 to 4, wherein the FGFR inhibitor is erdafitinib. 6. The method or use of claim 5, wherein erdafitinib is administered at a dose of 8 mg once daily.

Claims

1. 1. A composition comprising erdafitinib for use in a method of treating cholangiocarcinoma in a patient, the method comprising: evaluating a biological sample from the patient for the presence of one or more FGFR mutants comprising at least a fusion FGFR2-TACC2; and treating the patient with erdafitinib if one or more FGFR mutants comprising at least a fusion FGFR2-TACC2 are detected in the sample; A composition wherein erdafitinib is (i) administered at a dose of 8 mg daily, or (ii) administered at a dose of 8 mg daily and titrated to 9 mg if the patient's serum phosphate level is <5.5 mg / dL, <7 mg / dL, in the range of 7 mg / dL to ≤9 mg / dL, or ≤9 mg / dL, and depending on any treatment-related adverse events observed.

2. The composition described in claim 1, wherein the biological sample is a solid tumor sample.

3. 1. A composition comprising erdafitinib for use in a method of treating cholangiocarcinoma in patients with a fusion FGFR2-TACC2, comprising: A composition wherein erdafitinib is (i) administered at a dose of 8 mg daily, or (ii) administered at a dose of 8 mg daily and titrated to 9 mg if the patient's serum phosphate level is <5.5 mg / dL, <7 mg / dL, in the range of 7 mg / dL to ≤9 mg / dL, or ≤9 mg / dL, and depending on any treatment-related adverse events observed.

4. A composition described in any one of claims 1 to 3, wherein the dose of erdafitinib is gradually increased to 9 mg if the patient's serum phosphate level is <5.5 mg / dL.

5. A composition described in any one of claims 1 to 3, wherein the dose of erdafitinib is gradually increased to 9 mg if the patient's serum phosphate level is <7 mg / dL.

6. A composition described in any one of claims 1 to 3, wherein the dose of erdafitinib is gradually increased to 9 mg when the patient's serum phosphate level is in the range of ≥ 7 mg / dL and ≤ 9 mg / dL.

7. The composition of claim 1, wherein the dose of erdafitinib is gradually increased to 9 mg when the patient's serum phosphate level is ≦9 mg / dL.

8. The composition of any one of claims 1 to 7, wherein the serum phosphate level for determining whether to escalate is measured on the day of treatment during the first cycle of erdafitinib treatment.

9. 9. The composition of claim 8, wherein the serum phosphate level for determining whether to titrate is measured on day 14±2 of erdafitinib administration.

10. 10. The composition of claim 9, wherein the serum phosphate level for determining whether to escalate is measured on day 14 of erdafitinib administration.

11. A composition described in any one of claims 1 to 10, wherein erdafitinib is administered once a day.

12. The composition of any one of claims 1 to 11, wherein the patient is of Asian descent.

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