WO2016161239A1 - Fgfr/pd-1 combination therapy for the treatment of cancer - Google Patents

Abstract

Provided herein are combination therapies for the treatment of cancer. In particular, the disclosed methods are directed to treatment of cancer in a patient comprising administering an antibody that blocks the interaction between PD-1 and PD-L1 and an FGFR inhibitor, wherein the antibody that blocks the interaction between PD-1 and PD-L1 and the FGFR inhibitor are administered if one or more FGFR variants are present in a biological sample from the patient.

Description

FGFR/PD-1 COMBINATION THERAPY FOR THE TREATMENT OF CANCER

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.

62/142,569, filed April 3, 2015, the disclosure of which is hereby incorporated by reference in its entirety.

SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on March 22, 2016, is named PRD3366USNP_SL.txt and is 53,086 bytes in size.

TECHNICAL FIELD

[0003] Provided herein are combination therapies for the treatment of cancer. In particular, the disclosed methods are directed to treatment of cancer in a patient comprising administering an antibody that blocks the interaction between PD-1 and PD-Ll and a fibroblast growth factor receptor (FGFR) inhibitor.

BACKGROUND

[0004] For cancer patients failing the main therapeutic option (front-line therapy) for that cancer type, there is often no accepted standard of care for second and subsequent-line therapy, unless a particular genetic abnormality is identified and a specific therapy is available. Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases involved in regulating cell survival, proliferation, migration and differentiation. FGFR alterations have been observed in some cancers. To date, there are no approved therapies that are efficacious in patients with FGFR alterations.

SUMMARY

[0005] Disclosed herein are methods of using a combination therapy that comprises an antibody that blocks the interaction between PD-1 and PD-Ll and an FGFR inhibitor to treat cancer in a patient. In some embodiments, the methods comprise administering to a patient a pharmaceutically effective amount of an antibody that blocks the interaction between PD-1 and

„ i . PD-Ll and a pharmaceutically effective amount of an FGFR inhibitor, wherein the antibody that blocks the interaction between PD-1 and PD-Ll and the FGFR inhibitor are administered if one or more FGFR variants are present in a biological sample from the patient.

[0006] In other embodiments, the methods of treating cancer in a patient comprise: administering to the patient a pharmaceutically effective amount of an antibody that blocks the interaction between PD-1 and PD-Ll; monitoring the efficacy of the antibody: and, if the antibody is not efficacious, evaluating a biological sample from the patient for a presence of one or more FGFR variants and administering to the patient a pharmaceutically effective amount of an FGFR inhibitor if the one or more FGFR variants are present in the sample.

[0007] Also, d sclosed herein are uses of an antibody that blocks the interaction between PD-1 and PD-Ll and an FGFR inhibitor for the manufacture of a medicament for the treatment of cancer, in particular for the treatment of cancer in a patient wherein one or more FGFR variants are present in a biological sample from the patient. In some embodiments, the medicament contains a pharmaceutically effective amount of an antibody that blocks the interaction between PD-1 and PD-Ll and a pharmaceutically effective amount of an FGFR inhibitor, wherein the medicament is used in a patient wherein one or more FGFR variants are present in a biological sample from the patient.

[0008] Also disclosed herein are combinations of an antibody that blocks the interaction between PD-1 and PD-Ll and an FGFR inhibitor for use in the treatment of cancer, in particular for use in the treatment of cancer in a patient wherein one or more FGFR variants are present in a biological sample from the patient. In some embodiments, the combination comprises a pharmaceutically effective amount of an antibody that blocks the interaction between PD-1 and PD-LI and a pharmace tically effective amount of an FGFR inhibitor for use in the treatment of cancer in a patient wherein one or more FGFR variants are present in a biological sample from the patient. In other embodiments, the combination for treating cancer comprises administration of a pharmaceutically effective amount of an antibody that blocks the interaction between PD-1 and PD-Ll; monitoring the efficacy of the antibody; and, if the antibody is not efficacious, evaluating a biological sample from the patient for a presence of one or more FGFR variants, followed by administration to the patient a pharmaceutically effective amount of an FGFR inhibitor if the one or more FGFR variants are present in the sample.

Ί BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The summary, as well as the following detailed description, is further understood when read in conjunction with the appended drawings. For the purpose of illustrating the disclosed methods, there are shown in the drawings exemplar}' embodiments of the methods: however, the methods are not limited to the specific embodiments disclosed. In the drawings:

[0010] FIG. 1 illustrates PD-Ll expression in a 120 lung cancer samples set by histology and FGFR mutant and amplification status. PD-Ll H-scores (Y -axis) were plotted for NSCLC adenocarcinoma (left), small cell lung cancer (middle), and NSCLC squamous (right). The FGFR mutation and/or amplification status versus the PD-Ll staining for each of the 120 samples is shown . Mutation - an FGFR mutation was identified, but no amplification or fusion was detected; No FGFR Alteration - no mutation, amplification, or fusion was detected; Amplification - an FGFR gene amplification was identified, but no FGFR mutation or fusion was detected; Mutation + Amp - samples were positive for both FGFR mutation and gene amplification, but no fusion was detected; Not Tested - IHC for PD-L l was performed, but sample was not tested on Foundation Medicine panel.

[0011] FIG. 2 illustrates PD-Ll expression in an 80 non-small-cell lung carcinoma (NSCLC) sample set by FGFR fusion status by NSCLC histology, PD-Ll H-scores (Y-axis) were plotted for NSCLC adenocarcinoma (left), and NSCLC squamous (right). The FGFR fusion status versus the PD-Ll staining for each of the 80 samples is shown. Fusion Positive - an FGFR fusion was detected; Fusion Wild-Type - no FGFR fusion was detected; Not Tested - insufficient sample for testing or quality control (QC) failure.

[0012] FIG. 3 illustrates the effect of JNJ42756493 on immune cell viability. Normal donor peripheral blood mononuclear cells (PBMCs), either unstimulated or stimulated with anti-CD3 antibodies, were treated with increasing concentrations of JNJ42756493 ( 0.0000077, 0.000023, 0.000070, 0.00021, 0.00063, 0.00188, 0.00565, 0.01694, 0.051 , 0.152, 0.457, 1.372, 4.1 15, 12.346, 37.037, 1 1 1. I l l, 333.333, and 1000 nM). On days 1, 2, 5 and 6 after plating, cell viability was assessed by CellTiter-Glo (Promega).

100131 FIG. 4 illustrates the effect of JNJ42756493 on IFN-γ levels induced by anti- PD-l antibodies in a Mixed Lymphocyte Reaction (MLR) Assay . Cultures of CD4^" T and allogeneic dendritic ceils were treated with anti-PD-l antibodies (concentrations left to right - 30, 10, 3.33, 1 .1 1, 0.37, 0.12 nM). JNJ42756493 was added at 100, 1, or 0,01 nM alone (concentrations left to right), together with anti-PD- l antibodies (100, I, or 0.01 nM JNJ42756493 together with 30, 10, 3.33, 1.1 1, 0.37, or 0.12 riM of anti-PD- 1 antibody), or in the presence of isotype control (IC). 5 days after treatment, IFN-γ levels in the supernatant were measured by Meso Scale Discovery (MSD).

100141 FIG, 5 illustrates the effect of JNJ42756493 on IFN-γ levels induced by anti- PD-1 antibodies in a Cytomegalovirus antigen assay (CMV) Assay. Peripheral blood mononuclear cells (PMBCs) were stimulated with CMV antigen and treated with anti-PD- 1 antibodies (concentration left to right - 30, 10, 3.33, 1.1 1, 0.37, 0.12 iiM) as indicated.

JNJ42756493 was added at 100, 1 , or 0.01 nM alone (concentrations left to right), together with anti-PD-1 antibodies (100, 1, or 0.01 nM JNJ42756493 together with 30, 10, 3.33, 1.1 1, 0.37, or 0.12 nM of anti-PD- 1 antibody), or in the presence of isotype control (IC). 6 days after treatment IFN-γ levels in the supernatant were measured by MSD.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0015] The disclosed methods may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures, which form a part of this disclosure. It is to be understood that the disclosed methods are not limited to the specific methods described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods.

[0016] Unless specifically stated otherwise, any description as to a possible mechanism, or mode of action or reason for improvement is meant to be illustrative only, and die disclosed methods are not to be constrained by the correctness or incorrectness of any such suggested mechanism or mode of action or reason for improvement.

[0017] Reference to a particular 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 ranges include each and every value within that range. All ranges are inclusive and combinable.

[0018] When values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment.

[0019] The term "about" when used in reference to numerical ranges, cutoffs, or specific values is used to indicate that the recited values may vary by up to as much as .10% from die listed value. Tims, the term "about" is used to encompass variations of± 10% or less, variations of ± 5% or less, variations of± 1% or less, variations of ± 0.5% or less, or variations of ± 0.1% or less from the specified value.

[0020] It is to be appreciated that certain features of the disclosed methods which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed methods that are, for bre vity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0021] As used herein, the singular forms '"a," "an," and "the" include the plural.

[0022] The following abbreviations are used throughout the disclosure: FFPE (formalin-fixed, paraffin-embedded); NSCLC (non-small-cell lung carcinoma); SCLC (small- cell lung cancer); FGFR (fibroblast growth factor receptor); PD-1 (programmed cell death 1); PD-Ll (programmed death-ligand 1); FGFR3:TACC3 (fusion between genes encoding FGFR3 and transforming acidic coiled-coil containing protein 3); FGFR3:BAIAP2L1 (fusion between genes encoding FGFR3 and brain-specific angiogenesis inhibitor 1 -associated protein 2-like protein 1); FGFR2: AFF3 (fusion between genes encoding FGFR2 and AF4 FMR2 family, member 3); FGFR2:BICC1 (fusion between genes encoding FGFR2 and bi caudal C homolog 1); FGFR2: CASP7 (fusion between genes encoding FGFR2 and caspase 7); FGFR2:CCDC6 (fusion between genes encoding FGFR2 and coiled-coil domain containing 6); FGFR2:OFD l (fusion between genes encoding FGFR2 and oral-facial -digital syndrome 1).

[0023] The term "antibody" refers to (a) immunoglobulin polypeptides, i.e., polypeptides of the immunoglobulin family that contain an antigen binding site that specifically binds to a specific antigen (e.g., PD-1 or PD-Ll), including all immunoglobulin isotvpes (IgG, IgA, IgE, IgM, IgD, and IgY), classes (e.g. IgGl, lgG2, IgG3, IgG4, IgAl, IgA2), subclasses, and various monomelic and polymeric forms of each isotype, unless otherwise specified, and (b) conservatively substituted variants of such immunoglobulin polypeptides that

immunospecifically bind to the antigen (e.g., PD-1 or PD-Ll). Antibodies are generally described in, for example, Harlow & Lane, Antibodies: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 1988). Unless otherwise apparent from the context, reference to an antibody also includes antibody derivatives as described in more detail below.

[0024] "Antibody fragments" comprise a portion of a full length antibody, generally the antigen-binding or variable region thereof, such as Fab, Fab'^', F(ab')₂ , and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. Various techni ues have been developed for the production of antibody fragments, including proteolytic digestion of antibodies and recombinant production in host ceils; however, other techniques for the production of antibody fragments will be apparent to the skilled practitioner. In some embodiments, the antibody fragment of choice is a single chain Fv fragment (scFv). "Single-chain Fv" or "scFv" antibody fragments comprise the VH and domains of antibody, wherein these domains are present in a single polypeptide chain. Generally, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form, the desired structure for antigen binding. For a review of scFv and other antibody fragments, see James D. Marks, Antibody Engineering, Chapter 2, Oxford University Press (1995) (Carl K. Borrebaeck, Ed.).

[0025] An "antibody derivative" means an antibody, as defined above, that is modified by covalent attachment of a heterologous molecule such as, e.g., by attachment of a heterologous polypeptide (e.g., a cytotoxin) or therapeutic agent (e.g., a chemotherapeutic agent), or by glycosylation, deglycosylation, acetylation or phosphorylation not normally associated with the antibody, and the like.

[0026] The term "monoclonal antibody" refers to an antibody that is derived from a single ceil clone, including any eukaryotic or prokaryotic cell clone, or a phage clone, and not the method by which it is produced. Thus, the term "monoclonal antibody" is not limited to antibodies produced through hybridoma technology.

[0027] "Biological sample" refers to any sample from a patient in which cancerous cells can be obtained and protein expression can be evaluated and/or RNA can be isolated. Suitable biological samples include, but are not limited to, blood, lymph fluid, bone marrow, sputum, a solid tumor sample, or any combination thereof. In some embodiments, the biological sample can be formalin-fixed paraffin-embedded tissue (FFPET).

[0028] As used here, "biock(s) the interaction" refers to the ability of an anti-PD-1 antibody or an anti-PD-Ll antibody to inhibit or reduce binding of PD-L1 to PD-1, such that signaling/functioning through PD-1 is abolished or diminished.

[0029] As used herein, "FGFR variant" refers to an alteration in the wild type FGFR gene, including, but not limited to, FGFR fusion genes, FGFR mutations, FGFR amplifications, or any combination thereof. The terms "variant" and "alteration" are used interchangeably herein. "FGFR fusion" or "FGFR fusion gene" refers to a gene encoding a portion of FGFR (e.g., FGRF2 or FGFR3) and one of the herein disclosed fusion partners created by a translocation between the two genes. 100301 As used herein, '"patient" is intended to mean any animal, in particular, mammals. Thus, the methods are applicable to human and nonhuman animals, although most preferably with humans. "Patient" and "subject" may be used interchangeably herein.

[0031] "Pharmaceutically effective amount" refers to an amount of an antibody that blocks the interaction between PD-1 and PD-Ll and an amount of an FGFR inhibitor that treats the patient.

[0032] As used herein, "pharmaceutically acceptable salt" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Examples of pharmaceutically acceptable salts are discussed in Berge, et ai. (1977) "Pharmaceutical! Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19.

100331 As used herein, "treating" and like terms refer to reducing the severity and/or frequency of cancer symptoms, eliminating cancer symptoms and/or the underlying cause of said symptoms, reducing the frequency or likelihood of cancer symptoms and/or their underlying cause, and improving or remediating damage caused, directly or indirectly, by- cancer.

100341 Disclosed herein are methods of treating cancer in a patient comprising: administering to the patient a pharmaceutically effective amount of an antibody that blocks the interaction between PD-1 and PD-Ll and a pharmaceutically effective amount of an FGFR inhibitor, wherein the antibody that blocks the interaction between PD-1 and PD-Ll and the FGFR inhibitor are administered if one or more FGFR variants are present in a biological sample from the patient.

100351 PD-1 is a cell surface receptor expressed on the surface of CD4+ and CD8+ T cells, B ceils, and myeloid cells. The ligands of PD-1, PD-L l and PD-L2, are expressed on immune cells; in addition, PD-Ll is also expressed on cancer cells. When engaged by its ligands, PD-1 downregulat.es the immune response by reducing T cell proliferation, cytokine production and effector function. Antibodies against PD-1 (anti-PD-1 antibodies) and/or its ligands (anti -PD-Ll antibodies, for example) can block the interaction between PD-1 and PD- Ll, thereby inhibiting the downregulation of the immune response. The disclosed methods comprise administering to the patient a pharmaceutically effective amount of an antibody that blocks the interaction between PD-1 and PD-Ll . In some embodiments, the methods can comprise administering to the patient a pharmaceutically effective amount of an anti-PD-1 antibody. In some embodiments, the methods can comprise administering to the patient a pharmaceutically effective amount of an anti-PD-Ll antibody. In some embodiments, the methods can comprise administering to the patient a pharmaceutically effective amount of an anti-PD-1 antibody and an anti -PD-Ll antibody.

[0036] Exemplar}' anti-PD-1 antibodies include, but are not limited to, OPDIVO® (nivolumab) (Bristol-Myers Squibb) and KEYTRUDA® (pembrolizumab) (Merck),

Exemplar}' anti-PD-Ll antibodies include, but are not limited to, MPDL3208A (Roche) and MEDI4736 (AstraZeneca).

[0037] Exemplar}' FGFR inhibitors are described in U.S. Publ. No. 2013/0072457 Al (incorporated herein by reference) and include N-(3, 5 -dimethoxyphenyl)-N'-(l -methyl ethyl)-N- [ 3 -(1 -methyl- lH-pyrazol-4-yl)qumoxalm-6-yl] ethane- 1,2-diamine (referred to herein '^"JNJ- 42756493"), including any tautomeric or stereochemical!}' isomeric forms thereof, N-oxides thereof, pharmaceutically acceptable salts thereof, or solvates thereof (suitable R groups are also disclosed in U.S. Publ. No. 2013/0072457 Al). Thus, in some embodiments, the FGFR inhibitor can be the compound of formula (I):

or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutically acceptable salt is a HC1 salt.

100381 The antibody that blocks the interaction between PD-1 and PD-Ll and the FGFR inhibitor can be administered as a single therapeutic agent or can be co-administered as individual agents. When administered as individual agents, the antibody and FGF inhibitor can be administered contemporaneously or sequentially in either order. In some embodiments, the antibody that blocks the interaction between PD-1 and PD-Ll and the FGFR inhibitor can be admmistered contemporaneously. In some embodiments, the antibody that blocks the interaction between PD-1 and PD-Ll and the FGFR inhibitor can be administered sequentially. In some aspects, for example, the antibody that blocks the interaction between PD-1 and PD-Ll can be administered first, followed by administration of the FGFR inhibitor. In other aspects, the FGF inhibitor can be administered first, followed by administration of the antibody that blocks the interaction between PD-1 and PD-Ll . When administered sequentially, the antibody and FGFR inhibitor can be administered within seconds, minutes, hours, days, or weeks of each other.

100391 The pharmaceutically effective amount of the antibody that blocks the interaction between PD-1 and PD-L1 and of the FGFR inhibitor will be dependent on several factors including, but not limited to, stage and severity of the cancer, as well as other factors relating to the health of the patient. Those skilled in the art would know how to determine the pharmaceutically effective amount.

100401 The disclosed methods are suitable for treating cancer in a patient if one or more FGFR variants are present in a biological sample from the patient. In some embodiments, the FGFR variant can be one or more FGFR fusion genes. In some embodiments, the FGFR variant can be one or more FGFR mutations. In some embodiments, the FGFR variant can be one or more FGFR amplifications. In some embodiments, a combination of the one or more FGFR variants can be present in the biological sample from the patient. For example, in some embodiments, the FGFR variants can be one or more FGFR fusion genes and one or more FGFR mutations. In some embodiments, the FGFR variants can be one or more FGFR fusion genes and one or more FGFR amplifications. In some embodiments, the FGFR variants can be one or more FGFR mutations and one or more FGFR amplifications. In yet other

embodiments, the FGFR variants can be one or more FGFR fusion genes, mutations, and amplifications.

100411 Exemplary FGFR fusion genes are provided in Table 1 and include, but are not limited to: FGFR2:AFF3; FGFR2:BICC1; FGFR2:CASP7; FGFR2:CCDC6; FGFR2:0FD1: FGFR3 :BAIAP2L 1 ; FGFR3 : TACC3 -Intron; FGFR3:TACC3V1; FGFR3:TACC3V3; or a combination thereof. The sequences of the FGFR fusion genes are disclosed in Table 7.

Table 1. Exem lary FGFR fusion genes

FCFR3:TACC3 v3 18 10

100421 FGFR mutations include FGFR single nucleotide polymorphism (SNP).

"FGFR single nucleotide polymorphism" (SNP) refers to a FGFR2 or FGFR3 gene in which a single nucleotide differs among individuals. In particular, FGFR single nucleotide

polymorphism" (SNP) refers to a FGFR3 gene in which a single nucleotide differs among individuals. The presence of one or more of the following FGFR SNPs in a biological sample from, a patient can be determined by methods known to those of ordinary skill in the art or methods disclosed in U.S. Provisional Patent App. No. 62/056,159, U.S. Patent Publication No. US2016-0090633, and WO 2016/048833, FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, FGFR3 Y373C, or any combination thereof. The sequences of the FGFR SNPs are provided in Table 2.

Table 2

Sequences correspond to nucleotides 920-1510 of FGFR3 (Genebank ID # NM 000142.4).

Nucleotides in bold underline represent the SNP.

* Sometimes mistakenly referred to as Y375C in the literature. [0043] The methods can further comprise evaluating the presence of one or more FGFR variants in the biological sample before the administering step. Suitable methods for evaluating a biological sample for the presence of one or more FGFR variants are disclosed elsewhere herein.

100441 The disclosed methods can be dependent upon PD-L 1 expression in the cancer or can be carried out irrespectively of PD-Ll expression in the cancer. In some embodiments, for example, the methods can comprise administering to the patient a pharmaceutically effective amount of an antibody that blocks the interaction between PD-1 and PD-Ll and a pharmaceutically effective amount of an FGFR inhibitor, wherein the antibody that blocks the interaction between PD-1 and PD-L l and the FGFR inhibitor are administered if one or more FGFR variants are present in a biological sample from the patient and PD-Ll expression in the biological sample from the patient is at a specified level or within a specified range. In some aspects, for example, the methods can be carried out if the PD-Ll expression is high in the biological sample. Accordingly, in some embodiments the methods can comprise

administering to the patient a pharmaceutically effective amount of an antibody that blocks the interaction between PD-1 and PD-Ll and a pharmaceutically effective amount of an FGFR inhibitor, wherein the antibody that blocks the interaction between PD-1 and PD-L l and the FGFR inhibitor are administered if PD-Ll expression is high and one or more FGFR variants are present in a biological sample from the patient. Alternatively, the methods can be carried out if the PD-Ll expression is low in the biological sample. Accordingly, the methods can comprise administering to the patient a pharmaceutically effective amount of an antibody that blocks the interaction between PD-i and PD-Ll and a pharmaceutically effective amount of an FGFR inhibitor, wherein the antibody that blocks the interaction between PD-1 and PD-Ll and the FGFR inhibitor are administered if PD-L l expression is low and one or more FGFR variants are present in a biological sample from the patient. The methods can be carried out if the PD-Ll expression is moderate. Accordingly, the methods can comprise administering to die patient a pharmaceutically effective amount of an antibody that blocks the interaction between PD-1 and PD-Ll and a pharmaceutically effective amount of an FGFR inhibitor, wherein the antibody that blocks the interaction between PD-1 and PD-Ll and the FGFR inhibitor are administered if PD-Ll expression is moderate and one or more FGFR variants are present in a biological sample from the patient. As discussed elsewhere herein, PD-Ll expression levels can be based upon a numerical 1 1 -score (low includes an H-score of about 0 to about 99; moderate includes an H-score of about 100 to about 199: and high includes an H- score of about 200 to about 300) or can be based upon a comparison to a reference value.

100451 In other embodiments, the methods can be carried out irrespectively of PD-L1 expression in the biological sample from the patient and can be based on the presence of one or more FGFR variants without factoring in PD-L1 expression.

[0046] The methods can further comprise evaluating PD-L1 expression in the biological sample from the patient. Exemplary methods of evaluating PD-L1 expression are disclosed elsewhere herein. PD-L1 expression can be evaluated before, during, or after the administering step.

[0047] In some embodiments, the methods can comprise evaluating the presence of one or more FGFR variants and PD-L1 expression in the biological sample from the patient before the administering step.

[0048] Suitable biological samples for evaluating PD-L1 expression, evaluating the presence of one or more FGFR variants, or for evaluating both PD-L1 expression and the presence of one or more FGFR variants include, but are not limited to, blood, lymph fluid, bone marrow, a solid tumor sample, or any combination thereof.

[0049] The disclosed methods can be used to treat a variety of cancer types including, but not limited to, lung cancer, bladder cancer, gastric cancer, breast cancer, ovarian cancer, head and neck cancer, esophageal cancer, glioblastoma, or any combination thereof. In some embodiments, the methods can be used to treat lung cancer. The lung cancer can be non-small cell lung cancer (NSCLC) adenocarcinoma, NSCLC squamous cell carcinoma, small cell lung cancer, or any combination thereof. Thus, in some aspects, the methods can be used to treat NSCLC adenocarcinoma. In other aspects, the methods can be used to treat NSCLC squamous cell carcinoma. In yet other aspects, the methods can be used to treat small cell lung cancer. In some embodiments, the methods can be used to treat bladder cancer. In some embodiments, the methods can be used to treat gastric cancer. In some embodiments, the methods can be used to treat breast cancer. In some embodiments, the methods can be used to treat ovarian cancer. In some embodiments, the methods can be used to treat head and neck cancer. In some embodiments, the methods can be used to treat esophageal cancer. In some embodiments, the methods can be used to treat glioblastoma. In some embodiments, the methods can be used to treat any combination of the above cancers.

100501 Also disclosed are methods of treating cancer in a patient comprising;

administering to the patient a pharmaceutically effective amount of an antibody that blocks the interaction between PD-1 and PD-L1 ; monitoring the efficacy of the antibody; and if the antibody is not efficacious, evaluating a biological sample from the patient for a presence of one or more FGFR variants and administering to the patient a pharmaceutically effective amount of an FGFR inhibitor if the one or more FGFR variants are present in the sample.

[0051] The efficacy of the antibody can be monitored by, for example, evaluating the patient's symptoms for progression of the cancer, evaluating the severity of the cancer symptoms, evaluating the frequency of the cancer symptoms, measuring tumor size, or any combination thereof. Without intent to be limiting, progression or failure to reduce the progression of the cancer, increased severity or no change in severity of the cancer sy mptoms, increased frequency or no change in the frequency of the cancer symptoms, increased size or no change in size of the tumor, or any combination thereof, can be indications that the antibody is not efficacious.

[0052] In some embodiments, the methods can comprise administering to the patient a pharmaceutically effective amount of an anti-PD-1 antibody. In some embodiments, the methods can comprise administering to the patient a pharmaceutically effective amount of an anti-PD-Ll antibody. In some embodiments, the methods can comprise administering to the patient a pharmaceutically effective amount of an anti-PD-1 antibody and an anti-PD-Ll antibody. Exemplary anti-PD-1 antibodies include, but are not limited to, OPDIVO®

(nivolumab) (Bristol-Myers Squibb) and KEYTRUDA® (pembrolizumab) (Merck).

Exemplary anti-PD-Ll antibodies include, but are not limited to, MPDL3208A (Roche) and MEDI4736 (AstraZeneca).

[0053] Exemplary FGFR inhibitors include those disclosed above, including N-(3,5- dimethoxyphenyl)- '-( 1 -methylethyl)-N-[3-( 1 -methyl- lH-pyrazol-4-yl)quinoxalin-6-yl]ethane- 1,2-diamine (referred to herein "JNJ-42756493"), including any tautomeric or stereochemicaliy isomeric forms thereof, N-oxides thereof, pharmaceutically acceptable salts thereof, or solvates thereof (suitable R groups are also disclosed in U.S. Publ. No. 2013/0072457 Al). In some embodiments, the FGFR inhibitor can be the compound of formula (I):

(I)

or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutically acceptable salt is a HC1 salt.

[0054] The pharmaceutically effective amount of the antibody and FGFR inhibitor will be dependent on several factors including, but not limited to, stage and severity of the cancer, as well as other factors relating to the health of the patient. Those skilled in the art would know how to determine the pharmaceutically effective amount.

100551 The disclosed methods are suitable for treating cancer in a patient if one or more FG FR variants are present in a biological sample from the patient. In some embodiments, the FGFR variant can be one or more FGFR fusion genes. In some embodiments, the FGFR variant can be one or more FGFR mutations. In some embodiments, the FGFR variant can be one or more FGFR amplifications. In some embodiments, a combination of the one or more FGFR variants can be present in the biological sample from the patient. For example, in some embodiments, the FGFR variants can be one or more FGFR fusion genes and one or more FGFR mutations. In some embodiments, the FGFR variants can be one or more FGFR fusion genes and one or more FGFR amplifications. In some embodiments, the FGFR variants can be one or more FGFR mutations and one or more FGFR amplifications. In yet other

embodiments, the FGFR variants can be one or more FGFR fusion genes, mutations, and amplifications. Exemplary FGFR fusion genes are provided in Table 1 and include, but are not limited to: FGFR2:AFF3; FGFR2:BICC 1; FGFR2:CASP7; FGFR2:CCDC6; FGFR2:OFDl; FGFR3 : BAIAP2L 1 ; FGFR3 :TACC3-Intron; FGFR3:TACC3V 1 ; FGFR3:TACC3V3; or a combination thereof.

100561 Suitable methods for evaluating a biological sample for the presence of one or more FGFR variants are disclosed elsewhere herein.

[0057] The disclosed methods can be dependent upon PD-L1 expression in the biological sample or can be carried out irrespectively of PD-L1 expression in the cancer. In some aspects, for example, if the antibody is not efficacious, the methods can comprise measuring an expression level of PD-Ll in the biological sample and administering to the patient a pharmaceutically effective amount of an FGFR inhibitor if the PD-L1 expression is at a specified level or within a specified range. Methods of evaluating PD-L1 expression are disclosed elsewhere herein. The methods can be earned out if the PD-1 expression in the biological sample is low. In some embodiments, for example, the evaluating step can further comprise measuring an expression level of PD-L1 in the biological sample and the second administering step can compri se administering the FGFR inhibitor if the expression level of PD-L1 is low. In some aspects, methods of treating cancer in a patient comprise:

administering to the patient a pharmaceutically effecti ve amount of an antibody that blocks the interaction between PD-1 and PD-Ll; monitoring the efficacy of the antibody; and if the antibody is not efficacious, evaluating a biological sample from the patient for a presence of one or more FGFR variants and measuring an expression level of PD-Ll in the biological sample, and administering to the patient a pharmaceutically effective amount of an FGFR inhibitor if the one or more FGFR variants are present and if the expression level of PD-Ll is low in the sample.

[0058] The methods can be carried out if the PD-1 expression in the biological sample is moderate. Thus, the evaluating step can further comprise measuring an expression level of PD-Ll in the biological sample and the second administering step can comprise administering the FGFR inhibitor if the expression level of PD-Ll is moderate. The methods can be carried out if the PD-1 expression in the biological sample is high. For example, the evaluating step can further comprise measuring an expression level of PD-Ll in the biological sample and the second administering step can comprise administering the FGFR inhibitor if the expression level of PD-Ll is high.

100591 As discussed elsewhere herein, PD-Ll expression levels can be based upon a numerical H-score (low includes an H-score of about 0 to about 99; moderate includes an H- score of about 100 to about 199; and high includes an H-score of about 200 to about 300) or can be based upon a comparison to a reference value.

[0060] In other embodiments, the methods can be carried out irrespectively of PD-Ll expression in the cancer and can be based on the presence of one or more FGFR variants in the biological sample without factoring in PD-Ll expression.

100611 Suitable biological samples include, but are not limited to, blood, lymph fluid, bone marrow, a solid tumor sample, or any combination thereof. [0062] The disclosed methods can be used to treat a variety of cancer types including, but not limited to, lung cancer, bladder cancer, gastric cancer, breast cancer, ovarian cancer, head and neck cancer, esophageal cancer, glioblastoma, or any combination thereof. In some embodiments, the methods can be used to treat lung cancer. The lung cancer can be non-small cell lung cancer (NSCLC) adenocarcinoma, NSCLC squamous cell carcinoma, small cell lung cancer, or any combination thereof. Thus, in some aspects, the methods can be used to treat NSCLC adenocarcinoma. In other aspects, the methods can be used to treat NSCLC squamous cell carcinoma. In yet other aspects, the methods can be used to treat small cell lung cancer. In some embodiments, the methods can be used to treat bladder cancer. In some embodiments, the methods can be used to treat gastric cancer. In some embodiments, the methods can be used to treat breast cancer. In some embodiments, the methods can be used to treat ovarian cancer. In some embodiments, the methods can be used to treat head and neck cancer. In some embodiments, the methods can be used to treat esophageal cancer. In some embodiments, the methods can be used to treat glioblastoma. In some embodiments, the methods can be used to treat any combination of the above cancers.

[0063] Also, disclosed herein are uses of an antibody that blocks the interaction between PD-1 and PD-Ll and an FGFR inhibitor for the manufacture of a medicament for the treatment of cancer, in particular for the treatment of cancer in a patient wherein one or more FGFR variants are present in a biological sample from the patient. Each of the above embodiments described in terms of a method of treating cancer can be employed in the use of an antibody that blocks the interaction between PD-1 and PD-Ll and an FGFR inhibitor for the manufacture of a medicament for the treatment of cancer, in particular for the treatment of cancer in a patient wherein one or more FGFR variants are present in a biological sample from the patient.

[0064] Also disclosed herein are combinations of an antibody that blocks the interaction between PD-1 and PD-Ll and an FGFR inhibitor for use in the treatment of cancer, in particular for the treatment of cancer in a patient wherein one or more FGFR variants are present in a biological sample from the patient. Each of the above embodiments described in terms of a method of treating cancer can be employed with a combination of an antibody that blocks the interaction between PD-1 and PD-Ll and an FGFR inhibitor for use in the treatment of cancer, in particular for the treatment of cancer in a patient wherein one or more FGFR variants are present in a biological sample from the patient. Evaluating a sample for the presence of one or more FGFR variants

[0065] The following methods for evaluating a biological sample for the presence of one or more FGFR variants apply equally to any of the above d sclosed methods of treatment,

[0066] Suitable methods for evaluating a biological sample for the presence of one or more FG FR variants are described in the methods section herein and in U.S. Provisional Patent App. No. 62/056,159, U.S. Patent Publication No. US2016-0090633, and WO 2016/048833, which are incorporated herein in their entirety. For example, and without intent to be limiting, evaluating a biological sample for the presence of one or more FGFR variants can comprise any combination of the following steps: isolating RNA from the biological sample: synthesizing cD A from the RNA; and amplifying the cDNA (preamplified or non-preamplified). In some embodiments, evaluating a biological sample for the presence of one or more FGFR variants can comprise: amplifying cDNA from the patient with a pair of primers that bind to and amplify one or more FGFR variants; and determining whether the one or more FGFR variants are present in the sample. In some aspects, the cDNA can be pre-amplified. In some aspects, the evaluating step can comprise isolating RNA from the sample, synthesizing cDNA from the isolated RNA, and pre-amplifying the cDNA.

[0067] Suitable primer pairs for performing an amplification step include, but are not limited to, those disclosed in U.S. Provisional Patent App. No. 62/056, 159, U.S. Patent

Publication No. US2016-0090633, and WO 2016/048833, as exemplified below:

FGFR3TACC3 VI Forward: GACCTGGACCGTGTCCTTACC (SEQ ID NO: !)

Reverse: CTTCCCCAGTTCCAGGTTCTT (SEQ ID NO:2)

FGFR3TACC3 V3 Forward: AGGACCTGGACCGTGTCCTT (SEQ ID NO:3)

Reverse: TATAGGTCCGGTGGACAGGG (SEQ ID NO: 4)

FGFR3TACC3 Intron Forward: GGCCATCCTGCCCCC (SEQ ID NO:5)

Reverse: GAGCAGTCCAGGTCAGCCAG (SEQ ID NO: 6)

FGFR3 B AIAP2L 1 Forward: CTGGACCGTGTCCTTACCGT (SEQ ID NO:7)

Reverse: GCAGCCCAGGATTGAACTGT (SEQ ID NO:8)

FGFR2BICC1 Forward: TGGATCGAATTCTCACTCTCACA (SEQ ID NO:9) Re verse: GCCAAGCAATCTGCGTATTTG (SEQ ID NO: 10)

FGFR2AFF3 Forward: TGGTAGAAGACTTGGATCGAATTCT (SEQ ID NO: 11)

Reverse: TCTCCCGGATTATTTCTTCAACA (SEQ ID NO: 12)

FGFR2CASP7 Forward: GCTCTTCAATACAGCCCTGATCA (SEQ ID NO: 13)

Reverse: ACTTGGATCGAATTCTCACTCTCA (SEQ ID NO: 14)

FGFR2CCDC6 Forward: TGGATCGAATTCTCACTCTCACA (SEQ ID NO: 15)

Reverse: GCAAAGCCTGAATTTTCTTGAATAA (SEQ ID NO: 16)

FGFR20FD1 Forward: AGGGTGCATCAACTCATGAATTAG (SEQ ID NO: 17)

Reverse: ACTTGGATCGAATTCTCACTCTCA (SEQ ID NO: 18)

[0068] The presence of one or more FGFR variants can be evaluated at any suitable time point including upon diagnosis, following tumor resection, following first-line therapy, during clinical treatment, or any combination thereof.

Evaluating PD-Ll expression in the cancer

[0069] The following methods for evaluating PD-Ll expression in a biological sample apply equally to any of the above disclosed methods of treatment.

[0070] In some embodiments, the disclosed methods can be dependent upon PD-Ll expression in the biological sample from the patient. T ms, administering to the patient a pharmaceutically effective amount of an antibody that blocks the interaction between PD-1 and PD-Ll and a pharmaceutically effective amount of an FGFR inhibitor may be based upon PD- Ll expression and the presence of one or more FGFR variants in the biological sample from the patient. The methods can comprise evaluating PD-Ll expression in a biological sample from the patient. The biological sample from which PD-Ll expression is evaluated can be the same biological sample from which the presence of one or more FGFR variants are evaluated, or the biological samples from which PD-Ll expression is evaluated can be a different biological sample from which the presence of one or more FGFR variants are evaluated. "Same biological sample" refers to a single sample from which both PD-Ll expression and FGFR variants are evaluated. "Different biological sample" includes the same source of sample (blood, lymph fluid, bone marrow, a solid tumor sample, etc.) taken at different time points or different sources of sample. For example, a blood sample can be obtained from the patient, e valuated for PD-L 1 expression or the presence of one or more FGFR variants, and at a later time point, another blood sample can be obtained from the patient and evaluated for the presence of one or more FGFR variants or PD-Ll expression. Conversely, a blood sample can be obtained from the patient and evaluated for PD-Ll expression and/or the presence of one or more FGFR variants and a solid tumor sample can be obtained from the patient and evaluated for the presence of one or more FGFR variants and/or PD-Ll expression.

100711 In some embodiments, the level of PD-Ll expression can be converted into a numerical H-score (as described in the methods section herein). The level of PD-Ll expression can be converted into a numerical H-score of: low PD-Ll expression, which includes an H- score of about 0 to about 99; moderate PD-Ll expression, which includes an H-score of about 100 to about 199; or high PD-Ll expression, which includes an H-score of about 200 to about 300. Treating the patient can be based upon these H-scores. For example, if the treatment methods are carried out on a patient with a low H-score, that patient would have PD-Ll expression corresponding to an H-score of about 0 to about 99. If the treatment methods are carried out on a patient with a moderate H-score, that patient would have PD-Ll expression corresponding to an H-score of about 100 to about 1 9. If the treatment methods are carried out on a patient with a high H-score, that patient would have PD-Ll expression corresponding to an H-score of about 200 to about 300.

[0072] In other embodiments, the level of PD-L l expression can be compared to a reference PD-Ll expression level. In a preferred embodiment, the reference PD-Ll expression level can be predetermined. For example, a reference data set may be established using samples from unrelated patients with low, moderate and high PD-Ll expression levels. This data set can represent a standard by which relative PD-Ll expression levels are compared among patients and/or quantified using the H-Score method. In some embodiments, the reference PD-Ll expression level can be determined by comparing a patient population that is administered the antibody that blocks the interaction between PD-1 and PD-Ll to a patient population that is administered placebo. The PD-Ll expression level for each patient in the respective populations can be determined in accordance with the methods described herein. Clinical outcomes (e.g., progression-free survival or overall survival) for the patient populations can be monitored. Clinical outcomes for the patient populations relative to PD-L l expression levels can then be compared. The reference PD-Ll expression level can correspond to the PD-Ll expression level above which the patient population that is administered the antibody that blocks the interaction between PD-1 and PD-Ll demonstrates a statistically significant improvement in at least one clinical outcome relative to the patient population that is administered placebo. A patient PD-Ll expression level that is less than the reference PD-Ll expression level, particularly when combined with the presence of one or more FGFR variants in a patient sample, can be indicative that the patient will benefit from treatment with the antibody that blocks the interaction between PD-1 and PD-Ll in combination with an FGFR inhibitor. For example, in some embodiments, the methods can comprise administering an antibody that blocks the interaction between PD-1 and PD-Ll and an FGFR inhibitor, wherein the antibody that blocks the interaction between PD-1 and PD-Ll and the FGFR inhibitor are administered if one or more FGFR variants are present in a biological sample from the patient and the PD-Ll expression in the biological sample is less than a reference PD-Ll expression level, wherein the reference PD-Ll expression level corresponds to a PD-Ll expression level above which treatment with the antibody that blocks the interaction between PD-1 and PD-Ll alone is likely to be efficacious.

[0073] Methods for determining PD-Ll expression include, but are not limited to, immunohistochemistry (IHC), Western Blotting, microscopy, immunoprecipitation, BCA assays, spectrophotometry, or any combination thereof. Exemplar}⁷ methods for evaluating PD- Ll expression are described in the methods section herein .

[0074] PD-Ll expression can be evaluated at any suitable time point including upon diagnosis, following tumor resection, following first-line therapy, during clinical treatment, or any combination thereof.

[0075] The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments.

EXAMPLES METHODS

PD-Ll Immunohistochemistry

[0076] PD-Li immunohistochemistry (IHC) was performed at a CRO (QualTek, Newtown, PA). Samples were stained using a CD274 PD-Ll (RUO) assay. Slides stained with a CD274 PD-Ll (RUO) assay were examined in random order and/or in blinded fashion by a board-certified clinical pathologist, the Medical Director of QualTek Clinical Laboratories (CAP/CLIA facility). The entire tissue section was evaluated for CD274 PD-Ll . Only viable tissue was evaluated; areas of necrosis or obviously poorly fixed areas of tissue were not evaluated.

[0077] The tumor H-Score was calculated from the intensity of CD274 PD-Ll membrane reactivity on a four-point semi-quantitative scale (0: null, negative or non-specific staining of cell membranes; 1+: low or weak intensity staining of cell membranes; 2+:

medium or moderate intensity staining of cell membranes; and 3+: high or strong intensity staining of cell membranes) and the estimated percentage of CD274 PD-Ll positive tumor cells (0 - 100%) for each discrete intensity value.

[0078] Tumor CD274 PD-L l membrane reactivity was captured by a standard H- Score - the tumor H-Score minimum of 0 and the tumor H-Score maximum of 300: Tumor Hi- Score = ([% positive cells at 1 +]* 1 ) + ([% positive cells at 2+]* 2) + ([% positive cells at 3+]*3)

Next-generation sequencing (NGS)

[0079] NGS for FGFR mutations and gene amplification was performed by

Foundation Medicine, Cambridge, MA using the FoundationOne panel

(h ft : //'www . foundationmedicine .com) .

FGFR. Fusions

100801 FGFR fusions were determined using a proprietary qRT-PCR assay developed by Janssen Oncology Translational Research as described in U.S. Provisional Application No.: 62/056,159, U.S. Patent Publication No. US2016-0090633, and WO 2016/048833.

RESULTS

PD-Ll Expressio in tumors with FGFR Fusions and Mutations

[0081] To determine the overlap of PD-Ll expression with FGFR alterations, immimohistochemistrv (IHC) for PD-L l was performed on human tumor tissue samples which were subsequently assessed for FGFR alterations. FGFR amplifications and mutations were identified using next-generation sequencing (Foundation Medicine panel, FMI). FGFR fusions were screened for using a Janssen-developed qRT-PCR assay.

Correlation of FGFR mutations and amplification with PD-Ll

[0082] PD-Ll expression was first assessed in a set of 120 commercially sourced lung

FFPE tumor tissues comprised of forty of each of the following lung tumor histologies; non- small-cell lung carcinoma (NSCLC) adenocarcinoma; NSCLC squamous cell carcinoma; and small-cell lung cancer (SCLC). FGFR mutations and gene amplification were detected using the Foundation Medicine panel, PD-Ll staining versus FGFR status was plotted for each tumor type (FIG 1 ). PD-Ll expression was largely reserved to tumors without FGFR mutations or amplifications. Out of nine samples with FGFR mutations, no PD-Ll staining was observed in seven samples (78%). Two of the nine samples showed very low PD-Ll staining with H-scores of 20 and 70, respectively. Of four samples with FGFR gene amplification, one sample showed moderate-high PD-Ll staining (H-score =^: 140), with three having almost no staining (H-score = 4, a i ). No staining was observed in the one tumor sample harboring both an FGFR mutation and FGFR gene ampl fication. FGFR mutation and amplification status was unknown for 24 tumor samples, of which nine exhibited PD-L l staining with H-scores ranging from 55 to 220.

FGFR fusions and PD-Ll expression in bladder and NSCLC

[0083] The set of 120 lung FFPE tumor tissues was subsequently screened for FGFR fusions using a Janssen-developed qRT-PCR assay (as described in U.S. Provisional

Application No.: 62/056, 159, U.S. Patent Publication No, US2016-0090633, and WO

2016/048833) detecting nine fusions (Table 1). Results for PD-Ll expression by FGFR fusion status for the NSCLC tumor samples (n=80) are shown in FIG. 2. Twenty-three percent (7/31) of NSCLC adenocarcinoma samples, and 52% (13/25) of NSCLC squamous cell carcinoma tumor samples were positive for FGFR fusions. All fusion-positive adenocarcinoma samples exhibited no or low PD-Ll expression, 6/7 (86%) or 1/7 (14%), respectively (Table 3). Fusion- negative adenocarcinoma samples showed a range of PD-Ll from no expression (12/31, 39%), low (12/31, 39%), moderate (4/31 , 13%), to high PD-Ll (3/31, 10%) (Table 3). Fusion- positive squamous cell carcinoma sample PD-Ll H-scores were equally distributed across the no expression, low, moderate, or high expression categories (4/31, 31 % each respectively) (Table 4). Fusion-negative squamous samples also showed a range of H-scores from no expression (6/25, 24%), low (11/25, 44%), moderate (5/25, 20%), and high expression (3/25, 12%) (Table 4), NSCLC Adenocarcinoma - PD-Ll H-Scores by FGFR fusion status

Table 4. NSCLC Squamous Cell Carcinoma - PD-Ll H-Scores by FGFR fusion status

100841 Forty-five commercially sourced bladder tumors were sequenced for mutations by the Foundation Medicine panel (FMI), stained for PD-Ll expression, and screened for FGFR gene fusions using the Janssen qRT-PCR assay. Forty-two of 45 samples (93%) were positive for FGFR fusions. Five samples (11%) were positive for an FGFR mutation (FGFR3- R248C or FGFR3-S249C), all of which were also positive for FGFR fusions. PD-Ll staining H-scores for samples with FGFR alterations are summarized in Table 5, and listed in Table 6. For FGFR fusion positive samples, 22/37 (59%) were negative for PD-Ll staining. Ten FGFR fusion-positive samples (27%) expressed low levels of PD-Ll, and five samples (14%) showed high PD-Ll expression. All samples with both FGFR mutations and FGFR fusions in the same tumor sample (n=5) were negative for PD-Ll staining. Overall, PD-Ll staining was absent in 64% (27/42) of bladder samples with FGFR alterations, keeping in mind that almost all of the tumors in this sample set were positive for FGFR fusions.

100851 FGFR mutation and PD-L l expression data were available for seven commercially sourced metastatic NSCLC samples with FGFR fusions (Janssen). No PD-Ll staining was observed in 4/7 (57%) of samples. Two samples exhibited very low PD-Ll staining, H-scores of 4 and 15. One sample showed moderate PD-Ll with an H-score of 160. Interestingly, the FGFR fusion-positive sample with moderate PD-Ll staining harbored an FGFR4 V550I mutation - an FGFR gatekeeper residue mutation with potential to confer resistance to tyrosine kinase inhibitors.

[0086] Overall these data show that the majority of commercially available tumor samples harboring FGFR alterations have very little expression or do not express PD-Ll ,

Table 5. PD-Ll staining in FGFR fusion positive bladder samples

Table 6. PD-Ll expression, FGFR fusion and mutation status in commercial bladder and NSCLC tumor samples

F27338.C4a Bladder FGFR3 : B AI A/FGFR2 : CA SP 7 None 6

F5242.G 10ba Bladder FGFR2:CASP7 None 3

2319 Bladder FGFR2:CASP7 None 0

2321 Bladder None None 0

2346 Bladder FGFR3:BAIA / FGFR2:CASP7 / None 0

FGFR2:0FD1

2347 Bladder FGFR3: BAIAP2L1 / FGFR3-S249C 0

FGFR2:CCDC6

2362 Bladder FGFR3 :TACC3vl/FGFR3:TACC3 FGFR3-S249C 0

V3/FGFR3 :B AIA/FGFR2 : BICC 1 /F

GFR2:AFF3/FGFR2:CASP7/FGFR

2 ( ( !.)( 6

2376 Bladder FGFR3:TACC3,vl / FGFR2: None 0

BICC ! / FGFR2:CASP7

2381 Bladder FGFR3:BAIA/FGFR2:AFF3/ FGFR3-R248C 0

FGFR2:CASP7 FGFR3-S249C

2430 Bladder FGFR3 : B AI A/FGFR2 : CA SP 7 None 0

2434 Bladder FGFR3:BAIA None 0

2458 Bladder FGFR3 :B AIA/FGFR2 : AFF3/ FGFR3-R248C 0

FGFR2-CASP7

2455 Bladder None None 0

2473 Bladder FGFR2:AFF3 / FGFR2:0FD1 None 0

2480 Bladder FGFR2 FD 1 None 0

2518 Bladder FGFR3 :B AIA/FGFR2 : AFF3 None 0

/FGFR2 : C ASP7/FGFGFR2 : OFD I

2533 Bladder FGFR2:0FD 1 None 0

2541 Bladder FGFR2:CASP7 / FGFR2:0FD1 None 0

2561 Bladder FGFR3 :BAIA/FGFR2:BICC 1 / None 0

FGFR2 : AFF3/FGFR2 : CASP7

2563 Bladder FGFR2 FD 1 None 0

4916 Bladder FGFR2 FD 1 None 0

F27064.CFS Bladder FGFR3 : B AIA/FG FR2 : AFF/ None 0

FGFR2:CASP7

F28132.Ba Bladder FGFR3 :TACC3 v 1/FGFR3 :BAIAP2 None 0

L/FGFR2 : BICC 1 /FGFR2 : CCDC6

F7269.C2 Bladder FGFR3 :BAI AP2L/FGFR2 : CA SP7 None 0

F7271.AFSb Bladder FGFR2:AFF3/FGFR2:CASP7 None 0

F7467.Dlbb Bladder FGFR2 : AFF3/FGFR2 : CASP7/ None 0

FGFR2:CCDC6

F7484.BFSc Bladder FGFR2:AFF3 None 0

F7502.Dlb Bladder FGFR2:AFF3/FGFR2:CASP7 FGFR3-S249C 0

F7789.DFSb Bladder FGFR3 : B AIAP2 L/FGFR2 : CASP7 FGFR2-M537I 0

F7876.Dlbb Bladder FGFR3 : B AIAP2L FGFR2 : OFD 1 None 0

I-7290.E13a Bladder FGFR2:CASP7 None 0

CNT06GK 1NSCLC FGFR3 : TACC 3 intron FGFR4-V550I 160 CNTORHX NSCLC FGFR3 : B AIAP2L None 15

CNTORFD NSCLC FGFR2:BICC 1 None 4

CNT06FI NSCLC FGFR2:AFF3 None 0

CNT06FJ NSCLC FGFR2-CCDC6 None 0

CNT06G5 NSCLC FGFR3 :TACC3vl FGFR3:TACC3i None 0

ntron/FGFR2 : AFF3

CNTORFX NSCLC FGFR3:BAIAP2L/FGFR2:CASP7 None 0

FGFR in vitro experiments

[0087] To determine the effects of JNJ427564493 on immune ceil viability in vitro, peripheral blood mononuclear cells (PBMCs) from normal donors were stimulated with anti- CD3 antibodies to activate T cells, in the presence of increasing concentrations of

JNJ42756493. Unstimulated PBMCs were also included to determine if JNJ42756493 affected unactivated immune populations. Ceil viability was assessed at four different time points, over 6 days, FIG. 3 shows the luminescence signal, as a measurement of cell viability, in the presence of increasing concentrations of JNJ42756493 (up to I μΜ) at days I, 2, 5 and 6 post- treatment. For both the stimulated and unstimulated groups, at ail time points tested, cell viability remained constant with increasing concentrations of compound. These data suggest that the addition of JNJ42756493 does not impair immune cell viability.

[0088] JNJ42756493 was next tested to analyze the impact on the activity of anti-PD- 1 antibodies in two in vitro functional assays: Mixed Lymphocyte Reaction (MLR); and Cytomegalovirus antigen assay (CMV). For the MLR assay, CD4 ^" T cells are stimulated with allogeneic dendritic cells, leading to T ceil activation and IFN-γ secretion. In this assay, anti- PD-1 antibodies caused dose-dependent increases in IFN-γ levels (FIG. 4, PD-1 alone). When T cells and DCs were treated with 0.01, 1 or 100 nM of JNJ42756493, IFN-γ levels were similar to those observed in the untreated samples (FIG. 4, JNJ-493 alone vs controls), suggesting that FGFR inhibition does not affect T cell activation . Furthermore, combinations of JNJ42756493 with anti-PD-1 antibodies caused similar IFN-γ secretion as observed with anti-PD-1 treatment alone (FIG. 4, JNJ-493+ anti-PD-1 compared to PD-1 alone). These results suggest that JNJ42756493 does not impair the functional activity of anti-PD-1 antibodies in the MLR assay.

[0089] In the CMV assay, PBMCs from CMV-reactive donors were stimulated by the addition of CMV antigen. CMV-reactive T cells are active, expand and secrete proinflammatory cytokines such as IFN-γ. In the presence of anti-PD-1 antibodies, significantly higher levels of IFN-γ were secreted upon CMV stimulation (FIG. 5, PD-1 alone). In contrast, JNJ42756493 alone had no impact on cytokine levels (FIG. 5, JNJ-493 alone). Similarly, JNJ42756493 combinations with anti-PD-1 antibodies led to similar increases of !FN-γ as seen with anti-PD-1 alone (FIG. 5, JNJ42756493 + anti-PD-1 compared to PD-1 alone). These data show that JNJ42756493 does not affect the activity of anti-PD-1 antibodies in the CMV assay.

[0090] Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention.

100911 The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, in its entirety.

Nucleotide Sequence of FGFR fusion genes

100921 The nucleotide sequences for the FGFR fusion cDNA are provided in Table 7. The underlined sequences correspond to either FGFR3 or FGFR2, the sequences in black represent the fusion partners and the sequence in italic fonts represent the intron sequence of the FGFR3 gene.

Table 7

FGFR3;TACC3 v l >ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCC (2850 base pairs) GGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCA (SEQ ID NO: i9) GAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGG

GATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTG

TCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGC

CCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCT

GCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAG

ACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACA

GGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAG

CTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCA

ACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGC

ACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAA

GCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTG

GCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGC

CCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACG

TGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCA

AGCACGTGGAGGTGAATGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTA

CCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCT

CCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCA

ATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGA

GGAGCTGGTGGAGGCTGACGAGGCGGGCAGTGTGTATGCAGGCATCCTCAGCTA

CGGGGTGGGCTTCTTCCTGTTCATCCTGGTGGTGGCGGCTGTGACGCTCTGCCGC

CTGCGCAGCCCCCCCAAGAAAGGCCTGGGCTCCCCCACCGTGCACAAGATCTCCC

GCTTCCCGCTCAAGCGACAGGTGTCCCTGGAGTCCAACGCGTCCATGAGCTCCAA

CACACCACTGGTGCGCATCGCAAGGCTGTCCTCAGGGGAGGGCCCCACGCTGGC

CAATGTCTCCGAGCTCGAGCTGCCTGCCGACCCCAAATGGGAGCTGTCTCGGGCC

CGGCTGACCCTGGGCAAGCCCCTTGGGGAGGGCTGCTTCGGCCAGGTGGTCATG

GCGGAGGCCATCGGCATTGACAAGGACCGGGCC(K AAGCCTGTCACCGTAGCC

GTGAAGATGCTGAAAGACGATGCCACTGACAAGGACCTGTCGGACCTGGTGTCT

GAGATGGAGATGATGAAGATGATCGGGAAACACAAAAACATCATCAACCTGCTG

GGCGCCTGCACGCAGGGCGGGCCCCTGTACGTGCTGGTGGAGTACGCGGCCAAG

GGTAACCTGCGGGAGTTTCTGCGGGCGCGGCGGCCCCCGGGCCTGGACTACTCCT

TCGACACCTGCAAGCCGCCCGAGGAGCAGCTCACCTTCAAGGACCTGGTGTCCTG

TGCCTACCAGGTGGCCCGGGGCATGGAGTACTTGGCCTCCCAGAAGTGCATCCAC

AGGGACCTGGCTGCCCGCAATGTGCTGGTGACCGAGGACAACGTGATGAAGATC

GCAGACTTCGGGCTGGCCCGGGACGTGCACAACCTCGACTACTACAAGAAGACG

ACCAACGGCCGGCTGCCCGTGAAGTGGATGGCGCCTGAGGCCTTGTTTGACCGA

GTCTACACTCACCAGAGTGACGTCTGGTCCTTTGGGGTCCTGCTCTGGGAGATCT

TCACGCTGGGGGGCTCCCCGTACCCCGGCATCCCTGTGGAGGAGCTCTTCAAGCT

GCTGAAGGAGGGCCACCGCATGGACAAGCCCGCCAACTGCACACACGACCTGTA

CATGATCATGCGGGAGTGCTGGCATGCCGCGCCCTCCCAGAGGCCCACCTTCAAG

CAGCTGGTGGAGGACCTGGACCGTGTCCTTACCGTGACGTCCACCGACGTAAAG

GCGACACAGGAGGAGAACCGGGAGCTGAGGAGCAGGTGTGAGGAGCTCCACGG GAAGAACCTGGAACTGGGGAAGATCATGGACAGGTTCGAAGAGGTTGTGTACCA GGCCATGGAGGAAGTTCAGAAGCAGAAGGAACTTTCCAAAGCTGAAATCCAGAA AGTTCTAAAAGAAAAAGACCAACTTACCACAGATCTGAACTCCATGGAGAAGTC CTTCTCCGACCTCTTCAAGCGTTTTGAGAAACAGAAAGAGGTGATCGAGGGCTAC

CGCAAGAACGAAGAGTCACTGAAGAAGTGCGTGGAGGATTACCTGGCAAGGATC

ACCCAGGAGGGCCAGAGGTACCAAGCCCTGAAGGCCCACGCGGAGGAGAAGCT

GCAGCTGGCAAACGAGGAGATCGCCCAGGTCCGGAGCAAGGCCCAGGCGGAAG

CGTTGGCCCTCCAGGCCAGCCTGAGGAAGGAGCAGATGCGCATCCAGTCGCTGG

AGAAGACAGTGGAGCAGAAGACTAAAGAGAACGAGGAGCTGACCAGGATCTGC

GACGACCTCATCTCCAAGATGGAGAAGATCTGA

FGFR3:TACC3 v3 >ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCC (2955 base pairs) GGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCA (SEQ ID \Ό.20 ί GAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGG

GATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTG

TCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGC

CCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCT

GCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAG

ACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACA

GGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAG

CTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCA

ACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGC

ACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAA

GCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTG

GCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGC

CCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACC^^

TGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCA

AGCACGTGGAGGTGAATGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTA

CCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCT

CCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCA

ATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGA

GGAGCTGGTGGAGGCTGACGAGGCGGGCAGTGTGTATGCAGGCATCCTCAGCTA

CGGGGTGGGCTTCTTCCTGTTCATCCTGGTGGTGGCGGCTGTGACGCTCTGCCGC

CTGCGCAGCCCCCCCAAGAAAGGCCTGGGCTCCCCCACCGTGCACAAGATCTCCC

GCTTCCCGCTCAAGCGACAGGTGTCCCTGGAGTCCAACGCGTCCATGAGCTCCAA

CACACCACTGGTGCGCATCGCAAGGCTGTCCTCAGGGGAGGGCCCCACGCTGGC

CAATGTCTCCGAGCTCGAGCTGCCTGCCGACCCCAAATGGGAGCTGTCTCGGGCC

CGGCTGACCCTGGGCAAGCCCCTTGGGGAGGGCTGCTTCGGCCAGGTGGTCATG

GCGGAGGCCATCGGCATTGACAAGGACCGGGCCGCCAAGCCTGTCACCGTAGCC

GTGAAGATGCTGAAAGACGATGCCACTGACAAGGACCTGTCGGACCTGGTGTCT

GAGATGGAGATGATGAAGATGATCGGGAAACACAAAAACATCATCAACCTGCTG

GGCGCCTGCACGCAGGGCGGGCCCCTGTACGTGCTGGTGGAGTACGCGGCCAAG

GGTAACCTGCGGGAGTTTCTGCGGGCGCGGCGGCCCCCGGGCCTGGACTACTCCT

TCGACACCTGCAAGCCGCCCGAGGAGCAGCTCACCTTCAAGGACCTGGTGTCCTG

TGCCTACCAGGTGGCCCGGGGCATGGAGTACTTGGCCTCCCAGAAGTGCATCCAC

AGGGACCTGGCTGCCCGCAATGTGCTGGTGACCGAGGACAACGTGATGAAGATC

GCAGACTTCGGGCTGGCCCGGGACGTGCACAACCTCGACTACTACAAGAAGACG

ACCAACGGCCGGCTGCCCGTGAAGTGGATGGCGCCTGAGGCCTTGTTTGACCGA

GTCTACACTCACCAGAGTGACGTCTGGTCCTTTGGGGTCCTGCTCTGGGAGATCT

TCACGCTGGGGGGCTCCCCGTACCCCGGCATCCCTGTGGAGGAGCTCTTCAAGCT

GCTGAAGGAGGGCCACCGCATGGACAAGCCCGCCAACTGCACACACGACCTGTA

CATGATCATGCGGGAGTGCTGGCATGCCGCGCCCTCCCAGAGGCCCACCTTCAAG

CAGCTGGTGGAGGACCTGGACCGTGTCCTTACCGTGACGTCCACCGACGTGCCAG

GCCCACCCCCAGGTGTTCCCGCGCCTGGGGGCCCACCCCTGTCCACCGGACCTAT AGTGGACCTGCTCCAGTACAGCCAGAAGGACCTGGATGCAGTGGTAAAGGCGAC ACAGGAGGAGAACCGGGAGCTGAGGAGCAGGTGTGAGGAGCTCCACGGGAAGA

ACCTGGAACTGGGGAAGATCATGGACAGGTTCGAAGAGGTTGTGTACCAGGCCA

TGGAGGAAGTTCAGAAGCAGAAGGAACTTTCCAAAGCTGAAATCCAGAAAGTTC

TAAAAGAAAAAGACCAACTTACCACAGATCTGAACTCCATGGAGAAGTCCTTCT

CCGACCTCTTCAAGCG^'i'i'i'i GAGAAACAGAAAGAGGTGATCGAGGGCTACCGCA

AGAACGAAGAGTCACTGAAGAAGTGCGTGGAGGATTACCTGGCAAGGATCACCC

AGGAGGGCCAGAGGTACCAAGCCCTGAAGGCCCACGCGGAGGAGAAGCTGCAG

CTGGCAAACGAGGAGATCGCCCAGGTCCGGAGCAAGGCCCAGGCGGAAGCGTTG GCCCTCCAGGCCAGCCTGAGGAAGGAGCAGATGCGCATCCAGTCGCTGGAGAAG

ACAGTGGAGCAGAAGACTAAAGAGAACGAGGAGCTGACCAGGATCTGCGACGA

CCTCATCTCCAAGATGGAGAAGATCTGA

FGFR3 >ATGGGCGC^'CCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCC Intron:TACC3 GGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCA (4462 base pairs) GAAGTCCCGGGCCCAGAGCC^'CGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGG (SEQ ID NO:21) GATGCTGTGGAGCTGAGCTGTCC^'CCCGCCCGGGGGTGGTCCCATGGGGCCCACTG

TCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGC

CCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCT

GCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAG

ACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACA

GGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAG

CTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCA

ACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGC

ACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAA

GCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTG

GCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGC

CCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACG

TGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCA

AGCACGTGGAGGTGAATGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTA

CCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCT

CCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCA

ATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGA

GGAGCTGGTGGAGGCTGACGAGGCGGGCAGTGTGTATGCAGGCATCCTCAGCTA

CGGGGTGGGCTTCTTCCTGTTCATCCTGGTGGTGGCGGCTGTGACGCTCTGCCGC

CTGCGCAGCCCCCCCAAGAAAGGCCTGGGCTCCCCCACCGTGCACAAGATCTCCC

GCTTCCCGCTCAAGCGACAGGTGTCCCTGGAGTCCAACGCGTCCATGAGCTCCAA

CACACCACTGGTGCGCATCGCAAGGCTGTC^'CTCAGGGGAGGGCCCCACGCTGGC

CAATGTCTCCGAGCTCGAGCTGCCTGCCGACCCCAAATGGGAGCTGTCTCGGGCC

CGGCTGACCCTGGGCAAGCCCCTTGGGGAGGGCTGCTTCGGCCAGGTGGTCATG

GCGGAGGCCATCGGCATTGACAAGGACCGGGCCGCCAAGCCTGTCACCGTAGCC

GTGAAGATGCTGAAAGACGATGCCACTGACAAGGACCTGTCGGACCTGGTGTCT

GAGATGGAGATGATGAAGATGATCGGGAAACACAAAAACATCATCAACCTGCTG

GGCGCCTGCACGCAGGGCGGGCCCCTGTACGTGCTGGTGGAGTACGCGGCCAAG

GGTAACCTGCGGGAGTTTCTGCGGGCGCGGCGGCCCCCGGGCCTGGACTACTCCT

TCGACACCTGCAAGCCGCCCGAGGAGCAGCTCACCTTCAAGGACCTGGTGTCCTG

TGCCTACCAGGTGGCCCGGGGCATGGAGTACTTGGCCTCCCAGAAGTGCATCCAC

AGGGACCTGGCTGCCCGCAATGTGCTGGTGACCGAGGACAACGTGATGAAGATC

GCAGACTTCGGGCTGGCCCGGGACGTGCACAACCTCGACTACTACAAGAAGACG

ACCAACGGCCGGCTGCCCGTGAAGTGGATGGCGCCTGAGGCCTTGTTTGACCGA

GTCTACACTCACCAGAGTGACGTCTGGTCCTTTGGGGTCCTGCTCTGGGAGATCT

TCACGCTGGGGGGCTCCCCGTACCCCGGCATCCCTGTGGAGGAGCTCTTCAAGCT

GCTGAAGGAGGGCCACCGCATGGACAAGCCCGCCAACTGCACACACGACCTGTA

CATGATCATGCGGGAGTGCTGGCATGCCGCGCCCTCCCAGAGGCCCACCTTCAAG

CAGCTGGTGGAGGACCTGGACCGTGTCCTTACCGTGACGTCCACCGACgfeagftfcteg ctctggcciggigccacccgcctaigcccctccc^

ci/TCTGGCCCAGGTGCCCTGGCTGACCTGGACTGCTCAAGCTCTTCCCAGAGCCCA GGAAGTTCTGAGAACCAAATGGTGTCTCCAGGAAAAGTGTCTGGCAGCCCTGAG

CAAGCCGTGGAGGAAAACCTTAGTTCCTATTCCTTAGACAGAAGAGTGACACCC

GCCTCTGAGACCCTAGAAGACCCTTGCAGGACAGAGTCCCAGCACAAAGCGGAG

ACTCCGCACGGAGCCGAGGAAGAATGCAAAGCGGAGACTCCGCACGGAGCCGA

GGAGGAATGCCGGCACGGTGGGGTCTGTGCTCCCGCAGCAGTGGCCACTTCGCC

TCCTGGTGCAATCCCTAAGGAAGCCTGCGGAGGAGCACCCCTGCAGGGTCTGCCT

GGCGAAGCCCTGGGCTGCCCTGCGGGTGTGGGCACCCCCGTGCCAGCAGATGGC

ACTCAGACCCTTACCTGTGCACACACCTCTGCTCCTGAGAGCACAGCCCCAACCA

ACCACCTGGTGGCTGGCAGGGCCATGACCCTGAGTCCTCAGGAAGAAGTGGCTG

CAGGCCAAATGGCCAGCTCCTCGAGGAGCGGACCTGTAAAACTAGAATTTGATG

TATCTGATGGCGCCACCAGCAAAAGGGCACCCCCACCAAGGAGACTGGGAGAGA

GGTCCGGCCTCAAGCCTCCCTTGAGGAAAGCAGCAGTGAGGCAGCAAAAGGCCC CGCAGGAGGTGGAGGAGGACGACGGTAGGAGCGGAGCAGGAGAGGACCCCCCC

ATGCCAGCTTCTCGGGGCTCTTACCACCTCGACTGGGACAAAATGGATGACCCAA

ACTTCATCCCGTTCGGAGGTGACACCAAGTCTGGTTGCAGTGAGGCCCAGCCCCC

AGAAAGCCCTGAGACCAGGCTGGGCCAGCCAGCGGCTGAACAGTTGCATGCTGG

GCCTGCCACGGAGGAGCCAGGTCCCTGTCTGAGCCAGCAGCTGCATTCAGCCTCA

GCGGAGGACACGCCTGTGGTGCAGTTGGCAGCCGAGACCCCAACAGCAGAGAGC

AAGGAGAGAGCCTTGAACTCTGCCAGCACCTCGCTTCCCACAAGCTGTCCAGGC

AGTGAGCCAGTGCCCACCCATCAGCAGGGGCAGCCTGCCTTGGAGCTGAAAGAG

GAGAGCTTCAGAGACCCCGCTGAGGTTCTAGGCACGGGCGCGGAGGTGGATTAC

CTGGAGCAGTT GGAACTTCCTCGTTTAAGGAGTCGGCCTTGAGGAAGCAGTCCT

TATACCTCAAGTTCGACCCCCTCCTGAGGGACAGTCCTGGTAGACCAGTGCCCGT

GGCCACCGAGACCAGCAGCATGCACGGTGCAAATGAGACTCCCTCAGGACGTCC

GCGGGAAGCCAAGCTTGTGGAGTTCGATTTCTTGGGAGCACTGGACATTCCTGTG

CCAGGCCCACCCCCAGGTGTTCCCGCGCCTGGGGGCCCACCCCTGTCCACCGGAC

CTATAGTGGACCTGCTCCAGTACAGCCAGAAGGACCTGGATGCAGTGGTAAAGG

CGACACAGGAGGAGAACCGGGAGCTGAGGAGCAGGTGTGAGGAGCTCCACGGG

AAGAACCTGGAACTGGGGAAGATCATGGACAGGTTCGAAGAGGTTGTGTACCAG

GCCATGGAGGAAGTTCAGAAGCAGAAGGAACTTTCCAAAGCTGAAATCCAGAAA

GTTCTAAAAGAAAAAGACCAACTTACCACAGATCTGAACTCCATGGAGAAGTCC

TTCTCCGACCTCTTCAAGCGTTTTGAGAAACAGAAAGAGGTGATCGAGGGCTACC

GCAAGAACGAAGAGTCACTGAAGAAGTGCGTGGAGGATTACCTGGCAAGGATCA

CCCAGGAGGGCCAGAGGTACCAAGCCCTGAAGGCCCACGCGGAGGAGAAGCTG

CAGCTGGCAAACGAGGAGATCGCCCAGGTCCGGAGCAAGGCCCAGGCGGAAGC

GTTGGCCCTCCAGGCCAGCCTGAGGAAGGAGCAGATGCGCATCCAGTCGCTGGA

GAAGACAGTGGAGCAGAAGACTAAAGAGAACGAGGAGCTGACCAGGATCTGCG

ACGACCTCATCTCCAAGATGGAGAAGATCTGA

FGFR3 :BAIAP2L 1 >ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCC

(3765 base pairs) GGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCA (SEQ ID NO:22) GAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGG

GATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTG

TCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGC

CCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCT

GCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAG

ACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACA

GGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAG

CTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCA

ACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGC

ACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAA

GCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTG

GCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGC

CCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACG

TGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCA

AGCACGTGGAGGTGAATGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTA

CCGTGCTCAAGTCCTGGATCAGTGAGAGTGTGGAGGCCGACGTGCGCCTCCGCCT

GGCCAATGTGTCGGAGCGGGACGGGGGCGAGTACCTCTGTCGAGCCACCAATTT

CATAGGCGTGGCCGAGAAGGCCTTTTGGCTGAGCGTTCACGGGCCCCGAGCAGC

CGAGGAGGAGCTGGTGGAGGCTGACGAGGCGGGCAGTGTGTATGCAGGCATCCT

CAGCTACGGGGTGGGCTTCTTCCTGTTCATCCTGGTGGTGGCGGCTGTGACGCTC

TGCCGCCTGCGCAGCCCCCCCAAGAAAGGCCTGGGCTCCCCCACCGTGCACAAG

ATCTCCCGCTTCCCGCTCAAGCGACAGGTGTCCCTGGAGTCCAACGCGTCCATGA

GCTCCAACACACCACTGGTGCGCATCGCAAGGCTGTCCTCAGGGGAGGGCCCCA

CGCTGGCCAATGTCTCCGAGCTCGAGCTGCCTGCCGACCCCAAATGGGAGCTGTC

TCGGGCCCGGCTGACCCTGGGCAAGCCCCTTGGGGAGGGCTGCTTCGGCCAGGT

GGTCATGGCGGAGGCCATCGGCATTGACAAGGACCGGGCCGCCAAGCCTGTCAC

CGTAGCCGTGAAGATGCTGAAAGACGATGCCACTGACAAGGACCTGTCGGACCT

GGTGTCTGAGATGGAGATGATGAAGATGATCGGGAAACACAAAAACATCATCAA

CCTGCTGGGCGCCTGCACGCAGGGCGGGCCCCTGTACGTGCTGGTGGAGTACGC

GGCCAAGGGTAACCTGCGGGAGTTTCTGCGGGCGCGGCGGCCCCCGGGCCTGGA

CTACTCCTTCGACACCTGCAAGCCGCCCGAGGAGCAGCTCACCTTCAAGGACCTG GTGTCCTGTGCCTACCAGGTGGCCCGGGGCATGGAGTACTTGGCCTCCCAGAAGT

GCATCCACAGGGACCTGGCTGCCCGCAATGTGCTGGTGACCGAGGACAACGTGA

TGAAGATCGCAGACTTCGGGCTGGCCCGGGACGTGCACAACCTCGACTACTACA

AGAAGACGACCAACGGCCGGCTGCCCGTGAAGTGGATGGCGCCTGAGGCCTTGT

TTGACCGAGTCTACACTCACCAGAGTGACGTCTGGTCCTTTGGGGTCCTGCTCTG

GGAGATCTTCACGCTGGGGGGCTCCCCGTACCCCGGCATCCCTGTGGAGGAGCTC

TTCAAGCTGCTGAAGGAGGGCCACCGCATGGACAAGCCCGCCAACTGCACACAC

GACCTGTACATGATCATGCGGGAGTGCTGGCATGCCGCGCCCTCCCAGAGGCCC

ACCTTCAAGCAGCTGGTGGAGGACCTGGACCGTGTCCTTACCGTGACGTCCACCG

ACAATGTTATGGAACAGTTCAATCCTGGGCTGCGAAATTTAATAAACCTGGGGA

AAAATTATGAGAAAGCTGTAAACGCTATGATCCTGGCAGGAAAAGCCTACTACG

ATGGAGTGGCCAAGATCGGTGAGATTGCCACTGGGTCCCCCGTGTCAACTGAACT

GGGACATGTCCTCATAGAGATTTCAAGTACCCACAAGAAACTCAACGAGAGTCT

TGATGAAAATTTTAAAAAATTCCACAAAGAGATTATCCATGAGCTGGAGAAGAA

GATAGAACTTGACGTGAAATATATGAACGCAACTCTAAAAAGATACCAAACAGA

ACACAAGAATAAATTAGAGTCTTTGGAGAAATCCCAAGCTGAGTTGAAGAAGAT

CAGAAGGAAAAGCCAAGGAAGCCGAAACGCACTCAAATATGAACACAAAGAAA

TTGAGTATGTGGAGACCGTTACTTCTCGTCAGAGTGAAATCCAGAAATTCATTGC

AGATGGTTGCAAAGAGGCTCTGCTTGAAGAGAAGAGGCGCTTCTGCTTTCTGGTT

GATAAGCACTGTGGCTTTGCAAACCACATACATTATTATCACTTACAGTCTGCAG

AACTACTGAATTCCAAGCTGCCTCGGTGGCAGGAGACCTGTGTTGATGCCATCAA

AGTGCCAGAGAAAATCATGAATATGATCGAAGAAATAAAGACCCCAGCCTCTAC

CCCCGTGTCTGGAACTCCTCAGGCTTCACCCATGATCGAGAGAAGCAATGTGGTT

AGGAAAGATTACGACACCCTTTCTAAATGCTCACCAAAGATGCCCCCCGCTCCTT

CAGGCAGAGCATATACCAGTCCCTTGATCGATATGTTTAATAACCCAGCCACGGC

TGCCCCGAATTCACAAAGGGTAAATAATTCAACAGGTACTTCCGAAGATCCCAGT

TTACAGCGATCAGTTTCGGTTGCAACGGGACTGAACATGATGAAGAAGCAGAAA

GTGAAGACCATCTTCCCGCACACTGCGGGCTCCAACAAGACCTTACTCAGCTTTG

CACAGGGAGATGTCATCACGCTGCTCATCCCCGAGGAGAAGGATGGCTGGCTCT

ATGGAGAACACGACGTGTCCAAGGCGAGGGGTTGGTTCCCGTCGTCGTACACGA

AGTTGCTGGAAGAAAATGAGACAGAAGCAGTGACCGTGCCCACGCCAAGCCCCA

CACCAGTGAGAAGCATCAGCACCGTGAACTTGTCTGAGAATAGCAGTGTTGTCAT

CCCCCCACCCGACTACTTGGAATGCTTGTCCATGGGGGCAGCTGCCGACAGGAG

AGCAGATTCGGCCAGGACGACATCCACCTTTAAGGCCCCAGCGTCCAAGCCCGA

GACCGCGGCTCCTAACGATGCCAACGGGACTGCAAAGCCGCCTTTTCTCAGCGG

AGAAAACCCCTTTGCCACTGTGAAACTCCGCCCGACTGTGACGAATGATCGCTCG

GCACCCATCATTCGATGA

FGFR2:BICCi >ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGT (4989 base pairs) CCCTGGCCCGGCCCTCCTTCAGT TAGTTGAGGATACCACATTAGAGCCAGAAGA (SEQ ID NO:23) GCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGG

GGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACT

AAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTAC

TTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCA

GTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCAT

CTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGA

GAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAA

AGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGG

GGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCA

GGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTAT

GGA AAGTGTGGTCC C ATCTGA C A AGGG A A ATT ATAC CTGTGTAGTGGAGA ATG A

ATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCAC

CGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGA

GACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGA

TCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACC

TCAAGGTTCTCAAGGCCGCCGGTGTTAACACCACGGACAAAGAGATTGAGGTTC

TCTATATTCGGAATGTAACTTTTGAGGACGCTGGGGAATATACGTGCTTGGCGGG

TAATTCTATTGGGATATCCTTTCACTCTGCATGGTTGACAGTTCTGCCAGCGCCTG

GAAGAGAAAAGGAGATTACAGCTTCCCCAGACTACCTGGAGATAGCCATTTACT

GCATAGGGGTCTTCTTAATCGCCTGTATGGTGGTAACAGTCATCCTGTGCCGAAT GAAGAACACGACCAAGAAGCCAGACTTCAGCAGCCAGCCGGCTGTGCACAAGCT

GACCAAACGTATCCCCCTGCGGAGACAGGTAACAGTTTCGGCTGAGTCCAGCTCC

TCCATGAACTCCAACACCCCGCTGGTGAGGATAACAACACGCCTCTCTTCAACGG

CAGACACCCCCATGCTGGCAGGGGTCTCCGAGTATGAACTTCCAGAGGACCCAA

AATGGGAGTTTCCAAGAGATAAGCTGACACTGGGCAAGCCCCTGGGAGAAGGTT

GCTTTGGGCAAGTGGTCATGGCGGAAGCAGTGGGAATTGACAAAGACAAGCCCA

AGGAGGCGGTCACCGTGGCCGTGAAGATGTTGAAAGATGATGCCACAGAGAAAG

ACCTTTCTGATCTGGTGTC A G AG ATGG A G ATG ATGAA G ATG ATTGGGA A A C AC A

AGAATATCATAAATCTTCTTGGAGCCTGCACACAGGATGGGCCTCTCTATGTCAT

AGTTGAGTATGCCTCTAAAGGCAACCTCCGAGAATACCTCCGAGCCCGGAGGCC

ACCCGGGATGGAGTACTCCTATGACATTAACCGTGTTCCTGAGGAGCAGATGACC

TTCAAGGACTTGGTGTCATGCACCTACCAGCTGGCCAGAGGCATGGAGTACTTGG

CTTCCCAAAAATGTATTCATCGAGATTTAGCAGCCAGAAATGTTTTGGTAACAGA

AAACAATGTGATGAAAATAGCAGACTTTGGACTCGCCAGAGATATCAACAATAT

AGACTATTACAAAAAGACCACCAATGGGCGGCTTCCAGTCAAGTGGATGGCTCC

AGAAGCCCTGTTTGATAGAGTATACACTCATCAGAGTGATGTCTGGTCCTTCGGG

GTGTTAATGTGGGAGATCTTCACTTTAGGGGGCTCGCCCTACCCAGGGATTCCCG

TGGAGGAACTTTTTAAGCTGCTGAAGGAAGGACACAGAATGGATAAGCCAGCCA

ACTGCACCAACGAACTGTACATGATGATGAGGGACTGTTGGCATGCAGTGCCCTC

CCAGAGACCAACGTTCAAGCAGTTGGTAGAAGACTTGGATCGAATTCTCACTCTC

ACAACCAATGAGATCATGGAGGAAACAAATACGCAGATTGCTTGGCCATCAAAA

CTGAAGATCGGAGCCAAATCCAAGAAAGATCCCCATATTAAGGTTTCTGGAAAG

AAAGAAGATGTTAAAGAAGCCAAGGAAATGATCATGTCTGTCTTAGACACAAAA

AGCAATCGAGTCACACTGAAGATGGATGTTTCACATACAGAACATTCACATGTA

ATCGGCAAAGGTGGCAACAATATTAAAAAAGTGATGGAAGAAACCGGATGCCAT

ATCCACTTTCCAGATTCCAACAGGAATAACCAAGCAGAAAAAAGCAACCAGGTA

TCTATAGCGGGACAACCAGCAGGAGTAGAATCTGCCCGAGTTAGAATTCGGGAG

CTGCT CCT TGGTGCTGATGTTTGAGCTACCAATTGCTGGAATTCTTCAACCGGT

TCCTGATCCTAATTCCCCCTCTATTCAGCATATATCACAAACGTACAATATTTCAG

TATCAT TAAACAGCGTTCCCGAATGTATGGTGCTACTGTCATAGTACGAGGGTC

TCAGAATAACACTAGTGCTGTGAAGGAAGGAACTGCCATGCTGTTAGAACATCTT

GCTGGGAGCTTAGCATCAGCTATTCCTGTGAGCACACAACTAGATATTGCAGCTC

AACATCATCTCTTTATGATGGGTCGAAATGGGAGCAACATCAAACATATCATGCA

GAGAACAGGTGCTCAGATCCACTTTCCTGATCCCAGTAATCCACAAAAGAAATCT

ACCGTCTACCTCCAGGGCACCATTGAGTCTGTCTGTCTTGCAAGGCAATATCTCA

TGGGTTGTCTTCCTCTTGTGTTGATGTTTGATATGAAGGAAGAAATTGAAGTAGA

TCCACAATTCATTGCGCAGTTGATGGAACAGCTTGATGTCTTCATCAGTATTAAA

CCAAAGCCCAAACAGCCAAGCAAGTCTGTGATTGTGAAAAGTGTTGAGCGAAAT

GCCTTAAATATGTATGAAGCAAGGAAATGTCTCCTCGGACTTGAAAGCAGTGGG

GTTACCATAGCAACCAGTCCATCCCCAGCATCCTGCCCTGCCGGCCTGGCATGTC

CCAGCCTGGATATCTTAGCTTCAGCAGGCCTTGGACTCACTGGACTAGGTCTTTT

GGGACCCACCACCTTATCTCTGAACACTTCAACAACCCCAAACTCACTCTTGAAT

GCTCTTAATAGCTCAGTCAGTCCTTTGCAAAGTCCAAGTTCTGGTACACCCAGCC

CCACATTATGGGCACCCCCACTTGCTAATACTTCAAGTGCCACAGGTTTTTCTGCT

ATACCACACCTTATGATTCCATCTACTGCCCAAGCCACATTAACTAATAi'i'l'rGTT

GTCTGGAGTGCCCACCTATGGGCACACAGCTCCATCTCCCCCTCCTGGCTTGACT

CCTGTTGATGTCCATATCAACAGTATGCAGACCGAAGGCAAAAAAATCTCTGCTG

CTTTAAATGGACATGCACAGTCTCCAGATATAAAATATGGTGCAATATCCACTTC

ATCACTTGG AGAAAA AGTGCTGAGTGCAA ATC ACGGGGATCCGTCC ATCCAGAC

AAGTGGGTCTGAGCAGACATCTCCCAAATCAAGCCCCACTGAAGGTTGTAATGA

TGCTTTTGTTGAAGTAGGCATGCCTCGAAGTCCTTCCCATTCTGGGAATGCTGGT

GACTTGAAACAGATGATGTGTCCCTCCAAG i'i^'CCTGTGCCAAAAGGCAGACA

GTGGAACTATTGCAAGGCACGAAAAACTCACACTTACACAGCACTGACAGGTTG

CTCTCAGACCCTGAACTGAGTGCTACCGAAAGCCCTTTGGCTGACAAGAAGGCTC

CAGGGAGTGAGCGCGCTGCAGAGAGGGCAGCAGCTGCCCAGCAAAACTCCGAA

AGGGCCCACCTTGCTCCACGGTCATCATATGTCAACATGCAGGCATTTGACTATG

AACAGAAGAAGCTATTAGCCACCAAAGCTATGTTAAAGAAACCAGTGGTGACGG

AGGTCAGAACGCCCACAAATACCTGGAGTGGCCTGGGTTTTTCTAAATCCATGCC

AGCTGAAACTATCAAGGAGTTGAGAAGGGCCAATCATGTGTCCTATAAGCCCAC AATGACAACCACTTATGAGGGCTCATCCATGTCCCTTTCACGGTCCAACAGTCGT

GAGCACTTGGGAGGTGGAAGCGAATCTGATAACTGGAGAGACCGAAATGGAATT

GGACCTGGAAGTCATAGTGAATTTGCAGCTTCTATTGGCAGCCCTAAGCGTAAAC

AAAACAAATCAACGGAACACTATCTCAGCAGTAGCAATTACATGGACTGCATTT

CCTCGCTGACAGGAAGCAATGGCTGTAACTTAAATAGCTCTTTCAAAGGTTCTGA

CCTCCCTGAGCTCTTCAGCAAACTGGGCCTGGGCAAATACACAGATG i'i'i'i CCAG

CAACAAGAGATCGATCTTCAGACATTCCTCACTCTCACAGATCAGGATCTGAAGG

AGCTGGGAATAACTACTTTTGGTGCCAGGAGGAAAATGCTGCTTGCAATTTCAGA

ACTAAATAAAAACCGAAGAAAGCTTTTTGAATCGCCAAATGCACGCACCTCTTTC

CTGGAAGGTGGAGCGAGTGGAAGGCTACCCCGTCAGTATCACTCAGACATTGCT

AGTGTCAGTGGCCGCTGGTAG

FGFR2:AFF3 >ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGT (5109 base pairs) CCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGA (SEQ ID NO:24) GCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGG

GGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACT

AAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTAC

TTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCA

GTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCAT

CTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGA

GAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAA

AGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGG

GGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCA

GGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTAT

GGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTAGTGGAGAATGA

ATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCAC

CGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGA

GACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGA

TCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACC

TCAAGC_LTTXiTC .GG^

TCTATATTCGGAATGTAACTTTTGAGGACGCTGGGGAATATACGTGCTTGGCGGG

TAATTCTATTGGGATATCCTTTCACTCTGCATGGTTGACAGTTCTGCCAGCGCCTG

GAAGAGAAAAGGAGATTACAGCTTCCCCAGACTACCTGGAGATAGCCATTTACT

GCATAGGGGTCTTCTTAATCGCCTGTATGGTGGTAACAGTCATCCTGTGCCGAAT

GAAGAACACGACCAAGAAGCCAGACTTCAGCAGCCAGCCGGCTGTGCACAAGCT

GACCAAACGTATCCCCCTGCGGAGACAGGTAACAGTTTCGGCTGAGTCCAGCTCC

TCCATGAACTCCAACACCCCGCTGGTGAGGATAACAACACGCCTCTCTTCAACGG

CAGACACCCCCATGCTGGCAGGGGTCTCCGAGTATGAACTTCCAGAGGACCCAA

AATGGGAGTTTCCAAGAGATAAGCTGACACTGGGCAAGCCCCTGGGAGAAGGTT

GCTTTGGGCAAGTGGTCATGGCGGAAGCAGTGGGAATTGACAAAGACAAGCCCA

AGGAGGCGGTCACCGTGGCCGTGAAGATGTTGAAAGATGATGCCACAGAGAAAG

ACCTTTCTGATCTGGTGTCAGAGATGGAGATGATGAAGATGATTGGGAAACACA

AGAATATCATAAATCTTCTTGGAGCCTGCACACAGGATGGGCCTCTCTATGTCAT

AGTTGAGTATGCCTCTAAAGGCAACCTCCGAGAATACCTCCGAGCCCGGAGGCC

ACCCGGGATGGAGTACTCCTATGACATTAACCGTGTTCCTGAGGAGCAGATGACC

TTCAAGGACTTGGTGTCATGCACCTACCAGCTGGCCAGAGGCATGGAGTACTTGG

CTTCCCAAAAATGTATTCATCGAGATTTAGCAGCCAGAAATGTTTTGGTAACAGA

AAACAATGTGATGAAAATAGCAGACTTTGGACTCGCCAGAGATATCAACAATAT

AGACTATTACAAAAAGACCACCAATGGGCGGCTTCCAGTCAAGTGGATGGCTCC

AGAAGCCCTGTTTGATAGAGTATACACTCATCAGAGTGATGTCTGGTCCTTCGGG

GTGTTAATGTGGGAGATCTTCACTTTAGGGGGCTCGCCCTACCCAGGGATTCCCG

TGGAGGAACTTTTTAAGCTGCTGAAGGAAGGACACAGAATGGATAAGCCAGCCA

ACTGCACCAACGAACTGTACATGATGATGAGGGACTGTTGGCATGCAGTGCCCTC

CCAGA( CCAACGTTCAAGCAGTTGGTAGAAGACTTGGATCGAATTCTX:ACTCTC ACAACCAATGAGGAGAGTAGATCTGGAGAAACCAACAGCTGTGTTGAAGAAATA

ATCCGGGAGATGACCTGGCTTCCACCACTTTCTGCTATTCAAGCACCTGGCAAAG

TGGAACCAACCAAATTTCCATTTCCAAATAAGGACTCTCAGCTTGTATCCTCTGG

ACACAATAATCCAAAGAAAGGTGATGCAGAGCCAGAGAGTCCAGACAGTGGCA

CATCGAATACATCAATGCTGGAAGATGACCTTAAGCTAAGCAGTGATGAAGAGG

AGAATGAACAGCAGGCAGCTCAGAGAACGGCTCTCCGCGCTCTCTCTGACAGCG

CCGTGGTCCAGCAGCCCAACTGCAGAACCTCGGTGCCTTCCAGCAAGGGCAGCA

GCAGCAGCAGCAGCAGCGGCAGCAGCAGCTCCTCCAGCGACTCAGAGAGCAGCT

CCGGATCTGACTCGGAGACCGAGAGCAGCTCCAGCGAGAGTGAGGGCAGCAAGC

CCCCCCACTTCTCCAGCCCCGAGGCTGAACCGGCATCCTCTAACAAGTGGCAGCT

GGATAAATGGCTAAACAAAGTTAATCCCCACAAGCCTCCTATTCTGATCCAAAAT

GAAAGCCACGGGTCAGAGAGCAATCAGTACTACAACCCGGTGAAAGAGGACGTC

CAGGACTGTGGGAAAGTCCCCGACGTTTGCCAGCCCAGCCTGAGAGAGAAGGAG

ATCAAGAGCACTTGCAAGGAGGAGCAAAGGCCAAGGACAGCCAACAAGGCCCC

TGGGAGTAAAGGCGTGAAGCAGAAGTCCCCGCCCGCGGCCGTGGCCGTGGCGGT

GAGCGCAGCCGCCCCGCCACCCGCAGTGCCCTGTGCGCCCGCGGAGAACGCGCC

CGCGCCTGCCCGGAGGTCCGCGGGCAAGAAGCCCACCAGGCGCACCGAGAGGAC

CTCAGCCGGGGACGGCGCCAACTGCCACCGGCCCGAGGAGCCCGCGGCCGCGGA

CGCGCTGGGGACGAGCGTGGTGGTCCCCCCGGAGCCCACCAAAACCAGGCCCTG

TGGCAACAACAGAGCGAGCCACCGCAAGGAGCTGCGCTCCTCCGTGACCTGCGA

GAAGCGCCGCACGCGGGGGCTAAGCAGGATCGTCCCCAAATCCAAGGAGTTCAT

TGAGACAGAGTCGTCATCTTCATCCTCCTCCTCGGACTCCGACCTGGAGTCCGAG

CAGGAGGAGTACCCTCTGTCCAAAGCACAGACCGTGGCTGCCTCTGCCTCCTCCG

GGAATGATCAGAGGCTGAAGGAGGCCGCTGCCAACGGGGGCAGTGGTCCTAGGG

CCCCTGTAGGCTCCATCAACGCCAGGACCACCAGTGACATCGCCAAGGAGCTGG

AGGAGCAGTTCTACACACTGGTCCCCTTTGGCCGGAACGAACTTCTCTCCCCTCT

AAAGGACAGTGATGAGATCAGGTCTCTCTGGGTCAAAATCGACCTGACCCTCCTG

TCCAGGATCCCAGAACACCTGCCCCAGGAGCCAGGGGTATTGAGCGCCCCTGCC

ACCAAGGACTCTGAGAGCGCACCGCCCAGCCACACCTCGGACACACCTGCAGAA

AAGGCTTTGCCAAAATCCAAGAGGAAACGCAAGTGTGACAACGAAGACGACTAC

AGGGAGATCAAGAAGTCCCAGGGAGAGAAAGACAGCTCTTCAAGACTGGCCACC

TCCACCAGTAATACTTTGTCTGCAAACCACTGCAACATGAACATCAACAGTGTGG

CAATACCAATAAATAAAAATGAAAAAATGCTTCGGTCGCCCATCTCACCCCTCTC

TGATGCATCTAAACACAAATACACCAGCGAGGACTTAACTTCTTCCAGCCGACCT

AATGGCAACAGTTTGTTTACTTCAGCCTCTTCCAGCAAAAAGCCTAAGGCCGACA

GCCAGCTGCAGCCTCACGGCGGAGACCTCACGAAAGCAGCTCACAACAATTCTG

AAAACATTCCCCTCCACAAGTCACGGCCGCAGACGAAGCCGTGGTCTCCAGGCT

CCAACGGCCACAGGGACTGCAAGAGGCAGAAACTTGTCTTCGATGATATGCCTC

GCAGTGCCGAT ATTTTATGCAAGAAGCTAAACGAATGAAGCATAAAGCAGATG

CAATGGTGGAAAAGTTTGGAAAGGCTTTGAACTATGCTGAAGCAGCATTGTCGTT

TATCGAGTGTGGAAATGCAATGGAACAAGGCCCCATGGAATCCAAATCTCCTTAT

ACGATGTATTCAGAAACAGTAGAGCTCATCAGGTATGCTATGAGACTAAAAACC

CACTCAGGCCCCAATGCCACACCAGAAGACAAACAACTGGCTGCATTATGTTAC

CGATGCCTGGCCCTCCTGTACTGGCGGATGTTTCGACTCAAAAGGGACCACGCTG

TAAAGTATTCAAAAGCACTAATCGACTATTTCAAGAACTCATCTAAAGCCGCCCA

AGCCCCATCTCCGTGGGGGGCCAGTGGAAAGAGCACTGGAACCCCATCCCCCAT

GTCTCCCAACCCCTCTCCCGCCAGCTCCGTGGGGTCTCAGGGCAGCCTCTCCAAC

GCCAGCGCCCTGTCCCCGTCGACCATCGTCAGCATCCCACAGCGCATCCACCAGA

TGGCGGCCAACCACGTCAGCATCACCAACAGCATCCTGCACAGCTACGACTACT

GGGAGATGGCCGACAACCTGGCCAAGGAAAACCGAGAATTCTTCAACGACCTGG

ATCTGCTCATGGGGCCGGTCACCCTGCACAGCAGCATGGAGCACCTGGTCCAGTA CTCCCAACAGGGCCTGCACTGGCTGCGGAACAGCGCCCACCTGTCATAG

FGFR2:CASP7 >ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGT (3213 base pairs) CCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGA (SEQ ID NO:25) GCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGG

GGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACT

AAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTAC

TTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCA

GTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCAT

CTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGA

GAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAA

AGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGG

GGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCA

GGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTAT

GGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTAGTGGAGAATGA

ATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCAC

CGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGA

GACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGA

TCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACC

TCAAGGTTCTCAAGGCCGCCGGTGTTAACACCACGGACAAAGAGATTGAGGTTC

TCTATATTCGGAATGTAACTTTTGAGGACGCTGGGGAATATACGTGCTTGGCGGG

TAATTCTATTGGGATATCCTTTCACTCTGCATGGTTGACAGTTCTGCCAGCGCCTG

GAAGAGAAAAGGAGATTACAGCTTCCCCAGACTACCTGGAGATAGCCATTTACT

GCATAGGGGTCTTCTTAATCGCCTGTATGGTGGTAACAGTCATCCTGTGCCGAAT

GAAGAACACGACCAAGAAGCCAGACTTCAGCAGCCAGCCGGCTGTGCACAAGCT

GACCAAACGTATCCCCCTGCGGAGACAGGTAACAGTTTCGGCTGAGTCCAGCTCC

TCCATGAACTCCAACACCCCGCTGGTGAGGATAACAACACGCCTCTCTTCAACGG

CAGACACCCCCATGCTGGCAGGGGTCTCCGAGTATGAACTTCCAGAGGACCCAA

AATGGGAGTTTCCAAGAGATAAGCTGACACTGGGCAAGCCCCTGGGAGAAGGTT

GCTTTGGGCAAGTGGTCATGGCGGAAGCAGTGGGAATTGACAAAGACAAGCCCA

AGGAGGCGGTCACCGTGGCCGTGAAGATGTTGAAAGATGATGCCACAGAGAAAG

ACCTTTCTGATCTGGTGTC AG AG ATGG AG ATG ATG AA G ATG ATTGGGA AAC AC A

AGAATATCATAAATCTTCTTGGAGCCTGCACACAGGATGGGCCTCTCTATGTCAT

AGTTGAGTATGCCTCTAAAGGCAACCTCCGAGAATACCTCCGAGCCCGGAGGCC

ACCCGGGATGGAGTACTCCTATGACATTAACCGTGTTCCTGAGGAGCAGATGACC

TTCAAGGACTTGGTGTCATGCACCTACCAGCTGGCCAGAGGCATGGAGTACTTGG

CTTCCCAAAAATGTATTCATCGAGATTTAGCAGCCAGAAATGTTTTGGTAACAGA

AAACAATGTGATGAAAATAGCAGACTTTGGACTCGCCAGAGATATCAACAATAT

AGACTATTACAAAAAGACCACCAATGGGCGGCTTCCAGTCAAGTGGATGGCTCC

AGAAGCCCTGTTTGATAGAGTATACACTCATCAGAGTGATGTCTGGTCCTTCGGG

GTGTTAATGTGGGAGATCTTCACTTTAGGGGGCTCGCCCTACCCAGGGATTCCCG

TGGAGGAACTTTTTAAGCTGCTGAAGGAAGGACACAGAATGGATAAGCCAGCCA

ACTGCACCAACGAACTGTACATGATGATGAGGGACTGTTGGCATGCAGTGCCCTC

CCAGAGACCAACGTTCAAGCAGTTGGTAGAAGACTTGGATCGAATTCTCACTCTC

ACAACCAATGAGATGGCAGATGATCAGGGCTGTATTGAAGAGCAGGGGGTTGAG

GATTCAGCAAATGAAGATTCAGTGGATGCTAAGCCAGACCGGTCCTCGTTTGTAC

CGTCCCTCTTCAGTAAGAAGAAGAAAAATGTCACCATGCGATCCATCAAGACCA

CCCGGGACCGAGTGCCTACATATCAGTACAACATGAA'i'i'i'i GAAAAGCTGGGCA

AATGCATCATAATAAACAACAAGAACTTTGATAAAGTGACAGGTATGGGCGTTC

GAAACGGAACAGACAAAGATGCCGAGGCGCTCTTCAAGTGCTTCCGAAGCCTGG

GTTTTGACGTGATTGTCTATAATGACTGCTCTTGTGCCAAGATGCAAGATCTGCTT

AAAAAAGCTTCTGAAGAGGACCATACAAATGCCGCCTGCTTCGCCTGCATCCTCT

TAAGCCATGGAGAAGAAAATGTAATTTATGGGAAAGATGGTGTCACACCAATAA

AGGATT GACAGCCCACT TAGGGGGGATAGATGCAAAACCCTTTTAGAGAAAC

CCAAACTCTTCTTCATTCAGGCTTGCCGAGGGACCGAGCTTGATGATGGCATCCA

GGCCGACTCGGGGCCCATCAATGACACAGATGCTAATCCTCGATACAAGATCCC

AGTGGAAGCTGACTTCCTCTTCGCCTATTCCACGGTTCCAGGCTATTACTCGTGG

AGGAGCCCAGGAAGAGGCTCCTGGTTTGTGCAAGCCCTCTGCTCCATCCTGGAGG

AGCACGGAAAAGACCTGGAAATCATGCAGATCCTCACCAGGGTGAATGACAGAG

T GCCAGGCACTTTGAGTCTCAGTCTGATGACCCACACTTCCATGAGAAGAAGCA GATCCCCTGTGTGGTCTCCATGCTCACCAAGGAACTCTACTTCAGTCAATAG

FGFR2:CCDC6 >ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGT

(3423 base pairs) CCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGA (SEQ ID NO:26) GCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGG

GGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACT

AAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTAC

TTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCA

GTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCAT

CTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGA

GAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAA

AGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGG

GGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCA

GGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTAT

GGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTAGTGGAGAATGA

ATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCAC

CGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGA

GACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGA

TCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACC

TCAAGGTTCTCAAGGCCGCCGGTGTTAACACCACGGACAAAGAGATTGAGGTTC

TCTATATTCGGAATGTAACTTTTGAGGACGCTGGGGAATATACGTGCTTGGCGGG

TAATTCTATTGGGATATCCTTTCACTCTGCATGGTTGACAGTTCTGCCAGCGCCTG

GAAGAGAAAAGGAGATTACAGCTTCCCCAGACTACCTGGAGATAGCCATTTACT

GCATAGGGGTCTTCTTAATCGCCTGTATGGTGGTAACAGTCATCCTGTGCCGAAT

GAAGAACACGACCAAGAAGCCAGACTTCAGCAGCCAGCCGGCTGTGCACAAGCT

GACCAAACGTATCCCCCTGCGGAGACAGGTAACAGTTTCGGCTGAGTCCAGCTCC

TCCATGAACTCCAACACCCCGCTGGTGAGGATAACAACACGCCTCTCTTCAACGG

C^'AGACACCCCCATGCTGGCAGGGGTCTCCGAGTATGAACTTCCAGAGGACCCAA

AATGGGAGTTTCCAAGAGATAAGCTGACACTGGGCAAGCCCCTGGGAGAAGGTT

GCTTTGGGCAAGTGGTCATGGCGGAAGCAGTGGGAATTGACAAAGACAAGCCCA

AGGAGGCGGTCACCGTGGCCGTGAAGATGTTGAAAGATGATGCCACAGAGAAAG

ACCTTTCTGATCTGGTGTCAGAGATGGAGATGATGAAGATGATTGGGAAACACA

AGAATATCATAAATCTTCTTGGAGCCTGCACACAGGATGGGCCTCTCTATGTCAT

AGTTGAGTATGCCTCTAAAGGCAACCTCCGAGAATACCTCCGAGCCCGGAGGCC

ACCCGGGATGGAGTACTCCTATGACATTAACCGTGTTCCTGAGGAGCAGATGACC

TTCAAGGACTTGGTGTCATGCACCTACCAGCTGGCCAGAGGCATGGAGTACTTGG

CTTCCCAAAAATGTAT CATCGAGATTTAGCAGCCAGAAATGTTTTGGTAACAGA

AAACAATGTGATGAAAATAGCAGACTTTGGACTCGCCAGAGATATCAACAATAT

AGACTATTACAAAAAGACCACCAATGGGCGGCTTCCAGTCAAGTGGATGGCTCC

AGAAGCCCTGTTTGATAGAGTATACACTCATCAGAGTGATGTCTGGTCCTTCGGG

GTGTTAATGTGGGAGATCTTCACTTTAGGGGGCTCGCCCTACCCAGGGATTCCCG

TGGAGGAACTTTTTAAGCTGCTGAAGGAAGGACACAGAATGGATAAGCCAGCCA

ACTGCACCAACGAACTGTACATGATGATGAGGGACTGTTGGCATGCAGTGCCCTC

CCAGAGACCAACGTTCAAGCAGTTGGTAGAAGACTTGGATCGAATTCTCACTCTC

ACAACCAATGAGCAAGCCAGGGCTGAGCAGGAAGAAGAATTCATTAGTAACACT

TTATTCAAGAAAATTCAGGCTTTGCAGAAGGAGAAAGAAACCCTTGCTGTAAATT

ATGAGAAAGAAGAAGAATTCCTCACTAATGAGCTCTCCAGAAAATTGATGCAGT

TGCAGCATGAGAAAGCCGAACTAGAACAGCATCTTGAACAAGAGCAGGAATTTC

AGGTCAACAAACTGATGAAGAAAATTAAAAAACTGGAGAATGACACCATTTCTA

AGCAACTTACATTAGAACAGTTGAGACGGGAGAAGATTGACCTTGAAAATACAT

TGGAACAAGAACAAGAAGCACTAGTTAATCGCCTCTGGAAAAGGATGGATAAGC

TTGAAGCTGAAAAGCGAATCCTGCAGGAAAAATTAGACCAGCCCGTCTCTGCTC

CACCATCGCCTAGAGATATCTCCATGGAGATTGATTCTCCAGAAAATATGATGCG

TCACATCAGGT^'i'i'l'lAAAGAATGAAGTGGAACGGCTGAAGAAGCAACTGAGAGC

TGCTCAGTTACAGCATTCAGAGAAAATGGCACAGTATCTGGAGGAGGAACGTCA

CATGAGAGAAGAGAACTTGAGGCTCCAGAGGAAGCTGCAGAGGGAGATGGAGA

GAAGAGAAGCCCTCTGTCGACAGCTCTCCGAGAGTGAGTCCAGCTTAGAAATGG

ACGACGAAAGGTAiT^'i AATGAGATGTCTGCACAAGGATTAAGACCTCGCACTGT

GTCCAGCCCGATCCCTTACACACCTTCTCCGAGTTCAAGCAGGCCTATATCACCT

GGTCTATCATATGCAAGTCACACGGTTGGTTTCACGCCACCAACTTCACTGACTA GAGCTGGAATGTCTTATTACAATTCCCCGGGTCTTCACGTGCAGCACATGGGAAC

ATCCCATGGTATCACAAGGCCTTCACCACGGAGAAGCAACAGTCCTGACAAATT

CAAACGGCCCACGCCGCCTCCATCTCCCAACACACAGACCCCAGTCCAGCCACCT

CCGCCTCCACCTCCGCCACCCATGCAGCCCACGGTCCCCTCAGCAGCCACCTCGC

AGCCTACTCCTTCGCAACATTCGGCGCACCCCTCCTCCCAGCCTTAA

FGFR2:OFDl >ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGT

(5229 base pairs) CCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGA (SEQ ID NO:27) GCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGG

GGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACT

AAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTAC

TTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCA

GTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCAT

CTCA CCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGA

GAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAA

AGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGG

GGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCA

GGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTAT

GGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTAGTGGAGAATGA

ATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCAC

CGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGA

GACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGA

TCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACC

TCAAGGTTCTCAAGGCCGCCGGTGTTAACACCACGGACAAAGAGATTGAGGTTC

TCTATATTCGGAATGTAACTTTTGAGGACGCTGGGGAATATACGTGCTTGGCGGG

TAATTCTATTGGGATATCCTTTCACTCTGCATGGTTGACAGTTCTGCCAGCGCCTG

GAAGAGAAAAGGAGATTACAGCTTCCCCAGACTACCTGGAGATAGCCATTTACT

GCATAGGGGTCTTCTTAATCGCCTGTATGGTGGTAACAGTCATCCTGTGCCGAAT

GAAGAACACGACCAAGAAGCCAGACTTCAGCAGCCAGCCGGCTGTGCACAAGCT

GACCAAACGTATCCCCCTGCGGAGACAGGTAACAGTTTCGGCTGAGTCCAGCTCC

TCCATGAACTCCAACACCCCGCTGGTGAGGATAACAACACGCCTCTCTTCAACGG

CAGACACCCCCATGCTGGCAGGGGTCTCCGAGTATGAACTTCCAGAGGACCCAA

AATGGGAGTTTCCAAGAGATAAGCTGACACTGGGCAAGCCCCTGGGAGAAGGTT

GCTTTGGGCAAGTGGTCATGGCGGAAGCAGTGGGAATTGACAAAGACAAGCCCA

AGGAGGCGGTCACCGTGGCCGTGAAGATGTTGAAAGATGATGCCACAGAGAAAG

ACCTTTCTGATCTGGTGTCAGAGATGGAGATGATGAAGATGATTGGGAAACACA

AGAATATCATAAATCTTCTTGGAGCCTGCACACAGGATGGGCCTCTCTATGTCAT

AGTTGAGTATGCCTCTAAAGGCAACCTCCGAGAATACCTCCGAGCCCGGAGGCC

ACCCGGGATGGAGTACTCCTATGACATTAACCGTGTTCCTGAGGAGCAGATGACC

TTCAAGGACTTGGTGTCATGCACCTACCAGCTGGCCAGAGGCATGGAGTACTTGG

CTTCCCAAAAATGTATTCATCGAGATTTAGCAGCCAGAAATGTTTTGGTAACAGA

AAACAATGTGATGAAAATAGCAGACTTTGGACTCGCCAGAGATATCAACAATAT

AGACTATTACAAAAAGACCACCAATGGGCGGCTTCCAGTCAAGTGGATGGCTCC

AGAAGCCCTGTTTGATAGAGTATACACTCATCAGAGTGATGTCTGGTCCTTCGGG

GTGTTAATGTGGGAGATCTTCACTTTAGGGGGCTCGCCCTACCCAGGGATTCCCG

TGGAGGAACTTTTTAAGCTGCTGAAGGAAGGACACAGAATGGATAAGCCAGCCA

ACTGCACCAACGAACTGTACATGATGATGAGGGACTGTTGGCATGCAGTGCCCTC

CCAGAGACCAACGTTCAAGCAGTTGGTAGAAGACTTGGATCGAATTCTCACTCTC

ACAACCAATGAGACACAACTTCGAAACCAGCTAATTCATGAGTTGATGCACCCT

GTATTGAGTGGAGAACTGCAGCCTCGGTCCATTTCAGTAGAAGGGAGCTCCCTCT

TAATAGGCGCCTCTAACTCTTTAGTGGCAGATCACTTACAAAGATGTGGCTATGA

ATATTCACTTTCTGTTTTCTTTCCAGAAAGTGGTTTGGCAAAAGAAAAGGTATTTA

CTATGCAGGATCTATTACAACTCATTAAAATCAACCCTACTTCCAGTCTCTACAA

ATCACTGGTTTCAGGATCTGATAAAGAAAATCAAAAAGGi'l Ί 'I^'CTTATGCATTTT

TTAAAAGAATTGGCAGAATATCATCAAGCTAAAGAGAGTTGTAATATGGAAACT

CAGACAAGTTCGACATTTAACAGAGATTCTCTGGCTGAGAAGCTTCAGCTTATTG

ATGATCAGTTTGCAGATGCTTACCCTCAGCGTATCAAGTTCGAATCTTTAGAAAT

AAAGCTAAATGAGTATAAGAGAGAAATAGAAGAGCAACTTCGGGCAGAAATGT

GTCAAAAGTTGAAGTTTTTTAAAGATACCGAGATAGCAAAAATTAAAATGGAAG

C AA A A A A AA AGTATGA AA AGG AGTTA ACC ATGTTCC AG AATG ATTTTGA AA AA G CTTGTCAAGCAAAATCTGAAGCTCTCGTTCTTCGGGAAAAGAGTACCCTTGAAAG

AATTCACAAGCACCAAGAGATTGAAACAAAAGAAATTTATGCTCAAAGGCAACT

TTTACTAAAAGATATGGATTTGCTAAGAGGAAGAGAAGCAGAGCTGAAGCAAAG

AGTTGAAGCTTTTGAATTGAACCAGAAGCTCCAGGAAGAAAAACATAAAAGCAT

AACTGAGGCACTTAGGAGACAGGAGCAGAATATAAAGAGTTTTGAGGAGACCTA

TGACCGAAAGCTCAAGAATGAACTTCTAAAGTATCAACTTGAACTGAAGGATGA

CTACATCATTAGAACTAATCGACTGATTGAAGATGAAAGGAAGAATAAAGAAAA

AGCTGTTCATTTGCAAGAGGAGCTCATAGCTATTAATTCAAAAAAGGAGGAACT

CAATCAATCTGTAAATCGTGTGAAAGAACTTGAGCTTGAATTAGAGTCTGTCAAA

GCCCAGTCTTTGGCAATAACAAAACAAAACCATATGCTGAATGAAAAGGTTAAA

GAGATGAGTGATTATTCACTACTAAAAGAAGAGAAACTGGAGCTTCTGGCACAA

AATAAATTACTTAAACAACAACTGGAAGAGAGTAGAAATGAAAACCTGCGTCTC

CTAAACCGCCTAGCTCAGCCGGCTCCTGAACTTGCAGTCTTTCAGAAAGAACTAC

GGAAAGCCGAAAAGGCTATAGTGGTTGAGCATGAGGAGTTCGAAAGCTGCAGGC

AAGCTCTGCACAAACAACTGCAAGACGAAATTGAGCATTCTGCACAGCTGAAGG

CCCAGATTCTAGGTTACAAAGCTTCTGTAAAGAGTTTAACTACTCAGGTTGCCGA

TTTAAAATTGCAACTGAAGCAAACTCAGACAGCCCTAGAGAATGAAGTGTACTG

CAATCCAAAGCAGTCTGTGATCGATCGTTCTGTCAATGGATTAATAAATGGCAAT

GTGGTGCCTTGCAATGGTGAGATAAGTGGGGATTTCTTGAACAATCCTTTTAAAC

AGGAAAACGTTCTAGCACGTATGGTTGCATCAAGGATCACAAATTATCCAACTGC

ATGGGTGGAGGGTAGTTCCCCTGATTCTGACCTTGAGTTTGTAGCCAATACTAAG

GCAAGGGTCAAAGAGCTTCAGCAAGAGGCCGAACGCTTGGAAAAGGCTTTCAGA

AGTTACCATCGGAGAGTCATTAAAAACTCTGCCAAAAGCCCACTAGCAGCAAAG

AGCCCACCATCTCTGCACTTGCTGGAAGCCTTCAAAAACATTACTTCCAGTTCCC

CGGAAAGACATATTTTTGGAGAGGACAGAGTTGTCTCTGAGCAGCCTCAAGTGG

GCACACTTGAAGAAAGGAATGACGTCGTGGAAGCACTGACAGGCAGTGCAGCCT

CGAGGCTCCGCGGGGGCACTTCCTCCAGACGCCTCTCTTCCACACCCCTTCCAAA

AGCAAAAAGAAGCCTCGAAAGTGAAATGTATCTGGAAGGTCTGGGCAGATCACA

CATTGCTTCCCCCAGTCCTTGTCCTGACAGAATGCCCCTACCATCACCCACTGAGT

CTAGGCACAGCCTCTCCATCCCTCCTGTCTCCAGCCCTCCGGAGCAGAAAGTGGG

TCTTTATCGAAGACAAACTGAACTTCAAGACAAAAGTGAATTTTCAGATGTGGAC

AAGCTAGCTTTTAAGGATAATGAGGAGTTTGAATCATCTTTTGAATCTGCAGGGA

ACATGCCAAGGCAGTTGGAAATGGGCGGGCTTTCTCCTGCCGGGGATATGTCTCA

TGTGGACGCTGCTGCAGCTGCTGTGCCCCTCTCATATCAGCACCCAAGTGTAGAT

CAGAAACAAATTGAAGAACAAAAGGAAGAAGAAAAAATACGGGAACAGCAAGT

GAAAGAACGAAGGCAGAGAGAAGAAAGAAGGCAGAGTAACCTACAAGAAGTTT

TAGAAAGGGAACGAAGAGAACTAGAAAAACTGTATCAGGAAAGGAAGATGATT

GAAGAATCACTGAAGATTAAAATAAAAAAGGAATTAGAAATGGAAAATGAATT

AGAAATGAGTAATCAAGAAATAAAAGACAAATCTGCTCACAGTGAAAATCCTTT

AGAGAAATACATGAAAATCATCCAGCAGGAGCAAGACCAGGAGTCGGCAGATA

AGAGCTCAAAAAAGATGGTCCAAGAAGGCTCCCTAGTGGACACGCTGCAATCTA

GTGACAAAGTCGAAAGTTTAACAGGCTTTTCTCATGAAGAACTAGACGACTCTTG

GTAA

Claims

What is Claimed:

1. A method of treating cancer in a patient, comprising:

administering to the patient a pharmaceutically effective amount of an antibody that blocks the interaction between PD-1 and PD-Ll and a pharmaceutically effective amount of an FGFR inhibitor, wherein the antibody that blocks the interaction between PD-1 and PD-Ll and the FGFR inhibitor are administered if one or more FGFR variants are present in a biological sample from the patient.

2. The method of claim 1, further comprising evaluating the presence of one or more FGFR variants in the biological sample before the administering step,

3. The method of claim 1 or 2, further comprising evaluating PD-Ll expression in a biological sample.

4. The method of claim 3, wherein the biological sample for the one or more FGFR variants and the PD-Ll is the same biological sample.

5. The method of claim 3, wherein the biological sample for the one or more FGF variants is different from the biological sample for PD-Ll expression.

6. The method of any one of the previous claims, wherein the biological sample is blood, lymph fluid, bone marrow, a solid tumor sample, or any combination thereof.

7. The method of any one of the previous claims, wherein the administering step is performed if PD-L l expression is low in the biological sample.

8. The method of any one of the previous claims, wherein the cancer is lung cancer, bladder cancer, gastric cancer, breast cancer, ovarian cancer, head and neck cancer, esophageal cancer, glioblastoma, or any combination thereof.

9. The method of claim 8, wherein the lung cancer is non-small cell lung cancer (NSCLC) adenocarcinoma, NSCLC squamous ceil carcinoma, small cell lung cancer, or any combination thereof

10. The method of any one of the pre vious claims, wherein the one or more FGFR variants comprise an FGFR mutation, an FGFR amplification, an FGFR fusion gene, or a combination thereof.

11. The method of claim 10, wherein the FGFR fusion gene is FGFR2:AFF3;

FGFR2:BICC1; FGFR2:CASP7; FGFR2:CCDC6; FGFR2:OFDl; FGFR3 : B AIAP2L ; FGFR3 :TACC3-Intron; FGFR3:TACC3V1 ; FGFR3:TACC3V3; or a combination thereof.

12. The method of any one of the previous claims, wherein the antibody that blocks the interaction between PD-1 and PD-Ll is an anti-PD-l antibody, an anti -PD-Ll antibody, or a combination thereof.

13. The method of any one of the previous claim s, wherein the FGFR inhibitor is the compound of formula (I):

or a pharmaceutically acceptable salt thereof.

14. A method of treating cancer in a patient comprising:

administering to the patient a pharmaceutically effective amount of an antibody that blocks the interaction between PD-1 and PD-Ll ;

monitoring the efficacy of the antibody; and

if the antibody is not efficacious,

evaluating a biological sample from, the patient for a presence of one or more FGFR variants; and

administering to the patient a pharmaceutically effective amount of an FGFR inhibitor if the one or more FGFR variants are present in the sample.

15. The method of claim 14, wherein the evaluating step further comprises measuring an expression level of PD-Ll in a biological sample and wherein the second administering step comprises administering the FGFR inhibitor if the expression level of PD-Ll is low.

16. The method of claim 15, wherein the biological sample for the one or more FGFR variants and the PD-Ll is the same biological sample.

17. The method of claim 15, wherein the biological sample for the one or more FGFR variants is different from the biological sample for PD-Ll expression.

18. The method of claim 16 or 17, wherein the biological sample is blood, lymph fluid, bone marrow, a solid tumor sample, or any combination thereof.

19. The method of any one of claims 16-18, wherein the cancer is Sung cancer, bladder cancer, gastric cancer, breast cancer, ovarian cancer, head and neck cancer, esophageal cancer, glioblastoma, or any combination thereof.

20. The method of claim 19, wherein the lung cancer is non-small cell lung cancer (NSCLC) adenocarcinoma, NSCLC squamous cell carcinoma, small cell lung cancer, or any combination thereof.

21. The method of any one of claims 16-20, wherein the one or more FG FR variants comprise an FGFR mutation, an FGFR amplification, an FGFR fusion gene, or a combination thereof.

22. The method of claim 21, wherein the FGFR fusion gene is FGFR2:AFF3;

FGFR2:BICC1; FGFR2:CASP7; FGFR2:CCDC6; FGFR2:OFD l; FGFR3 : B Al AP2L 1 : FGFR3:TACC3-Intron; FGFR3:TACC3V1; FGFR3:TACC3V3; or a combination thereof.

23. The method of any one of claims 16-22, wherein the antibody that blocks an interaction between PD-1 and PD-Ll is an anti-PD-1 antibody, an anti-PD-Ll antibody, or a combination thereof.

24. The method of any one of claims 16-23, wherein the FGFR inhibitor is the compound of formula (I):

(I)

or a pharmaceutically acceptable salt thereof.