Use of FGFR inhibitors in FGFR gene - modified cancers to enhance patient response to immune checkpoint inhibitors in continuous treatment settings

Abstract

An embodiment of the present invention relates to a method of treating cancer in a patient, comprising administering an immune checkpoint inhibitor to the patient, wherein the patient has been diagnosed with an FGFR genetically altered cancer and has been pre-treated with an FGFR inhibitor, such as erdafitinib.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 906,517, filed on September 26, 2019, which is hereby incorporated by reference in its entirety for all purposes.

[0002] The present invention relates to a method of treating cancer using fibroblast growth factor receptor (FGFR) inhibitors. In particular, the present invention relates to a method of using FGFR inhibitors in FGFR gene - modified cancers to enhance a patient's response to immune checkpoint inhibitors in a continuous treatment setting.

Background Art

[0003] Urothelial carcinoma (UC) is the most common type of bladder cancer, and approximately 20% of patients with metastatic UC (mUC) have fibroblast growth factor receptor (FGFR) gene alterations. The clinical outcomes with platinum - based or taxane chemotherapy and immunotherapy (checkpoint inhibitors) are sub - optimal, and there is a large unmet therapeutic need for mUC. Accordingly, an object of the present invention is to provide such a method.

Summary of the Invention

Means for Solving the Problems

[0004] According to certain embodiments, the present invention is a method of treating FGFR gene - modified cancer by continuous systemic or local therapy, wherein the patient is first administered an FGFR inhibitor that primes the immune system for a predetermined period, and then the patient is administered an immune checkpoint inhibitor for a predetermined period, for example until the disease progresses.

[0005] According to certain embodiments, the patient's response to an immune checkpoint inhibitor after administration of an FGFR inhibitor is greater than the patient's response to an immune checkpoint inhibitor without prior treatment with an FGFR inhibitor. According to certain embodiments, the present invention provides a method of treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of an immune checkpoint inhibitor, wherein the patient has an FGFR gene variant (particularly, an FGFR mutation or FGFR fusion) and has been treated with an FGFR inhibitor. In other words, the method may comprise administering to the patient an FGFR inhibitor for a predetermined period (e.g., as monotherapy and / or without co - administration of an immune checkpoint inhibitor), and after said period, administering to the patient an immune checkpoint inhibitor for a subsequent predetermined period (e.g., as monotherapy and / or without co - administration of an FGFR inhibitor). According to certain embodiments, the present invention provides an immune checkpoint inhibitor for use in treating cancer in a patient, wherein the patient has an FGFR gene variant (particularly, an FGFR mutation or FGFR fusion) and has been treated with an FGFR inhibitor. In other words, the present invention provides an FGFR inhibitor for use in treating cancer in a patient for a predetermined period (e.g., as monotherapy and / or without co - administration of an immune checkpoint inhibitor), and after said period, administering to the patient an immune checkpoint inhibitor for a subsequent predetermined period (e.g., as monotherapy and / or without co - administration of an FGFR inhibitor). According to certain embodiments, the present invention provides the use of an immune checkpoint inhibitor for manufacturing a medicament for use in treating cancer in a patient, wherein the patient has an FGFR gene variant (particularly, an FGFR mutation or FGFR fusion) and has been treated with an FGFR inhibitor. In other words, the present invention provides the use of an FGFR inhibitor for manufacturing a medicament for treating cancer in a patient for a predetermined period (e.g., as monotherapy and / or without co - administration of an immune checkpoint inhibitor), and after said period, administering to the patient an immune checkpoint inhibitor for a subsequent predetermined period (e.g., as monotherapy and / or without co - administration of an FGFR inhibitor).

[0006] As used herein, administering a drug for a predetermined period refers to the specific number of days, weeks, or months during which the drug is administered to a patient according to the dosing regimen prescribed for the drug (e.g., daily, twice daily, etc.). According to certain embodiments, when an FGFR inhibitor is administered for a predetermined period, an immune checkpoint inhibitor is not administered during that period. Similarly, according to certain embodiments, when an immune checkpoint inhibitor is administered for a predetermined period, an FGFR inhibitor is not administered during that period.

[0007] According to certain embodiments, the FGFR inhibitor is erdafitinib or a pharmaceutically acceptable salt thereof.

[0008] According to certain embodiments, prior to the step of administering an immune checkpoint inhibitor, the patient did not respond to, and / or showed disease progression with, the FGFR inhibitor. According to certain embodiments, prior to the step of administering an immune checkpoint inhibitor, the patient no longer responded to the FGFR inhibitor or the response to the FGFR inhibitor decreased.

[0009] According to certain embodiments, prior to the step of administering an FGFR inhibitor, the patient was treated with a first immune checkpoint inhibitor (before treatment with the FGFR inhibitor) and showed disease progression with respect to the first immune checkpoint inhibitor (thus, according to this embodiment, the patient previously did not respond to an immune checkpoint inhibitor and, after exposure to the FGFR inhibitor, is retreated or "re-dosed" with a checkpoint inhibitor).

[0010] According to certain embodiments, the immune checkpoint inhibitor is an antibody that blocks the interaction between PD-1 and PD-L1, such as pembrolizumab, atezolizumab, nivolumab, cemiplimab, etc. Alternatively, it is an antibody that blocks the interaction between CTLA-4 and CD80 or CD86 on the surface of antigen-presenting cells. Non-limiting examples of immune checkpoint inhibitors that may be suitable according to the present invention include atezolizumab, pembrolizumab, nivolumab, durvalumab, avelumab, anti-CSF1R antibody, tremelimumab, ipilimumab, and the like.

[0011] According to certain embodiments, the patient is diagnosed with bladder cancer such as locally advanced or metastatic urothelial carcinoma; or locally advanced or metastatic urothelial carcinoma having a genetic alteration in FGFR2 or FGFR3; or locally advanced or metastatic urothelial carcinoma having a genetic alteration in FGFR2 or FGFR3, and is a patient who has progressed during or after at least 1 line of platinum-containing neoadjuvant or adjuvant platinum-containing chemotherapy within 12 months.

[0012] According to certain embodiments, the FGFR variant is selected from the group consisting of FGFR2:AFF3, FGFR2:BICC1, FGFR2:CASP7, FGFR2:CCDC6, FGFR2:OFD1, FGFR3:BAIAP2L1, FGFR3:TACC3-intron; FGFR3:TACC3v1, FGFR3:TACC3v3, and combinations thereof, particularly combinations consisting of FGFR2:BICC1, FGFR2:CASP7, FGFR3:BAIAP2L1, FGFR3:TACC3v1, FGFR3:TACC3v3, and combinations thereof.

[0013] According to certain embodiments, the FGFR variant is an FGFR3 mutation selected from the group consisting of FGFR3 mutations, particularly FGFR3 R248C, FGFR3 S249C; FGFR3 G370C, FGFR3 Y373C, and combinations thereof.

[0014] According to certain embodiments, the FGFR inhibitor is erdafitinib and is administered in an amount of about 8 mg to about 9 mg per day.

[0015] According to certain embodiments, the method is effective in achieving complete or partial response in a patient, e.g., reducing the tumor volume of the patient and / or arresting or alleviating the progression of the disease.

[0016] In the following sections, different aspects of the present disclosure are defined in more detail. Each aspect so defined may be combined with any other aspect, unless specifically and explicitly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature indicated as being preferred or advantageous.

[0017] Embodiments of the present invention can be further understood when read in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0018]

Figure 1

Figure 2

Figure 3

Figure 4-1

Figure 4-2

Figure 4-3

Figure 5-1

Figure 5-2

Figure 5-3

Figure 6-1

Figure 6-2

Mode for Carrying Out the Invention

[0019] Immune checkpoint inhibitor Immune checkpoint inhibitors (CPIs) can restore existing immune responses that are suppressed in certain solid cancers. The conventional paradigm when combining chemotherapy with CPIs has become the standard first-line treatment for non-small cell lung cancer (NSCLC). This may indicate that conventional cytotoxic drugs can disrupt or prime the tumor microenvironment such that they regulate T cell-mediated antitumor activity. Solid cancer patients are likely to respond to CPIs in NSCLC with a high level of tumor mutational burden (TMB), or metastatic high-frequency microsatellite instability (MSI-H) or mismatch repair-deficient solid cancers such as colon cancer or ovarian cancer. Some targeted drugs may affect the expression of checkpoint inhibitor molecules such as PD-L1 on tumor cells or increase the sensitivity of tumors to immune-mediated killing by another mechanism. The BRAF inhibitor vemurafenib has been shown to increase the expression of tumor antigens gp100 and MART1, increase tumor T cell infiltration, decrease the tumor secretion of immunosuppressive cytokines, and decrease PD-L1 expression (see Hughes et al., Targeted Therapy and Checkpoint Immunotherapy Combinations for the Treatment of Cancer, Trends Immunol. 2016 Jul;37(7):462-476., and Vanneman et al., Combining immunotherapy and targeted therapies in cancer treatment, Nat Rev Cancer.2012 Mar 22;12(4):237-51 (these documents are incorporated herein by reference)).

[0020] Furthermore, it has gradually become clear that previous immune modulation can prime solid cancers to respond to conventional cytotoxic therapies such as chemotherapy and targeted agents. The response to conventional treatments (cytotoxic and targeted) after progression following CPI would suggest a unique synergy within the tumor microenvironment. Improvements in response rates to systemic chemotherapy after CPI have been reported in several case series of NSCLC, and patients demonstrate higher than expected response rates (RR) to subsequent chemotherapy after CPI (see Schvartsman et al. Lung Cancer 2017, Park et al. J Thorac Oncol. 2018, Grigg et al. J Clin Oncol. 2017).

[0021] Urothelial Carcinoma and Immunotherapy Urothelial carcinoma has the third highest gene mutation rate among all cancers investigated, after NSCLC and melanoma (see Alexandrov et al., Signatures of mutational processes in human cancer, Nature. 2013 Aug 22;500(7463):415-21). The high amount of tumor gene mutations is predicted to correlate with the response to immunotherapy due to the generation of neoantigens that can be recognized by the immune system. Recently, checkpoint inhibitors including atezolizumab, pembrolizumab, nivolumab, durvalumab, and avelumab have been approved for the treatment of advanced urothelial carcinoma, and the observed response rate is approximately 13 - 30%. However, despite these improvements, most patients have not been able to benefit from checkpoint inhibition. The response to checkpoint inhibitors largely depends on the existing anti-tumor T cell response, including sufficient T cell infiltration in the tumor microenvironment (see Harlin et al., Chemokine expression in melanoma metastases associated with CD8+T-cell recruitment, Cancer Res.2009 Apr 1;69(7):3077-85). However, not all urothelial carcinomas show high T cell infiltration. In one report, the tumor microenvironment of urothelial carcinoma has been classified into T cell inflammatory and non-T cell inflammatory. FGFR mutations are significantly enriched in the non-T cell inflammatory group, and no changes in the FGFR pathway were confirmed in T cell inflammatory samples (see Sweis et al., Molecular Drivers of the Non-T-Cell-Inflamed Tumor Microenvironment in Urothelial Bladder Cancer, Cancer Immunol Res.2016 Jul;4(7):563-8). Differences in the response to immunotherapy have been observed in urothelial carcinoma based on the molecular subtypes of bladder cancer and the immune status underlying these subtypes. Urothelial carcinoma, like breast cancer, can be classified into luminal subtypes and basal subtypes (luminal 1, 2, or basal 3, 4) according to gene expression characteristics.Luminal type 1 tumors are reported to be rich in FGFR3 mutations and lack immune marker expression and immune cell infiltration. The Luminal 1 subtype had the lowest response rates to the anti-PD-(L)1 inhibitors atezolizumab and nivolumab compared to other bladder cancer subtypes. Analysis of phase 2 data of atezolizumab showed that PD-L1 expression on tumor-infiltrating immune cells was prominent in the basal subtype compared to the Luminal subtype, and the response to atezolizumab was lowest in the Luminal 1 group.

[0022] Immune priming with erdafitinib Erdafitinib is an FGFR kinase inhibitor approved by the U.S. Food and Drug Administration for the treatment of adults with locally advanced or metastatic urothelial carcinoma (mUC) with sensitive FGFR3 or FGFR2 gene alterations, during or after at least 1 line of platinum-containing pre-chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. The present invention provides an improved treatment regimen comprising an FGFR inhibitor such as erdafitinib in this well-defined and molecularly defined population of FGFR-positive patients with mUC.

[0023] The chemical name of erdafitinib is N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, and its chemical structure is as follows.

Chemical formula

[0024] The clinical evidence described herein indicates that erdafitinib can not only prime the immune system in FGFR driver changes such as mutations and fusions in solid cancers, but also enhance the subsequent antitumor effect when continuously exposed to immune checkpoint inhibition (CPI). As described in the following examples, it was unexpectedly observed in the clinical setting that treatment of patients with erdafitinib improved the subsequent response of the patients to immune checkpoint inhibitors. In that phase 2 trial, it was observed that urothelial cancer patients with FGFR alterations were less responsive to checkpoint inhibitors (only 1 out of 22 patients responded to prior treatment with immunotherapy, and that prior response was in combination with another experimental therapy). However, the response rate of subsequent immunotherapy after erdafitinib treatment was higher in objective response rate (ORR) and disease control rate (DCR) than that of patients who received chemotherapy after erdafitinib treatment (see Table 5). Therefore, erdafitinib is considered to enhance the sensitivity of patients to immunotherapy with checkpoint inhibitors. In other words, the effect of immunotherapy after treatment with erdafitinib was better than the effect of immunotherapy without prior administration of erdafitinib.

[0025] According to one embodiment, a method of treating a patient's cancer includes the step of administering an immune checkpoint inhibitor to the patient, where the patient has an FGFR variant and has been pretreated with an FGFR inhibitor such as erdafitinib. According to one embodiment, an immune checkpoint inhibitor for use in treating a patient's cancer is provided, where the patient has an FGFR variant and has been pretreated with an FGFR inhibitor such as erdafitinib. According to one embodiment, the use of an immune checkpoint inhibitor for the manufacture of a medicament for treating a patient's cancer is provided, where the patient has an FGFR variant and has been pretreated with an FGFR inhibitor such as erdafitinib.

[0026] If a patient's biological sample tests positive for the presence of one or more FGFR variants, particularly one or more FGFR mutations or fusions, more particularly one or more FGFR2 or FGFR3 mutations or fusions, or one or more FGFR3 mutations or FGFR2 or FGFR3 fusions, the patient is determined to have an FGFR variant (i.e., an FGFR gene change).

[0027] As used herein, "biological sample" refers to any sample derived from a patient from which cancerous cells can be obtained, e.g., any sample obtained by tumor tissue biopsy or liquid biopsy from circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) from which DNA and / or RNA can be isolated. Suitable biological samples include, but are not limited to, blood, lymph, bone marrow, plasma, solid cancer samples, or any combination thereof. In some embodiments, the biological sample can be formalin-fixed paraffin-embedded tissue (FFPET).

[0028] As used herein, "FGFR variant" refers to a change in the wild-type FGFR gene that includes, but is not limited to, FGFR fusion genes, FGFR mutations, FGFR amplifications, or any combination thereof. "FGFR fusion" or "FGFR fusion gene" refers to a gene encoding a portion of FGFR (e.g., FGRF2 or FGFR3) and one of the fusion partners disclosed herein that results from a translocation between two genes. "FGFR-altered cancer" or "FGFR gene-altered cancer" is a cancer in which a patient is diagnosed with a solid tumor cancer and one or more FGFR variants are present in a biological sample from the patient.

[0029] As used herein, "patient" is intended to mean any animal, particularly a mammal. Thus, the methods are applicable to humans and non-human animals, although humans are most preferred. "Patient" and "subject" may be used interchangeably herein.

[0030] As used herein, "being treated with an FGFR inhibitor" or "being pre-treated with an FGFR inhibitor" is intended to mean that the patient has received treatment with an FGFR inhibitor before being treated with an immune checkpoint inhibitor. According to one embodiment, the patient continues to receive treatment with an FGFR inhibitor during treatment with an immune checkpoint inhibitor. According to another embodiment, the patient discontinues treatment with an FGFR inhibitor during treatment with an immune checkpoint inhibitor. In certain embodiments described herein, the patient has received one or more cancer treatments, such as chemotherapy or an immune checkpoint inhibitor, prior to treatment with an FGFR inhibitor.

[0031] Exemplary FGFR inhibitors are described in U.S. Patent Application Publication No. 2013 / 0072457A1, which is incorporated herein by reference, and include, for example, N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine (referred to herein as erdafitinib) (including any N-oxide thereof, any pharmaceutically acceptable salt thereof, or any solvate thereof). Thus, in some embodiments, the FGFR inhibitor can be erdafitinib or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutically acceptable salt is the HCl salt. In some aspects, the FGFR inhibitor is the erdafitinib free base.

[0032] The disclosed method or use is 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 one or more FGFR alterations can be present in a biological sample from the patient. For example, in some embodiments, the FGFR variant can be one or more FGFR fusion genes and one or more FGFR mutations. In some embodiments, the FGFR variant can be one or more FGFR fusion genes and one or more FGFR amplifications. In some embodiments, the FGFR variant can be one or more FGFR mutations and one or more FGFR amplifications. In still other embodiments, the FGFR variant can be one or more FGFR fusion genes, mutations, and amplifications.

[0033] Exemplary FGFR variants are described, for example, in U.S. Patent Application Publication No. 2019 / 0078166, which is incorporated herein by reference. Exemplary FGFR fusion genes include, but are not limited to, FGFR2:AFF3; FGFR2:BICC1; FGFR2:CASP7; FGFR2:CCDC6; FGFR2:OFD1; FGFR3:BAIAP2L1; FGFR3:TACC3-intron; FGFR3:TACC3v1; FGFR3:TACC3v3; or combinations thereof. Exemplary FGFR mutations include, but are not limited to, FGFR3R248C; FGFR3S249C; FGFR3G370C; FGFR3Y373C; or combinations thereof.

[0034] The methods or uses described herein may further include a step of evaluating the presence of one or more FGFR variants in a biological sample prior to an administration step, particularly a step of administering an FGFR inhibitor, for the presence of one or more FGFR variants in the biological sample. Suitable methods for evaluating a biological sample for the presence of one or more FGFR variants are disclosed, for example, in U.S. Patent Application Publication Nos. 2019 / 0078166 and 2016 / 0090633, which are hereby incorporated by reference herein. For example, without limitation, the step of evaluating a biological sample for the presence of one or more FGFR variants may include any combination of the following steps: isolating RNA from the biological sample; synthesizing cDNA from the RNA; and amplifying the cDNA (either pre-amplified or not pre-amplified). In certain embodiments, the step of evaluating a biological sample for the presence of one or more FGFR variants includes next-generation sequencing (NGS) or real-time polymerase chain reaction (RT-PCR). In some aspects, the cDNA may be pre-amplified. In some aspects, the evaluation step may include isolating RNA from the sample, synthesizing cDNA from the isolated RNA, and pre-amplifying the cDNA.

[0035] Embodiments of the invention relate to the use of an FGFR inhibitor (e.g., erdafitinib) to prime, increase, and enhance the subsequent response of cancer patients to immune checkpoint inhibitors. Patients treated with such erdafitinib have FGFR gene alterations. The enhanced response may be seen by a physician, for example, if the patient had previously progressed on an immune checkpoint inhibitor and responded after re-administration of the immune checkpoint inhibitor after treatment with an FGFR inhibitor; or if the efficacy rate of the cancer for an immune checkpoint inhibitor is generally low from clinical literature.

[0036] A further embodiment of the present invention relates to the use of an immune checkpoint inhibitor in the treatment of cancer patients after disease progression following treatment with an FGFR inhibitor (e.g., erdafitinib). According to one aspect, an immune checkpoint inhibitor for the treatment of cancer patients after disease progression following treatment with an FGFR inhibitor (e.g., erdafitinib) is provided. Disease progression can be determined, for example, by the patient's clinical condition rapidly deteriorating due to cancer despite treatment, radiographic evidence of tumor enlargement according to RECIST criteria or the radiologist's impression, and / or evidence based on symptoms.

[0037] According to one embodiment, a method of treating a patient's cancer includes administering to the patient a therapeutically effective amount of an immune checkpoint inhibitor, wherein the patient has an FGFR variant and is being treated with an FGFR inhibitor. In other words, the method can include administering an FGFR inhibitor to the patient for a first period, and after that period, administering an immune checkpoint inhibitor to the patient for a subsequent predetermined period.

[0038] According to certain embodiments, the FGFR inhibitor is erdafitinib or a pharmaceutically acceptable salt thereof, particularly the erdafitinib free base.

[0039] According to certain embodiments, prior to the step of administering the immune checkpoint inhibitor, the patient has shown disease progression in response to the FGFR inhibitor.

[0040] According to certain embodiments, prior to the step of administering the FGFR inhibitor, the patient has been treated with a first immune checkpoint inhibitor and has shown disease progression in response to the first immune checkpoint inhibitor. Thus, according to these embodiments, the patient did not respond to the "first immune checkpoint inhibitor", but after treatment with the FGFR inhibitor (e.g., increased sensitivity), the patient responded to a subsequent immune checkpoint inhibitor (which can be the same or a different compound than the "first immune checkpoint inhibitor").

[0041] According to certain embodiments, the immune checkpoint inhibitor is an antibody that blocks the interaction between PD-1 and PD-L1, such as pembrolizumab, or atezolizumab, or nivolumab. According to alternative embodiments, the immune checkpoint inhibitor is an antibody that blocks the interaction between CTLA-4 and CD80 or CD86. According to certain embodiments, the immune checkpoint inhibitor is cetrelimab.

[0042] According to certain embodiments, the patient is diagnosed with FGFR gene-altered solid cancer. For example, the cancer can be located in the breast, lung, or bladder.

[0043] According to certain embodiments, the patient is diagnosed with locally advanced or metastatic urothelial cancer; or locally advanced or metastatic urothelial cancer having a genetic change in FGFR2 or FGFR3; or bladder cancer such as locally advanced or metastatic urothelial cancer having a genetic change in FGFR2 or FGFR3, and is a patient who has progressed during or after at least one line of platinum-containing neoadjuvant or adjuvant platinum-containing chemotherapy within 12 months.

[0044] According to certain embodiments, the FGFR variant is selected from the group consisting of FGFR2:AFF3; FGFR2:BICC1; FGFR2:CASP7; FGFR2:CCDC6; FGFR2:OFD1; FGFR3:BAIAP2L1; FGFR3:TACC3-intron; FGFR3:TACC3v1; FGFR3:TACC3v3; and combinations thereof. In particular, the FGFR variant is selected from the group consisting of FGFR2:BICC1; FGFR2:CASP7; FGFR3:BAIAP2L1; FGFR3:TACC3v1; FGFR3:TACC3v3; and combinations thereof.

[0045] According to certain embodiments, the FGFR variant is selected from the group consisting of FGFR3 R248C; FGFR3 S249C; FGFR3 G370C; FGFR3 Y373C; and combinations thereof.

[0046] According to certain embodiments, the immune checkpoint inhibitor is an antibody that blocks the interaction between PD-1 and PD-L1.

[0047] According to certain embodiments, the immune checkpoint inhibitor is an antibody that blocks the interaction between CTLA-4 and CD80 or CD86 on the surface of antigen-presenting cells, such as ipilimumab.

[0048] According to certain embodiments, the immune checkpoint inhibitor is pembrolizumab, atezolizumab, cetrelizumab, nivolumab, durvalumab, avelumab, ipilimumab, an anti-CSF1R antibody, tremelimumab.

[0049] According to certain embodiments, the FGFR inhibitor is erdafitinib and is administered in an amount of about 8 mg to about 9 mg per day.

[0050] According to certain embodiments, the method is effective in achieving complete or partial response in a patient, e.g., reducing the tumor volume of the patient and / or inhibiting or alleviating the progression of the disease.

[0051] According to certain embodiments, the method or use comprises administering the FGFR inhibitor systemically (e.g., by oral administration of tablets).

[0052] According to certain embodiments, the present invention is a method of treating a patient diagnosed with cancer by administering to the patient an effective amount of an FGFR inhibitor (e.g., erdafitinib) to increase the patient's sensitivity to an immune checkpoint inhibitor, administering the FGFR inhibitor to the patient during a second period, wherein the immune checkpoint inhibitor is not administered to the patient during the second period; and after the second period, administering the immune checkpoint inhibitor to the patient during a third period, wherein the FGFR inhibitor is not administered to the patient during the third period, and the patient (a) is diagnosed with FGFR gene-altered cancer, (b) The first immune checkpoint inhibitor is administered during a first period prior to a second period, the FGFR inhibitor is not administered to the patient during the first period, and (c) did not respond to the first immune checkpoint inhibitor during the first period (e.g., showed disease progression)) A method is provided that includes.

[0053] According to certain embodiments, the patient responded to the FGFR inhibitor during the second period (e.g., disease progression was arrested or suppressed).

[0054] According to certain embodiments, the patient's response to the immune checkpoint inhibitor administered during a third period (after administration of the FGFR inhibitor) is greater than the patient's response to the immune checkpoint inhibitor without prior treatment with the FGFR inhibitor (e.g., during or after the first period). FGFR gene - modified tumors may be "immunologically cold" or unresponsive to I / O therapy, but after exposure to an FGFR inhibitor such as erdafitinib during the second period, the tumor becomes "hot", i.e., its sensitivity to immune checkpoint inhibitors can increase, and as a result, the patient is thought to respond to the immune checkpoint inhibitor administered during the third period.

[0055] According to certain embodiments, the present invention is a method of treating a patient diagnosed with cancer by administering to the patient an effective amount of an FGFR inhibitor (e.g., erdafitinib) effective to increase the patient's sensitivity to an immune checkpoint inhibitor, administering an FGFR inhibitor to a patient during a first period, wherein an immune checkpoint inhibitor is not administered to the patient during the first period; and administering an immune checkpoint inhibitor to the patient during a second period after the first period, wherein the FGFR inhibitor is not administered to the patient during the second period and the patient is diagnosed with FGFR gene-altered cancer. According to certain embodiments, the present invention provides an FGFR inhibitor (e.g., erdafitinib) for use in treating cancer in a patient diagnosed with cancer by administering an amount of the FGFR inhibitor (e.g., erdafitinib) effective to increase the patient's sensitivity to an immune checkpoint inhibitor, the method comprising administering an FGFR inhibitor to a patient during a first period, wherein the immune checkpoint inhibitor is not administered to the patient during the first period; and administering an immune checkpoint inhibitor to the patient during a second period after the first period, wherein the FGFR inhibitor is not administered to the patient during the second period and the patient is diagnosed with FGFR gene-altered cancer comprising.

[0056] Further embodiments of the present invention are provided below: (1) Use of an immune checkpoint inhibitor (e.g., an antibody that blocks the interaction between PD-1 and PD-L1, such as pembrolizumab or atezolizumab) for the manufacture of a medicament for treating a cancer patient who has progressed after treatment with an FGFR inhibitor (e.g., erdafitinib). (2) An immune checkpoint inhibitor (e.g., an antibody that blocks the interaction between PD-1 and PD-L1, such as pembrolizumab or atezolizumab) for use in treating a cancer patient who has progressed after treatment with an FGFR inhibitor (e.g., erdafitinib). (3) Use of an immune checkpoint inhibitor (e.g., an antibody that blocks the interaction between PD-1 and PD-L1, such as pembrolizumab or atezolizumab or nivolumab; or an antibody that blocks the interaction between CTLA-4 and CD80 or CD86) for the manufacture of a medicament for treating cancer patients, wherein the patient is a patient who has progressed after treatment with an FGFR inhibitor (e.g., erdafitinib), and the patient has received an FGFR inhibitor after a biological sample from the cancer patient tested positive for the presence of one or more FGFR variants, particularly one or more FGFR mutations and / or fusions. (4) An immune checkpoint inhibitor for use in the treatment of cancer patients, wherein the patient is a patient who has progressed after treatment with an FGFR inhibitor, and the patient has received an FGFR inhibitor after a biological sample from the cancer patient tested positive for the presence of one or more FGFR variants, particularly one or more FGFR mutations and / or fusions. (5) Use of an FGFR inhibitor to increase the sensitivity of cancer patients to an immune checkpoint inhibitor. (6) An FGFR inhibitor for use in increasing the sensitivity of cancer patients to an immune checkpoint inhibitor. (7) Use of an FGFR inhibitor to increase the sensitivity of cancer patients to an immune checkpoint inhibitor again. (8) An FGFR inhibitor for use in increasing the sensitivity of cancer patients to an immune checkpoint inhibitor again. (9) An FGFR inhibitor for use in a treatment sequence in which an immune checkpoint inhibitor is re-administered to a cancer patient, wherein the cancer patient's disease has progressed with a previous immune checkpoint inhibitor. (10) An FGFR inhibitor for use in a treatment sequence, wherein the cancer patient has the disease progress during treatment with an FGFR inhibitor and then an immune checkpoint inhibitor is re-administered, and the cancer patient's disease has progressed with a previous immune checkpoint inhibitor. (11) Use of an FGFR inhibitor for the preparation of a medicament for the treatment of cancer patients, wherein the FGFR inhibitor is used in a treatment sequence, the cancer patient is re-administered an immune checkpoint inhibitor after treatment with the FGFR inhibitor, and the cancer patient's disease has progressed with a previous immune checkpoint inhibitor. Use of the FGFR inhibitor. (12) Use of an FGFR inhibitor for the preparation of a medicament for the treatment of cancer patients, wherein the FGFR inhibitor is used in a treatment sequence, the cancer patient is re-administered an immune checkpoint inhibitor after the disease has progressed during treatment with the FGFR inhibitor, and the cancer patient's previous disease has progressed with a previous immune checkpoint inhibitor. Use of the FGFR inhibitor.

[0057] The term "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical (such as an FGFR inhibitor, e.g., erdafitinib, or an immune checkpoint inhibitor) that elicits a biological or pharmaceutical response (e.g., a decrease or inhibition of the activity of an enzyme or protein or remission of symptoms, reduction of a pathological condition, slowing or delaying of disease progression, or prevention of a disease) in a tissue system, animal, or human as determined by a researcher, veterinarian, physician, or other clinician. In other words, the term therapeutically effective amount can refer to an amount that achieves a therapeutic effect by inhibiting, reducing, or treating a disease, pathological condition, syndrome, or disorder in a subject, or by prophylactically inhibiting, preventing, or delaying the onset of a disease, pathological condition, syndrome, or disorder, or its symptoms. A therapeutically effective amount can be an amount that reduces to some extent one or more symptoms of a disease, pathological condition, syndrome, or disorder in a subject, and / or partially or completely normalizes one or more physiological or biochemical parameters associated with or causing the disease, pathological condition, syndrome, or disorder, and / or reduces the likelihood of the onset of a disease, pathological condition, syndrome, or disorder, or its symptoms.

[0058] As used herein, the term "FGFR inhibitor" refers to a compound that inhibits the enzymatic activity of one or more fibroblast growth factor receptors (FGFRs), such as FGFR1, FGFR2, FGFR3, FGFR4.

[0059] According to certain embodiments, the effectiveness of the methods described herein is evaluated by determining the time to disease progression in a patient or the patient response rate. In some embodiments, effectiveness is evaluated by determining the time to disease progression in a patient, e.g., by determining a decrease in disease progression over time in response to treatment by the methods of the present disclosure. Disease progression can be measured by cancer cell growth (local or systemic), and / or recurrence of disease side effects, and / or occurrence of new side effects of the disease. In other embodiments, effectiveness is evaluated by determining the patient response rate. As used herein, "response rate" is the ratio of the number of patients who responded to treatment (as evidenced by effectiveness) to the number of patients treated. According to certain embodiments, the effectiveness of the treatment methods of the present disclosure is measured by one or more of a decrease in cancer cell growth (local or systemic), disappearance of cancer cells (local or systemic), decrease in disease side effects, or disappearance of disease side effects. According to certain embodiments, the method or use of the present invention is effective to reduce the tumor volume of a patient after treatment. Evaluation of a patient's tumor response can be performed according to known criteria called Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

[0060] In the methods or uses described herein, administration of the FGFR inhibitor by any acceptable route is possible. In some embodiments, the FGFR inhibitor is administered orally, parenterally (i.e., in liquid form), rectally (i.e., in the form of a suppository), topically (i.e., in the form of a transdermal patch, ointment, or cream), or intranasally. Examples of parenteral administration include intravenous (IV), intramuscular (IM), and subcutaneous (SC) injection. Preferably, the FGFR inhibitor is administered orally, particularly once daily.

[0061] According to certain embodiments, the immune checkpoint inhibitor is administered intravenously.

[0062] Although it is possible to administer the active ingredient alone, i.e., as is, it can also be included in a pharmaceutical composition. Accordingly, the present disclosure further provides a pharmaceutical composition and, as an active ingredient, an FGFR inhibitor described herein. Accordingly, the FGFR inhibitor can be formulated into various pharmaceutical forms for any conventional route of administration.

[0063] When formulating an FGFR inhibitor in a pharmaceutical composition, the composition also includes one or more pharmaceutically acceptable carriers, diluents, and / or excipients. Specific carriers, diluents, and / or excipients depend on the route of administration and can be determined by those skilled in the art. The carrier, diluent, and / or excipient must be "acceptable" in the sense that it is compatible with the other components of the composition and not harmful to its recipient. Examples of excipients include diluents, lubricants, binders, disintegrants, suspending agents, penetration enhancers, and / or suitable wetting agents. The excipient can be in the form of a liquid such as water, glycol, oil, or alcohol, or a solid such as starch, sugar, or kaolin.

[0064] According to an embodiment, erdafitinib is formulated as a tablet for oral administration. The table can include excipients selected from croscarmellose sodium, magnesium stearate, mannitol, meglumine, microcrystalline cellulose, etc. According to one embodiment, erdafitinib is formulated as a tablet containing 3 mg of erdafitinib equivalent to the base. According to one embodiment, erdafitinib is formulated as a tablet containing 4 mg of erdafitinib equivalent to the base. According to one embodiment, erdafitinib is formulated as a tablet containing 5 mg of erdafitinib equivalent to the base. According to one embodiment, erdafitinib is administered at a dose of 8 mg per day, particularly once a day, as two tablets containing 4 mg of erdafitinib equivalent to the base. According to one embodiment, erdafitinib is administered at a dose of 9 mg per day, particularly once a day, as three tablets containing 3 mg of erdafitinib equivalent to the base.

[0065] Pharmaceutical compositions designed for oral administration can be in solid or liquid form. In some embodiments, the oral formulation is a liquid formulation such as a suspension, syrup, elixir, emulsion, or solution. In other embodiments, the oral formulation is a solid formulation such as a tablet (including a divided tablet or a coated tablet), capsule, caplet (including a divided or coated caplet), pill, powder, or wafer.

Example

[0066] Example 1. Clinical trial In this analysis, the clinical responses to pre-treatment and subsequent treatment in FGFR-positive patients with mUC obtained from the main phase 2 trial of erdafitinib were evaluated.

[0067] Test summary: This study is a retrospective analysis of data collected from patients randomly assigned to regimen 3 (once-daily administration of 8 mg of erdafitinib) of the phase 2 multicenter open-label trial of erdafitinib (BLC2001; NCT02365597). The phase 2 trial is described, for example, in Loriot Y, et al. N Engl J Med. 2019;25;381(4):338 - 348, which is incorporated herein by reference.

[0068] Patients had pre-specified FGFR2 / 3 mutations / fusions, locally advanced or metastatic urothelial carcinoma, and progression during or after pre-treatment with one or more lines of chemotherapy, or progression within 12 months of adjuvant / neoadjuvant chemotherapy, or were cisplatin-ineligible and chemotherapy-naive.

[0069] Pre-treatment with systemic therapy received for metastatic or surgically unresectable UC and the treatment lines up to erdafitinib thereafter were reported by the study investigator.

[0070] The endpoints of the study included the following: 1. Prior treatment period: The time interval from the start of the first administration in the current treatment line to the start of the first administration in the next treatment line for prior treatment. 2. Time to progression (TTP): The time interval from the start of prior treatment until disease progression on the same treatment. 3. Efficacy of prior treatment: Efficacy was evaluated based on the best efficacy reported by the principal investigator of the clinical trial. a) Objective response rate (ORR): The proportion of patients who showed a complete response and a partial response to treatment b) Disease control rate (DCR): The proportion of patients who achieved a complete response, partial response, and stable disease 6. Progression-free survival (PFS): The time interval from the first administration of the investigational drug / initiation of subsequent treatment until the first occurrence of disease progression or death from any cause 7. Overall survival (OS): The time interval from the first administration of the investigational drug / initiation of subsequent treatment until death from any cause 8. The efficacy of subsequent treatment was evaluated by calculating ORR and DCR using the best efficacy reported by the principal investigator of the clinical trial.

[0071] Response was evaluated by the principal investigator of the clinical trial, and response rates were summarized using frequencies and percentages. Survival outcomes (TTP, PFS, and OS) were estimated using the Kaplan-Meier method, showing the median value together with the 95% CI.

[0072] Of the 210 eligible patients, 99 were enrolled in the erdafitinib group at 8 mg once daily (increased up to 9 mg).

[0073]

Table 1

[0074] Overall, 88 / 99 (88.9%) patients received prior treatment with systemic therapy (Table 2). Overall, 34 / 99 (34.3%) patients received subsequent systemic therapy after treatment with erdafitinib, 19 / 99 (19.2%) patients received subsequent chemotherapy, and 15 / 99 (15.2%) patients received subsequent immunotherapy.

[0075] [Table 2]

[0076] [Table 3]

[0077] The median treatment duration of erdafitinib in the BLC2001 trial was 5.3 months. See, for example, Loriot Y, et al. N Engl J Med. 2019;25;381(4):338-348. This reference is incorporated herein by reference.

[0078] [Table 4]

[0079] Regarding the time to progression (TTP) in prior treatment: The median TTP (95% CI) in the first line of prior treatment (7.34 [5.91; 8.80] months) was longer than the median TTP in the second line (7.13 [3.78; 9.36] months) or the third line (5.70 [2.33; 8.64] months).

[0080] [Table 5]

[0081] Regarding the response rates of pre-treatment and subsequent treatment: In the BLC2001 trial, treatment with erdafitinib showed a confirmed ORR of 40% (95% CI: 30.7; 50.1) as evaluated by the treating physicians. It is noted that pre-treatment with I / O therapy was effective in only 1 out of 22 patients (less than 5%) before receiving treatment with erdafitinib. Furthermore, the one patient in whom pre-treatment with I / O therapy was effective had a combination with an experimental I / O agent. In short, these observations support the clinical observation that FGFR gene-altered tumors (luminal 1) may be "immunologically cold" or refractory to I / O therapy.

[0082] In the first-line and second-line chemotherapy of pre-treatment, the ORR and DCR were higher compared to the third-line chemotherapy. Please refer to Figure 1.

[0083] The ORR and DCR of pre-treatment with first-line systemic therapy for patients with FGFR3 mutations (n = 65) versus patients with FGFR2 / 3 fusions (n = 23) were as follows: ORR: 20 (30.8%), 95% CI: 19.5; 42.0 vs 8 (34.8%), 95% CI: 15.3 vs 54.2 DCR: 40 (61.5%), 95% CI: 49.7; 73.4 vs 11 (47.8%), 95% CI: 27.4, 68.2

[0084] Regarding the response rates of subsequent treatment: Patients receiving immunotherapy after treatment with erdafitinib had higher ORR and DCR than patients who received chemotherapy after erdafitinib. It is noted that the ORR before I / O therapy was less than 5% in the 22-patient cohort.

[0085]

Table 6

[0086] Regarding the progression-free survival (PFS) and overall survival (OS) after subsequent treatment: In the BLC2001 trial, the median PFS with erdafitinib therapy was 5.5 months (95% CI: 4.2, 6.0), and the median OS was 13.8 months (95% CI: 9.8, not reached).

[0087] The median PFS and OS in patients with FGFR3 mutations (n = 74) and FGFR2 / 3 fusions (n = 25) were as follows: Median OS (95% CI): 13.80 months (10.71, not estimable) vs. 10.32 months (6.97, not estimable) Median PFS (95% CI): 5.59 months (4.90, 7.39) vs. 2.83 months (1.64, 5.95).

[0088] The median PFS in patients who received subsequent anti-cancer therapy after erdafitinib treatment was 2.27 months (95% CI: 0.79, 2.86), and the median OS was 3.52 months (95% CI: 2.04, 8.90). See Figures 2 and 3.

[0089] The lack of observed objective response rate (ORR) in the immunotherapy cohort seen before the ORR was obtained with third-line immunotherapy in patients exposed to the I / O therapy (n = 22) approved by the FDA in BLC-2001 clinically supports the possibility that erdafitinib monotherapy had an immune priming effect on the tumor microenvironment, and emphasizes the potential clinical benefit of a sequential approach using checkpoint inhibitors (e.g., administration of immune checkpoint inhibitors after monotherapy with an FGFR inhibitor such as erdafitinib).

[0090] Example 2. Clinical Trial BLC2002 (NCT03473743) is a Phase 1b-2 trial evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of erdafitinib + cetrelimab (an anti-PD-1 monoclonal antibody) in subjects with metastatic or locally advanced urothelial carcinoma with specific FGFR gene changes.

[0091] The 1b phase is the dose escalation part of the trial that examined two dosing cohorts of erdafitinib (standard cohort and alternative cohort), with a fixed intravenous (IV) dose of cetrelizumab. In the standard cohort (DL1, DL2, or DL2A), erdafitinib and cetrelizumab are started simultaneously on Day 1 of Cycle 1 (C1D1). In the alternative cohort (DL1B or DL2B), dosing of erdafitinib starts on C1D1, but cetrelizumab is started on Day 1 of Cycle 2 (C2D1) after 1 cycle (4 weeks) (also referred to as a 28-day run-in of erdafitinib).

[0092] Blood for immunocyte profiling was collected at four time points (C1D1, C1D15, C2D1, and C3D1) and subjected to flow cytometry analysis on a real-time basis. T cell activation was quantified as the doubling rate of the ratio of 1) CD38+CD3, CD38+CD4, or CD38+CD8 T cells among the lymphocyte or CD3 T cell population, and 2) CD38+ cells among the CD4+ or CD8+ T cell population, compared to the baseline ratio level at C1D1.

[0093] Longitudinal blood samples were analyzed from DL2A (E8J cohort: erdafitinib 8 mg + cetrelizumab 240 mg), DL2B (E8RJ cohort: erdafitinib 8 mg 28-day run-in + cetrelizumab 240 mg), and DL2 (EJ cohort: erdafitinib 8 mg (with the potential for dose adjustment up to 9 mg depending on the phosphate level concentration measured at C1D15) + cetrelizumab 240 mg).

[0094] In the E8RJ cohort, a sustained increase was detected in the proportions of CD38+CD3 T cells (Figure 4a) and CD38+CD4 T cell subsets (Figure 4b) in the lymphocyte population. Interestingly, the proportion of CD38+CD8 T cells in E8RJ increased dramatically at C1D15 in response to erlotinib monotherapy and further increased at C3D1 when cetrelizumab was applied at C2D1 (Figure 4c). Similar findings were also observed in the proportions of CD38+CD3 T cells (Figure 5a), CD38+CD4 T cell subsets (Figure 5b), and CD38+CD8 T cell subsets (Figure 5c) among the CD3 T cell population, as well as in the proportions of CD38+ cells among the CD4+T cell population (Figure 6a) and CD8+ cells among the CD8+T cell population (Figure 6b). In contrast, in E8J and EJ, the proportion of CD38+T cells only showed a peak increase at C1D15 and then decreased to a level similar to that at C1D1 at later time points. These results indicate that sequential administration of erlotinib followed by cetrelizumab can promote and prolong peripheral blood T cell activation. It may include the following aspects. [1] A method for treating cancer in a patient, comprising the step of administering to the patient a therapeutically effective amount of an immune checkpoint inhibitor, wherein the patient has an FGFR variant and is being treated with an FGFR inhibitor. [2] The method according to [1] above, wherein the FGFR inhibitor is erdafitinib or a pharmaceutically acceptable salt thereof. [3] The method according to [1] or [2] above, wherein prior to the step of administering the immune checkpoint inhibitor, the patient shows disease progression in response to the FGFR inhibitor. [4] The method according to any one of [1] to [3] above, wherein prior to the step of administering the FGFR inhibitor, the patient has been treated with a first immune checkpoint inhibitor and shows disease progression in response to the first immune checkpoint inhibitor. [5] The method according to any one of [1] to [4] above, wherein the immune checkpoint inhibitor is an antibody that blocks the interaction between PD-1 and PD-L1. [6] The method according to any one of [1] to [4] above, wherein the immune checkpoint inhibitor is pembrolizumab, atezolizumab, or nivolumab. [7] The method according to any one of [1] to [4] above, wherein the immune checkpoint inhibitor is an antibody that blocks the interaction between CTLA-4 and CD80 or CD86. [8] The method according to any one of [1] to [4] above, wherein the immune checkpoint inhibitor is selected from the group consisting of atezolizumab, pembrolizumab, nivolumab, durvalumab, avelumab, an anti-CSF1R antibody, tremelimumab, and ipilimumab. [9] The method according to any one of [1] to [8] above, wherein the patient is diagnosed with an FGFR gene-altered tumor.

[10] The method according to any one of [1] to [8] above, wherein the patient is diagnosed with bladder cancer.

[11] The method according to any one of [1] to [8] above, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma.

[12] The method according to any one of [1] to [8] above, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma having a genetic alteration in FGFR2 or FGFR3.

[13] The method according to any one of [1] to [8] above, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma having a gene change in FGFR2 or FGFR3, and is a patient who has progressed during or after at least one line of platinum-containing pre-chemotherapy including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

[14] The FGFR variant is selected from the group consisting of FGFR2:AFF3; FGFR2:BICC1; FGFR2:CASP7; FGFR2:CCDC6; FGFR2:OFD1; FGFR3:BAIAP2L1; FGFR3:TACC3-intron; FGFR3:TACC3V1; FGFR3:TACC3V3; and combinations thereof, according to any one of [1] to

[13] above.

[15] The FGFR inhibitor is erdafitinib and is administered in an amount of about 8 mg to about 9 mg per day, according to any one of [1] to

[14] above.

[16] The method according to any one of [1] to

[15] above, which is effective for achieving complete or partial response in the patient, for example, reducing the tumor volume of the patient and / or suppressing or alleviating the progression of the disease state.

[17] The immune checkpoint inhibitor is cetrelimab, the multimeric polypeptide according to any one of [1] to

[16] above.

[18] A method of treating a patient diagnosed with cancer by administering to the patient an FGFR inhibitor in an amount effective to increase the sensitivity of the patient to an immune checkpoint inhibitor, comprising the step of administering an FGFR inhibitor to the patient during a second period (wherein no immune checkpoint inhibitor is administered to the patient during the second period); and after the second period, administering an immune checkpoint inhibitor to the patient during a third period (wherein no FGFR inhibitor is administered to the patient during the third period), wherein the patient (a) is diagnosed with FGFR gene-altered cancer, (b) was administered a first immune checkpoint inhibitor during a first period prior to the second period, no FGFR inhibitor was administered to the patient during the first period, and (c) did not respond to the first immune checkpoint inhibitor during the first period is a method comprising the step of administering.

[19] The FGFR inhibitor is erdafitinib or a pharmaceutically acceptable salt thereof, according to the method described in

[18] above. ​

[20] The method according to

[18] above, wherein the FGFR inhibitor is erdafitinib free base.

[21] The method according to any one of

[18] to

[20] above, wherein the patient responded to the FGFR inhibitor during the second period.

[22] The method according to any one of

[18] to

[21] above, wherein the immune checkpoint inhibitor is an antibody that blocks the interaction between PD-1 and PD-L1.

[23] The method according to any one of

[18] to

[21] above, wherein the immune checkpoint inhibitor is pembrolizumab, atezolizumab, or nivolumab.

[24] The method according to any one of

[18] to

[21] above, wherein the immune checkpoint inhibitor is an antibody that blocks the interaction between CTLA-4 and CD80 or CD86.

[25] The method according to any one of

[18] to

[21] above, wherein the immune checkpoint inhibitor is selected from the group consisting of atezolizumab, pembrolizumab, nivolumab, durvalumab, avelumab, an anti-CSF1R antibody, tremelimumab, and ipilimumab.

[26] The method according to any one of

[18] to

[21] above, wherein the immune checkpoint inhibitor is cetrelimab.

[27] The method according to any one of

[18] to

[26] above, wherein the patient is diagnosed with bladder cancer.

[28] The method according to any one of

[18] to

[26] above, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma.

[29] The method according to any one of

[18] to

[26] above, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma having a genetic alteration in FGFR2 or FGFR3.

[30] The method according to any one of

[18] to

[26] above, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma having a genetic alteration in FGFR2 or FGFR3 and has progressed during or after at least 1 line of platinum-containing neoadjuvant or adjuvant platinum-containing chemotherapy within 12 months.

[31] The method according to any one of

[18] to

[30] above, wherein the patient has an FGFR variant selected from the group consisting of FGFR2:AFF3; FGFR2:BICC1; FGFR2:CASP7; FGFR2:CCDC6; FGFR2:OFD1; FGFR3:BAIAP2L1; FGFR3:TACC3-intron; FGFR3:TACC3v1; FGFR3:TACC3v3; and combinations thereof.

[32] The method according to any one of

[18] to

[31] above, wherein the FGFR inhibitor is erdafitinib and is administered in an amount of about 8 mg to about 9 mg per day during the second period.

[33] The method according to any one of

[18] to

[32] above, which is effective for achieving complete or partial response in the patient, for example, reducing the tumor volume of the patient and / or inhibiting or alleviating the progression of the disease state.

[34] An immune checkpoint inhibitor for use in the treatment of cancer in a patient, wherein the patient has an FGFR variant and has been pre-treated with an FGFR inhibitor.

[35] The immune checkpoint inhibitor for use according to

[34] above, wherein the FGFR inhibitor is erdafitinib or a pharmaceutically acceptable salt thereof.

[36] The immune checkpoint inhibitor for use according to

[34] or

[35] above, wherein the patient shows disease progression in response to the FGFR inhibitor prior to the use of the immune checkpoint inhibitor.

[37] The immune checkpoint inhibitor for use according to any one of

[34] to

[36] above, wherein the patient has been treated with a first immune checkpoint inhibitor and shows disease progression in response to the first immune checkpoint inhibitor prior to the use of the FGFR inhibitor.

[38] The immune checkpoint inhibitor for use according to any one of

[34] to

[37] above, which is an antibody that blocks the interaction between PD-1 and PD-L1.

[39] The immune checkpoint inhibitor for use according to any one of

[34] to

[37] above, which is pembrolizumab, atezolizumab, or nivolumab.

[40] The immune checkpoint inhibitor for use according to any one of

[34] to

[37] above, which is an antibody that blocks the interaction between CTLA-4 and CD80 or CD86.

[41] An immune checkpoint inhibitor for use as described in any one of

[34] to

[37] above, selected from the group consisting of atezolizumab, pembrolizumab, nivolumab, durvalumab, abelumab, an anti-CSF1R antibody, tremelimumab, and ipilimumab.

[42] An immune checkpoint inhibitor for use as described in any one of

[34] to

[41] above, wherein the patient is diagnosed with an FGFR gene-altered tumor.

[43] An immune checkpoint inhibitor for use as described in any one of

[34] to

[41] above, wherein the patient is diagnosed with bladder cancer.

[44] An immune checkpoint inhibitor for use as described in any one of

[34] to

[41] above, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma.

[45] An immune checkpoint inhibitor for use as described in any one of

[34] to

[41] above, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma having a genetic alteration in FGFR2 or FGFR3.

[46] An immune checkpoint inhibitor for use as described in any one of

[34] to

[41] above, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma having a genetic alteration in FGFR2 or FGFR3 and has progressed during or after at least 1 line of platinum-containing neoadjuvant or adjuvant platinum-containing chemotherapy within 12 months.

[47] An immune checkpoint inhibitor for use as described in any one of

[34] to

[46] above, wherein the FGFR variant is selected from the group consisting of FGFR2:AFF3; FGFR2:BICC1; FGFR2:CASP7; FGFR2:CCDC6; FGFR2:OFD1; FGFR3:BAIAP2L1; FGFR3:TACC3-intron; FGFR3:TACC3V1; FGFR3:TACC3V3; and combinations thereof.

[48] An immune checkpoint inhibitor for use as described in any one of

[34] to

[47] above, wherein the FGFR inhibitor is erdafitinib and is administered in an amount of about 8 mg to about 9 mg per day.

[49] The use according to any one of

[34] to

[48] above, wherein the use is effective for achieving complete or partial response of the patient, for example, reducing the tumor volume of the patient and / or inhibiting or alleviating the progression of the disease state, and the immune checkpoint inhibitor for such use.

[50] The immune checkpoint inhibitor for the use according to any one of

[34] to

[49] above, which is cetrelimab.

[51] An FGFR inhibitor for use in increasing the sensitivity of a cancer patient to an immune checkpoint inhibitor.

[52] The FGFR inhibitor for the use according to

[51] above, wherein the immune checkpoint inhibitor is an antibody that blocks the interaction between PD-1 and PD-L1.

[53] The FGFR inhibitor for the use according to

[51] above, wherein the immune checkpoint inhibitor is pembrolizumab, atezolizumab, or nivolumab.

[54] The FGFR inhibitor for the use according to

[51] above, wherein the immune checkpoint inhibitor is an antibody that blocks the interaction between CTLA-4 and CD80 or CD86.

[55] The FGFR inhibitor for the use according to

[51] above, wherein the immune checkpoint inhibitor is selected from the group consisting of atezolizumab, pembrolizumab, nivolumab, durvalumab, avelumab, an anti-CSF1R antibody, tremelimumab, and ipilimumab.

[56] The FGFR inhibitor for the use according to

[51] above, wherein the immune checkpoint inhibitor is cetrelimab.

[57] The FGFR inhibitor for the use according to any one of

[51] to

[56] above, wherein the patient has an FGFR variant.

[58] The FGFR inhibitor for the use according to any one of

[51] to

[56] above, wherein the patient is diagnosed with an FGFR gene-altered tumor.

[59] The FGFR inhibitor for the use according to any one of

[51] to

[56] above, wherein the patient is diagnosed with bladder cancer.

[60] The FGFR inhibitor for the use according to any one of

[51] to

[56] above, wherein the patient is diagnosed with locally advanced or metastatic urothelial cancer.

[61] The FGFR inhibitor for the use according to any one of

[51] to

[56] above, wherein the patient is diagnosed with locally advanced or metastatic urothelial cancer having a genetic alteration in FGFR2 or FGFR3.

[62] The FGFR inhibitor for use according to any one of

[51] to

[56] above, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma having a genetic alteration in FGFR2 or FGFR3, and is a patient who has progressed during or after at least one line of platinum-containing pre-chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

[63] The FGFR inhibitor for use according to any one of

[51] to

[56] above, wherein the FGFR variant is selected from the group consisting of FGFR2:AFF3; FGFR2:BICC1; FGFR2:CASP7; FGFR2:CCDC6; FGFR2:OFD1; FGFR3:BAIAP2L1; FGFR3:TACC3-intron; FGFR3:TACC3V1; FGFR3:TACC3V3; and combinations thereof.

[64] The FGFR inhibitor for use according to any one of

[51] to

[63] above, which is erdafitinib.

[65] The FGFR inhibitor for use according to any one of

[51] to

[63] above, which is erdafitinib and is administered in an amount of about 8 mg to about 9 mg per day.

[66] The FGFR inhibitor for use according to any one of

[51] to

[65] above, wherein the immune checkpoint inhibitor is cetrelimab.

Claims

A pharmaceutical composition for use in a method of treating bladder cancer, or locally advanced or metastatic urothelial carcinoma, in a patient diagnosed with said cancer, wherein said pharmaceutical composition comprises erdafitinib free base or a pharmaceutically acceptable salt thereof, wherein said method comprises administering an effective amount of erdafitinib free base or a pharmaceutically acceptable salt thereof to increase the sensitivity of said patient to an antibody that blocks the interaction between PD-1 and PD-L1, wherein said method comprises administering to said patient erdafitinib free base or a pharmaceutically acceptable salt thereof during a second period (wherein during said second period said antibody that blocks the interaction between PD-1 and PD-L1 is not administered); and after said second period, administering to said patient said antibody that blocks the interaction between PD-1 and PD-L1 during a third period (wherein during said third period erdafitinib free base or a pharmaceutically acceptable salt thereof is not administered to said patient), wherein said patient is diagnosed with (a) an FGFR gene modified cancer, was administered a first antibody that blocks the interaction between PD-1 and PD-L1 during a first period prior to said second period, and during said first period erdafitinib free base or a pharmaceutically acceptable salt thereof was not administered to said patient, and did not respond to said first antibody that blocks the interaction between PD-1 and PD-L1 during said first period administering step A pharmaceutical composition comprising

2. The pharmaceutical composition for use according to claim 1, wherein the erdafitinib free base or a pharmaceutically acceptable salt thereof is erdafitinib free base.

3. The pharmaceutical composition for use according to claim 1 or 2, wherein said patient responded to the erdafitinib free base or a pharmaceutically acceptable salt thereof during said second period.

4. The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the antibody that blocks the interaction between PD-1 and PD-L1 is pembrolizumab, atezolizumab, or nivolumab.

5. The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the antibody that blocks the interaction between PD-1 and PD-L1 is selected from the group consisting of atezolizumab, pembrolizumab, nivolumab, durvalumab, and avelumab. A pharmaceutical composition for use according to any one of claims 1 to 3, wherein the antibody that blocks the interaction between PD-1 and PD-L1 is cetrelimab.

7. A pharmaceutical composition for use according to any one of claims 1 to 6, wherein the patient is diagnosed with bladder cancer.

8. A pharmaceutical composition for use according to any one of claims 1 to 6, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma.

9. A pharmaceutical composition for use according to any one of claims 1 to 6, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma having a genetic alteration in FGFR2 or FGFR3.

10. A pharmaceutical composition for use according to any one of claims 1 to 6, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma having a genetic alteration in FGFR2 or FGFR3 and has progressed during or after at least one line of platinum-containing neoadjuvant or adjuvant platinum-containing chemotherapy within 12 months.

11. A pharmaceutical composition for use according to any one of claims 1 to 10, wherein the patient has an FGFR variant selected from the group consisting of FGFR2: AFF3; FGFR2: BICC1; FGFR2: CASP7; FGFR2: CCDC6; FGFR2: OFD1; FGFR3: BAIAP2L1; FGFR3: TACC3-intron; FGFR3: TACC3v1; FGFR3: TACC3v3; and combinations thereof.

12. A pharmaceutical composition for use according to any one of claims 1 to 11, wherein the erdafitinib free base or a pharmaceutically acceptable salt thereof is the erdafitinib free base and is administered in an amount of about 8 mg to about 9 mg per day during the second period.

13. A pharmaceutical composition for use according to any one of claims 1 to 12, wherein the method is effective for achieving complete or partial response in the patient.

14. A pharmaceutical composition for use according to any one of claims 1 to 12, wherein the method reduces the tumor volume of the patient and / or inhibits or alleviates the progression of cancer.

15. A pharmaceutical composition for use in a method of treating bladder cancer, or locally advanced or metastatic urothelial carcinoma, in a patient diagnosed with said cancer, The pharmaceutical composition includes an antibody that blocks the interaction between PD-1 and PD-L1, The patient has an FGFR variant and has been pre-treated with erdafitinib free base or a pharmaceutically acceptable salt thereof, a pharmaceutical composition. **Claim 16**: The pharmaceutical composition for use according to claim 15, wherein the erdafitinib free base or a pharmaceutically acceptable salt thereof is erdafitinib free base. **Claim 17**: The pharmaceutical composition for use according to claim 15 or 16, wherein the patient shows disease progression in response to the erdafitinib free base or a pharmaceutically acceptable salt thereof before the use of the antibody that blocks the interaction between PD-1 and PD-L1. **Claim 18** The pharmaceutical composition for use according to any one of claims 15 to 17, wherein the patient has been treated with a first antibody that blocks the interaction between PD-1 and PD-L1 and shows disease progression in response to the first antibody that blocks the interaction between PD-1 and PD-L1 before the use of the erdafitinib free base or a pharmaceutically acceptable salt thereof. **Claim 19**: The pharmaceutical composition for use according to any one of claims 15 to 18, wherein the antibody that blocks the interaction between PD-1 and PD-L1 is pembrolizumab, atezolizumab, or nivolumab. **Claim 20**: The pharmaceutical composition for use according to any one of claims 15 to 18, wherein the antibody that blocks the interaction between PD-1 and PD-L1 is selected from the group consisting of atezolizumab, pembrolizumab, nivolumab, durvalumab, and avelumab. **Claim 21** The pharmaceutical composition for use according to any one of claims 15 to 20, wherein the patient is diagnosed with an FGFR gene-altered tumor. **Claim 22** The pharmaceutical composition for use according to any one of claims 15 to 21, wherein the patient is diagnosed with bladder cancer. **Claim 23** The pharmaceutical composition for use according to any one of claims 15 to 21, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma. **Claim 24** The pharmaceutical composition for use according to any one of claims 15 to 20, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma having a genetic alteration in FGFR2 or FGFR3. **Claim 25** The patient is diagnosed with locally advanced or metastatic urothelial carcinoma having a genetic alteration in FGFR2 or FGFR3, and is a patient who has progressed during or after at least one line of platinum-containing pre-chemotherapy including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. A pharmaceutical composition for use according to any one of claims 15 to 20.

26. The FGFR variant is selected from the group consisting of FGFR2: AFF3; FGFR2: BICC1; FGFR2: CASP7; FGFR2: CCDC6; FGFR2: OFD1; FGFR3: BAIAP2L1; FGFR3: TACC3-intron; FGFR3: TACC3V1; FGFR3: TACC3V3; and combinations thereof. A pharmaceutical composition for use according to any one of claims 15 to 25.

27. The erdafitinib free base or a pharmaceutically acceptable salt thereof is the erdafitinib free base and is administered in an amount of about 8 mg to about 9 mg per day. A pharmaceutical composition for use according to any one of claims 15 to 26.

28. The method is effective for achieving complete or partial response in the patient. A pharmaceutical composition for use according to any one of claims 15 to 27.

29. The method reduces the tumor volume of the patient and / or inhibits or alleviates the progression of the disease state. A pharmaceutical composition for use according to any one of claims 15 to 27.

30. The antibody that blocks the interaction between PD-1 and PD-L1 is cetrelimab. A pharmaceutical composition for use according to any one of claims 15 to 29.

31. A pharmaceutical composition for use in a method for increasing the sensitivity of a cancer in a patient diagnosed with bladder cancer, or locally advanced or metastatic urothelial carcinoma, to an antibody that blocks the interaction between PD-1 and PD-L1 administered later, A pharmaceutical composition comprising an erdafitinib free base or a pharmaceutically acceptable salt thereof.

32. The antibody that blocks the interaction between PD-1 and PD-L1 is pembrolizumab, atezolizumab, or nivolumab. A pharmaceutical composition for use according to claim 31.

33. The pharmaceutical composition for use according to claim 31, wherein the antibody that blocks the interaction between PD-1 and PD-L1 is selected from the group consisting of atezolizumab, pembrolizumab, nivolumab, durvalumab, and avelumab.

34. The pharmaceutical composition for use according to claim 31, wherein the antibody that blocks the interaction between PD-1 and PD-L1 is cetrelimab.

35. The pharmaceutical composition for use according to any one of claims 31 to 34, wherein the patient has an FGFR variant.

36. The pharmaceutical composition for use according to any one of claims 31 to 34, wherein the patient is diagnosed with an FGFR gene-altered tumor.

37. The pharmaceutical composition for use according to any one of claims 31 to 36, wherein the patient is diagnosed with bladder cancer.

38. The pharmaceutical composition for use according to any one of claims 31 to 36, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma.

39. The pharmaceutical composition for use according to any one of claims 31 to 36, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma having a genetic alteration in FGFR2 or FGFR3.

40. The pharmaceutical composition for use according to any one of claims 31 to 36, wherein the patient is diagnosed with locally advanced or metastatic urothelial carcinoma having a genetic alteration in FGFR2 or FGFR3 and has progressed during or after at least one line of platinum-containing neoadjuvant or adjuvant platinum-containing chemotherapy within 12 months.

41. The pharmaceutical composition for use according to any one of claims 31 to 36, wherein the FGFR variant is selected from the group consisting of FGFR2: AFF3; FGFR2: BICC1; FGFR2: CASP7; FGFR2: CCDC6; FGFR2: OFD1; FGFR3: BAIAP2L1; FGFR3: TACC3-intron; FGFR3: TACC3V1; FGFR3: TACC3V3; and combinations thereof.

42. The pharmaceutical composition for use according to any one of claims 31 to 41, wherein the erdafitinib free base or a pharmaceutically acceptable salt thereof is the erdafitinib free base.

43. The pharmaceutical composition for use according to claim 42, wherein the erdafitinib free base is administered in an amount of about 8 mg to about 9 mg per day.

Images