WO2018223040A1 - Methods of treating a tumor using an anti-pd-1 antibody - Google Patents

Methods of treating a tumor using an anti-pd-1 antibody Download PDF

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Publication number
WO2018223040A1
WO2018223040A1 PCT/US2018/035670 US2018035670W WO2018223040A1 WO 2018223040 A1 WO2018223040 A1 WO 2018223040A1 US 2018035670 W US2018035670 W US 2018035670W WO 2018223040 A1 WO2018223040 A1 WO 2018223040A1
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Prior art keywords
antibody
tumor
subject
mutation
tmb
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English (en)
French (fr)
Inventor
Robin EDWARDS
William J. Geese
Danielle M. GREENAWALT
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Priority to US16/617,725 priority Critical patent/US11566073B2/en
Priority to EP18733121.0A priority patent/EP3630840A1/en
Priority to KR1020247032911A priority patent/KR20240149982A/ko
Priority to KR1020197038639A priority patent/KR102714702B1/ko
Priority to CN201880035434.1A priority patent/CN110678483B/zh
Priority to CN202311104154.0A priority patent/CN117462668A/zh
Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Priority to JP2019566619A priority patent/JP7780857B2/ja
Publication of WO2018223040A1 publication Critical patent/WO2018223040A1/en
Anticipated expiration legal-status Critical
Priority to US18/161,713 priority patent/US12227576B2/en
Priority to JP2023127759A priority patent/JP2023159179A/ja
Priority to US19/015,341 priority patent/US20250145713A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • This disclosure relates to methods for treating a tumor comprising administering to the subject a an anti -Programmed Death- 1 (PD-1) antibody, wherein the subject carries wild- type STK11.
  • PD-1 anti -Programmed Death- 1
  • PD-1 is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression.
  • PD-1 is a member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA.
  • Two cell surface glycoprotein ligands for PD- 1 have been identified, Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2), that are expressed on antigen-presenting cells as well as many human cancers and have been shown to down-regulate T cell activation and cytokine secretion upon binding to PD-1.
  • PD-L1 Programmed Death Ligand-1
  • PD-L2 Programmed Death Ligand-2
  • Nivolumab (formerly designated 5C4, BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the down- regulation of antitumor T-cell functions (U.S. Patent No. 8,008,449; Wang et al., 2014 Cancer Immunol Res. 2(9) ⁇ -5 ⁇ ).
  • NSCLC is the leading cause of cancer death in the U.S. and worldwide (NCCN).
  • NSCLCs are relatively insensitive to chemotherapy but patients with Stage IV disease who have a good performance status (PS) benefit from treatment with chemotherapeutic drugs, including platinum agents (e.g., cisplatin, carboplatin), taxanes agents (e.g., paclitaxel, albumin-bound paclitaxel, docetaxel), vinorelbine, vinblastine, etoposide, pemetrexed and gemcitabine, and various combinations of these drugs.
  • platinum agents e.g., cisplatin, carboplatin
  • taxanes agents e.g., paclitaxel, albumin-bound paclitaxel, docetaxel
  • vinorelbine paclitaxel
  • vinblastine etoposide
  • pemetrexed pemetrexed
  • gemcitabine various combinations of these drugs.
  • the present disclosure provides a method for treating a subject afflicted with a tumor comprising (i) determining a mutation status of an STK1 1 gene in the subject; and (ii) administering to the subject an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death- 1 (PD-1) receptor and inhibits PD-1 activity ("anti-PD-1 antibody”) if the STK1 1 gene is wild-type.
  • the present disclosure relates to methods for treating a subject afflicted with a tumor comprising administering to the subject an anti-PD-1 antibody, wherein the subject is identified as having a wild-type STK1 1 gene.
  • the present disclosure relates to methods for identifying a subject afflicted with a tumor suitable for an anti-PD-1 antibody treatment comprising (i) determining a mutation status of an STK1 1 gene in the subject; and (ii) administering to the subject anti-PD-1 antibody if the STK1 1 gene is wild-type.
  • the method further comprises detecting a mutation status of a marker gene selected from the group consisting of KRAS, TP53, CDKN2A, PTP D, CUBN, HERCl, and any combination thereof.
  • the present disclosure relates to methods for treating a subject afflicted with a tumor comprising (i) determining a mutation status of marker gene in the subject; and (ii) administering to the subject an anti-PD-1 antibody if the marker gene is mutated; wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERCl, and any combination thereof.
  • the present disclosure relates to methods for treating a subject afflicted with a tumor comprising administering to the subject an anti-PD-1 antibody, wherein the subject is identified as having a mutated marker gene, wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERCl, and any combination thereof.
  • the present disclosure relates to methods for identifying a subject afflicted with a tumor suitable for an anti-PD-1 antibody treatment comprising (i) determining a mutation status of a marker gene in the subject; and (ii) administering to the subject anti-PD-1 antibody if the marker gene is mutated; wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERCl, and any combination thereof.
  • TP53 is mutated.
  • CDKN2A is mutated.
  • PTP D, CUBN, and HERC1 are mutated.
  • the marker gene comprises a non- synonymous mutation. In certain embodiments, the marker gene comprises a nonsense, frameshift, or splicing mutation.
  • the methods further comprise detecting PD-L1 expression in the tumor prior to administration.
  • the tumor expresses PD-L1 in a diffuse pattern.
  • the tumor expresses PD-L1 in a heterogeneous pattern.
  • the mutation status of the STK11 gene is determined by sequencing the STK11 gene.
  • the tumor has a tumor mutational burden (TMB) status that is a high TMB.
  • TMB tumor mutational burden
  • the tumor TMB status is determined by sequencing nucleic acids in the tumor and identifying a genomic alteration in the sequenced nucleic acids.
  • the tumor exhibits high inflammation.
  • the inflammation is measured according to the expression of STK11.
  • the anti-PD-1 antibody is administered at a dose ranging from at least about 0.1 mg/kg to at least about 10.0 mg/kg body weight once about every 1, 2 or 3 weeks. In some embodiments, the anti-PD-1 antibody or antigen-binding portion thereof is administered at a flat dose. In some embodiments, the anti-PD-1 antibody or antigen-binding portion thereof is administered at a flat dose or about 240 mg.
  • the administering treats the tumor. In some embodiments, the administering reduces the size of the tumor. In some embodiments, the subject exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after the initial administration. In some embodiments, the subject exhibits a partial response after the administration. In some embodiments, the subject exhibits a complete response after the administration.
  • this disclosure provides a kit for treating a subject afflicted with a tumor, the kit comprising: (a) a dosage ranging from about 4 mg to about 500 mg of an anti-PD-1 antibody; and (b) instructions for using the anti-PD-1 antibody in any method disclosed herein.
  • the kit further comprises an anti-PD-Ll antibody.
  • a method for treating a subject afflicted with a tumor comprising (i) determining a mutation status of an STK11 gene in the subject; and (ii) administering to the subject an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity (“anti-PD-1 antibody”) if the STK11 gene is wild-type.
  • PD-1 Programmed Death-1
  • E2 A method for treating a subject afflicted with a tumor comprising administering to the subject an anti-PD-1 antibody, wherein the subject is identified as having a wild-type STK11 gene.
  • a method for identifying a subject afflicted with a tumor suitable for an anti-PD-1 antibody treatment comprising (i) determining a mutation status of an STK11 gene in the subject; and (ii) administering to the subject anti-PD-1 antibody if the STK11 gene is wild- type.
  • E4 The method of any one of El to E3, further comprising detecting a mutation status of a marker gene selected from the group consisting of KRAS, TP53, CDKN2A, PTP D, CUBN, HERC1, and any combination thereof.
  • E5. A method for treating a subject afflicted with a tumor comprising (i) determining a mutation status of marker gene in the subject; and (ii) administering to the subject an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death- 1 (PD-1) receptor and inhibits PD-1 activity ("anti-PD-1 antibody”) if the marker gene is mutated; wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTP D, CUBN, HERC1, and any combination thereof.
  • PD-1 antibody Programmed Death- 1
  • E6 A method for treating a subject afflicted with a tumor comprising administering to the subject an anti-PD-1 antibody, wherein the subject is identified as having a mutated marker gene, wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERC1, and any combination thereof.
  • a method for identifying a subject afflicted with a tumor suitable for an anti-PD-1 antibody treatment comprising (i) determining a mutation status of a marker gene in the subject; and (ii) administering to the subject anti-PD-1 antibody if the marker gene is mutated; wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERC1, and any combination thereof.
  • E8 The method of any one of E4 to E7, wherein TP53 is mutated.
  • E10 The method of any one of E4 to E9, wherein PTPND, CUBN, and HERC1 are mutated.
  • E14 The method of E13, wherein the tumor is derived from a small cell lung cancer (SCLC) or a non-small cell lung cancer (NSCLC).
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • E15 The method of E14, wherein the tumor is derived from an NSCLC.
  • E16 The method of E15, wherein the tumor is derived from a non-squamous cell NSCLC.
  • E17 The method of E15, wherein the tumor is derived from a squamous cell
  • El 8. The method of any one of El to El 7, further comprising detecting PD-L1 expression in the tumor prior to administration.
  • E19. The method of E18, wherein the tumor expresses PD-L1 in a diffuse pattern.
  • E20 The method of El 9, wherein the diffuse pattern of PD-L1 expression is characterized by a PD-L1 H-score of from about 60 to about 500, from about 80 to about 480, from about 100 to about 460, from about 120 to about 440, from about 140 to about 420, from about 160 to about 400, from about 180 to about 380, from about 200 to about 360, from about 200 to about 340, from about 200 to about 320, or from about 200 to about 300.
  • a PD-L1 H-score of from about 60 to about 500, from about 80 to about 480, from about 100 to about 460, from about 120 to about 440, from about 140 to about 420, from about 160 to about 400, from about 180 to about 380, from about 200 to about 360, from about 200 to about 340, from about 200 to about 320, or from about 200 to about 300.
  • E21 The method of El 9, wherein the diffuse pattern of PD-L1 expression is characterized by a PD-L1 H-score of at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, at least about 200, at least about 225, at least about 250, at least about 275, or at least about 300.
  • a PD-L1 H-score of at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, at least about 200, at least about 225, at least about 250, at least about 275, or at least about 300.
  • E22 The method of E21, wherein the diffuse pattern of PD-L1 expression is characterized by a PD-L1 H-score of at least about 200.
  • E23 The method of El 8, wherein the tumor expresses PD-L1 in a heterogeneous pattern.
  • E24 The method of E23, wherein the heterogeneous pattern of PD-L1 expression is characterized by a PD-L1 H-score of from about 1 to about 50, from about 5 to about 45, from about 10 to about 40, or from about 15 to about 35, and wherein the PD-L1 expression is restricted to one or more distinct portions of the tumor.
  • E25 The method E23, wherein the heterogeneous pattern of PD-L1 expression is characterized by a PD-L1 H-score of at least about 5, at least about 10, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, or at least about 40.
  • E26 The method of E25, wherein the heterogeneous pattern of PD-L1 expression is characterized by a PD-L1 H-score of at least about 15.
  • E27 The method of any one of El, 3, 4, and 13 to E26, wherein the mutation status of the STK11 gene is determined by sequencing the STK11 gene.
  • E28 The method of any one of El 8 to E27, wherein PD-L1 expression is detected using an immunohistochemistry (THC) assay.
  • THC immunohistochemistry
  • E29 The method of E28, wherein the IHC assay is an automated IHC assay.
  • E30 The method of E28 or E29, wherein the IHC assay is performed using an anti-PD-Ll monoclonal antibody that specifically binds to the PD-L1 and wherein the anti-PD- Ll monoclonal antibody is selected from the group consisting of 28-8, 28-1, 28-12, 29-8, 5H1, and any combination thereof.
  • E31 The method of any one of El 8 to E30, wherein at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%), at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%), at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%), at least about 95%, or about 100% of tumor cells express PD-L1.
  • E32 The method of any one of El to E31, wherein the tumor has a tumor mutational burden (TMB) status that is a high TMB.
  • TMB tumor mutational burden
  • E33 The method of E32, wherein the tumor TMB status is determined by sequencing nucleic acids in the tumor and identifying a genomic alteration in the sequenced nucleic acids.
  • E34 The method of E33, wherein the genomic alteration comprises one or more somatic mutations.
  • E36 The method of any one of E33 to E35, wherein the genomic alteration comprises one or more missense mutations.
  • E37 The method of any one of E33 to E36, wherein the genomic alteration comprises one or more alterations selected from the group consisting of a base pair substitution, a base pair insertion, a base pair deletion, a copy number alteration (CNAs), a gene rearrangement, and any combination thereof.
  • the genomic alteration comprises one or more alterations selected from the group consisting of a base pair substitution, a base pair insertion, a base pair deletion, a copy number alteration (CNAs), a gene rearrangement, and any combination thereof.
  • E39 The method of any one of E32 to E38, wherein the high TMB has a score of at least 215, at least 220, at least 221, at least 222, at least 223, at least 224, at least 225, at least 226, at least 227, at least 228, at least 229, at least 230, at least 231, at least 232, at least 233, at least 234, at least 235, at least 236, at least 237, at least 238, at least 239, at least 240, at least 241, at least 242, at least 243, at least 244, at least 245, at least 246, at least 247, at least 248, at least 249, or at least 250.
  • E40 The method of any one of E32 to E39, wherein the high TMB has a score of at least 243.
  • E44 The method of any one of E32 to E43, wherein the TMB status is determined by genome sequencing.
  • E45 The method of any one of E32 to E43, wherein the TMB status is determined by exome sequencing.
  • E46 The method of any one of E32 to E45, wherein the TMB status is determined by genomic profiling.
  • E47 The method of any one of El to E46, wherein the tumor exhibits high inflammation.
  • E48 The method of E47, wherein the inflammation is measured according to the expression of STK11.
  • E49 The method of any one of El to E48, wherein the anti-PD-1 antibody cross-competes with nivolumab for binding to human PD-1.
  • E50 The method of any one of El to E49, wherein the anti-PD-1 antibody binds to the same epitope as nivolumab.
  • E53 The method of any one of El to E52, wherein the anti-PD-1 antibody is nivolumab.
  • E54 The method of any one of El to E53, wherein the anti-PD-1 antibody is pembrolizumab.
  • E55 The method of any one of El to E54, wherein the anti-PD-1 antibody is administered at a dose ranging from at least about 0.1 mg/kg to at least about 10.0 mg/kg body weight once about every 1, 2 or E3 weeks.
  • E56 The method of E55, wherein the anti-PD-1 antibody is administered at a dose of at least about 3 mg/kg body weight once about every 2 weeks.
  • E57 The method of any one of El to E56, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered at a flat dose.
  • E58 The method of any one of El to E54 and 57, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered at a flat dose of at least about 200, at least about 220, at least about 240, at least about 260, at least about 280, at least about 300, at least about 320, at least about 340, at least about 360, at least about 380, at least about 400, at least about 420, at least about 440, at least about 460, at least about 480, at least about 500 or at least about 550 mg.
  • E59 The method of any one of El to E54, 57, and 58, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered at a flat dose of about 240 mg.
  • E60 The method of any one of El to E54, and 57 to E59, wherein the anti-PD-1 antibody or antigen-binding portion thereof is administered at a flat dose about once every 1, 2, 3 or E4 weeks.
  • E61 The method of any one of El to E60, wherein the anti-PD-1 antibody is administered for as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs.
  • E62 The method of any one of El to E61, wherein the anti-PD-1 antibody is formulated for intravenous administration.
  • E63 The method of any one of El to E62, wherein the anti-PD-1 antibody is administered at a subtherapeutic dose.
  • E64 The method of any one of El to E63, wherein the administering treats the tumor.
  • E65 The method of any one of El to E64, wherein the administering reduces the size of the tumor.
  • E66 The method of E65, wherein the size of the tumor is reduced by at least about 10%, about 20%, about 30%>, about 40%, or about 50% compared to the tumor size prior to the administration.
  • E67 The method of any one of El to E66, wherein the subject exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after the initial administration.
  • E68 The method of any one of El to E67, wherein the subject exhibits stable disease after the administration.
  • E69 The method of any one of El to E67, wherein the subject exhibits a partial response after the administration.
  • E70 The method of any one of El to E67, wherein the subject exhibits a complete response after the administration.
  • kits for treating a subj ect afflicted with a tumor comprising:
  • E72 The kit of E71, further comprising an anti -PD-Ll antibody.
  • FIGs. 1A-1D present immunohistochemistry (IHC) images showing distinct patterns of PD-Ll expression in NSCLC commercial tumors.
  • the patterns of PD-Ll expression are designated diffuse (FIG. 1A), heterogeneous (FIG. IB), tumor-stroma interface (FIG. 1C), and negative (FIG. ID).
  • FIGs. 2A-2B shows the distribution of PD-Ll H-scores in each PD-Ll pattern as shown in FIGs. 1A-1D, i.e., diffuse (D), heterogeneous (H), negative (N), and tumor-stroma interface (T) (FIG. 2A), and the distribution of PD-Ll H-scores in two NSCLC subtypes, namely adenocarcinoma and squamous cell carcinoma (FIG. 2D).
  • FIGs. 3A-3C show IHC images corresponding to diffuse (FIG. 3A), tumor-stroma interface (FIG. 3B) and negative (FIG. 3C) PD-Ll expression patters corresponding to trial biopsies from patients treated with nivolumab monotherapy.
  • FIG. 4 shows the PD-Ll H-score of patients undergoing nivolumab monotherapy.
  • the predominant PD-Ll pattern in the majority of complete responders (CR) and partial responders (PR) is the diffuse pattern.
  • FIGs. 5A-5B show the Overall CI Score (FIG. 5 A) and PD-Ll CI Score (FIG. 5B) according to PD-Ll tumor predominant pattern.
  • FIG. 6 presents a multiplexed IHC image stained for PD-Ll, CD68, and CD3.
  • FIGs. 7A-7B show PD-Ll expression in NSCLC tumors according to PD-Ll expression pattern as measured using RNA sequencing (FIG. 7A), and the mutation load in NSCLC tumors according to PD-Ll expression pattern as measured using exome sequencing (FIG. 7B).
  • FIGs. 8A-8B show the relationship between the number of missense mutations in
  • NSCLC tumors versus overall inflammation as measured by the CI Score (FIG. 8A), and the relationship between the number of missense mutation in NSCLC tumors versus PD-L1 + inflammation as measured by the PDLPlpos CI Score (FIG. 8B).
  • FIGs. 9A-9B show the frequency of mutations in different biomarkers (TP53,
  • FIG. 9A shows PD-Ll expression measured by RNA sequencing (RNAseq) versus presence ("y") or absence ("n") of STK11 mutations.
  • FIG. lOA-lOC show the relationship between presence ("y") or absence ("n") of
  • FIG. 10A shows numeric data corresponding to overall inflammation scores in NSCLC tumors depending on the presence ("STK11-MUT") or absence ("STK11-WT") of STK11 mutations.
  • FIG. 11 shows an immunoprint analysis of 24 NSCLC tumor samples in which levels of FOLR2, VSIG4, CD163, CLEC4D, CSF1R, CD86, MS4A1, CD79B, CD19, KIR2DS4, CD3E, CCR4, CCR8, and CD8A were analyzed to classify the samples according to inflammation patterns (sigClass).
  • Samples were classified as low (“sigClass low”), medium (“sigClass med”) and high (“sigClass hi”) inflammation. Samples were classified also according to presence (“STKl l mut”) or absence (“STKl l wt”) of STKl l mutations. In addition, samples were classified according to PD-Ll expression pattern as negative (“PDLl _pattern 2 Negative"), diffuse, (“PDLl _pattern 2 Diffuse”), heterogeneous (“PDLl _pattern 2 Heterogeneous”), and tumor-stroma interface (“PDLl _pattern 2 TS”).
  • PDLl _pattern 2 Negative negative
  • Diffuse diffuse
  • PDLl _pattern 2 Heterogeneous heterogeneous
  • tumor-stroma interface PDLl _pattern 2 TS
  • FIGs. 12A-12B are graphical representations of survival probability for advanced
  • FIG. 12A includes mutant STKl l subjects having all non-synonymous mutations to STKl l
  • FIG. 12B includes only mutant STKl l subjects having nonsense, frameshift, or splicing mutations to STKl l .
  • the numbers of subjects at risk at each time point for each group is shown below the X axis.
  • FIG. 13 is a graphical representation of survival probability for advanced NSCLC subjects having a KRAS mutation and either wild type STK1 1 (data labels 2 and 4) or mutated STKl l (data labels 1 and 3), wherein the subjects were treated with investigator choice chemotherapy (data labels 1 and 2) or first-line 3 mg/kg anti-PD-1 antibody therapy (Nivolumab; data labels 3 and 4). The numbers of subjects at risk at each time point for each group is shown below the X axis.
  • FIGs. 14A-14B are graphical representations of survival probability for non- squamous cell NSCLC subjects having wild type STKl l (data labels 2 and 4) or any non- synonymous mutation in STKl l (data labels 1 and 3) treated with investigator choice chemotherapy (data labels 1 and 2) or first-line 3 mg/kg anti-PD-1 antibody therapy (Nivolumab; data labels 3 and 4).
  • FIG. 14A includes all subjects meeting this criteria, whereas FIG. 14B includes only subjects that further have a KRAS mutation. The numbers of subjects at risk at each time point for each group is shown below the X axis.
  • FIGs. 15A-15E are graphical representation that show the relationship between
  • FIGs. 15A and 15B show the distribution of WT or mutated STKl l subjects experiencing a complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) following treatment with either an investigator choice chemotherapy (FIG. 15 A) or first-line 3 mg/kg anti-PD-1 antibody therapy (Nivolumab; FIG. 15B).
  • FIG. 15 A shows the distribution of WT or mutated STKl l subjects experiencing a complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) following treatment with either an investigator choice chemotherapy (FIG. 15 A) or first-line 3 mg/kg anti-PD-1 antibody therapy (Nivolumab; FIG. 15B).
  • FIG. 15 A first-line 3 mg/kg anti-PD-1 antibody therapy
  • FIG. 15C is a graphical representation of the distribution of WT or mutated STKl l subjects experiencing a complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) following treatment with either an investigator choice chemotherapy or first-line 3 mg/kg anti-PD-1 antibody therapy (Nivolumab) as related to PDLl expression levels.
  • FIGs. 15D and 15E show the distribution PDLl expression in WT or mutated STKl l subjects treated with either an investigator choice chemotherapy (FIG. 15D) or first-line 3 mg/kg anti- PD-1 antibody therapy (Nivolumab; FIG. 15E).
  • the Y axes show the percent of tumor cells that express PD-L1 (FIGs. 15A-15E).
  • FIG. 15F is a table providing the status, including the specific mutations, for a subset of the subjects having STK11 mutations.
  • FIGs. 16B-16C are graphical representations of survival probability for advanced NSCLC subjects having wild type (data labels 2 and 4) or mutated (data labels 1 and 3) CDKN2A (FIG. 16B) or PTPND/ CUBN/HERC 1 (FIG.
  • FIG. 16C is a screenshot showing the distribution of HERC1, CUBNM, and PTPRD mutations in the 1144 subjects analyzed.
  • FIGs. 17A-17B are scatter plots, illustrating the relationship between tumor mutational burden and STKl l mutation status in all advanced NSCLC subjects analyzed (FIG. 17A) or in a subpopulation further having a KRAS mutation (FIG. 17B).
  • FIG. 17C is a graphical representation showing the distribution of WT or mutated STKl l subjects experiencing a complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) following treatment with either an investigator choice chemotherapy or first-line 3 mg/kg anti- PD-1 antibody therapy (Nivolumab) as related to tumor mutational burden (TMB; FIG. 17C).
  • FIGs. 18A-18D are graphical representations of survival probability for non- squamous cell NSCLC subjects having wild type STKl l (data labels 2 and 4) or a mutation in STKl l (data labels 1 and 3) treated with docetaxel (data labels 1 and 2) or second-line 3 mg/kg anti-PD-1 antibody therapy (Nivolumab; data labels 3 and 4).
  • FIG. 18A includes all subjects having any non-synonymous STKl l mutation
  • FIG. 18B includes subjects having any non- synonymous STKl l mutation and a KRAS mutation
  • FIG. 18C includes all subjects having any nonsense, frameshift, or splicing mutations in STKl l
  • FIG. 18D includes subjects having any nonsense, frameshift, or splicing mutations in STK11 and a KRAS mutation.
  • the numbers of subjects at risk at each time point for each group is shown below the X axes (FIGs. 18A-18D).
  • FIG. 19 is a graphical representation of survival probability for squamous cell
  • NSCLC subjects having wild type STKl l (data labels 2 and 4) or a mutation in STKl l (data labels 1 and 3) treated with docetaxel (data labels 1 and 2) or second-line 3 mg/kg anti-PD-1 antibody therapy (Nivolumab; data labels 3 and 4).
  • the numbers of subjects at risk at each time point for each group is shown below the X axis (FIGs. 19).
  • the present disclosure relates to methods for treating a subject afflicted with a tumor comprising (i) determining a mutation status of an STKl l gene in the subject; and (ii) administering to the subject an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death- 1 (PD-1) receptor and inhibits PD-1 activity ("anti-PD-1 antibody”) or to a Programmed Death Ligand 1 (PD-L1) and inhibits PD-1 activity (“anti-PD-Ll antibody”) if the STKl l gene is wild-type.
  • the tumor is derived from a NSCLC.
  • administering refers to the physical introduction of a composition comprising a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art.
  • Routes of administration for the anti-PD-1 antibody include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation.
  • the combination is administered via a non-parenteral route, in some embodiments, orally.
  • non-parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • An "adverse event” as used herein is any unfavorable and generally unintended or undesirable sign (including an abnormal laboratory finding), symptom, or disease associated with the use of a medical treatment.
  • an adverse event can be associated with activation of the immune system or expansion of immune system cells ⁇ e.g., T cells) in response to a treatment.
  • a medical treatment can have one or more associated AEs and each AE can have the same or different level of severity.
  • Reference to methods capable of "altering adverse events” means a treatment regime that decreases the incidence and/or severity of one or more AEs associated with the use of a different treatment regime.
  • the Y H and Y L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • Each Y H and Vz comprises three CDRs and four FRs, arranged from amino-terminus to carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • An immunoglobulin can derive from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG and IgM.
  • IgG subclasses are also well known to those in the art and include but are not limited to human IgGl, IgG2, IgG3 and IgG4.
  • immunotype refers to the antibody class or subclass (e.g., IgM or IgGl) that is encoded by the heavy chain constant region genes.
  • antibody includes, by way of example, both naturally occurring and non-naturally occurring Abs; monoclonal and polyclonal Abs; chimeric and humanized Abs; human or nonhuman Abs; wholly synthetic Abs; and single chain antibodies.
  • a nonhuman antibody can be humanized by recombinant methods to reduce its immunogenicity in man.
  • antibody also includes an antigen-binding fragment or an antigen-binding portion of any of the aforementioned immunoglobulins, and includes a monovalent and a divalent fragment or portion, and a single chain antibody.
  • an "isolated antibody” refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that binds specifically to PD-1 is substantially free of antibodies that bind specifically to antigens other than PD-1).
  • An isolated antibody that binds specifically to PD-1 can, however, have cross-reactivity to other antigens, such as PD-1 molecules from different species.
  • an isolated antibody can be substantially free of other cellular material and/or chemicals.
  • mAb monoclonal antibody
  • mAb refers to a non-naturally occurring preparation of antibody molecules of single molecular composition, i.e., antibody molecules whose primary sequences are essentially identical, and which exhibits a single binding specificity and affinity for a particular epitope.
  • a monoclonal antibody is an example of an isolated antibody.
  • MAbs can be produced by hybridoma, recombinant, transgenic or other techniques known to those skilled in the art.
  • a “human” antibody refers to an antibody having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences.
  • the human antibodies of the disclosure can include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • the term "human antibody,” as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • a “humanized antibody” refers to an antibody in which some, most or all of the amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins. In one embodiment of a humanized form of an antibody, some, most or all of the amino acids outside the CDR domains have been replaced with amino acids from human immunoglobulins, whereas some, most or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they do not abrogate the ability of the antibody to bind to a particular antigen.
  • a "humanized” antibody retains an antigenic specificity similar to that of the original antibody.
  • a "chimeric antibody” refers to an antibody in which the variable regions are derived from one species and the constant regions are derived from another species, such as an antibody in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody.
  • an "anti-antigen” antibody refers to an antibody that binds specifically to the antigen.
  • an anti-PD-1 antibody binds specifically to PD-1.
  • an "antigen-binding portion" of an antibody refers to one or more fragments of an antibody that retain the ability to bind specifically to the antigen bound by the whole antibody.
  • a "cancer” refers a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth divide and grow results in the formation of malignant tumors that invade neighboring tissues and can also metastasize to distant parts of the body through the lymphatic system or bloodstream.
  • Protein LKB1 refers to a member of the serine/threonine kinase family that regulates cell polarity and functions as a tumor suppressor.
  • STK11 controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage response.
  • AMPK AMP-activated protein kinase
  • STK11 is ubiquitously expressed, with the strongest expression in the testis and the fetal liver.
  • STKl l is commonly inactivated in NSCLC, especially in tumors harboring KRAS mutations.
  • mutated STKl l correlates with decreased or aberrant PD-L1 expression in tumors derived from an SCLC.
  • mutated STKl l e.g., loss of wild type expression of STKl l
  • the STKl 1 mutant is an STKl 1 mutant previously described in, e.g., Koyama et al., Cancer Res.
  • KRAS refers to the gene encoding the GTPase KRas protein, which is a member of the ras subfamily of small GTPases. Approximately 15-25% of patients with lung adenocarcinoma have tumor associated KRAS mutations, the majority of which mutations result in constitutively activated KRAS signaling.
  • TP53 refers to the gene encoding the tumor suppressor protein p53. p53 acts to control cell division, and loss of function mutations lead to unregulated cell division and growth. Approximately half of all cancers comprise a somatic mutation of TP53.
  • immunotherapy refers to the treatment of a subject afflicted with, or at risk of contracting or suffering a recurrence of, a disease by a method comprising inducing, enhancing, suppressing or otherwise modifying an immune response.
  • Treatment or “therapy” of a subject refers to any type of intervention or process performed on, or the administration of an active agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, slowing down or preventing the onset, progression, development, severity or recurrence of a symptom, complication or condition, or biochemical indicia associated with a disease.
  • PD-L1 positive tumors can thus have at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%>, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% of the tumor cells expressing PD-L1 as measured by an automated IHC.
  • "PD- Ll positive" means that there are at least 100 cells that express PD-L1 on the surface of the cells.
  • PD-1 Programmed Death-1
  • PD-1 refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo, and binds to two ligands, PD-L1 and PD-L2.
  • the term "PD-1 " as used herein includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1. The complete hPD-1 sequence can be found under GenBank Accession No. U64863.
  • P-L1 Programmed Death Ligand-1
  • PD-L1 is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that downregulate T cell activation and cytokine secretion upon binding to PD-1.
  • the term "PD-L1 " as used herein includes human PD-L1 (hPD- Ll), variants, isoforms, and species homologs of hPD-Ll, and analogs having at least one common epitope with hPD-Ll .
  • the complete hPD-Ll sequence can be found under GenBank Accession No. Q9NZQ7.
  • a “subject” includes any human or nonhuman animal.
  • the term “nonhuman animal” includes, but is not limited to, vertebrates such as nonhuman primates, sheep, dogs, and rodents such as mice, rats and guinea pigs. In some embodiments, the subject is a human.
  • the terms, "subject” and “patient” are used interchangeably herein.
  • a "therapeutically effective amount” or “therapeutically effective dosage” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject against the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • the ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.
  • subtherapeutic dose means a dose of a therapeutic compound
  • an antibody that is lower than the usual or typical dose of the therapeutic compound when administered alone for the treatment of a hyperproliferative disease ⁇ e.g., cancer).
  • an "anti-cancer agent” promotes cancer regression in a subject or prevents further tumor growth.
  • a therapeutically effective amount of the drug promotes cancer regression to the point of eliminating the cancer.
  • Promote cancer regression means that administering an effective amount of the drug, alone or in combination with an anti -neoplastic agent, results in a reduction in tumor growth or size, necrosis of the tumor, a decrease in severity of at least one disease symptom, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • the terms “effective” and “effectiveness” with regard to a treatment includes both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of the drug to promote cancer regression in the patient.
  • Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug.
  • a therapeutically effective amount of an anti-cancer agent can inhibit cell growth or tumor growth by at least about 20%, by at least about 40%, by at least about 60%, or by at least about 80% relative to untreated subjects.
  • tumor regression can be observed and continue for a period of at least about 20 days, at least about 40 days, or at least about 60 days. Notwithstanding these ultimate measurements of therapeutic effectiveness, evaluation of immunotherapeutic drugs must also make allowance for "immune-related" response patterns.
  • An "immune-related" response pattern refers to a clinical response pattern often observed in cancer patients treated with immunotherapeutic agents that produce antitumor effects by inducing cancer-specific immune responses or by modifying native immune processes.
  • This response pattern is characterized by a beneficial therapeutic effect that follows an initial increase in tumor burden or the appearance of new lesions, which in the evaluation of traditional chemotherapeutic agents would be classified as disease progression and would be synonymous with drug failure. Accordingly, proper evaluation of immunotherapeutic agents can require long- term monitoring of the effects of these agents on the target disease.
  • a therapeutically effective amount of a drug includes a "prophylactically effective amount," which is any amount of the drug that, when administered alone or in combination with an anti -neoplastic agent to a subject at risk of developing a cancer (e.g., a subject having a pre- malignant condition) or of suffering a recurrence of cancer, inhibits the development or recurrence of the cancer.
  • the prophylactically effective amount prevents the development or recurrence of the cancer entirely. “Inhibiting" the development or recurrence of a cancer means either lessening the likelihood of the cancer's development or recurrence, or preventing the development or recurrence of the cancer entirely.
  • wild-type refers to a gene that has a nucleotide sequence that encodes a protein that has an amino acid sequence known in the art to be the common sequence.
  • the "wild-type" STK11 has a nucleotide sequence that encodes an STK11 protein having an amino acid sequence identical to the amino acid sequence of the protein having UniProt identifier Ql 5831-1.
  • a "wild-type" gene can have mutations relative to the canonical nucleotide sequence for that gene, so long as the mutations are synonymous, e.g., the nucleotide mutations do not result in changes to the amino acid sequence of the resulting protein.
  • mutant genes refer to genes that have one or more nucleotide substitution, insertion, or deletion that changes the resulting amino acid sequence, e.g., a non-synonymous mutation. Mutated genes can be expressed or unexpressed.
  • the non-synonymous mutation is a "nonsense mutation,” wherein the nucleotide substitution or deletion results in the generation of a premature stop codon.
  • the non-synonymous mutation is a "frameshift mutation,” wherein the nucleotide substitution or deletion comprises an insertion or deletion of a number of nucleotides not divisible by three, resulting in a shift in the translation of the sequence.
  • the non-synonymous mutation is a "splicing mutation,” wherein the nucleotide substitution or deletion interferes with or creates a splice site.
  • TMB tumor mutation burden
  • tissue sample for example, a minimum of 10 slides
  • the TMB status can be a numerical value or a relative value, e.g., high, medium, or low; within the highest fractile, or within the top tertile, of a reference set.
  • a TMB has a score of at least 210, at least 215, at least 220, at least 225, at least 230, at least 235, at least 240, at least 245, at least 250, at least 255, at least 260, at least 265, at least 270, at least 275, at least 280, at least 285, at least 290, at least 295, at least 300, at least 305, at least 310, at least 315, at least 320, at least 325, at least 330, at least 335, at least 340, at least 345, at least 350, at least 355, at least 360, at least 365, at least 370, at least 375, at least 380, at least 385, at least 390, at least 395, at least 400, at least 405, at least
  • a "high TMB” refers to a TMB within the highest fractile of the reference TMB value.
  • a "reference TMB value” can be determined by grouping all subject's with evaluable TMB data according to fractile distribution of TMB, i.e., subjects are rank ordered from highest to lowest number of genetic alterations and divided into a defined number of groups. In one embodiment, all subjects with evaluable TMB data are rank ordered and divided into thirds and a "high TMB" is within the top tertile of the reference TMB value.
  • the tertile boundaries are 0 ⁇ 100 genetic alterations; 100 to 243 genetic alterations; and > 243 genetic alterations.
  • subjects with evaluable TMB data can be divided into any number of groups, e.g., quartiles, quintiles, etc.
  • the term “medium TMB” refers to a number of somatic mutations in a tumor's genome that is at or around a number of somatic mutations that is normal or average and the term “low TMB” refers to a number of somatic mutations in a tumor's genome that is below a number of somatic mutations that is normal or average.
  • a "high TMB” has a score of at least 243
  • a “medium TMB” has a score of between 100 and 242
  • a “low TMB” has a score of less than 100 (or between 0 and 100).
  • TMB status can correlate with smoking status.
  • subjects who currently or formerly smoke(d) often have more genetic alterations, e.g., missense mutations, than subjects who never smoke(d).
  • a tumor with a high TMB can also have a high neoantigen load.
  • neoantigen refers to a newly formed antigen that has not been previously recognized by the immune system.
  • a neoantigen can be a protein or peptide that is recognized as foreign (or non-self) by the immune system. Transcription of a gene in the tumor genome harboring a somatic mutation results in mutated mRNA that, when translated, gives rise to a mutated protein, which is then processed and transported to the ER lumen and binds to MHC class I complex, facilitating T-cell recognition of the neoantigen.
  • Neoantigen recognition can promote T-cell activation, clonal expansion, and differentiation into effector and memory T-cells.
  • the term "benefit from therapy” refers to an improvement in one or more of overall survival, progression-free survival, partial response, complete response, and overall response rate and can also include a reduction in tumor growth or size, a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • measuring when referring to TMB status or mutation status of a gene means determining a measurable quantity of somatic mutations in a biological sample of the subject. It will be appreciated that measuring can be performed by sequencing nucleic acids, e.g., cDNA, mRNA, exoRNA, ctDNA, and cfDNA, in the sample. The measuring is performed on a subject's sample and/or a reference sample or samples and can, for example, be detected de novo or correspond to a previous determination.
  • nucleic acids e.g., cDNA, mRNA, exoRNA, ctDNA, and cfDNA
  • the measuring can be performed, for example, using PCR methods, qPCR methods, Sanger sequencing methods, genomic profiling methods (including comprehensive gene panels), exome sequencing methods, genome sequencing methods, and/or any other method disclosed herein, as is known to a person of skill in the art.
  • the measuring identifies a genomic alteration in the sequenced nucleic acids.
  • the genomic (or gene) profiling methods can involve panels of a predetermined set of genes, e.g., 150-500 genes, and in some instances the genomic alterations evaluated in the panel of genes are correlated with total somatic mutations evaluated.
  • genomic alteration refers to a change (or mutation) in the nucleotide sequence of the genome of a tumor, which change is not present in the germline nucleotide sequence, and which in some embodiments is a non-synonymous mutation including, but not limited to, a base pair substitution, a base pair insertion, a base pair deletion, a copy number alteration (CNA), a gene rearrangement, and any combination thereof.
  • the genomic alterations measured in the biological sample are missense mutations.
  • the term "biological sample” as used herein refers to biological material isolated from a subject.
  • the biological sample can contain any biological material suitable for determining TMB, for example, by sequencing nucleic acids in the tumor (or circulating tumor cells) and identifying a genomic alteration in the sequenced nucleic acids.
  • the biological sample can be any suitable biological tissue or fluid such as, for example, tumor tissue, blood, blood plasma, and serum.
  • the sample is a tumor tissue biopsy, e.g., a formalin- fixed, paraffin-embedded tumor tissue or a fresh-frozen tumor tissue or the like.
  • the biological sample is a liquid biopsy that, in some embodiments, comprises one or more of blood, serum, plasma, circulating tumor cells, exoRNA, ctDNA, and cfDNA.
  • the terms "about” or “comprising essentially of refer to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system.
  • “about” or “comprising essentially of can mean within 1 or more than 1 standard deviation per the practice in the art.
  • “about” or “comprising essentially of can mean a range of up to 10% or 20% (i.e., ⁇ 10%) or ⁇ 20%>).
  • about 3mg can include any number between 2.7 mg and 3.3 mg (for 10%>) or between 2.4 mg and 3.6 mg (for 20%>).
  • the terms can mean up to an order of magnitude or up to 5-fold of a value.
  • the meaning of "about” or “comprising essentially of should be assumed to be within an acceptable error range for that particular value or composition.
  • the terms "once about every week,” “once about every two weeks,” or any other similar dosing interval terms as used herein mean approximate numbers. "Once about every week” can include every seven days ⁇ one day, i.e., every six days to every eight days. “Once about every two weeks” can include every fourteen days ⁇ three days, i.e., every eleven days to every seventeen days. Similar approximations apply, for example, to once about every three weeks, once about every four weeks, once about every five weeks, once about every six weeks and once about every twelve weeks.
  • a dosing interval of once about every six weeks or once about every twelve weeks means that the first dose can be administered any day in the first week, and then the next dose can be administered any day in the sixth or twelfth week, respectively.
  • a dosing interval of once about every six weeks or once about every twelve weeks means that the first dose is administered on a particular day of the first week (e.g., Monday) and then the next dose is administered on the same day of the sixth or twelfth weeks (i.e., Monday), respectively.
  • weight based dose means that a dose that is administered to a patient is calculated based on the weight of the patient. For example, when a patient with 60 kg body weight requires 3 mg/kg of an anti-PD-1 antibody, one can calculate and use the appropriate amount of the anti-PD-1 antibody (i.e., 180 mg) for administration.
  • the use of the term "fixed dose” with regard to a method of the disclosure means that two or more different antibodies in a single composition (e.g., anti-PD-1 antibody and a second antibody) are present in the composition in particular (fixed) ratios with each other.
  • the fixed dose is based on the weight (e.g., mg) of the antibodies.
  • the fixed dose is based on the concentration (e.g., mg/ml) of the antibodies.
  • the 3 : 1 ratio of an anti-PD-1 antibody and an second antibody can mean that a vial can contain about 240 mg of the anti-PD-1 antibody and 80 mg of the second antibody or about 3 mg/ml of the anti-PD-1 antibody and 1 mg/ml of the second antibody.
  • flat dose means a dose that is administered to a patient without regard for the weight or body surface area (BSA) of the patient.
  • the flat dose is therefore not provided as a mg/kg dose, but rather as an absolute amount of the agent (e.g., the anti-PD-1 antibody).
  • the agent e.g., the anti-PD-1 antibody
  • a 60 kg person and a 100 kg person would receive the same dose of an antibody (e.g., 240 mg of an anti- PD-1 antibody).
  • any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
  • This disclosure provides for treating a subject afflicted with a tumor comprising
  • the subject afflicted with a tumor e.g. , NSCLC, e.g., non-squamous NSCLC
  • a tumor e.g., NSCLC, e.g., non-squamous NSCLC
  • the disclosure relates to methods for treating a subject afflicted with a tumor (e.g.
  • NSCLC e.g., non-squamous NSCLC
  • NSCLC e.g., non-squamous NSCLC
  • the disclosure relates to methods for identifying a subject afflicted with a tumor (e.g. , NSCLC, e.g. , non-squamous NSCLC) suitable for an anti-PD-1 antibody treatment comprising (i) determining a mutation status of an STK1 1 gene in the subject; and (ii) administering to the subject anti-PD-1 antibody if the STK11 gene is wild-type.
  • This disclosure further provides for treating a subject afflicted with a tumor comprising (i) determining a mutation status of an STK11 gene in the subject; and (ii) administering to the subject an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death-Ligand 1 (PD-Ll) and inhibits PD-1 activity ("anti-PD-Ll antibody").
  • a tumor e.g., NSCLC, e.g., non- squamous NSCLC
  • an anti-PD-Ll antibody is administered an anti-PD-Ll antibody if the STK11 gene is wild-type.
  • the disclosure relates to methods for treating a subject afflicted with a tumor (e.g., NSCLC, e.g., non-squamous NSCLC) comprising administering to the subject an anti-PD- Ll antibody, wherein the subject is identified as having a wild-type STK11 gene.
  • a tumor e.g., NSCLC, e.g., non-squamous NSCLC
  • the disclosure relates to methods for identifying a subject afflicted with a tumor (e.g., NSCLC, e.g., non-squamous NSCLC) suitable for an anti-PD-Ll antibody treatment comprising (i) determining a mutation status of an STK11 gene in the subject; and (ii) administering to the subject anti-PD-Ll antibody if the STK11 gene is wild-type.
  • a tumor e.g., NSCLC, e.g., non-squamous NSCLC
  • the present disclosure relates to methods for treating a subject afflicted with a tumor (e.g., NSCLC, e.g., non-squamous NSCLC) comprising (i) determining a mutation status of an STK11 gene in the subject; and (ii) identifying the subject as not being eligible for the anti-PD-1 antibody administration, e.g., not administering to the subject an anti- PD-1 antibody or terminating or augmenting an anti-PD-1 antibody therapy, e.g., administering an anti-cancer agent that is not a PD-1 antagonist, if the STK11 gene comprises a non- synonymous mutation.
  • a tumor e.g., NSCLC, e.g., non-squamous NSCLC
  • the present disclosure relates to methods for treating a subject afflicted with a tumor (e.g., NSCLC, e.g., non-squamous NSCLC) comprising (i) determining a mutation status of an STK11 gene in the subject; and (ii) identifying the subject as not being eligible for the anti-PD-Ll antibody administration, e.g., not administering to the subject an anti- PD-L1 antibody or terminating or augmenting an anti-PD-Ll antibody therapy, e.g., administering an anti-cancer agent that is not a PD-L1 antagonist, if the STK11 gene comprises a non-synonymous mutation.
  • a tumor e.g., NSCLC, e.g., non-squamous NSCLC
  • a subject afflicted with a tumor e.g., NSCLC, e.g., non-squamous NSCLC
  • a tumor e.g., NSCLC, e.g., non-squamous NSCLC
  • identifying the subject as not being eligible for the anti- PD-Ll antibody administration e.g., not administering to the subject an anti-PD-Ll antibody or terminating or augmenting an anti-PD-1 antibody therapy, e.g., administering an anti-cancer agent that is not a PD-L1 antagonist, if the STK11 gene comprises a non-synonymous mutation.
  • the disclosure relates to methods for treating a subject afflicted with a tumor comprising (i) determining a mutation status of marker gene in the subject; and (ii) administering to the subject an anti-PD-1 antibody if the marker gene is mutated; wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTP D, CUBN, HERC1, and any combination thereof.
  • aspects of the present disclosure relate to methods for treating a subject afflicted with a tumor comprising administering to the subject an anti-PD-1 antibody, wherein the subject is identified as having a mutated marker gene, wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERC1, and any combination thereof.
  • Still other aspects of the present disclosure relate to methods for identifying a subject afflicted with a tumor suitable for an anti-PD-1 antibody treatment comprising (i) determining a mutation status of a marker gene in the subject; and (ii) administering to the subject anti-PD-1 antibody if the marker gene is mutated; wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERC1, and any combination thereof.
  • the disclosure relates to methods for treating a subject afflicted with a tumor comprising (i) determining a mutation status of marker gene in the subject; and (ii) administering to the subject an anti-PD-Ll antibody if the marker gene is mutated; wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERC1, and any combination thereof.
  • aspects of the present disclosure relate to methods for treating a subject afflicted with a tumor comprising administering to the subject an anti-PD-Ll antibody, wherein the subject is identified as having a mutated marker gene, wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERC1, and any combination thereof.
  • Still other aspects of the present disclosure relate to methods for identifying a subject afflicted with a tumor suitable for an anti-PD-Ll antibody treatment comprising (i) determining a mutation status of a marker gene in the subject; and (ii) administering to the subject anti-PD-Ll antibody if the marker gene is mutated; wherein the marker gene is selected from the group consisting of TP53, CDKN2A, PTPND, CUBN, HERCl, and any combination thereof.
  • the subject carries a mutated variant of TP53. In certain embodiments, the subject carries a mutated variant of CDKN2A. In certain embodiments, the subject carries a mutated variant of PTPND. In certain embodiments, the subject carries a mutated variant of CUBN. In certain embodiments, the subject carries a mutated variant of HERCl . In certain embodiments, the subject carries a mutated variant of PTPND and CUBN. In certain embodiments, the subject carries a mutated variant of PTPND and HERCl . In certain embodiments, the subject carries a mutated variant of CUBN and HERCl . In certain embodiments, the subject carries a mutated variant of PTPND, CUBN, and HERCl . In certain embodiments, the subject carries a mutated variant of PTPND, CUBN, and HERCl . In certain embodiments, the subject carries a mutated variant of P
  • the wild-type STK11 comprises one or more synonymous mutations, wherein the mutation in the genomic sequence does not affect the sequence of the expressed protein.
  • the mutated STK11 comprises a non-synonymous mutation.
  • the mutated STK11 comprises a nonsense mutation.
  • the mutated STK11 comprises a frameshift mutation.
  • the mutated STK11 comprises a splicing mutation.
  • the mutated STK11 is expressed as an mRNA and ultimately a protein.
  • the mutated STK11 protein is functional.
  • the mutated STK11 protein has reduced activity.
  • the mutated STK11 protein is non-functional.
  • the mutated TP53 comprises a non-synonymous mutation.
  • the mutated TP53 comprises a nonsense mutation. In some embodiments, the mutated TP53 comprises a frameshift mutation. In some embodiments, the mutated TP53 comprises a splicing mutation. In some embodiments, the mutated TP53 is expressed as an mRNA and ultimately a protein. In some embodiments, the mutated TP53 protein is functional. In other embodiments, the mutated TP53 protein has reduced activity. In other embodiments, the mutated TP53 protein is non-functional.
  • the mutated CDKN2A comprises a non-synonymous mutation. In some embodiments, the mutated CDKN2A comprises a nonsense mutation. In some embodiments, the mutated CDKN2A comprises a frameshift mutation. In some embodiments, the mutated CDKN2A comprises a splicing mutation. In some embodiments, the mutated CDKN2A is expressed as an mRNA and ultimately a protein. In some embodiments, the mutated CDKN2A protein is functional. In other embodiments, the mutated CDKN2A protein has reduced activity. In other embodiments, the mutated CDKN2A protein is non-functional.
  • the mutated PTP D comprises a non-synonymous mutation.
  • the mutated PTPND comprises a nonsense mutation.
  • the mutated PTPND comprises a frameshift mutation.
  • the mutated PTPND comprises a splicing mutation.
  • the mutated PTPND is expressed as an mRNA and ultimately a protein.
  • the mutated PTPND protein is functional.
  • the mutated PTPND protein has reduced activity.
  • the mutated PTPND protein is non-functional.
  • the mutated CUBN comprises a non-synonymous mutation. In some embodiments, the mutated CUBN comprises a nonsense mutation. In some embodiments, the mutated CUBN comprises a frameshift mutation. In some embodiments, the mutated CUBN comprises a splicing mutation. In some embodiments, the mutated CUBN is expressed as an mRNA and ultimately a protein. In some embodiments, the mutated CUBN protein is functional. In other embodiments, the mutated CUBN protein has reduced activity. In other embodiments, the mutated CUBN protein is non-functional.
  • the mutated HERO comprises a non-synonymous mutation.
  • the mutated HERC1 comprises a nonsense mutation.
  • the mutated HERC1 comprises a frameshift mutation.
  • the mutated HERC1 comprises a splicing mutation.
  • the mutated HERC1 is expressed as an mRNA and ultimately a protein.
  • the mutated HERC1 protein is functional.
  • the mutated HERC 1 protein has reduced activity.
  • the mutated HERC1 protein is non-functional.
  • the tumor is derived from a lung cancer. In some embodiments, the tumor is derived from a NSCLC. In some embodiments, the subject is a human patient. In certain embodiments, the subject is a chemotherapy-naive patient (e.g., a patient who has not previously received any chemotherapy). In other embodiments, the subject for the present combination therapy has received another cancer therapy (e.g., a chemotherapy), but is resistant or refractory to such another cancer therapy.
  • another cancer therapy e.g., a chemotherapy
  • the disclosure provides for treating a subject afflicted with a squamous NSCLC comprising (i) determining a mutation status of an STK1 1 gene in the subject; and (ii) administering to the subject an anti-PD-1 antibody (or an anti-PD-Ll antibody) if the STK1 1 gene is mutated.
  • the disclosure relates to methods for treating a subject afflicted with a squamous NSCLC comprising administering to the subject an anti-PD-1 antibody, wherein the subject is identified as having a mutated STK1 1 gene.
  • the disclosure relates to methods for identifying a subject afflicted with a squamous NSCLC suitable for an anti-PD-1 antibody treatment comprising (i) determining a mutation status of an STK1 1 gene in the subject; and (ii) administering to the subject anti-PD-1 antibody if the STK1 1 gene is mutated.
  • the present disclosure relates to methods for treating a subject afflicted with a squamous NSCLC comprising (i) determining a mutation status of an STK1 1 gene in the subject; and (ii) administering to the subject an anti-PD-1 antibody (or an anti-PD-Ll antibody) or terminating or augmenting an anti-PD-1 antibody (or an anti-PD-Ll antibody) therapy if the STK1 1 gene comprises a non-synonymous mutation.
  • the therapy of the present disclosure e.g., administration of an anti-PD-1 antibody or an anti-PD-Ll antibody
  • the anti-PD-1 antibody therapy of the present disclosure increases the progression-free survival of the subject.
  • the anti- PD-1 antibody therapy of the present disclosure increases the progression-free survival of the subject in comparison to standard-of-care therapies.
  • the subject having a tumor can exhibit an overall survival of at least about 10 months, at least about 1 1 months, at least about 12 months, at least about 13 months, at least about 14 months at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after the administration.
  • the duration of survival or the overall survival of the subject is increased by at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, or at least about 1 year when compared to another subject treated with only a standard-of-care therapy (e.g., docetaxel) or a different dosing schedule of the therapy.
  • a standard-of-care therapy e.g., docetaxel
  • the duration of survival or the overall survival of the subject treated with an anti-PD-1 antibody disclosed herein is increased by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50% or at least about 75% when compared to another subject treated with only a standard-of-care therapy (e.g., docetaxel) or a different dosing schedule of the combination therapy.
  • a standard-of-care therapy e.g., docetaxel
  • the therapy of the present disclosure effectively increases the duration of progression free survival of the subject.
  • the subject exhibits a progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years.
  • the administering of the anti-PD-1 antibody treats the tumor. In certain embodiments, the administering reduces the size of the tumor. In one embodiment, the size of the tumor is reduced by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 100% compared to the tumor size prior to the administration.
  • the subject exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after the initial administration.
  • the subject exhibits stable disease after the administration.
  • the subject exhibits a partial response after the administration.
  • the subject exhibits a complete response after the administration.
  • the subject exhibits an improved objective response rate (ORR) after the administration as compared to a subject treated with a standard of care treatment.
  • ORR objective response rate
  • the subject has tumor cells that are PD-L1+. In certain embodiments, the subject has cancer cells that are PD-L1-. In some embodiments, the subject never smoked. In certain embodiments, the subject formerly smoked. In one embodiments, the subject currently smokes. In certain embodiments, the subject has cancer cells that are squamous. In certain embodiments, the subject has cancer cells that are non-squamous.
  • the tumor exhibits a diffuse pattern of PD-Ll expression.
  • the diffuse pattern of PD-Ll expression is characterized by a PD-Ll H- score of from about 60 to about 500, from about 70 to about 490, from about 80 to about 480, from about 90 to about 470, from about 100 to about 460, from about 110 to about 450, from about 120 to about 440, from about 130 to about 430, from about 140 to about 420, from about 150 to about 410, from about 160 to about 400, from about 170 to about 390, from about 180 to about 380, from about 190 to about 370, from about 200 to about 360, from about 20 to about 350, from about 200 to about 340, from about 200 to about 330, from about 200 to about 320, from about 200 to about 310, or from about 200 to about 300.
  • a PD-Ll H- score of from about 60 to about 500, from about 70 to about 490, from about 80 to about 480, from about 90 to about 470, from about 100 to about 460, from about 110 to about 450, from about 120
  • the diffuse pattern of PD-Ll expression is characterized by a PD-Ll H-score of at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, at least about 200, at least about 210, at least about 220, at least about 225, at least about 230, at least about 240, at least about 250, at least about 260, at least about 270, at least about 275, at least about 280, at least about 290, or at least about 300.
  • a PD-Ll H-score of at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180,
  • the diffuse pattern of PD-Ll expression is characterized by a PD- Ll H-score of at least about 200. In other embodiments, the diffuse pattern of PD-Ll expression is characterized by a PD-Ll H-score of at least about 240. In certain embodiments, the diffuse pattern of PD-Ll expression is characterized by a PD-Ll H-score of at least about 260.
  • the tumor exhibits a heterogeneous pattern of PD-Ll expression.
  • the heterogeneous pattern of PD-Ll expression is characterized by a PD-Ll H-score of from about 1 to about 50, from about 5 to about 45, from about 10 to about 40, or from about 15 to about 35, and wherein the PD-Ll expression is restricted to one or more distinct portions of the tumor.
  • the heterogeneous pattern of PD-Ll expression is characterized by a PD-Ll H-score of at least about 5, at least about 10, at least about 15, at least about 20, at least about 25, at least about 30, at least about 35, or at least about 40.
  • the heterogeneous pattern of PD-Ll expression is characterized by a PD-Ll H-score of at least about 15. In another embodiment, the heterogeneous pattern of PD-Ll expression is characterized by a PD-Ll H-score of at least about 20. In some embodiments, the heterogeneous pattern of PD-Ll expression is characterized by a portion of the tumor comprising at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 150, or at least 150 expressing PD-Ll .
  • the tumor exhibits PD-Ll expression at the tumor-stroma interface.
  • the tumor-stroma interface PD-Ll expression is characterized by expression of PD-Ll by tumor cells adjacent (e.g., with in about 1 cell diameter, about 2 cell diameters, about 3 cell diameters, about 4 cell diameters, about 5 cell diameters, about 6 cell diameters, about 7 cell diameters, about 8 cell diameters, about 9 cell diameters, or about 10 cell diameters) of the stroma.
  • the tumor-stroma interface PD-Ll expression is characterized by PD-Ll expression on the surface of the tumor.
  • the PD-Ll expression status of a tumor in a subject can be measured prior to administering any composition or utilizing any method disclosed herein.
  • the PD-Ll expression level of a tumor is at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%), at least about 10%, at least about 1 1%, at least about 12%, at least about 13%, at least about 14%), at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%), at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%), at least about 85%, at least about 90%, at least about 95%, or about 100%.
  • the PD-Ll status of a tumor is at least about 1%. In other embodiments, the PD-Ll status of the subject is at least about 5%. In a certain embodiment, the PD-Ll status of a tumor is at least about 10%. In a one embodiment, the PD-Ll status of the tumor is at least about 25%. In a particular embodiment, the PD-Ll status of the tumor is at least about 50%.
  • the method of the present disclosure comprises (i) determining a mutation status of an STK1 1 gene in the subject afflicted with a tumor (e.g., NSCLC, e.g., non-squamous NSCLC); (ii) detecting PD-Ll expression in the tumor; and (iii) administering to the subject an anti-PD-1 antibody if the STK1 1 gene is wild-type and if the PD- Ll expression is at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%), at least about 1 1%, at least about 12%, at least about 13%, at least about 14%, at least about 15%), at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%,
  • a tumor e.
  • the method of the present disclosure comprises (i) determining a mutation status of an STK11 gene in the subject afflicted with a tumor (e.g., NSCLC, e.g., non-squamous NSCLC); (ii) detecting PD-Ll expression in the tumor; and (iii) administering to the subject an anti-PD-1 antibody if the STK11 gene is wild-type and if the PD-Ll expression is at least about 15%.
  • a tumor e.g., NSCLC, e.g., non-squamous NSCLC
  • the method of the present disclosure comprises (i) determining a mutation status of an STK11 gene in the subject afflicted with a tumor (e.g., NSCLC, e.g., non-squamous NSCLC); (ii) detecting PD-Ll expression in the tumor; and (iii) administering to the subject an anti-PD-1 antibody if the STK11 gene is wild-type and if the PD-Ll expression is at least about 25%.
  • a tumor e.g., NSCLC, e.g., non-squamous NSCLC
  • the method of the present disclosure comprises (i) determining a mutation status of an STK11 gene in the subject afflicted with a tumor (e.g., NSCLC, e.g., non-squamous NSCLC); (ii) detecting PD-Ll expression in the tumor; and (iii) administering to the subject an anti-PD-1 antibody if the STK11 gene is wild-type and if the PD-Ll expression is at least about 50%.
  • a tumor e.g., NSCLC, e.g., non-squamous NSCLC
  • the method of the present disclosure comprises (i) determining a mutation status of an STK11 gene in the subject afflicted with a tumor (e.g., NSCLC, e.g., non-squamous NSCLC); (ii) detecting PD-Ll expression in the tumor; and (iii) identifying the subject as not being eligible for the anti-PD-1 antibody administration, e.g., not administering to the subject an anti-PD-1 antibody or terminating or augmenting an anti-PD-1 antibody therapy, e.g., administering an anti-cancer agent that is not a PD-1 antagonist, if the STK11 gene comprises a non-synonymous mutation and the tumor PD-Ll expression is less than about 50%.
  • a tumor e.g., NSCLC, e.g., non-squamous NSCLC
  • detecting PD-Ll expression in the tumor e.g., detecting PD-Ll expression in the tumor
  • identifying the subject
  • the method of the present disclosure comprises (i) determining a mutation status of an STK11 gene in the subject afflicted with a tumor (e.g., NSCLC, e.g., non-squamous NSCLC); (ii) detecting PD-Ll expression in the tumor; and (iii) identifying the subject as not being eligible for the anti-PD-1 antibody administration, e.g., not administering to the subject an anti-PD-1 antibody or terminating or augmenting an anti-PD-1 antibody therapy, e.g., administering an anti-cancer agent that is not a PD-1 antagonist, if the STK11 gene comprises a non-synonymous mutation and the tumor PD-Ll expression is less than about 40%).
  • a tumor e.g., NSCLC, e.g., non-squamous NSCLC
  • detecting PD-Ll expression in the tumor e.g., detecting PD-Ll expression in the tumor
  • identifying the subject
  • the method of the present disclosure comprises (i) determining a mutation status of an STK11 gene in the subject; (ii) detecting PD-Ll expression in the tumor afflicted with a tumor (e.g., NSCLC, e.g., non-squamous NSCLC); and (iii) identifying the subject as not being eligible for the anti-PD-1 antibody administration, e.g., not administering to the subject an anti-PD-1 antibody or terminating or augmenting an anti-PD-1 antibody therapy, e.g., administering an anti-cancer agent that is not a PD-1 antagonist, if the STK11 gene comprises a non-synonymous mutation and the tumor PD-Ll expression is less than about 30%.
  • a tumor e.g., NSCLC, e.g., non-squamous NSCLC
  • identifying the subject as not being eligible for the anti-PD-1 antibody administration, e.g., not administering to the subject an anti-PD-1 antibody
  • the method of the present disclosure comprises (i) determining a mutation status of an STK11 gene in the subject; (ii) detecting PD-Ll expression in the tumor; and (iii) identifying the subject as not being eligible for the anti-PD-1 antibody administration, e.g., not administering to the subject an anti-PD-1 antibody or terminating or augmenting an anti-PD-1 antibody therapy, e.g., administering an anti-cancer agent that is not a PD-1 antagonist, if the STK11 gene comprises a non-synonymous mutation and the tumor PD-Ll expression is less than about 25%.
  • the method of the present disclosure comprises (i) determining a mutation status of an STK11 gene in the subject; (ii) detecting PD- Ll expression in the tumor; and (iii) identifying the subject as not being eligible for the anti-PD-1 antibody administration, e.g., not administering to the subject an anti-PD-1 antibody or terminating or augmenting an anti-PD-1 antibody therapy, e.g., administering an anti-cancer agent that is not a PD-1 antagonist, if the STK11 gene comprises a non-synonymous mutation and the tumor PD-Ll expression is less than about 20%.
  • the method of the present disclosure comprises (i) determining a mutation status of an STK11 gene in the subject; (ii) detecting PD-Ll expression in the tumor; and (iii) identifying the subject as not being eligible for the anti-PD-1 antibody administration, e.g., not administering to the subject an anti-PD-1 antibody or terminating or augmenting an anti-PD-1 antibody therapy, e.g., administering an anticancer agent that is not a PD-1 antagonist, if the STK11 gene comprises a non-synonymous mutation and the tumor PD-Ll expression is less than about 15%.
  • the method of the present disclosure comprises (i) determining a mutation status of an STK11 gene in the subject; (ii) detecting PD-Ll expression in the tumor; and (iii) identifying the subject as not being eligible for the anti-PD-1 antibody administration, e.g., not administering to the subject an anti-PD-1 antibody or terminating or augmenting an anti-PD-1 antibody therapy, e.g., administering an anti-cancer agent that is not a PD-1 antagonist, if the STK11 gene comprises a non-synonymous mutation and the tumor PD-Ll expression is less than about 10%.
  • the method of the present disclosure comprises (i) determining a mutation status of an STK11 gene in the subject; (ii) detecting PD-Ll expression in the tumor; and (iii) identifying the subject as not being eligible for the anti-PD-1 antibody administration, e.g., not administering to the subject an anti-PD-1 antibody or terminating or augmenting an anti-PD-1 antibody therapy, e.g., administering an anti-cancer agent that is not a PD-1 antagonist, if the STK11 gene comprises a non-synonymous mutation and the tumor PD-Ll expression is less than about 5%.
  • the method of the present disclosure comprises (i) determining a mutation status of an STK11 gene in the subject; (ii) detecting PD-Ll expression in the tumor; and (iii) identifying the subject as not being eligible for the anti-PD-1 antibody administration, e.g., not administering to the subject an anti-PD-1 antibody or terminating or augmenting an anti-PD-1 antibody therapy, e.g., administering an anti-cancer agent that is not a PD-1 antagonist, if the STKl 1 gene comprises a non-synonymous mutation and the tumor PD-Ll expression is less than about 3%.
  • the method of the present disclosure comprises (i) determining a mutation status of an STK11 gene in the subject; (ii) detecting PD-Ll expression in the tumor; and (iii) identifying the subject as not being eligible for the anti-PD-1 antibody administration, e.g., not administering to the subject an anti-PD-1 antibody or terminating or augmenting an anti- PD-1 antibody therapy, e.g., administering an anti-cancer agent that is not a PD-1 antagonist, if the STK11 gene comprises a non-synonymous mutation and the tumor PD-Ll expression is less than about 2%.
  • the method of the present disclosure comprises (i) determining a mutation status of an STK11 gene in the subject; (ii) detecting PD-Ll expression in the tumor; and (iii) identifying the subject as not being eligible for the anti-PD-1 antibody administration, e.g., not administering to the subject an anti-PD-1 antibody or terminating or augmenting an anti-PD-1 antibody therapy, e.g., administering an anti-cancer agent that is not a PD-1 antagonist, if the STKl 1 gene comprises a non-synonymous mutation and the tumor PD-Ll expression is less than about 1%.
  • the tumor can exhibit a high level of inflammation.
  • Certain aspects of the present disclosure relate to determining the mutational status of one or more marker genes, e.g., STKl 1, in a subject. Any methods known in the art can be used to determine whether a subject carries wild-type or mutant variants of a marker gene.
  • the target marker gene is sequenced using any means available in the art, and the sequence of the marker gene is compared to the known sequence of the same marker gene in the art.
  • the marker gene has a non-synonymous mutation.
  • the marker gene has a nonsense mutation.
  • the marker gene has a frameshift mutation.
  • the marker gene has a splicing mutation.
  • the mutant marker gene is expressed. In other embodiments, the mutant marker gene is not expressed.
  • the mutational status of the marker gene is determined by detecting the expression of the marker gene. In certain embodiments, the mutant variant of the target gene is not expressed, and a lack of the resulting mRNA and/or protein indicates the presence of the mutant variant. In certain embodiments, the mutational status of the marker gene is determined by sequencing the resulting mRNA and/or the resulting protein. In some embodiments, the mutational status of the marker gene is determined by immunohistochemistry directed to the resulting protein.
  • the subject has one wild-type copy of the marker gene and one mutant copy of the marker gene. In some embodiment, the subject has two wild-type copies of the marker gene and no mutant copies of the marker gene. In some embodiments, the subject has two mutant copies of the marker gene and no copies of the wild-type marker gene. In some embodiments the two mutant copies of the marker gene are the same. In some embodiments, the subject has two different mutant copies of the marker gene.
  • Some aspects of the present disclosure relate to determining and/or measuring the expression level of one or more marker genes in the tumor of a subject.
  • a test tissue sample can be obtained from the patient who is in need of the therapy.
  • the assessment of PD-Ll expression can be achieved without obtaining a test tissue sample.
  • selecting a suitable patient includes (i) optionally providing a test tissue sample obtained from a patient with cancer of the tissue, the test tissue sample comprising tumor cells and/or tumor-infiltrating inflammatory cells; and (ii) assessing the proportion of cells in the test tissue sample that express PD-Ll on the surface of the cells based on an assessment that the proportion of cells in the test tissue sample that express PD-Ll on the cell surface is higher than a predetermined threshold level.
  • the step comprising the provision of a test tissue sample obtained from a patient is an optional step.
  • the "measuring” or “assessing” step to identify, or determine the number or proportion of, cells in the test tissue sample that express PD-Ll is performed by a transformative method of assaying for PD-Ll expression, for example by performing a reverse transcriptase-polymerase chain reaction (RT-PCR) assay or an IHC assay.
  • RT-PCR reverse transcriptase-polymerase chain reaction
  • no transformative step is involved and PD-L1 expression is assessed by, for example, reviewing a report of test results from a laboratory.
  • the steps of the methods up to, and including, assessing PD-L1 expression provides an intermediate result that may be provided to a physician or other healthcare provider for use in selecting a suitable candidate for the anti-PD-1 antibody or anti-PD-Ll antibody therapy.
  • the steps that provide the intermediate result is performed by a medical practitioner or someone acting under the direction of a medical practitioner. In other embodiments, these steps are performed by an independent laboratory or by an independent person such as a laboratory technician.
  • the proportion of cells that express PD-L1 is assessed by performing an assay to determine the presence of PD-L1 RNA.
  • the presence of PD-L1 RNA is determined by RT-PCR, in situ hybridization or RNase protection.
  • the proportion of cells that express PD-L1 is assessed by performing an assay to determine the presence of PD-L1 polypeptide.
  • the presence of PD-L1 polypeptide is determined by immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), in vivo imaging, or flow cytometry.
  • IHC immunohistochemistry
  • ELISA enzyme-linked immunosorbent assay
  • IHC enzyme-linked immunosorbent assay
  • flow cytometry in some embodiments, PD-L1 expression is assayed by IHC.
  • cell surface expression of PD-L1 is assayed using, e.g., IHC or in vivo imaging.
  • Imaging techniques have provided important tools in cancer research and treatment. Recent developments in molecular imaging systems, including positron emission tomography (PET), single-photon emission computed tomography (SPECT), fluorescence reflectance imaging (FRI), fluorescence-mediated tomography (FMT), bioluminescence imaging (BLI), laser-scanning confocal microscopy (LSCM) and multiphoton microscopy (MPM), will likely herald even greater use of these techniques in cancer research.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • FMT fluorescence reflectance imaging
  • FMT fluorescence-mediated tomography
  • BLI bioluminescence imaging
  • LSCM laser-scanning confocal microscopy
  • MCM multiphoton microscopy
  • PD-Ll expression is assayed by immunoPET imaging.
  • the proportion of cells in a test tissue sample that express PD-Ll is assessed by performing an assay to determine the presence of PD-Ll polypeptide on the surface of cells in the test tissue sample.
  • the test tissue sample is a FFPE tissue sample.
  • the presence of PD-Ll polypeptide is determined by IHC assay.
  • the IHC assay is performed using an automated process.
  • the IHC assay is performed using an anti-PD- Ll monoclonal antibody to bind to the PD-Ll polypeptide.
  • an automated IHC method is used to assay the expression of PD-Ll on the surface of cells in FFPE tissue specimens.
  • This disclosure provides methods for detecting the presence of human PD-Ll antigen in a test tissue sample, or quantifying the level of human PD-Ll antigen or the proportion of cells in the sample that express the antigen, which methods comprise contacting the test sample, and a negative control sample, with a monoclonal antibody that specifically binds to human PD-Ll, under conditions that allow for formation of a complex between the antibody or portion thereof and human PD-Ll .
  • the test and control tissue samples are FFPE samples. The formation of a complex is then detected, wherein a difference in complex formation between the test sample and the negative control sample is indicative of the presence of human PD-Ll antigen in the sample.
  • Various methods are used to quantify PD-Ll expression.
  • the automated IHC method comprises: (a) deparaffinizing and rehydrating mounted tissue sections in an autostainer; (b) retrieving antigen using a decloaking chamber and pH 6 buffer, heated to 110°C for 10 min; (c) setting up reagents on an autostainer; and (d) running the autostainer to include steps of neutralizing endogenous peroxidase in the tissue specimen; blocking non-specific protein-binding sites on the slides; incubating the slides with primary Ab; incubating with a postprimary blocking agent; incubating with NovoLink Polymer; adding a chromogen substrate and developing; and counterstaining with hematoxylin.
  • a pathologist examines the number of membrane PD-L1 + tumor cells in each field under a microscope and mentally estimates the percentage of cells that are positive, then averages them to come to the final percentage.
  • the different staining intensities are defined as 0/negative, l+/weak, 2+/moderate, and 3+/strong. Typically, percentage values are first assigned to the 0 and 3+ buckets, and then the intermediate 1+ and 2+ intensities are considered.
  • the specimen is divided into zones, and each zone is scored separately and then combined into a single set of percentage values.
  • the threshold number of cells that needs to be PD-L1 positive is at least about 100, at least about 125, at least about 150, at least about 175, or at least about 200 cells. In certain embodiments, the threshold number or cells that needs to be PD-L1 positive is at least about 100 cells.
  • Staining is also assessed in tumor-infiltrating inflammatory cells such as macrophages and lymphocytes.
  • macrophages serve as an internal positive control since staining is observed in a large proportion of macrophages. While not required to stain with 3+ intensity, an absence of staining of macrophages should be taken into account to rule out any technical failure.
  • Macrophages and lymphocytes are assessed for plasma membrane staining and only recorded for all samples as being positive or negative for each cell category. Staining is also characterized according to an outside/inside tumor immune cell designation. "Inside" means the immune cell is within the tumor tissue and/or on the boundaries of the tumor region without being physically intercalated among the tumor cells.
  • Outside means that there is no physical association with the tumor, the immune cells being found in the periphery associated with connective or any associated adjacent tissue.
  • the samples are scored by two pathologists operating independently, and the scores are subsequently consolidated.
  • the identification of positive and negative cells is scored using appropriate software.
  • H-score A histoscore, or "H-score,” is used as a more quantitative measure of the IHC data.
  • the histoscore is calculated as follows:
  • Histoscore [(% tumor x 1 (low intensity)) + (% tumor x 2 (medium intensity))
  • the pathologist estimates the percentage of stained cells in each intensity category within a specimen. Because expression of most biomarkers is heterogeneous the histoscore is a truer representation of the overall expression. The final histoscore range is 0 (no expression) to 300 (maximum expression).
  • An alternative means of quantifying PD-L1 expression in a test tissue sample IHC is to determine the adjusted inflammation score (AIS) score defined as the density of inflammation multiplied by the percent PD-L1 expression by tumor-infiltrating inflammatory cells (Taube et al, "Colocalization of inflammatory response with B7-hl expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape,” Sci. Transl. Med. 4(127) ⁇ 2 ⁇ (2012)).
  • AIS adjusted inflammation score
  • TLB Tumor Mutational Burden
  • TMB Tumor mutation burden
  • TMB refers to the number of somatic mutations in a tumor's genome and/or the number of somatic mutations per area of the tumor genome (after taking into account germline variant DNA).
  • exogenous mutagen exposure e.g., tobacco smoking or UV light exposure
  • DNA mismatch repair mutations e.g., MSI in colorectal and esophageal cancers.
  • a “non-synonymous mutation” herein refers to a nucleotide mutation that alters the amino acid sequence of a protein. Missense mutations and nonsense mutations can be both non-synonymous mutations.
  • a “missense mutation” herein refers to a non-synonymous point mutation in which a single nucleotide change results in a codon that codes for a different amino acid.
  • a “non-sense mutation” herein refers to a non-synonymous point mutation in which a codon is changed to a premature stop codon that leads to truncation of the resulting protein.
  • somatic mutations can be expressed at the RNA and/or protein level, resulting in neoantigens (also referred to as neoepitopes).
  • Neoantigens can influence an immune-mediated anti-tumor response.
  • neoantigen recognition can promote T-cell activation, clonal expansion, and differentiation into effector and memory T-cells.
  • tumors with a high TMB can also have a high neoantigen load, which can lead to high tumor immunogenicity and increased T-cell reactivity and anti-tumor response.
  • cancers with a high TMB can respond well to treatment with immune- therapies, e.g., an anti-PD-1 antibody or anti-PD-Ll antibody.
  • Genomic profiling involves analyzing nucleic acids from tumor samples, including coding and non-coding regions, and can be performed using methods having integrated optimized nucleic acid selection, read alignment, and mutation calling.
  • gene profiling provides next generation sequencing (NGS)-based analysis of tumors that can be optimized on a cancer-by-cancer, gene-by-gene and/or site-by-site basis.
  • NGS next generation sequencing
  • Genome profiling can integrate the use of multiple, individually tuned, alignment methods or algorithms to optimize performance in sequencing methods, particularly in methods that rely on massively parallel sequencing of a large number of diverse genetic events in a large number of diverse genes.
  • Genomic profiling provides for a comprehensive analysis of a subject's cancer genome, with clinical grade quality, and the output of the genetic analysis can be contextualized with relevant scientific and medical knowledge to increase the quality and efficiency of cancer therapy.
  • Genomic profiling involves a panel of a predefined set of genes comprising as few as five genes or as many as 1000 genes, about 25 genes to about 750 genes, about 100 genes to about 800 genes, about 150 genes to about 500 genes, about 200 genes to about 400 genes, about 250 genes to about 350 genes.
  • the genomic profile comprises at least 300 genes, at least 305 genes, at least 310 genes, at least 315 genes, at least 320 genes, at least 325 genes, at least 330 genes, at least 335 genes, at least 340 genes, at least 345 genes, at least 350 genes, at least 355 genes, at least 360 genes, at least 365 genes, at least 370 genes, at least 375 genes, at least 380 genes, at least 385 genes, at least 390 genes, at least 395 genes, or at least 400 genes.
  • the genomic profile comprises at least 325 genes.
  • the genomic profile comprises at least 315 cancer-related genes and introns in 28 genes (FOU DATIONO E®) or the complete DNA coding sequence of 406 genes, introns in 31 genes with rearrangements, and the RNA sequence (cDNA) of 265 genes (FOUNDATIONONE® Heme).
  • the genomic profile comprises 26 genes and 1000 associated mutations (EXODX® Solid Tumor).
  • the genomic profile comprises 76 genes (Guardant360).
  • the genomic profile comprises 73 genes (Guardant360).
  • the genomic profile comprises 354 genes and introns in 28 genes for rearrangements (FOUNDATIONONE® CDXTM).
  • the genomic profile is FOUNDATIONONE® FICDx.
  • the genomic profile comprises 468 genes (MSK-IMPACTTM). One or more genes can be added to the genome profile as more genes are identified to be related to oncology.
  • the genomic profiling detects all mutation types, i.e., single nucleotide variants, insertions/deletions (indels), copy number variations, and rearrangements, e.g., translocations, expression, and epigenetic markers.
  • mutation types i.e., single nucleotide variants, insertions/deletions (indels), copy number variations, and rearrangements, e.g., translocations, expression, and epigenetic markers.
  • genomic profile used to measure TMB status can be selected based on the type of tumor the subject has.
  • the genomic profile can include a set of genes particular to a solid tumor.
  • the genomic profile can include a set of genes particular to hematologic malignancies and sarcomas.
  • the genomic profile comprises one or more genes selected from the group consisting ofABLl, BRAF, CHEK1, FANCC, GATA3, JAK2, MITF, PDCD1LG2, RBM10, STAT4, ABL2, BRCA1, CHEK2, FANCD2, GATA4, JAK3, MLH1, PDGFRA, RET, STK11, ACVR1B, BRCA2, CIC, FANCE, GATA6, JUN, MPL, PDGFRB, RICTOR, SUFU, AKT1, BRD4, CREBBP, FANCF, GID4 (C17orf39), KAT6A (MY ST 3), MREllA, PDKl, RNF43, SYK, AKT2, BRIPI, CRKL, FANCG, GLIl, KDM5A, MSH2, PIK3C2B, ROSl, TAFl, AKT3, BTGl, CRLF2, FANCL, GNA11, KDM5C, M
  • the TMB analysis further comprises identifying a genomic alteration in one or more of ETV4, TMPRSS2, ETV5, BCR, ETV1, ETV6, and MYB.
  • the mutation status of SKT11 gene can be assessed as part of the TMB analysis or as described above.
  • TMB status based on genomic profiling is highly correlated with TMB status based on whole-exome or whole-genome sequencing.
  • TMB can be measured using a tissue biopsy sample or, alternatively, ctDNA and/or a liquid biopsy sample.
  • ctDNA can be used to measure TMB status according to whole- exome or whole-genome sequencing or genomic profiling using available methodologies, e.g., GRAIL, Inc.
  • TMB status can be used alone or in combination with other factors as a means to predict a tumor's response to therapy and, in particular, treatment with an immuno-oncology agent, such as an anti-PD-1 antibody or an anti-PD-Ll antibody.
  • an immuno-oncology agent such as an anti-PD-1 antibody or an anti-PD-Ll antibody.
  • only the TMB status of a tumor is used to identify patients with a tumor more likely to respond to therapy with an anti-PD-1 antibody or an anti-PD-Ll antibody.
  • the PD-Ll status and TMB status is used to identify patients with a tumor more likely to respond to therapy with an anti-PD-1 antibody or an anti-PD-Ll antibody.
  • the methods of the present disclosure further comprise measuring the TMB status of the subject prior to administering the anti-PD-1 antibody.
  • the methods comprise administering an anti-PD-1 antibody to a subject who carries wild-type STK11 and has a high TMB status.
  • the methods comprise not administering to the subject an anti-PD-1 antibody or terminating or augmenting an anti-PD-1 antibody therapy if the subject carries a mutant variant of STKl 1 and the subject has a high TMB status.
  • the methods of the present disclosure further comprise measuring the TMB status of the subject prior to administering the anti-PD-1 antibody.
  • the methods comprise administering an anti-PD-1 antibody to a subject who carries wild-type STK11 and has a medium TMB status. In other embodiments, the methods comprise not administering to the subject an anti-PD-1 antibody or terminating or augmenting an anti-PD-1 antibody therapy if the subject carries a mutant variant of STKl 1 and the subject has a medium TMB status. In other embodiments, the methods comprise not administering to the subject an anti-PD-1 antibody or terminating or augmenting an anti-PD-1 antibody therapy if the subject carries a mutant variant of STKl 1 and the subject has a low TMB status.
  • the FOUND ATIONO E® assay is comprehensive genomic profiling assay for solid tumors, including but not limited to solid tumors of the lung, colon, and breast, melanoma, and ovarian cancer.
  • the FOUND ATIONONE® assay uses a hybrid-capture, next-generation sequencing test to identify genomic alterations (base substitutions, insertions and deletions, copy number alterations, and rearrangements) and select genomic signatures ⁇ e.g., TMB and microsatellite instability).
  • the assay covers 322 unique genes, including the entire coding region of 315 cancer-related genes, and selected introns from 28 genes.
  • the full list of F OUND ATIONONE® assay genes is provided in Tables 1 and 2. See FOUND ATIONONE: Technical Specifications, Foundation Medicine, Inc., available at FoundationMedicine.com, last visited March 16, 2018, which is incorporated by reference herein in its entirety.
  • Table 1 List of genes wherein entire coding sequences are assayed in the
  • ARID2 CCNE1 1 FGF4 HGF (MLL2) 2 PPP2R1A SLIT2 TP53
  • Table 2 List of genes wherein selected introns are assayed in the FOUND ATIONONE® assay.
  • the FOUNDATIONONE® Heme assay is comprehensive genomic profiling assay for hematologic malignancies and sarcomas.
  • the FOUNDATIONONE® Heme assay uses a hybrid-capture, next-generation sequencing test to identify genomic alterations (base substitutions, insertions and deletions, copy number alterations, and rearrangements).
  • the assay analyzes the coding regions of 406 genes, selected introns of 31 genes, and the RNA sequences of 265 genes commonly rearranged in cancer.
  • the full list of FOUND ATIONONE® Heme assay genes is provided in Tables 3, 4, and 5. See FOUNDATIONONE® HEME: Technical Specifications, Foundation Medicine, Inc., available at FoundationMedicine.com, last visited March 16, 2018, which is incorporated by reference herein in its entirety.
  • Table 3 List of genes wherein entire coding sequences are assayed in the
  • BACH1 CREBBP FANCC GNAS JAK1 MET PBRMl ROS1 (E2A)
  • Table 4 List of genes wherein selected introns are assayed in the FOUND ATIONONE® Heme assay.
  • Table 5 List of genes wherein RNA sequences are assayed in the FOUND ATIONONE® Heme assay.
  • TMB is measured using the EXODX® Solid Tumor assay.
  • the EXODX® Solid Tumor assay is an exoRNA- and cfDNA-based assay, which detects actionable mutations in cancer pathways.
  • the EXODX® Solid Tumor assay is a plasma-based assay that does not require a tissue sample.
  • the EXODX® Solid Tumor assay covers 26 genes and 1000 mutations. The specific genes covered by the EXODX® Solid Tumor assay are shown in Table 6. See Plasma-Based Solid Tumor Mutation Panel Liquid Biopsy, Exosome Diagnostics, Inc., available at exosomedx.com, last accessed on March 16, 2018.
  • TMB status is determined using the Guardant360 assay.
  • the Guardant360 assay measures mutations in at least 73 genes (Table 7), 23 indels (Table 8), 18 CNVs (Table 9), and 6 fusion genes (Table 10). See GuardantHealth.com, last accessed on March 16, 2018.
  • TMB is determined using the TruSight Tumor 170 assay
  • the TruSight Tumor 170 assay is a next-generation sequencing assay that covers 170 genes associated with common solid tumors, which simultaneously analyzes DNA and RNA.
  • the TruSight Tumor 170 assay assesses fusions, splice variants, insertions/deletions, single nucleotide variants (SNVs), and amplifications.
  • the TruSight Tumor 170 assay gene lists are shown in Tables 11-13.
  • Table 11 TruSight Tumor 170 assay genes (amplifications).
  • Table 12 TruSight Tumor 170 assay genes (fusions).
  • Table 13 TruSight Tumor 170 assay genes (small variants).
  • FOUND ATIONONE® CDXTM (“FlCDx”) is a next generation sequencing based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutation burden (TMB) using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens.
  • FlCDx is approved by the United States Food and Drug Administration (FDA) for several tumor indications, including NSCLC, melanoma, breast cancer, colorectal cancer, and ovarian cancer.
  • the FlCDx assay employs a single DNA extraction method from routine FFPE biopsy or surgical resection specimens, 50-1000 ng of which will undergo whole-genome shotgun library construction and hybridization-based capture of all coding exons from 309 cancer-related genes, one promoter region, one non-coding (ncRNA), and selected intronic regions from 34 commonly rearranged genes, 21 of which also include the coding exons.
  • Tables 14 and 15 provide the complete list of genes included in FlCDx. In total, the assay detects alterations in a total of 324 genes.
  • hybrid capture- selected libraries are sequenced to high uniform depth (targeting >500X median coverage with >99% of exons at coverage >100X). Sequence data is then processed using a customized analysis pipeline designed to detect all classes of genomic alterations, including base substitutions, indels, copy number alterations (amplifications and homozygous gene deletions), and selected genomic rearrangements ⁇ e.g., gene fusions). Additionally, genomic signatures including microsatellite instability (MSI) and tumor mutation burden (TMB) are reported. Table 14: Genes with full coding exonic regions included in FOUND ATIONONE® CDXTM for the detection of substitutions, insertions and deletions (indels), and copy number alterations
  • Table 15 Genes with selected intronic regions for the detection of gene rearrangements, one with 3'UTR, one gene with a promoter region and one ncRNA gene.
  • the FICDx assay identifies various alterations in the gene and/or intron sequences, including substitutions, insertions/deletions, and CNAs.
  • the FICDx assay was previously identifies as having concordance with an externally validated NGS assay and the FOUND ATIONO E® (Fl LDT) assay. See FOUND ATIONONE® CDXTM: Technical Information, Foundation Medicine, Inc., available at FoundationMedicine.com, last visited March 16, 2018, which is incorporated by reference herein in its entirety.
  • TMB status is assessed using the MSK-IMPACTTM assay.
  • the MSK-FMPACTTM assay uses next-generation sequencing to analyze the mutation status of 468 genes.
  • Target genes are captured and sequenced on an ILLUMINA® HISEQTM instrument.
  • the MSK-IMPACTTM assay is approved by the US FDA for detection of somatic mutations and microsatellite instability in solid malignant neoplasms.
  • the full list of 468 genes analyzed by the MSK-IMPACTTM assay is shown in Table 16. See Evaluation of Automatic Class III Designation for MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets): Decision Summary, United States Food and Drug Administration, November 15, 2017, available at accessdata.fda.gov.
  • Table 16 Genes analyzed by the MSK-FMPACTTM assay.
  • TMB is determined using a NEOGENOMICS®
  • the TMB is determined using a NEOTYPETM Discovery Profile. In some embodiments, the TMB is determined using a NEOTYPETM Solid Tumor Profile.
  • the NEOGENOMICS® assays measure the number of non-synonymous DNA coding sequence changes per megabase of sequenced DNA.
  • TMB is determined using a THERMOFISHER
  • TMB is determined using a THERMOFISHER SCIENTIFIC® ION TORRENTTM ONCOMINETM Tumor Mutation assay.
  • the ION TORRENTTM ONCOMINETM Tumor Mutation assay is a targeted NGS assay that quantitates somatic mutations to determine tumor mutation load. The assay covers 1.7 Mb of DNA.
  • TMB is determined using a NOVOGENETM NOVOPMTM assay. In some embodiments, TMB is determined using a NOVOGENETM NOVOPMTM Cancer Panel assay.
  • the NOVOGENETM NOVOPMTM Cancer Panel assay is a comprehensive NGS cancer panel that analyzes the complete coding regions of 548 genes and the introns of 21 genes, representing about 1.5 Mb of DNA, and that are relevant for the diagnosis and/or treatment of solid tumors according to the National Comprehensive Cancer Network (NCCN) guidelines and medical literature. The assay detects SNV, InDel, fusion, and copy number variation (CNV) genomic abnormalities.
  • TMB is determined using a TMB assay provided by
  • TMB is determined using the PESONALIS® ACE ImmunoID assay. In some embodiments, TMB is determined using the PGDX® CANCERXOMETM-R assay.
  • the genomic profiling detects all mutation types, i.e., single nucleotide variants, insertions/deletions (indels), copy number variations, and rearrangements, e.g., translocations, expression, and epigenetic markers.
  • genomic profile used to measure TMB status can be selected based on the type of tumor the subject has.
  • the genomic profile can include a set of genes particular to a solid tumor.
  • the genomic profile can include a set of genes particular to hematologic malignancies and sarcomas.
  • the genomic profile comprises one or more genes selected from the group consisting ofABLl, BRAF, CHEK1, FANCC, GATA3, JAK2, MITF, PDCD1LG2, RBM10, STAT4, ABL2, BRCA1, CHEK2, FANCD2, GATA4, JAK3, MLH1, PDGFRA, RET, STK11, ACVR1B, BRCA2, CIC, FANCE, GATA6, JUN, MPL, PDGFRB, RICTOR, SUFU, AKT1, BRD4, CREBBP, FANCF, GID4 (C17orf39), KAT6A (MY ST 3), MRE11A, PDK1, RNF43, SYK, AKT2, BRIPI, CRKL, FANCG, GLIl, KDM5A, MSH2, PIK3C2B, ROSl, TAFl, AKT3, BTGl, CRLF2, FANCL, GNA11, KDM5C, MSH
  • the genomic profile comprises one or more genes selected from the group consisting oiABLl, 12B, ABL2, ACTB, ACVR1, ACVR1B, AG02, AKT1, AKT2, AKT3, ALK, ALOX, ALOX12B, AMERl, AMER1 (FAM123B or WTX), AMERl (FAM123B), ANKRDII, APC, APHIA, AR, ARAF, ARFRPl, ARHGAP26 (GRAF), ARIDIA, ARIDIB, ARID2, ARID5B, ARv7, ASMTL, ASXL1, ASXL2, ATM, ATR, ATRX, AURKA, AURKB, AXIN1, AXIN2, AXL, B2M, BABAMl, BAP1, BARD1, BBC3, BCL10, BCL11B, BCL2, BCL2L1, BCL2L11, BCL2L2, BCL6, BCL7A, BCOR, BCORL1, BIRC
  • the genomic profiling assay comprises at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, at least about 200, at least about 210, at least about 220, at least about 230, at least about 240, at least about 250, at least about 260, at least about 270, at least about 280, at least about 290, or at least about 300 genes selected from the group consisting of ABL1, 12B, ABL2, ACTB, ACVR1, ACVR1B, AG02, AKT1, AKT2, AKT3, ALK, ALOX, ALOX12B, AMER1, AMER1 (FAM123B or WTX), AMERl (FAM123B), ANKRD11, APC,
  • the genomic profile comprises one or more genes selected from the genes listed in Tables 1-16.
  • TMB status based on genomic profiling is highly correlated with TMB status based on whole-exome or whole-genome sequencing.
  • Evidence provided herein shows that the use of genomic profiling assays, such as the FICDx assay, have concordance with whole-exome and/or whole genome sequencing assays.
  • TMB can be measured using a tissue biopsy sample or, alternatively, circulating tumor DNA (ctDNA), cfDNA (cell-free DNA), and/or a liquid biopsy sample.
  • ctDNA can be used to measure TMB status according to whole-exome or whole-genome sequencing or genomic profiling using available methodologies, e.g., GRAIL, Inc.
  • a subject is identified as suitable for an immunotherapy, e.g., with an anti-PD-1 antibody or antigen-binding portion thereof or an anti-PD-Ll antibody or antigen-binding portion thereof, based on the measurement of TMB status and identification of a high TMB.
  • a TMB score is calculated as the total number of nonsynonymous missense mutations in a tumor, as measured by whole exome sequencing or whole genome sequencing.
  • the high TMB has a score of at least 210, at least 215, at least 220, at least 225, at least 230, at least 235, at least 240, at least 245, at least 250, at least 255, at least 260, at least 265, at least 270, at least 275, at least 280, at least 285, at least 290, at least 295, at least 300, at least 305, at least 310, at least 315, at least 320, at least 325, at least 330, at least 335, at least 340, at least 345, at least 350, at least 355, at least 360, at least 365, at least 370, at least 375, at least 380, at least 385, at least 390, at least 395, at least 400, at least 405, at least 410, at least 415, at least 420, at least 425, at least 430, at least 435, at least 440, at least 445, at least 450, at least 455, at least 460
  • the high TMB has a score of at least 215, at least 220, at least 221, at least 222, at least 223, at least 224, at least 225, at least 226, at least 227, at least 228, at least 229, at least 230, at least 231, at least 232, at least 233, at least 234, at least 235, at least 236, at least 237, at least 238, at least 239, at least 240, at least 241, at least 242, at least 243, at least 244, at least 245, at least 246, at least 247, at least 248, at least 249, or at least 250.
  • the high TMB has a score of at least 243.
  • the high TMB has a score of at least 244. In some embodiments, the high TMB has a score of at least 245. In other embodiments, the high TMB has a score of at least 246. In other embodiments, the high TMB has a score of at least 247. In other embodiments, the high TMB has a score of at least 248. In other embodiments, the high TMB has a score of at least 249. In other embodiments, the high TMB has a score of at least 250. In other embodiments, the high TMB has a score of any integer between 200 and 300 or higher. In other embodiments, the high TMB has a score of any integer between 210 and 290 or higher.
  • the high TMB has a score of any integer between 220 and 280 or higher. In other embodiments, the high TMB has a score of any integer between 230 and 270 or higher. In other embodiments, the high TMB has a score of any integer between 235 and 265 or higher.
  • the high TMB can be a relative value rather than an absolute value.
  • the subject's TMB status is compared to a reference TMB value. In one embodiment, the subject's TMB status is within the highest fractile of the reference TMB value. In another embodiment, the subject's TMB status is within the top tertile of the reference TMB value.
  • TMB status is expressed as the number of mutations per sample, per cell, per exome, or per length of DNA (e.g., Mb).
  • a tumor has a high TMB status if the tumor has at least about 50 mutations/tumor, at least about 55 mutations/tumor, at least about 60 mutations/tumor, at least about 65 mutations/tumor, at least about 70 mutations/tumor, at least about 75 mutations/tumor, at least about 80 mutations/tumor, at least about 85 mutations/tumor, at least about 90 mutations/tumor, at least about 95 mutations/tumor, at least about 100 mutations/tumor, at least about 105 mutations/tumor, at least about 110 mutations/tumor, at least about 115 mutations/tumor, or at least about 120 mutations/tumor.
  • a tumor has a high TMB status if the tumor has at least about 125 mutations/tumor, at least about 150 mutations/tumor, at least about 175 mutations/tumor, at least about 200 mutations/tumor, at least about 225 mutations/tumor, at least about 250 mutations/tumor, at least about 275 mutations/tumor, at least about 300 mutations/tumor, at least about 350 mutations/tumor, at least about 400 mutations/tumor, or at least about 500 mutations/tumor.
  • a tumor has a high TMB status if the tumor has at least about 100 mutations/tumor.
  • a tumor has a high TMB status if the tumor has at least about 5 mutations per megabase of genes, e.g., genome sequenced according to a TMB assay, e.g., genome sequenced according to a FOUND ATIONO E® CDXTM assay, (mutations/Mb), at least about 6 mutations/Mb, at least about 7 mutations/Mb, at least about 8 mutations/Mb, at least about 9 mutations/Mb, at least about 10 mutations/Mb, at least about 11 mutations/Mb, at least about 12 mutations/Mb, at least about 13 mutations/Mb, at least about 14 mutations/Mb, at least about 15 mutations/Mb, at least about 20 mutations/Mb, at least about 25 mutations/Mb, at least about 30 mutations/Mb, at least about 35 mutations/Mb, at least about 40 mutations/Mb, at least about 45 mutations/Mb, at least about 50 mutations/M
  • a tumor has a high TMB status if the tumor has at least about 5 mutations/Mb. In certain embodiments, a tumor has a high TMB status if the tumor has at least about 10 mutations/Mb. In some embodiments, a tumor has a high TMB status if the tumor has at least about 11 mutations/Mb. In some embodiments, a tumor has a high TMB status if the tumor has at least about 12 mutations/Mb. In some embodiments, a tumor has a high TMB status if the tumor has at least about 13 mutations/Mb. In some embodiments, a tumor has a high TMB status if the tumor has at least about 14 mutations/Mb. In certain embodiments, a tumor has a high TMB status if the tumor has at least about 15 mutations/Mb.
  • the present methods can treat a tumor at any stage.
  • the tumor is derived from an NSCLC of any stage.
  • NSCLC NSCLC of any stage.
  • occult stage the cancer cannot be seen by imaging or bronchoscopy.
  • Stage 0 cancer cells are found in the lining of the airways.
  • the present methods treat a Stage I non-squamous NSCLC.
  • Stage I NSCLC is divided in Stage IA and IB.
  • Stage IA the tumor is in the lung only and is 3 centimeters or smaller.
  • Stage IB the cancer has not spread to the lymph nodes and one or more of the following is true: 1) the tumor is larger than 3 centimeters but not larger than 5 centimeters; 2) the cancer has spread to the main bronchus and is at least 2 centimeters below where the trachea joins the bronchus; 3) cancer has spread to the innermost layer of the membrane that covers the lung; or 4) part of the lung has collapsed or developed pneumonitis (inflammation of the lung) in the area where the trachea joins the bronchus.
  • Stage II NSCLC is divided into Stage IIA and IIB.
  • Stage IIA the cancer has either spread to the lymph nodes or not. If the cancer has spread to the lymph nodes, then the cancer can only have spread to the lymph nodes on the same side of the chest as the tumor, the lymph nodes with cancer or within the lung or near the bronchus, and one or more of the following is true: 1) the tumor is not larger than 5 centimeters; 2) the cancer has spread to the main bronchus and is at least 2 centimeters below where the trachea joins the bronchus; 3) cancer has spread to the innermost layer of the membrane that covers the lung; or 4) part of the lung has collapsed or developed pneumonitis (inflammation of the lung) in the area where the trachea joins the bronchus.
  • the tumor is also considered Stage IIA if the cancer has not spread to the lymph nodes and one or more of the following is true: 1) the tumor is larger than 5 centimeters but not larger than 7 centimeters; 2) the cancer has spread to the main bronchus and is at least 2 centimeters below where the trachea joins the bronchus; 3) cancer has spread to the innermost layer of the membrane that covers the lung; or 4) part of the lung has collapsed or developed pneumonitis (inflammation of the lung) in the area where the trachea joins the bronchus. In stage IIB, the cancer has either spread to the lymph nodes or not.
  • the cancer can only have spread to the lymph nodes on the same side of the chest as the tumor, the lymph nodes with cancer are within the lung or near the bronchus and one or more of the following is true: 1) the tumor is larger than 5 centimeters but not larger than 7 centimeters; 2) the cancer has spread to the main bronchus and is at least 2 centimeters below where the trachea joins the bronchus; 3) cancer has spread to the innermost layer of the membrane that covers the lung; or 4) part of the lung has collapsed or developed pneumonitis (inflammation of the lung) in the area where the trachea joins the bronchus.
  • the tumor is also considered Stage IIB if the cancer has not spread to the lymph nodes and one or more of the following is true: 1) the tumor is larger than 7 centimeters; 2) the cancer has spread to the main bronchus (and is at least 2 centimeters below where the trachea joins the bronchus), the chest wall, the diaphragm, or the nerve that controls the diaphragm; 3) cancer has spread to the membrane around the heart or lining the chest wall; 4) the whole lung has collapsed or developed pneumonitis (inflammation of the lung); or 5) there are one or more separate tumors in the same lobe of the lung.
  • any methods of the present disclosure treats Stage III non- squamous NSCLC.
  • Stage IIIA is divided into 3 sections. These 3 sections are based on 1) the size of the tumor; 2) where the tumor is found and 3) which (if any) lymph nodes have cancer.
  • the cancer has spread to the lymph nodes on the same side of the chest as the tumor, and the lymph nodes with the cancer are near the sternum or where the bronchus enters the lung.
  • the tumor may be any size; 2) part of the lung (where the trachea joins the bronchus) or the whole lung may have collapsed or developed pneumonitis (inflammation of the lung); 3) there may be one or more separate tumors in the same lobe of the lung; and 4) cancer can have spread to any of the following: a) main bronchus, but not the area where the trachea joins the bronchus, b) chest well, c) diaphragm and the nerve that controls it, d) membrane around the lung or lining the chest wall, e) membrane around the heart.
  • the cancer has spread to the lymph nodes on the same side of the chest as the tumor, and the lymph nodes with the cancer are within the lung or near the bronchus. Additionally: 1) the tumor may be any size; 2) the whole lung may have collapsed or developed pneumonitis (inflammation of the lung); 3) there may be one or more separate tumors in the any of the lobes of the lung with cancer; and 4) cancer can have spread to any of the following: a) main bronchus, but not the area where the trachea joins the bronchus, b) chest well, c) diaphragm and the nerve that controls it, d) membrane around the lung or lining the chest wall, e) heart or the membrane around it, f) major blood vessels that lead to or from the heart, g) trachea, h) esophagus, i) nerve that controls the larynx (voice box), j) sternum (chest bone) or back
  • the cancer has not spread to the lymph nodes
  • the tumor may be any size, and cancer has spread to any one of the following: a) heart, b) major blood vessels that lead to or from the heart, c) trachea, d) esophagus, e) nerve that controls the larynx (voice box), f) sternum (chest bone) or backbone, or g) carina (where the trachea joins the bronchi).
  • Stage IIIB is divided into 2 sections depending on 1) the size of the tumor, 2) where the tumor is found, and 3) which lymph nodes have cancer.
  • the cancer has spread to the lymph nodes on the opposite side of the chest as the tumor. Additionally, 1) the tumor may be any size; 2) part of the lung (where the trachea joins the bronchus) or the whole lung may have collapsed or developed pneumonitis (inflammation of the lung); 3) there may be one or more separate tumors in any of the lobs of the lung with cancer; and 4) cancer may have spread to any of the following: a) main bronchus, b) chest well, c) diaphragm and the nerve that controls it, d) membrane around the lung or lining the chest wall, e) heart or the membrane around it, f) major blood vessels that lead to or from the heart, g) trachea, h) esophagus, i) nerve that controls the larynx (voice box), j) sternum (chest bone) or backbone, or k) carina (where the trachea joins the tumor.
  • the tumor may be any size; 2)
  • the cancer has spread to lymph nodes on the same side of the chest as the tumor.
  • the lymph nodes with cancer are near the sternum (chest bone) or where the bronchus enters the lung.
  • the tumor may be any size; 2) there may be separate tumors in different lobes of the same lung; and 3) cancer has spread to any of the following: a) heart, b) major blood vessels that lead to or from the heart, c) trachea, d) esophagus, e) nerve that controls the larynx (voice box), f) sternum (chest bone) or backbone, or g) carina (where the trachea joins the bronchi).
  • the methods of the disclosure treat a Stage IV non- squamous NSCLC.
  • the tumor may be any size and the cancer may have spread to the lymph nodes.
  • One or more of the following is true in Stage IV NSCLC: 1) there are one or more tumors in both lungs; 2) cancer is found in the fluid around the lungs or heart; and 3) cancer has spread to other parts of the body, such as the brain, liver, adrenal glands, kidneys or bone.
  • a NSCLC treatable by the present methods is squamous cell (epidermoid) carcinoma (squamous NSCLC).
  • squamous NSCLC squamous cell carcinoma
  • About 25% to 30% of all lung cancers are known to be squamous cell carcinomas.
  • These cancers start in early versions of squamous cells, which are flat cells that line the inside of the airways in the lungs. They are often linked to a history of smoking and tend to be found in the central part of the lungs, near a main airway (bronchus).
  • the anti-PD-1 antibody is nivolumab. In other embodiments, it is pembrolizumab.
  • the anti-PD-1 antibodies are formulated for intravenous administration. In certain embodiments, the anti-PD-1 antibody is administered by intravenous infusion over a period of 60 minutes. In certain embodiments, the anti-PD-1 antibody is administered as a pharmaceutically acceptable formulation. In certain embodiments, the anti-PD-1 antibody or antigen-binding portion thereof is administered at a subtherapeutic dose.
  • Anti-PD-1 antibodies that are known in the art can be used in the presently described compositions and methods.
  • Various human monoclonal antibodies that bind specifically to PD-1 with high affinity have been disclosed in U.S. Patent No. 8,008,449.
  • the anti-PD-1 antibody is selected from the group consisting of nivolumab (also known as OPDIVO®, 5C4, BMS-936558, MDX-1106, and ONO-4538), pembrolizumab (Merck; also known as KEYTRUDA®, lambrolizumab, and MK-3475; see WO2008/156712), PDR001 (Novartis; see WO 2015/112900), MEDI-0680 (AstraZeneca; also known as AMP-514; see WO 2012/145493), cemiplimab (Regeneron; also known as REGN- 2810; see WO 2015/112800), JS001 (TAIZHOU JUNSHI PHARMA; see Si-Yang Liu et al., J.
  • nivolumab also known as OPDIVO®, 5C4, BMS-936558, MDX-1106, and ONO-4538
  • pembrolizumab Merck; also
  • the anti-PD-1 antibody is nivolumab.
  • Nivolumab is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the down-regulation of antitumor T-cell functions (U.S. Patent No. 8,008,449; Wang et al., 2014 Cancer Immunol Res. 2(9) ⁇ -5 ⁇ ).
  • the anti-PD-1 antibody is pembrolizumab.
  • Pembrolizumab is a humanized monoclonal IgG4 (S228P) antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1).
  • S228P humanized monoclonal IgG4
  • Pembrolizumab is described, for example, in U.S. Patent Nos. 8,354,509 and 8,900,587.
  • Anti-PD-1 antibodies usable in the disclosed compositions and methods also include isolated antibodies that bind specifically to human PD-1 and cross-compete for binding to human PD-1 with any anti-PD-1 antibody disclosed herein, e.g., nivolumab ⁇ see, e.g., U.S. Patent No. 8,008,449 and 8,779, 105; WO 2013/173223).
  • the anti-PD-1 antibody binds the same epitope as any of the anti-PD-1 antibodies described herein, e.g., nivolumab.
  • cross-competing antibodies are expected to have functional properties very similar those of the reference antibody, e.g., nivolumab, by virtue of their binding to the same epitope region of PD-1.
  • Cross-competing antibodies can be readily identified based on their ability to cross-compete with nivolumab in standard PD-1 binding assays such as Biacore analysis, ELISA assays or flow cytometry ⁇ see, e.g., WO 2013/173223).
  • the antibodies that cross-compete for binding to human PD-1 with, or bind to the same epitope region of human PD-1 antibody, nivolumab are monoclonal antibodies.
  • these cross-competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies.
  • Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.
  • Anti-PD-1 antibodies usable in the compositions and methods of the disclosed disclosure also include antigen-binding portions of the above antibodies. It has been amply demonstrated that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • Anti-PD-1 antibodies suitable for use in the disclosed compositions and methods are antibodies that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and or PD-L2, and inhibit the immunosuppressive effect of the PD-1 signaling pathway.
  • an anti-PD-1 "antibody” includes an antigen-binding portion or fragment that binds to the PD-1 receptor and exhibits the functional properties similar to those of whole antibodies in inhibiting ligand binding and up-regulating the immune system.
  • the anti-PD-1 antibody or antigen-binding portion thereof cross- competes with nivolumab for binding to human PD-1.
  • an anti-PD-1 antibody used in the methods can be replaced with another PD-1 or anti-PD-Ll antagonist.
  • an anti-PD-Ll antibody prevents interaction between PD-1 and PD-L1, thereby exerting similar effects to the signaling pathway of PD-1
  • an anti-PD-Ll antibody can replace the use of an anti-PD-1 antibody in the methods disclosed herein.
  • Anti-PD-Ll antibodies that are known in the art can be used in the compositions and methods of the present disclosure. Examples of anti-PD-Ll antibodies useful in the compositions and methods of the present disclosure include the antibodies disclosed in US Patent No. 9,580,507. Anti-PD-Ll human monoclonal antibodies disclosed in U.S. Patent No.
  • 9,580,507 have been demonstrated to exhibit one or more of the following characteristics: (a) bind to human PD-L1 with a K D of 1 x 10 "7 M or less, as determined by surface plasmon resonance using a Biacore biosensor system; (b) increase T-cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay; (c) increase interferon- ⁇ production in an MLR assay; (d) increase IL-2 secretion in an MLR assay; (e) stimulate antibody responses; and (f) reverse the effect of T regulatory cells on T cell effector cells and/or dendritic cells.
  • Anti-PD-Ll antibodies usable in the present disclosure include monoclonal antibodies that bind specifically to human PD-L1 and exhibit at least one, in some embodiments, at least five, of the preceding characteristics.
  • the anti-PD-Ll antibody is selected from the group consisting of BMS-936559 (also known as 12A4, MDX-1105; see, e.g., U.S. Patent No. 7,943,743 and WO 2013/173223), atezolizumab (Roche; also known as TECENTRIQ®; MPDL3280A, RG7446; see US 8,217, 149; see, also, Herbst et al.
  • the PD-L1 antibody is atezolizumab (TECENTRIQ®).
  • Atezolizumab is a fully humanized IgGl monoclonal anti-PD-Ll antibody.
  • the PD-L1 antibody is durvalumab (IMFINZITM).
  • Durvalumab is a human IgGl kappa monoclonal anti-PD-Ll antibody.
  • the PD-L1 antibody is avelumab (BAVENCIO®).
  • Avelumab is a human IgGl lambda monoclonal anti-PD-Ll antibody.
  • Anti-PD-Ll antibodies usable in the disclosed compositions and methods also include isolated antibodies that bind specifically to human PD-L1 and cross-compete for binding to human PD-L1 with any anti-PD-Ll antibody disclosed herein, e.g., atezolizumab, durvalumab, and/or avelumab.
  • the anti-PD-Ll antibody binds the same epitope as any of the anti-PD-Ll antibodies described herein, e.g., atezolizumab, durvalumab, and/or avelumab.
  • Cross-competing antibodies can be readily identified based on their ability to cross-compete with atezolizumab and/or avelumab in standard PD-L1 binding assays such as Biacore analysis, ELISA assays or flow cytometry (see, e.g., WO 2013/173223).
  • the antibodies that cross-compete for binding to human PD- Ll with, or bind to the same epitope region of human PD-L1 antibody as, atezolizumab, durvalumab, and/or avelumab are monoclonal antibodies.
  • these cross-competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies.
  • Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.
  • Anti-PD-Ll antibodies usable in the compositions and methods of the disclosed disclosure also include antigen-binding portions of the above antibodies. It has been amply demonstrated that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • Anti -PD-Ll antibodies suitable for use in the disclosed compositions and methods are antibodies that bind to PD-Ll with high specificity and affinity, block the binding of PD-1, and inhibit the immunosuppressive effect of the PD-1 signaling pathway.
  • an anti-PD-Ll "antibody” includes an antigen-binding portion or fragment that binds to PD-Ll and exhibits the functional properties similar to those of whole antibodies in inhibiting receptor binding and up-regulating the immune system.
  • the anti-PD-Ll antibody or antigen-binding portion thereof cross-competes with atezolizumab, durvalumab, and/or avelumab for binding to human PD-Ll .
  • NCCN GUIDELINES® NCCN Clinical Practice Guidelines in Oncology
  • NSCLC is the leading cause of cancer death in the U.S. and worldwide, exceeding breast, colon and prostate cancer combined.
  • an estimated 228, 190 new cases of lung and bronchial will be diagnosed in the U.S., and some 159,480 deaths will occur because of the disease (Siegel et al. (2014) CA Cancer J Clin 64(l):9-29).
  • the majority of patients (approximately 78%) are diagnosed with advanced/recurrent or metastatic disease. Metastases to the adrenal gland from lung cancer are a common occurrence, with about 33% of patients having such metastases.
  • NSCLC therapies have incrementally improved OS, but benefit has reached a plateau (median OS for late stage patients is just 1 year).
  • RT radiation therapy
  • chemotherapy are the three modalities commonly used to treat NSCLC patients.
  • NSCLCs are relatively insensitive to chemotherapy and RT, compared to small cell carcinoma.
  • surgical resection provides the best chance for cure, with chemotherapy increasingly being used both pre-operatively and post-operatively.
  • RT can also be used as adjuvant therapy for patients with resectable NSCLC, the primary local treatment, or as palliative therapy for patients with incurable NSCLC.
  • Erlotinib is a small-molecule TKI of epidermal growth factor receptor (EGFR).
  • Crizotinib is a small-molecule TKI that targets ALK and MET, and is used to treat NSCLC in patients carrying the mutated ALK fusion gene.
  • Cetuximab is a monoclonal antibody that targets EGFR.
  • Pemetrexed and bevacizumab are not approved in squamous NSCLC, and molecularly targeted therapies have limited application.
  • the unmet need in advanced lung cancer has been compounded by the recent failure of Oncothyreon and Merck KgaA's STIMUVAX® to improve OS in a phase 3 trial, inability of ArQule's and Daiichi Sankyo's c-Met kinase inhibitor, tivantinib, to meet survival endpoints, failure of Eli Lilly's ALIMTA® in combination with Roche's AVASTIN® to improve OS in a late-stage study, and Amgen's and Takeda Pharmaceutical's failure to meet clinical endpoints with the small-molecule VEGF-R antagonist, motesanib, in late-stage trials.
  • Therapeutic agents of the present disclosure can be constituted in a composition, e.g., a pharmaceutical composition containing one or more antibodies and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier for a composition containing an antibody is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration ⁇ e.g., by injection or infusion).
  • a pharmaceutical composition of the disclosure can include one or more pharmaceutically acceptable salts, anti-oxidant, aqueous and non-aqueous carriers, and/or adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • the dosing schedule is typically designed to achieve exposures that result in sustained receptor occupancy (RO) based on typical pharmacokinetic properties of an antibody.
  • An exemplary treatment regime entails administration once about per week, once about every 2 weeks, once about every 3 weeks, once about every 4 weeks, once about every month, once about every 3-6 months or longer.
  • an anti-PD-1 antibody such as nivolumab is administered to the subject once about every 2 weeks.
  • the anti-PD-1 antibody can be administered in at least two doses, each of the doses is at an amount of about 0.01 mg/kg to about 5 mg/kg, e.g., 3 mg/kg, at a dosing interval of every two weeks between the two doses.
  • the anti-PD-1 antibody is administered in at least three, four, five, six, or seven doses (i.e., multiple doses), each of the doses is at an amount of about 0.01 mg/kg to about 10 mg/kg, e.g., 1 mg/kg, 3 mg/kg, or 6 mg/kg, at a dosing interval of every two weeks between two adjacently given doses.
  • the dosage and scheduling can change during a course of treatment.
  • the dosage can range from about 1 to about 20 mg/kg, about 1 to about 19 mg/kg, about 2 to about 18 mg/kg, about 3 to about 17 mg/kg, about 3 to about 16 mg/kg, about 4 to about 15 mg/kg, about 5 to about 14 mg/kg, about 6 to about 13 mg/kg, about 7 to about 12 mg/kg, or about 8 to about 12 mg/kg of the subject's body weight.
  • dosages can be about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, or about 18 mg/kg body weight.
  • the dosing schedule is typically designed to achieve exposures that result in sustained receptor occupancy (RO) based on typical pharmacokinetic properties of an antibody.
  • An exemplary treatment regime entails administration once about per week, once about every 2 weeks, once about every 3 weeks, once about every 4 weeks, once about every month, once about every 3-6 months or longer.
  • an anti-PD-Ll antibody is administered to the subject once about every 2 weeks.
  • the anti-PD-Ll antibody can be administered in at least two doses, each of the doses is at an amount of about 6 mg/kg to about 18 mg/kg, e.g., 10 mg/kg, at a dosing interval of every two weeks between the two doses.
  • the anti-PD-1 antibody is administered in at least three, four, five, six, or seven doses (i.e., multiple doses), each of the doses is at an amount of about 6 mg/kg to about 18 mg/kg, e.g., 10 mg/kg or 15 mg/kg, at a dosing interval of every two weeks between two adjacently given doses.
  • the dosage and scheduling can change during a course of treatment.
  • a dosage regimen for an anti-PD-Ll antibody of the disclosure comprises about 1 to about 18 mg/kg body weight, about 6 to about 15 mg/kg body weight, or about 10 to about 15 mg/kg body weight via intravenous administration, with the antibody being given every about 14-21 days in up to about 6-week or about 12-week cycles until complete response or confirmed progressive disease.
  • the antibody treatment, or any combination treatment disclosed herein is continued for at least about 1 month, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 18 months, at least about 24 months, at least about 3 years, at least about 5 years, or at least about 10 years.
  • the dosage of an anti-PD-1 antibody can be lowered compared to the monotherapy dose.
  • the subtherapeutic doses of an anti-PD-1 antibody used in the methods herein are higher than 0.001 mg/kg and lower than 3mg/kg.
  • a subtherapeutic dose is about 0.001 mg/kg-about 1 mg/kg, about 0.01 mg/kg-about 1 mg/kg, about 0.1 mg/kg-about 1 mg/kg, or about 0.001 mg/kg-about 0.1 mg/kg body weight.
  • the subtherapeutic dose is at least about 0.001 mg/kg, at least about 0.005 mg/kg, at least about 0.01 mg/kg, at least about 0.05 mg/kg, at least about 0.1 mg/kg, at least about 0.5 mg/kg, or at least about 1.0 mg/kg body weight.
  • Receptor-occupancy data from 15 subjects who received 0.3 mg/kg to 10 mg/kg dosing with nivolumab indicate that PD-1 occupancy appears to be dose-independent in this dose range. Across all doses, the mean occupancy rate was 85% (range, 70% to 97%), with a mean plateau occupancy of 72% (range, 59% to 81%) (Brahmer et al. (2010) J Clin Oncol 28:3167-75). Thus, 0.3 mg/kg dosing can allow for sufficient exposure to lead to maximal biologic activity.
  • the anti-PD-1 antibody is administered at a dose of 3 mg/kg. In other embodiments of the disclosure, the anti-PD-1 antibody is administered at a dose of 1 mg/kg.
  • the dose of an anti-PD-1 antibody is a flat dose in a pharmaceutical composition.
  • the method of the present disclosure can be used with a flat dose (a dose given to a patient irrespective of the body weight of the patient).
  • the flat dose of the anti-PD-1 antibody or antigen binding portion thereof is at least about 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 600 mg, 640 mg, 680 mg, 720 mg, 760 mg, 800 mg, 840 mg, 880 mg, 920 mg, 960 mg, 1000 mg, 1040 mg, 1080 mg, 1120 mg, 1160 mg, or 1200 mg.
  • a flat dose of a nivolumab can be about 240 mg.
  • a flat dose of pembrolizumab can be about 200 mg.
  • the anti-PD-1 antibody or antigen- binding portion thereof is administered at a dose of about 240 mg.
  • the anti-PD-1 antibody or antigen-binding portion thereof is administered at a dose of about 360 mg.
  • the anti-PD-1 antibody or antigen-binding portion thereof is administered at a dose of about 480 mg.
  • the flat dose of the anti-PD-1 antibody or antigen binding portion thereof is administered once about every week, every two weeks, every three weeks, every four weeks, every five weeks, or every six weeks.
  • 240 mg of the anti- PD-1 antibody or antigen binding fragment is administered once every 2 weeks.
  • 360 mg of the anti-PD-1 antibody or antigen binding fragment is administered once every 3 weeks.
  • 480 mg of the anti-PD-1 antibody or antigen binding fragment is administered once every 4 weeks.
  • the flat dose of the anti-PD-Ll antibody or antigen binding portion thereof is at least about 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, 800 mg, 820 mg, 840 mg, 860 mg, 880 mg, 900 mg, 920 mg, 940 mg, 960 mg, 1000 mg, 1040 mg, 1080 mg, 1120 mg, 1160 mg, 1200 mg, 1240 mg, 1280 mg, 1320 mg, 1360 mg, 1400 mg, 1440 mg, 1480 mg, 1520 mg, 1560 mg, 1600 mg, 1640 mg, 1680 mg, 1720 mg, 1760 mg, or 1800 mg.
  • a flat dose of a atezolizumab can be about 1200 mg.
  • a flat dose of durvalumab can be about 800 mg.
  • a flat dose of avelumab can be about 800 mg.
  • the anti-PD-Ll antibody or antigen-binding portion thereof is administered at a dose of about 800 mg.
  • the anti-PD-Ll antibody or antigen-binding portion thereof is administered at a dose of about 1200 mg.
  • the anti-PD-Ll antibody or antigen-binding portion thereof is administered at a dose of about 1600 mg.
  • the flat dose of the anti-PD-Ll antibody or antigen binding portion thereof is administered once about every week, every two weeks, every three weeks, every four weeks, every five weeks, or every six weeks. In one embodiment, about 800 mg of the anti-PD-Ll antibody or antigen binding fragment is administered once every 2 weeks. In another embodiment, about 1200 mg of the anti-PD-Ll antibody or antigen binding fragment is administered once every 4 weeks.
  • Dosage and frequency vary depending on the half-life of the antibody in the subject. In general, human antibodies show the longest half-life, followed by humanized antibodies, chimeric antibodies, and nonhuman antibodies.
  • the dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is typically administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, or until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a prophylactic regime.
  • compositions of the present disclosure can be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being unduly toxic to the patient.
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present disclosure employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a composition of the present disclosure can be administered via one or more routes of administration using one or more of a variety of methods well known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results.
  • kits comprising an anti-PD-1 antibody or an anti-PD-Ll antibody.
  • Kits typically include a label indicating the intended use of the contents of the kit and instructions for use.
  • the term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit. Accordingly, this disclosure provides a kit for treating a subject afflicted with a tumor, the kit comprising: (a) a dosage ranging from about 4 mg to about 500 mg of an anti-PD-1 antibody; and (b) instructions for using the anti-PD-1 antibody in any method described herein.
  • the kit comprises an anti -human PD-1 antibody disclosed herein, e.g., nivolumab or pembrolizumab. In some embodiments, the kit further comprises an anti-PD-Ll antibody . In some embodiments, the kit further comprises instructions for detecting the mutation status of STK11 in a tumor sample. In other embodiments, the kit further comprises instructions for detecting the expression of PD-L1 in a tumor sample.
  • PD-L1 is expressed in NSCLC tumors, e.g., commercial NSCLC tumors, according to different patterns of expressing (FIG. 1). These patterns were designated as diffuse, heterogenous, tumor-stroma interface, and negative. PD-L1 expression patterns can be linked to mechanistic hypotheses. For example, in tumors with diffuse patterns, the expression of PD-L1 is driven by 9p24 amplification in oncogenic signaling pathway instead of being driven by mutation. In tumors with tumor-stroma interface patterns, there are adaptive resistances instead of epithelial to mesenchymal transition (EMT).
  • EMT epithelial to mesenchymal transition
  • H-score as shown in FIG. 2. There is a substantial difference in the level of PD-L1 expression according to each pattern. For example, very high H-scores were observed in diffuse pattern samples, which suggested a potential dependence of these tumors on PD-L1 inhibition.
  • FIG. 3 shows PD-L1 expression patterns in trial biopsies corresponding to patients treated with nivolumab monotherapy, which corresponding to the same patterns observed in NSCLC commercial tumors.
  • the potential for false negative PD-L1 is impacted by pattern category, preanalytic variables, and by the size of the biopsy.
  • tumor-stroma interface patterns are heterogeneous and particularly susceptible to false negative results. Accordingly, there is a need for biomarkers that can facilitate the classification of NSCLC tumors, which in turn could be used to predict the tumor response to a certain therapeutic agent.
  • a correlation between patterns of PD-Ll expression and nivolumab efficacy was observed (FIG. 4). Most of complete responders in Grade 3 tumors had a diffuse pattern of PD- Ll expression, and high PD-Ll H-score. Accordingly, the identification of biomarkers specific for the diffuse PD-Ll expression pattern could be used to identify patients suitable for treatment for nivolumab based on the presence/absence of that biomarker.
  • the immune infiltrate can be potentially used as biomarker specific for NSCLC tumors with diffuse expression patterns (FIG. 5), since in the commercial NSCLC tumors used to generate the data presented in FIG. 5, those with diffuse or heterogeneous PD-Ll patterns were associated with more abundant immune infiltrate (higher PD-Ll H-score).
  • FIG. 7 panel A, shows that the level of PD-Ll expression correlates with RNA sequencing data, but RNA sequencing data alone does not provide geographical context for the PD-Ll expression patterns observed via IHC.
  • FIG. 7, panel B, which presents exome sequencing data shows that a PD-Ll diffuse expression pattern correlates with a higher mutation load.
  • A shows overall inflammation measured using a "CI Score” which is the intensity score of chronic inflammation infiltrate.
  • Panel B shows PD-Ll + inflammation measured using a "PD-Ll + CI Score” which is the intensity score of relative proportion of PD-L1+ immune infiltrate.
  • mutant STK11 correlated with the presence of the "N" (PD-Ll negative) expression pattern.
  • mutant STK11 did not correlate with the presence of the "D" (diffuse) pattern, which is the pattern observed in most responders to nivolumab therapy.
  • mutant forms of STKl l could be used as negative biomarker for treatment of NSCLC tumors with nivolumab (i.e., its presence would predict lack of response or poor response to nivolumab).
  • wild type forms of STKl l or absence of mutant forms could be used as a positive selection biomarker for treatment with nivolumab.
  • STKl l loss due to mutation is predicted to increase mTOR signaling.
  • Lung adenocarcinoma both mouse model and human tumors
  • KRAS and STKl l mutations show decreased expression of PD-Ll and diminished T-cell infiltrates.
  • the proposed mechanism of immune suppression mediated by mutations in SKT11 would include a switch to glycolytic metabolism with increased lactate production, and a frequent co-mutation of KEPI leading to an anti-inflammatory transcriptional program.
  • VSIG4, CD163, CLEC4D, CSF1R, CD86, MS4A1, CD79B, CD19, KIR2DS4, CD3E, CCR4, CCR8, and CD8A were analyzed was used to classify the samples according to inflammation patterns (sigClass). Samples were classified as low (“sigClass low”), medium (“sigClass med”) and high (“sigClass hi”) inflammation. Samples were classified also according to presence (“STKl l mut”) or absence (“STKl l wt”) of STKl l mutations (FIG. 10).
  • samples were classified according to PD-Ll expression pattern as negative (“PDLl _pattern 2 Negative”), diffuse, (“PDLl _pattern 2 Diffuse”), heterogenous (“PDLl _pattern 2 Heterogeneous”), and tumor-stroma interface (“PDLl _pattern 2 TS”).
  • Tumor with diffuse PD-Ll expression patterns were shown highly inflamed and presented the wild type form of STK11.
  • PD-Ll negative tumors cluster in two groups: moderate inflammation and low inflammation. There was no clear distinction in level of inflammation of PD-Ll negative tumors by STKl l mutation status. All the tumors with mutant STK11 were also negative for PD-Ll .
  • FIGs. 15A-15F Two patients exhibiting partial responses following anti-PD- 1 antibody therapy were found have STKl l mutations and high PD-L1 levels (FIG. 15B). However, in the anti-PD-1 antibody arm, PD-L1 expression levels were similar in the wild-type and STKl l mutant subgroups (FIG. 15E).
  • FIGs. 16A-16D Patients having mutations in both TP53 and KRAS showed greater PFS than patients having wild-type TP53 following treatment with first-line anti-PD-1 monoclonal antibody therapy (FIG. 16A). Patients having a mutation in CDKN2A also showed a higher PFS than those having wild-type CDKN2A (FIG. 16B), and the same was true for patients having mutated variants of PTPND, CUBN, and HERC1 (FIG. 16C- 16D).
  • nivolumab second-line anti-PD-1 monoclonal antibody
  • Patients were administered nivolumab (administered intravenously at a dose of 3 mg/kg of body weight once every 2 weeks) or docetaxel (administered at a dose of 75 mg/m 2 once every 3 weeks).
  • nivolumab second-line anti-PD-1 monoclonal antibody
  • Patients were administered nivolumab (administered intravenously at a dose of 3 mg/kg of body weight once every 2 weeks) or docetaxel (administered at a dose of 75 mg/m 2 once every 3 weeks).

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JP2019566619A JP7780857B2 (ja) 2017-06-01 2018-06-01 抗ｐｄ－１抗体を用いる腫瘍の治療方法
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CN111440822A (zh) * 2020-04-16 2020-07-24 苏州大学附属第二医院 一种突变lats1质粒的构建与应用
CN114931637A (zh) * 2022-06-27 2022-08-23 中山大学中山眼科中心 Pdl1抗体在角膜新生血管疾病中的应用

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