Methods of treating tumor

Abstract

The disclosure provides a method for treating a subject afflicted with a tumor derived from a small cell lung cancer (SCLC) having a high tumor mutational burden (TMB) status comprising administering to the SCLC Study TMB subject a monotherapy comprising an anti-PD-1 antibody or a combination therapy comprising an anti-PD-1 antibody and an anti-CTLA-4 antibody. The present disclosure also provides a method for identifying a subject suitable for treatment with an anti-PD-1 antibody or a combination therapy comprising an anti-PD-1 antibody and an anti-CTLA-4 antibody comprising measuring a TMB status of a biological sample of the subject. A high TMB status identifies the patient as suitable for treatment with an anti-PD-1 antibody or antigen-binding portion thereof. The TMB status can be determined by sequencing nucleic acids in the tumor and identifying a genomic alteration, e.g., a somatic nonsynonymous mutation, in the sequenced nucleic acids.

What is claimed is: 
     
         1 . A composition comprising an antibody or antigen-binding portion thereof that specifically binds to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity (“an anti-PD-1 antibody”) for use in the treatment of a subject afflicted with a tumor derived from a small cell lung cancer (SCLC), wherein the tumor has a tumor mutational burden (TMB) status that is a high TMB. 
     
     
         2 . A composition comprising an antibody or antigen-binding portion thereof that specifically binds to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity (“an anti-PD-1 antibody”) for use in the treatment of a subject afflicted with a tumor derived from an SCLC in combination with an antibody or antigen-binding portion thereof that specifically binds to CTLA-4 (“an anti-CTLA-4 antibody”), wherein the tumor has a TMB status that is a high TMB. 
     
     
         3 . The composition for use of  claim 1  or  2 , wherein the TMB status is determined by sequencing nucleic acids in the tumor and identifying a genomic alteration in the sequenced nucleic acids. 
     
     
         4 . The composition for use of  claim 3 , wherein the genomic alteration comprises:
 (i) one or more somatic mutations;   (ii) one or more nonsynonymous mutations;   (iii) one or more missense mutations;   (iv) 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; or   (v) any combination of (i)-(iv).   
     
     
         5 . The composition for use of any one of  claims 1  to  4 , wherein the high TMB has a score of at least 210, 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, 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, at least 465, at least 470, at least 475, at least 480, at least 485, at least 490, at least 495, or at least 500. 
     
     
         6 . The composition for use of any one of  claims 1  to  5 , wherein the subject's TMB status is compared to a reference TMB value, wherein the subject's TMB status is within the highest fractile of the reference TMB value, or wherein the subject's TMB status is within the top tertile of the reference TMB value. 
     
     
         7 . The composition for use of any one of  claims 1  to  6 , wherein the biological sample comprises a tumor tissue biopsy, a liquid biopsy, blood, serum, plasma, exoRNA, circulating tumor cells, ctDNA, cfDNA, or any combination thereof. 
     
     
         8 . The composition for use of any one of  claims 1  to  7 , wherein the TMB status is determined by:
 (i) genome sequencing, 
 (ii) exome sequencing, 
 (iii) genomic profiling, or 
 (iv) any combination of (i)-(iii). 
 
     
     
         9 . The composition for use of  claim 8 , wherein the genomic profile comprises one or more genes selected from the group consisting of ABL1, 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 (MYST3), MRE11A, PDK1, RNF43, SYK, AKT2, BRIP1, CRKL, FANCG, GL11, KDM5A, MSH2, PIK3C2B, ROS1, TAF1, AKT3, BTG1, CRLF2, FANCL, GNA11, KDM5C, MSH6, PIK3CA, RPTOR, TBX3, ALK, BTK, CSF1R, FAS, GNA13, KDM6A, MTOR, PIK3CB, RUNX1, TERC, AMER1 (FAM123B), C11orf30 (EMSY), CTCF, FAT1, GNAQ, KDR, MUTYH, PIK3CG, RUNX1T1, TERT (promoter only), APC, CARD11, CTNNA1, FBXW7, GNAS, KEAP1, MYC, PIK3R1, SDHA, TET2, AR, CBFB, CTNNB1, FGF10, GPR124, KEL, MYCL (MYCL1), PIK3R2, SDHB, TGFBR2, ARAF, CBL, CUL3, FGF14, GRIN2A, KIT, MYCN, PLCG2, SDHC, TNFAIP3, ARFRP1, CCND1, CYLD, FGF19, GRM3, KLHL6, MYD88, PMS2, SDHD, TNFRSF14, ARID1A, CCND2, DAXX, FGF23, GSK3B, KMT2A (MLL), NF1, POLD1, SETD2, TOP1, ARID1B, CCND3, DDR2, FGF3, H3F3A, KMT2C (MLL3), NF2, POLE, SF3B1, TOP2A, ARID2, CCNE1, DICER1, FGF4, HGF, KMT2D (MLL2), NFE2L2, PPP2RIA, SLIT2, TP53, ASXL1, CD274, DNMT3A, FGF6, HNFA, KRAS, NFKBIA, PRDM1, SMAD2, TSC1, ATM, CD79A, DOT1L, FGFR1, HRAS, LMO1, NKX2-1, PREX2, SMAD3, TSC2, ATR, CD79B, EGFR, FGFR2, HSD3B1, LRP1B, NOTCH1, PRKARIA, SMAD4, TSHR, ATRX, CDC73, EP300, FGFR3, HSP90AA1, LYN, NOTCH2, PRKCI, SMARCA4, U2AF1, AURKA, CDH1, EPHA3, FGFR4, IDH1, LZTR1, NOTCH3, PRKDC, SMARCB1, VEGFA, AURKB, CDK12, EPHA5, FH, IDH2, MAGI2, NPM1, PRSS8, SMO, VHL, AXIN1, CDK4, EPHA7, FLCN, IGF1R, MAP2K1, NRAS, PTCH1, SNCAIP, WISP3, AXL, CDK6, EPHB1, FLT1, IGF2, MAP2K2, NSD1, PTEN, SOCS1, WT1, BAP1, CDK8, ERBB2, FLT3, IKBKE, MAP2K4, NTRK1, PTPN11, SOX10, XPO1, BARD1, CDKN1A, ERBB3, FLT4, IKZF1, MAP3K1, NTRK2, QKI, SOX2, ZBTB2, BCL2, CDKN1B, ERBB4, FOXL2, IL7R, MCL1, NTRK3, RAC1, SOX9, ZNF217, BCL2L1, CDKN2A, ERG, FOXP1, INHBA, MDM2, NUP93, RAD50, SPEN, ZNF703, BCL2L2, CDKN2B, ERRFI1, FRS2, INPP4B, MDM4, PAK3, RAD51, SPOP, BCL6, CDKN2C, ESR1, FUBP1, IRF2, MED12, PALB2, RAF1, SPTA1, BCOR, CEBPA, EZH2, GABRA6, IRF4, MEF2B, PARK2, RANBP2, SRC, BCORL1, CHD2, FAM46C, GATA1, IRS2, MEN1, PAX5, RARA, STAG2, BLM, CHD4, FANCA, GATA2, JAK1, MET, PBRM1, RB1, STAT3, and any combination thereof. 
     
     
         10 . The composition for use of any one of  claims 1  to  9 , wherein:
 (i) the SCLC comprises a small cell carcinoma, 
 (ii) the SCLC comprises a combined small cell carcinoma, 
 (iii) the SCLC is recurrent or refractory following at least one previous line of therapy to treat the tumor, or 
 (iv) any combination of (i)-(iii). 
 
     
     
         11 . The composition for use of any one of  claims 1  to  10 , wherein the anti-PD-1 antibody is administered at a weight based dose ranging from 0.1 mg/kg to 10.0 mg/kg body weight or at a flat dose of at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 340 mg, at least about 360 mg, at least about 380 mg, at least about 400 mg, at least about 420 mg, at least about 440 mg, at least about 460 mg, at least about 480 mg, at least about 500 mg, or at least about 550 mg once every 2, 3, or 4 weeks. 
     
     
         12 . The composition for use of any one of  claims 1  to  11 , wherein the anti-PD-1 antibody is administered:
 (i) at a weight based dose of 3 mg/kg body weight once every 2 weeks; 
 (ii) at a weight based dose of 5 mg/kg body weight once every 3 weeks; 
 (iii) at a weight based dose of 10 mg/kg body weight once every 3 weeks; 
 (iv) at a flat dose of about 240 mg once every 2 weeks; or 
 (v) at a flat dose of about 480 mg once every 4 weeks. 
 
     
     
         13 . The composition for use of any one of  claims 2  to  12 , wherein the anti-CTLA-4 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, 3, or 4 weeks. 
     
     
         14 . The composition for use of  claim 8 , wherein the genomic profile comprises FOUNDATIONONE® CDX™. 
     
     
         15 . The composition for use of any one of  claims 1  to  14 , wherein the tumor has a TMB of at least about 10 mutations per megabase of genome sequenced.