1、展望未来：基于展望未来：基于BTK抑制剂的联合治疗抑制剂的联合治疗Faculty DisclosureAndrew D.Zelenetz,MD,PhD,has disclosed that he has received consulting fees from AbbVie,Adaptive Biotech,Amgen,AstraZeneca,Celgene,Genentech/Roche,Gilead Sciences,Janssen,MorphoSys,Novartis,Pharmacyclics,and Verastem;funds for research support from
2、BeiGene,Gilead Sciences,MEI Pharm,and Roche;and other funding/support from BeiGene and Juno.BTKi-based Combination Therapy What is the rationale for including BTK inhibitors in combination therapy?Time-limited therapy with outcome equivalent or superior to sequential single agents Potentially curati
3、ve therapy Time limited/curative therapy requires achievement of undetectable measurable residual diseaseByrd.Blood.2019;133:1003.MRD Detection in Lymphoid MalignanciesHerrera.J Clin Oncol.2017;35:3877.Figure not available010020030040050060070006121824Time post-dose(hours)560mg QD0100200300400500600
4、70006121824Time post-dose(hours)100mg QD Cmax and AUC of zanubrutinib at 80 mg QD1 similar to those of ibrutinib at 560 mg Free drug exposure of zanubrutinib at 40 mg QD appears to be comparable to ibrutinib at 560 mg Distinct profile compared to acalabrutinib,which has a short half-life(1 hour)3 an
5、d lower in vitro BTK inhibition IC501-4 In vitro BTK inhibition IC50 relative to ibrutinib:1.11(zanubrutinib)and 3.427.23(acalabrutinib)Zanubrutinib1Ibrutinib2Acalabrutinib3010020030040050060070006121824Plasma Concentration(ng/mL)Time post-dose(hours)40mg QD80mg QD160mg QD320mg QDPh III Dose:160 mg
6、BIDPh III Dose:100 mg BIDApproved Doses:420 mg QD for CLL/WM 560 mg QD for MCL/MZLData from separate Ph1/2 trialsCovalent BTK Inhibitors:Pharmacokinetics Profiles1.Tam.ASH 2015.Abstract 832.2.Advani.J Clin Oncol.2013;31:88.3.Byrd.NEJM.2016;374:323.4.Lannutti.AACR 2015.Abstract 408.BTK Inhibitors Mec
7、hanisms of Resistance and Strategies to Overcome ResistanceCovalent BTKi(ibrutinib,acalabrutinib,zanubrutinib)CysteineIrreversible(covalent)bindingPersistent/irreversible inhibitionATP binding pocketNo cysteineShort-lived transient inhibition due to short half life drugs leads to disease progression
8、Longer half life drugs with better PK leads to continual BTK phosphorylation inhibitionBTK mutations Reversible BTK Inhibitors(vecabrutinib,ARQ531,LOXO 305)Covalent BTKi(ibrutinib,acalabrutinib,zanubrutinib)bind reversibly in C481S mutation Adapted from Wiestner.Haematologica.2015;100:1495.BTK Inhib
9、itors:“Off-Target”Kinase InhibitionAgentTEC Family Kinases IC50(nM)Other Kinases IC50(nM)BTKITKTecTXKBMXLCKSRCBLKEGFRCovalentIbrutinib10.510.7782.00.833.217110.75.6Acalabrutinib25.11000093368461000100010001000Zanubrutinib30.22301.9NANANANANANANoncovalentVecabrutinib431414474224884146000ARQ 53154.231
10、00005.836.45.233.8657.79.71290Loxo-3056,78.715597181220141043358115899591.Honigberg.PNAS.2010;107:13075.2.Covey.AACR 2015.Abstract 2596.3.Tam.ASH 2016.Abstract 642.4.Neuman.ASH 2016.5.Eathiraj.PPLC 2016.6.Guisot.ASH 2016.Abstract 4399.7.Furman.CLL Expert Forum.2017.BTKi Plus CD20 AntibodyEffect of B
11、TK Inhibition on ADCCImpact of Various BTKi on ADCC Measured by NK IFN-SecretionIbrutinib has Less Impact on ADCC Induced by Obinutuzumab than RituximabRajasekaran.ASH 2014.Abstract 3118.Davis.ASH 2014.Abstract 3117.Randomized Phase II Study:Ibrutinib vs Ibrutinib Plus Rituximab in Previously Treate
12、d CLL/SLLBurger.Blood.2019;133:1011.Primary endpoint:PFS Secondary endpoints:safety,ORR,PFS in CLL,biomarker responses in CLLPatients with relapsed CLL/SLL(n=181)Patients with previously untreated CLL/SLL and del(17p)or mutated TP53(n=27)Treat until PD,death,or unacceptable toxicityIbrutinib420 mg P
13、O QD(n=104)Ibrutinib 420 mg PO QDRituximab 375 mg/m2 QW in C1,then Q4W(n=104)Stratified by ECOG PS(0-1 vs 2)and high-risk cytogenetic abnormalities*28-day cycles*TP53 mutation with del(17p)vs del(11q)alone vs none/unknownIbrutinib vs Ibrutinib Plus Rituximab in Previously Treated CLL/SLL:PFS and ALC
14、 PFSALCBurger.Blood.2019;133:1011.Ibrutinib vs Ibrutinib Plus Rituximab in Previously Treated CLL/SLL:ResponsesBurger.Blood.2019;133:1011.Patients in CR at 12 and 24 monthsBone Marrow CLL Disease LevelsA041202:Ibrutinib vs Ibrutinib/Rituximab vs BR in Treatment-Naive CLLMulticenter,randomized,double
15、-blind phase III study(data cutoff:October 4,2018)Untreated patients with CLL meeting IWCLL 2008 criteria for tx initiation;aged 65 yrs;EGOG PS 0-2;ANC 1000 unless due to BM involvement;PLT 30;CrClCG 40;AST/ALT 2.5 x ULN;no heparin or warfarin(N=547)Woyach.ASH 2018.Abstr 6.Woyach.N Engl J Med.2018;3
16、79:2517.Ibrutinib 420 mg QD(n=182)Ibrutinib 420 mg QD+Rituximab 375 mg/m2 wkly x 4 wks starting cycle 2 Day 1;cycles 3-6 Day 1*(n=182)Bendamustine 90 mg/m2 on Days 1,2+Rituximab 375 mg/m2 on cycle 1 Day 1;500 mg/m2 on cycles 2-6 Day 1*(n=183)Primary endpoint:PFS 2 primary comparisons of ibrutinib vs
17、 BR and ibrutinib+R vs BR with 90%power to detect HR of 0.586(estimated 2-yr PFS rates:ibrutinib,75%;BR,61%)and overall 1-sided =0.025 for each comparison If both primary comparisons significant,third planned comparison of ibrutinib+R vs ibrutinibStratified by Rai stage(high vs intermediate risk),de
18、l(11q22.3)or del(17p13.1)(presence vs absence),ZAP-70 methylation(vs 20%)Until PDCrossover to ibrutinib w/n 1 yr of PD allowedIbrutinib until PD*28-day cycles.A041202:Ibrutinib vs Ibrutinib/Rituximab vs BR in CLLPFS PFS significantly improved with ibrutinib vs BR and ibrutinib+R vs BR(both one-sided
19、 P .001)*HR for ibrutinib vs BR:0.39(95%CI:0.26-0.58)HR for ibrutinib+R vs BR:0.38(95%CI:0.25-0.59)No significant difference for ibrutinib+R vs ibrutinib only(one-sided P=.49)HR:1.00(95%CI:0.62-1.62)Woyach.N Engl J Med.2018;379:2517.*524 of 547 randomized patients.Events,n/NMedian PFS,Mos(95%CI)2-Yr
20、 PFS,%(95%CI)Ibrutinib34/178NR87(81-92)Ibrutinib+R32/170NR88(81-92)BR68/17643(38-NR)74(66-80)PFS(%)Patients at Risk,nIbrutinibIbrutinib+RBRMos17817017616515914015414512914713812278745713613210312011588454026222011000100806040200Mutated IgVHNonmutated IgVHPFS Probability0.80.60.40.201.0Mos06121824303
21、64248 52A041202:Ibrutinib vs Ibrutinib/Rituximab vs BR in CLLPFS by IGVH Mutation StatusWoyach.N Engl J Med.2018;379:2517.Events,n/NMedian PFS,Mos(95%CI)Ibrutinib7/45NEIbrutinib+R6/45NEBR12/5251(51-NE)Events,n/NMedian PFS,Mos(95%CI)Ibrutinib16/77NEIbrutinib+R20/70NE(48-NE)BR31/7139(32-NE)PFS Probabi
22、lity0.80.60.40.201.0Mos0612182430364248 52No significant interaction between IGVH mutation status and PFS benefit by regimenIncreased PFS among patients with mutated vs unmutated IGVH disease(HR:0.51;95%CI:0.32-0.81)iLLUMINATE:Ibrutinib/Obinutuzumab vs Chlorambucil/Obinutuzumab in Treatment-Naive CL
23、L/SLL Primary endpoint:PFS by IRC in ITT population Secondary endpoints:PFS in high-risk patients(positive for del(17p)or TP53 mutation,del(11q),or unmutated IGHV),MRD,ORR,OS,IRRs,safetyUntreated patients with CLL/SLL needing treatment by iwCLL criteria,65 yrs or 6,creatinine clearance 1,000/l,plate
24、lets 40,000/lAdequate renal and hepatic functionNo significant cardiac diseaseGrowth factor/transfusion allowed.Anti-coagulation allowed.Zanubrutinib+Obinutuzumab in B-Cell Malignancies:Phase I Study DesignDose EscalationCohortZanubrutinib*(D1-28/28-daycycles)ObinutuzumabPatientsDosed1a320mgQDCycle1
25、D2:100mg;D3:900mgD9,16:1000mgCycles2-6D1:1000mg41b160mgBID5ToxicityGrade 1-2 v 3-4Tam.ASH 2018.Eligibility:Zanubrutinib+Obinutuzumab:Efficacy in CLLTam.ASH 2018.Change in Tumor Size from BaselineSurvivalBTKi Plus VenetoclaxVenetoclax Venetoclax:orally bioavailable,selective BCL2 inhibitor,directly i
26、nducing apoptosis in CLL cells independent of p53 First-in-human study of venetoclax:79%ORR in relapsed/refractory CLLRoberts.NEJM.2015.BTKi Combinations:Preclinical RationaleSynergism Between Ibrutinib and Bcl-2 Family InhibitorsMathews.PNAS.2014;111:2349.ABC-DLBCL drug screen:459-drug panelPreclin
27、ical Promise:Combination of Ibrutinib Plus Venetoclax in MCLZhao.Br J Haemaol.2014;168:765.Other Select BTKi Combination Clinical Trials With VenetoclaxTrialPhasePopulationPlanned NTreatment Arm(s)NCT03836261IIIUntreated CLL w/out TP53/del(17p)780Acalabrutinib+Venetoclax+/-Obinutuzumab vs IC Chemoim
28、munotherapyNCT02717624IbMCL70Acalabrutinib+BR or Acalabrutinib+Venetoclax and RituximabNCT03946878IIRR MCL50Open-label acalabrutinib+venetoclaxBTKi Combinations:Clinical Trial ResultsPhase II Study:Ibrutinib Plus Venetoclax in Untreated CLLSchemaMRD byFlow 10-4N=80Jain.NEJM.2019;380:2095.Phase II CA
29、PTIVATE:First-line Ibrutinib+Venetoclax in CLL(MRD Cohort)Patients with untreated CLL/SLL requiring treatment,ECOG PS 0/1,70 yrs of age(N=164)Ibrutinib 420 mg/day PO3 28-day cyclesWierda.ASCO 2018.Abstract 7502.Ibrutinib 420 mg/day PO+Venetoclax up to 400 mg/day12 cyclesStratified by IGHV mutation s
30、tatusConfirmed undetectable MRD*Undetectable MRD not confirmedPlaceboIbrutinibIbrutinibIbrutinib+Venetoclax Ibrutinib lead-in to debulk disease,reduce risk of venetoclax-associated tumor lysis MRD status after 12 cycles of combination used to separate patients for randomization Prespecified interim
31、analysis of first 30 patients to complete 6 cycles of combinationTLS risk assessmentMRD assessment after 6,9,12 cycles*Serial undetectable blood MRD at least 3 cycles apart+undetectable marrow MRD.CAPTIVATE:TLS Risk and Bulky Disease After 3 Cycles Ibrutinib Lead-inPatient Characteristics,%Baseline(
32、N=164)After Ibrutinib Lead-in(N=164)TLS risk High Medium Low NA246312-365293LN bulk LDi 10 cm LDi 5 cm 10 cm LDi 5 cm NA32968-6913Wierda.ASCO 2018.Abstract 7502.After ibrutinib lead-in:90%of patients(36/40)with high baseline TLS risk changed to medium to low risk;no hospitalization in 30 patients19%
33、of patients(7/37)with medium baseline TLS risk plus CrCl 80 mL/mm changed to low risk;no hospitalizationin 29 patients0%25%50%75%100%ThrombocytopeniaHypertensionVomitingBack painMuscle spasmsNeutropeniaConstipationURTIBruisingNauseaHeadacheFatigueArthralgiaDiarrheaPatientsGrade 1Grade 2Grade 3Grade
34、40%25%50%75%100%ThrombocytopeniaHypertensionVomitingBack painMuscle spasmsNeutropeniaConstipationURTIBruisingNauseaHeadacheFatigueArthralgiaDiarrheaPatientsGrade 1Grade 2Grade 3Grade 4Atrial fibrillation:5 patients(3.0%;grade 3 in 1.2%)during ibrutinib lead-in;7 patients(4.3%;grade 3 in 0.6%)during
35、I+V combination;no grade 4 eventsGrade 3 infections:4 patients(2.4%)during ibrutinib lead-in;4 patients(2.4%)during I+V combination;no grade 4 infectionsSingle-Agent Ibrutinib3 Cycles Lead-inI+V CombinationMedian exposure=6 months(range,0.812 months)*Threshold based on any grade 15%or grade 34 2%dur
36、ing whole study period.Wierda.ASCO 2018.Abstract 7502.CAPTIVATE:Most-Common Adverse EventsCAPTIVATE:EfficacyOutcome,%After 6 Cycles of I+V(n=30)After 9 Cycles of I+V(n=14)After 12 Cycles of I+V(n=14)Blood MRD 0.01%(undetectable)0.01%-1.0%1.0%771310867NE93*7-Bone marrow MRD 0.01%(undetectable)0.01%-1
37、.0%-8614ORR CR CRi nPR PR-100(n=11)3618936Wierda.ASCO 2018.Abstract 7502.*79%with confirmed undetectable MRD.Assessed only after 12 cycles I+V.Reduction in LN SPD in all 30 patients with baseline lymphadenopathy Lymphadenopathy resolved to 1.5 cm in 14/30(47%)Reduction in spleen enlargement in all 2
38、4/24 patients with baseline splenomegaly on CT Enlarged spleen resolved to normal(spleen vertical length 13 cm Lugano criteria)in 15/24(63%)Reduction in Target Lesion SPD(n=30)Maximum Change From BaselineReduction in Enlarged Spleen(n=24)Maximum Change From BaselineCAPTIVATE:Reductions in Lymphadeno
39、pathy and Splenomegaly in All PatientsWierda.ASCO 2018.Abstract 7502.Frequent,undetectable MRD in PB on serial sampling+denotes del17p at baseline.Peripheral Blood Serial MRD Assessments:After C9After C12After C15 CAPTIVATE:Early Undetectable MRD in Peripheral BloodWierda.ASCO 2018.Abstract 7502.+de
40、notes del17p at baseline.BM,bone marrow.Bone Marrow Undetectable MRD in BM in 12/14 patients after 12 cycles I+VSerial MRD Assessments:After C9After C12After C15 CAPTIVATE:Early Undetectable MRD in Bone MarrowWierda.ASCO 2018.Abstract 7502.BTKi Plus CD20 Antibody and VenetoclaxPhase Ib/II Study:Obin
41、utuzumab,Ibrutinib,and Venetoclax-R/R CLL Cohort(N=12)CLL,relapse after 1 treatment and/or refractory,meets need for treatment per investigatorAge 18 yearsECOG performance status 1Adequate end-organ function including serum creatinine 2.0 mg/dL or creatinine clearance(Cockcroft)50 mL/min/1.73m2C1C2C
42、3C4C5C6C7C8C9C10C11C12C13C14Obinutuzumab 1000 mg IVIbrutinib 420 mg daily POVenetoclax(cohort dose)mg daily POResponse assessed(CT+BMBx)After Cycle 8 2 months beyond end Cycle 14 Drugs initiated sequentially to limit risk for tumor lysis syndrome(TLS)All patients discontinue treatment after Cycle 14
43、 Sequential cohorts of 3 underwent dose escalation to target venetoclax dose in Cycle 3 to establish MTD of venetoclax in combinationCycle=28 daysRogers.Blood.2018;132:1568.Adverse Event,n(%)Grade 4 dosesObinutuzumab,Ibrutinib,and Venetoclax in R/R CLL:Hematologic ToxicityRogers.Blood.2018;132:1568.
44、40Obinutuzumab,Ibrutinib,and Venetoclax in R/R CLL:MRD AnalysisRogers.Blood.2018;132:1568.ORR:96%(95%CI:80%to 100%)CR5 (20%)CRi*8 (32%)PR11(44%)NR1 (4%)All but 1 patient had no morphologic evidence of CLL in the bone marrow CRi was due to cytopenias(4/8,50%)or cytopenias+hypocellular marrow(4/8,50%)
45、6/11(55%)PR patients met count and marrow requirements for CR but had LN 1.5cm*CRi was due to cytopenias(4/8,50%)or cytopenias+hypocellular marrow(4/8,50%)CRCRiPRNRObinutuzumab,Ibrutinib,and Venetoclax in CLL:Responses(Post Cycle 8)in Tx-Naive CohortRogers.ASH 2017.MRD was measured by 4-color flow c
46、ytometry 14/24(58%)of patients were MRD(-)in both compartments 8/13(46%)CR/CRi 6/11(55%)PR All but 1 case of detectable CLL was 25%and all grade 3/4 AEs Data as of 11/22/2017 Grade 1/2 Adverse Eventsn(%)Infusion related reaction19(76)Nausea15(60)Bruising14(56)Oral Mucositis13(52)Dyspepsia12(48)Hyper
47、tension11(44)Diarrhea11(44)Fatigue10(40)Maculo-papular rash10(40)Myalgia9(36)Arthralgia8(32)Hyperuricemia8(32)Weight gain8(32)Bilirubin increased7(28)Chills7(28)Hypocalcemia7(28)Grade 3/4 Adverse Eventsn(%)Hypertension9(36)Dyspepsia1(4)Arthralgia1(4)Hyperuricemia1(4)Aspartate aminotransferase increa
48、sed1(4)Alanine aminotransferase increased1(4)Atrial fibrillation1(4)Colitis1(4)Pneumonia1(4)Menorrhagia1(4)Sepsis1(4)There were no cases of clinical or laboratory tumor lysis syndrome of any gradeRogers.ASH 2017.Obinutuzumab,Ibrutinib,and Venetoclax in CLL:Nonhematologic TRAEs*in Tx-Naive CohortBOVe
49、n:Response-Adapted Triple CombinationZanubrutinib:Irreversible BTK inhibitor With Favorable Pharmacologic and Toxicologic Profile Zanubrutinib is different from ibrutinib in the following ways:More selective in the relative inhibition of BTK versus off-target tyrosine kinases,including EGFR,FGR,FRK,
50、HER2,HER4,ITK,JAK 3,LCK,and TEC Increased selectivity may reduce toxicities possibly due to off-target inhibition such as diarrhea,thrombocytopenia,bleeding,atrial fibrillation,rash,and fatigue Improved oral bioavailability Biopsy of nodes on therapy demonstrate complete inhibition of BTK in tissue
