展望未来：基于BTK抑制剂的联合治疗课件

1、展望未来：基于BTK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 TherapyWhat is the rationale for including BTK inhibitors in combination therapy?Time-limited therapy with outcome equivalent or superior to sequential single agentsPotentially cur

3、ative therapyTime 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 availableCmax and AUC of zanubrutinib at 80 mg QD1 similar to those of ibrutinib

4、 at 560 mgFree drug exposure of zanubrutinib at 40 mg QD appears to be comparable to ibrutinib at 560 mgDistinct profile compared to acalabrutinib, which has a short half-life (1 hour)3 and lower in vitro BTK inhibition IC501-4In vitro BTK inhibition IC50 relative to ibrutinib: 1.11 (zanubrutinib) a

5、nd 3.427.23 (acalabrutinib)Zanubrutinib1Ibrutinib2Acalabrutinib3Ph III Dose: 160 mg 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 On

6、col. 2013;31:88. 3. Byrd. NEJM. 2016;374:323. 4. Lannutti. AACR 2015. Abstract 408. BTK Inhibitors Mechanisms of Resistance and Strategies to Overcome ResistanceAdapted from Wiestner. Haematologica. 2015;100:1495.BTK Inhibitors: “Off-Target” Kinase InhibitionAgentTEC Family Kinases IC50 (nM)Other Ki

7、nases IC50 (nM)BTKITKTecTXKBMXLCKSRCBLKEGFRCovalentIbrutinib10.510.7782.00.833.217110.75.6Acalabrutinib25.11000093368461000100010001000Zanubrutinib30.22301.9NANANANANANANoncovalentVecabrutinib431414474224884146000ARQ 53154.23100005.836.45.233.8657.79.71290Loxo-3056,78.715597181220141043358115899591.

8、 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 BTK Inhibition on ADCCImpact of Various BTKi on AD

9、CC 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 Treated CLL/SLLBurger. Blood. 2019;133:1011.Prim

10、ary endpoint: PFSSecondary 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 PO QD(n = 104)Ibrutinib 420 mg

11、 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 PFSALCBurger. Blo

12、od. 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-blind pha

13、se 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 Me

14、d. 2018;379:2517.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: PFS2 primary compari

15、sons of ibrutinib vs 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 comparisonIf both primary comparisons significant, third planned comparison of ibrutinib + R vs ibrutinibStratified by Rai sta

16、ge (high vs intermediate risk), del(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 CLLPFSPFS significantly improved with ibrutinib vs

17、BR and ibrutinib + R vs BR (both one-sided 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

18、 of 547 randomized patients.Events, n/NMedian PFS, Mos (95% CI)2-Yr PFS,% (95% CI)Ibrutinib34/178NR87 (81-92)Ibrutinib + R32/170NR88 (81-92)BR68/17643 (38-NR)74 (66-80)PFS (%)Patients at Risk, nIbrutinibIbrutinib + RBRMos1781701761651591401541451291471381227874571361321031201158845402622201100010080

19、6040200Mutated IgVHNonmutated IgVHPFS Probability0.80.60.40.201.0Mos061218243036424852A041202: 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/N

20、Median PFS, Mos (95% CI)Ibrutinib16/77NEIbrutinib + R20/70NE (48-NE)BR31/7139 (32-NE)PFS Probability0.80.60.40.201.0Mos061218243036424852No significant interaction between IGVH mutation status and PFS benefit by regimenIncreased PFS among patients with mutated vs unmutated IGVH disease (HR: 0.51; 95

21、% CI: 0.32-0.81)iLLUMINATE: Ibrutinib/Obinutuzumab vs Chlorambucil/Obinutuzumab in Treatment-Naive CLL/SLLPrimary endpoint: PFS by IRC in ITT populationSecondary endpoints: PFS in high-risk patients (positive for del(17p) or TP53 mutation, del(11q), or unmutated IGHV), MRD, ORR, OS, IRRs, safetyUntr

22、eated patients with CLL/SLL needing treatment by iwCLL criteria, 65 yrs or 6, creatinine clearance 1,000/l, platelets 40,000/lAdequate renal and hepatic functionNo significant cardiac diseaseGrowth factor/transfusion allowed. Anti-coagulation allowed.Zanubrutinib + Obinutuzumab in B-Cell Malignancie

23、s: Phase I Study DesignDose EscalationCohortZanubrutinib*(D1-28/28-daycycles)ObinutuzumabPatientsDosed1a320mgQDCycle1D2:100mg; D3:900mgD9, 16:1000mgCycles2-6D1:1000mg41b160mgBID5ToxicityGrade 1-2 v 3-4Tam. ASH 2018.Eligibility:Zanubrutinib + Obinutuzumab: Efficacy in CLLTam. ASH 2018.Change in Tumor

24、 Size from BaselineSurvivalBTKi Plus VenetoclaxVenetoclaxVenetoclax: orally bioavailable, selective BCL2 inhibitor, directly inducing apoptosis in CLL cells independent of p53First-in-human study of venetoclax: 79% ORR in relapsed/refractory CLLRoberts. NEJM. 2015.BTKi Combinations: Preclinical Rati

25、onaleSynergism Between Ibrutinib and Bcl-2 Family InhibitorsMathews. PNAS. 2014;111:2349.ABC-DLBCL drug screen: 459-drug panelPreclinical Promise: Combination of Ibrutinib Plus Venetoclax in MCLZhao. Br J Haemaol. 2014;168:765.Other Select BTKi Combination Clinical Trials With VenetoclaxTrialPhasePo

26、pulationPlanned NTreatment Arm(s)NCT03836261IIIUntreated CLL w/out TP53/del(17p)780Acalabrutinib + Venetoclax +/- Obinutuzumab vs IC ChemoimmunotherapyNCT02717624IbMCL70Acalabrutinib + BR or Acalabrutinib + Venetoclax and RituximabNCT03946878IIRR MCL50Open-label acalabrutinib + venetoclaxBTKi Combin

27、ations: Clinical Trial ResultsPhase II Study: Ibrutinib Plus Venetoclax in Untreated CLLSchemaMRD byFlow 10-4N=80Jain. NEJM. 2019;380:2095.Phase II CAPTIVATE: 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)

28、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 statusConfirmed undetectable MRD*Undetectable MRD not confirmedPlaceboIbrutinibIbrutinibIbrutinib +VenetoclaxIbrutinib lead-in to debulk dis

29、ease, reduce risk of venetoclax-associated tumor lysisMRD status after 12 cycles of combination used to separate patients for randomizationPrespecified interim analysis of first 30 patients to complete 6 cycles of combinationTLS risk assessmentMRD assessment after 6, 9, 12 cycles*Serial undetectable

30、 blood MRD at least 3 cycles apart + undetectable marrow MRD.CAPTIVATE: TLS Risk and Bulky Disease After 3 Cycles Ibrutinib Lead-inPatient Characteristics, %Baseline(N = 164)After Ibrutinib Lead-in(N = 164)TLS riskHighMediumLowNA246312-365293LN bulkLDi 10 cmLDi 5 cm 10 cmLDi 5 cmNA32968-6913Wierda.

31、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% of patients (7/37) with medium baseline TLS risk plus CrCl 80 mL/mm changed to low risk; no hospitalizationin 29 patientsAtrial fib

32、rillation: 5 patients (3.0%; grade 3 in 1.2%) during ibrutinib lead-in; 7 patients (4.3%; grade 3 in 0.6%) during 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 C

33、ycles Lead-inI+V CombinationMedian exposure = 6 months (range, 0.812 months) *Threshold based on any grade 15% or grade 34 2% during 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

34、+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% - 1.0%-8614ORRCRCRinPRPR-100 (n = 11)3618936Wierda. ASCO 2018. Abstract 7502.*79% with confirmed undetectable MRD. Assessed only after 12 cycles I + V.Redu

35、ction in LN SPD in all 30 patients with baseline lymphadenopathyLymphadenopathy resolved to 1.5 cm in 14/30 (47%)Reduction in spleen enlargement in all 24/24 patients with baseline splenomegaly on CTEnlarged spleen resolved to normal (spleen vertical length 13 cm Lugano criteria) in 15/24 (63%) Redu

36、ction in Target Lesion SPD (n=30)Maximum Change From BaselineReduction in Enlarged Spleen (n=24)Maximum Change From BaselineCAPTIVATE: Reductions in Lymphadenopathy and Splenomegaly in All PatientsWierda. ASCO 2018. Abstract 7502.Frequent, undetectable MRD in PB on serial sampling+ denotes del17p at

37、 baseline.Peripheral Blood Serial MRD Assessments:After C9After C12After C15 CAPTIVATE: Early Undetectable MRD in Peripheral BloodWierda. ASCO 2018. Abstract 7502.+ denotes del17p at baseline.BM, bone marrow.Bone Marrow Undetectable MRD in BM in 12/14 patients after 12 cycles I+VSerial MRD Assessmen

38、ts:After C9After C12After C15 CAPTIVATE: Early Undetectable MRD in Bone MarrowWierda. ASCO 2018. Abstract 7502.BTKi Plus CD20 Antibody and VenetoclaxPhase Ib/II Study: Obinutuzumab, Ibrutinib, and Venetoclax - R/R CLL Cohort (N = 12)CLL, relapse after 1 treatment and/or refractory, meets need for tr

39、eatment per investigatorAge 18 yearsECOG performance status 1Adequate end-organ function including serum creatinine 2.0 mg/dL or creatinine clearance (Cockcroft) 50 mL/min/1.73m2C1C2C3C4C5C6C7C8C9C10C11C12C13C14Obinutuzumab 1000 mg IVIbrutinib 420 mg daily POVenetoclax (cohort dose) mg daily PORespo

40、nse assessed (CT + BMBx) After Cycle 8 2 months beyond end Cycle 14Drugs initiated sequentially to limit risk for tumor lysis syndrome (TLS)All patients discontinue treatment after Cycle 14Sequential cohorts of 3 underwent dose escalation to target venetoclax dose in Cycle 3 to establish MTD of vene

41、toclax 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;132:1568.40Obinutuzumab, Ibrutinib, and Venetoclax in R/R CLL: MRD AnalysisRogers. Blood. 2018;132:1568.ORR: 9

42、6% (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%)6/11 (55%) PR patients met count and marrow requirements for CR but had LN 1.5cm*C

43、Ri 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 cytometry14/24 (58%) of patients were MRD (-) in both compartments8/

44、13 (46%) CR/CRi6/11 (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) Hypertension11 (44) Diarrhea11 (44) Fatigue10 (40) Mac

45、ulo-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 increased1 (4) Alanine a

46、minotransferase 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

47、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

48、, FRK, HER2, HER4, ITK, JAK 3, LCK, and TECIncreased selectivity may reduce toxicities possibly due to off-target inhibition such as diarrhea, thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigueImproved oral bioavailabilityBiopsy of nodes on therapy demonstrate complete inhibition of

49、BTK in tissueLess inhibitory effect on anti-CD20-induced antibody-dependent cell-mediated cytotoxicity, and so is unlikely to adversely impact the antitumor effects of rituximab. Tam. Future Oncol. 2018;14:2229.Phase II BOVEN Study: Zanubrutinib, Obinutuzumab, and Venetoclax in Previously Untreated

50、CLL/SLLNCT03824483.ZanubrutinibZanubrutinibPrimary objective: MRDSecondary objectives: RP2D, d/c after MRD neg, DOR, safety, TLS risk reductionObjectivesPrimary Objective: Rate of minimum residual disease (MRD) negative responseSecondary Objectives:Recommended phase 2/3 duration of therapy Proportio

51、n of patients who successfully discontinue therapy after achieving an MRD negative response Durability of clinical benefit after treatment discontinuation as measured by duration of peripheral blood MRD response and treatment-free survival Safety and tolerability To determine whether induction therapy with 2 cycles of zanubrutinib and obinutuzumab prior to venetoclax reduces TLS risk assignment Other Select BTKi Combination Clinical TrialsTrial