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Trial Design MDACC: Ibrutinib Venetoclax CLL14: Trial Design Safety Run-in Phase* Venetoclax–Obinutuzumab Venetoclax– Venetoclax Follow-up Phase Obinutuzumab Previously untreated 6 cycles 6 cycles Primary endpoint: patients with CLL and Progression-free coexisting medical survival conditions 1:1 Key secondary endpoints: randomization CIRS > 6 and/or CrCl < Response, Minimal 70mL/min Residual Disease, Overall Chlorambucil– Chlorambucil Survival Obinutuzumab 6 cycles 6 cycles * Fischer K et al. Venetoclax and Obinutuzumab in chronic lymphocytic leukemia, Blood 11 May 2017 Análise Primária: SLP avaliada pelo investigador (população ITT) Mediana de tempo fora de 100 tratamento: 17.1 meses (0.0–30.4) VenG (N=216) Mediana de duração do tratamento 11.1 meses (0.0–14.1) 80 Mediana de seguimento 28.1 meses 60 (0.0–35.9) GCIb (N=216) VenG GClb SLP (%) SLP (n=216) (n=216) 40 Mediana de tempo fora de tratamento : Eventos, n (%) 30 (13.9) 77 (35.6) 17.9 meses (0.0–30.2) HR (IC 95%), 0.35 (0.23–0.53) Mediana de duração do tratamento Valor de p 20 estratificado p<0.001* 10.8 meses ( 0.0–13.6) SLP 2 anos, 88.2 64.1 % (IC95%) (83.7–92.6) (57.4–70.8) 0 0 6 12 18 24 30 36 Tempo (Meses) No. of Pacientes com risco: VenG 216 195 192 183 153 25 0 GClb 216 194 184 152 110 21 0 O desfecho primário de SLP pelo invstigador foi atingido; pacientes que receberam VenG tiveram 65% menos risco de progressão ou morte em relação aos pacientes que receberam GClb (IC95% 0.23–0.53), p<0.001 O valor de p mostrado se refere ao valor de p controlado por alfa do teste log-rank estratificado pela classificação de Binet e região geográfica. IC – interval de confiança, SLP sobrevida livre de progressão Fischer K, et al. N Engl J Med 2019; DOI: 10.1056/NEJMoa1815281. A Novel Concept: Mimicking Autoinhibition of ABL1 by Myristate Binding to an Allosteric Site ABL1 kinase BCR-ABL1 kinase Hantschel O. Haematologica. 2012;97:195-97 Asciminib: Allosteric BCR-ABL1 Inhibition ▪ Binds with high affinity to the myristoyl pocket of ABL1 kinase to mimic the native myristate ligand ▪ Ba/F3 BCR-ABL1 IC50: ~3 nM (!) ▪ Demonstrates an extremely selective kinase profile ▪ Currently in Phase 1/2 Wylie et al. Nature. 2017;543(7647):733-737. Asciminib: Selectivity in Comparison Wylie et al. Nature. 2017;543(7647):733-737. CASSIOPEIA Study Design • Phase 3 study of D-VTd versus VTd in transplant-eligible NDMM (N = 1,085), 111 sites from 9/2015 to 8/2017 Induction Consolidation Maintenance D-VTd D-VTd D monotherapy D: 16 mg/kg IV QW Cycles 1-2, Q2W D: 16 mg/kg IV Q2W T ) D 16 mg/kg IV Q8W until 2 1 ) Cycles 3-4 V: 1.3 mg/m SC Days 1, 4, 8, 11 : 1 R 1 : 2 ( PD (2 years maximum, Key eligibility 1 V: 1.3 mg/m SC Days 1, 4, 8, 11 T: 100 mg/day PO ( n A R o then observation until n P a i T: 100 mg/day PO d: 20 mg IV/PO t ≥ criteria: o i N a t PD) a z a th d: 20-40 mg IV/PO up S - z mi wi • Transplant- w mi P o ts ll eligible NDMM o L ando en F i r t ando r • 18-65 years A d Pa st on ir N • ECOG 0-2 c F Observation VTd T VTd Se VTd administered as in the D-VTd arm VTd administered as in the D-VTd arm until PD (2 years maximum) 4 Cycles of 28 days 2 Cycles of 28 days Part 1 Part 2 D-VTd, daratumumab/bortezomib/thalidomide/dexamethasone; VTd, bortezomib/thalidomide/dexamethasone; ECOG, Eastern Cooperative Oncology Group; IV, intravenous; QW, weekly; Q2W, every 2 weeks; SC, subcutaneous; PO, oral; PR, partial response; Q8W, every 8 weeks; PD, progressive disease. aDexamethasone 40 mg on Days 1, 2, 8, 9, 15, 16, 22, 23 of Cycles 1-2 and Days 1 & 2 of Cycles 3-4; 20 mg on Days 8, 9, 15, 16 of Cycles 3-4; 20 mg on Days 1, 2, 8, 9, 15, 16 of Cycles 5-6. 6 Moreau P, Attal M, Hulin C, et al, The Lancet 394:29-38, 2019 Winship Cancer Institute | Emory University 8 PFS and OS PFS OS Moreau P, Attal M, Hulin C, et al, The Lancet 394:29-38, 2019 Winship Cancer Institute | Emory University 9 Phase III ALCYONE Trial: VMP± Daratumumab in ASCT- Ineligible Patients With Newly Diagnosed Myeloma Daratumumab monotherapy phase 100 24 mos 30 mos 80 D-VMP Median: 63% 60% 60 57% reduction in risk of not reached ) S progression or death in F % ( P 40 Dara-VMP arm 36% 28% VMP Median: 19.1 20 HR: 0.43 mos (95% CI: 0.35-0.54; P< .0001) 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Patients at Risk, n Mos VMP 356 304 277 262 245 206 169 127 102 59 27 5 0 0 D-VMP 350 322 312 298 292 265 243 220 203 138 73 31 9 0 Mateos MV, et al. N Engl J Med 2018; 378:518-52 Response Rates by Treatment Cohort Patients (%) with CR/ CRi shown at the 6 7 7 6 7 1 5 7 7 3 top of each bar 1 0 0 ) 9 0 % ( 8 0 O t h e r e s 3 8 7 0 3 5 RD n 2 6 o 3 0 6 0 M LFS p s 2 7 5 0 PR e R 4 0 4 5 CRi f 3 7 3 8 3 8 o 3 0 CR 3 0 e t 2 0 a R 1 0 0 Ve n 4 0 0 m g Ve n 8 0 0 m g All D o s e s * Aza D e c Aza D e c N =1 4 5 n =2 9 n =3 1 n =3 7 n =3 7 * All doses includes 11 patients that received 1200 mg venetoclax C DiNardo et al, Blood 2018 Luspatercept forthe treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Platzbecker et al, Lancet Oncology, 2017 Sotatercept with long-term extension forthe treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial Komrokji, Garcia-Manero et al, Lancet Haematology, 2018 The Medalist Trial: Results of a Phase 3, Randomized, Double- Blind, Placebo-Controlled Study of Luspatercept to Treat Anemia in Patients with Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions ASHPlenary, 2018 Luspatercept promotes late stages of erythroid differentiation by inhibiting SMAD2/3 activation MDS Collaboration with Ravi Kumar, Rajshekhar Suragini, Acceleron; Suragini et al, Nat Med 2014 C The Medalist Trial: Results of a Phase 3, Randomized, Study of Luspatercept to Treat Anemia in Patients with Very Low-, Low-, orIntermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Ghia, EHA 2019 ACALABRUTINIB ASCEND Study Design (ACE-CL-309) Primary endpoint: Acalabrutinib • PFS (assessed by Relapsed/Refract 100 mg PO BID IRC) Key secondary ory CLL (N= 310) R A endpoints: N • ORR (assessed by Stratification: D Idelalisib plus Rituximab (IdR) IRC and O 1:1 del(17p), y vs n M Idelalisib 150 mg PO BID + rituximaba investigator) ECOG PS 0-1 vs 2 I - or - • Duration of Z response 1-3 vs ≥4 prior E Bendamustine plus Rituximab (BR) therapies • PFS (assessed by Bendamustine 70 mg/m2 IVb + investigator) c rituximab • OS Crossover from IdR/BR arm allowed after confirmed disease progression • Interim analysis was planned after occurrence of ~79 PFS events (2/3 of primary event goal) Ghia et al, EHA2019 Ghia, EHA 2019 IRC-Assessed PFS Superior for Acalabrutinib vs IdR/BR Ghia et al, EHA2019 ADMIRAL Global Phase 3 Randomized Study (NCT02421939) Gilteritinib Resume HSCT 120 mg/day Gilteritinib n=247 Adult subjects with FLT3mut+ R/R AML Randomization 2:1 N=371 Salvage Chemotherapy* HSCT Key Eligibility Criteria: n=124 • Refractory to initial induction or untreated first relapse after prior CRc (defined as CR Co-Primary Endpoints: OS, plus CRi plus CRp) CR/CRh rate – Prior frontline midostaurin or sorafenib allowed Key Secondary Endpoints: EFS, – Prior gilteritinib or other FLT3 inhibitors CR rate excluded • Central laboratory-confirmed FLT3-ITD or *Salvage chemotherapy regimen was selected prior to randomization FLT3-TKD (D835/I836) by PCR MEC (mitoxantrone, etoposide, and cytarabine) • ECOG performance status <2 High intensity FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF) (1–2 cycles) • Normal liver, renal function Low-dose cytarabine Low intensity (given until disease progression or intolerance) • QTcF <450 msec by central ECG reading Azacitidine Abbreviations: CR, complete remission; CRc, composite complete remission; CRh, complete remission with incomplete hematologic recovery; CRi, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet recovery; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EFS, event-free survival; G-CSF, granulocyte colony-stimulating factor; HSCT, hematopoietic stem cell transplantation; ITD, internal tandem duplication; OS, overall survival; PCR, polymerase chain reaction; QTcF, Fridercia-corrected QT interval; R/R, relapsed/refractory; TKD, tyrosine kinase domain. Perl et al. AACR 2019 Overall Survival (ITT Population: N=371) Median OS (95% CI) Gilteritinib 120 mg/day 9.3 months (7.7, 10.7) Salvage chemotherapy 5.6 months (4.7, 7.3) + Censored HR=0.637 (95% CI: 0.490, 0.830); P=0.0007 CR/CRh Gilteritinib vs SC: 37% 34.0% vs.
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