MDACC: Ibrutinib Venetoclax

Safety Run-in Phase*

Venetoclax–Obinutuzumab

Previously untreated

patients with CLL and

coexisting medical

conditions

CIRS > 6 and/or CrCl <

70mL/min

* Fischer K et al. Venetoclax and Obinutuzumab in chronic lymphocytic leukemia, Blood 11 May 2017

Chlorambucil–

Obinutuzumab

6 cycles

Venetoclax–

Obinutuzumab

6 cycles

Venetoclax

6 cycles

Chlorambucil

6 cycles

Follow-up Phase

Primary endpoint:

Progression-free

survival

Key secondary endpoints:

Response, Minimal

Residual Disease,

Overall

Survival

1:1

randomization

CLL14: Trial Design

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.

Análise Primária: SLP avaliada pelo investigador (população ITT)

VenG (n=216)

GClb(n=216)

Eventos, n (%) 30 (13.9) 77 (35.6)

HR (IC 95%),Valor de p estratificado

0.35 (0.23–0.53)p<0.001*

SLP 2 anos, % (IC95%)

88.2(83.7–92.6)

64.1(57.4–70.8)

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

VenG 216 195 192 183 153 25 0

GClb 216 194 184 152 110 21 0

Tempo (Meses)

SLP

(%

)

0

20

40

60

80

100

0 24186 12 30 36

VenG (N=216)

GCIb (N=216)

No. of Pacientes com risco:

Mediana de tempo fora de tratamento: 17.1 meses (0.0–30.4)

Mediana de duração do tratamento11.1 meses (0.0–14.1)

Mediana de tempo fora de tratamento : 17.9 meses (0.0–30.2)

Mediana de duração do tratamento10.8 meses ( 0.0–13.6)

Mediana de seguimento 28.1 meses

(0.0–35.9)

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.

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

Part 1 Part 2

Key eligibility

criteria:

• Transplant-

eligible NDMM

• 18-65 years

• ECOG 0-2

Firstra

ndom

ization

(1:1

)

Induction Consolidation Maintenance

D-VTdD: 16 mg/kg IV QW Cycles 1-2, Q2W

Cycles 3-4

V: 1.3 mg/m2 SC Days 1, 4, 8, 11

T: 100 mg/day PO

d: 20-40 mg IV/POa

VTdVTd administered as in the D-VTd arm

T

R

A

N

S

P

L

A

N

T

D-VTdD: 16 mg/kg IV Q2W

V: 1.3 mg/m2 SC Days 1, 4, 8, 11

T: 100 mg/day PO

d: 20 mg IV/POa

VTdVTd administered as in the D-VTd arm

D monotherapyD 16 mg/kg IV Q8W until

PD (2 years maximum,

then observation until

PD)

Observationuntil PD

(2 years maximum)

Patients

with≥P

R

Second

random

ization

(1:1

)

4 Cycles of 28 days 2 Cycles of 28 days

Follo

w-u

p

Moreau P, Attal M, Hulin C, et al, The Lancet 394:29-38, 2019 Winship Cancer Institute | Emory University 8

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

PFS and OS

PFS

Moreau P, Attal M, Hulin C, et al, The Lancet 394:29-38, 2019 Winship Cancer Institute | Emory University 9

OS

Phase IIIALCYONETrial: VMP± Daratumumab in ASCT-

Ineligible Patients With Newly Diagnosed MyelomaDaratumumab monotherapy phase

PF

S

(%)

0

20

40

60

80

0 18 2721

MosPatients at Risk, n

24

(95% CI: 0.35-0.54; P< .0001)

3 6 9 12 15

HR: 0.43

VMP

Median: 19.1

mos

D-VMP

Median:

not reached60%63%

28%36%

100

30 33 36 39

24 mos 30 mos

57% reduction in risk of

progression or death in

Dara-VMP arm

Mateos MV, et al. N Engl J Med 2018; 378:518-52

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

Response Rates by Treatment Cohort

1 0 0

9 0

8 0

7 0

6 0

5 0

4 0

3 0

2 0

1 0

0

Ra

te

of

Re

sp

on

se

(%

)

O t h e r

RD

M LFS

PR

CRi

CR

6 7 7 6 7 1 5 7 7 3

3 7 3 8

4 5

3 0

3 8

3 0

3 82 6

2 7

3 5

N =1 4 5 n =2 9

* All doses includes 11 patients that received 1200 mg venetoclax

n =3 1 n =3 7 n =3 7

Ve n 4 0 0 m g Ve n 8 0 0 m gAll

D o s e s * Aza D e c Aza D e c

C DiNardo et al, Blood 2018

Patients (%) with CR/ CRi shown at the

top of each bar

Luspatercept for the treatment of anaemia in patients with lower-riskmyelodysplastic 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

Collaboration with Ravi Kumar, Rajshekhar Suragini, Acceleron; Suragini et al, Nat Med 2014 C

Luspatercept promotes late stages of erythroid differentiation by inhibiting SMAD2/3 activation

MDS

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)

Acalabrutinib

100 mg PO BIDRelapsed/Refract

ory CLL (N= 310)

Stratification:

del(17p), y vs n

ECOG PS 0-1 vs 2

1-3 vs ≥4 prior

therapies

Primary endpoint:

• PFS (assessed by

IRC)

Key secondary

endpoints:

• ORR (assessed by

IRC and

investigator)

• Duration of

response

• PFS (assessed by

investigator)

• OS

Idelalisib plus Rituximab (IdR)

Idelalisib 150 mg PO BID + rituximaba

- or -

Bendamustine plus Rituximab (BR)

Bendamustine 70 mg/m2 IVb +

rituximabc

R

A

N

D

O

M

I

Z

E

Crossover from IdR/BR arm allowed after confirmed disease progression

1:1

• Interim analysis was planned after occurrence of ~79 PFS events (2/3 of primary event goal)

Ghia et al, EHA2019

Ghia, EHA 2019

Ghia et al, EHA2019

IRC-Assessed PFS Superior for Acalabrutinib

vs IdR/BR

ADMIRAL Global Phase 3 Randomized Study (NCT02421939)

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.

Adult subjects with

FLT3mut+ R/R AML

N=371

Randomization

2:1

Gilteritinib

120 mg/day

n=247

Salvage

Chemotherapy*

n=124

HSCTResume

Gilteritinib

HSCT

Co-Primary Endpoints: OS,CR/CRh rateKey Secondary Endpoints: EFS,CR rate

Key Eligibility Criteria:• Refractory to initial induction or untreated

first relapse after prior CRc (defined as CR

plus CRi plus CRp)– Prior frontline midostaurin or sorafenib

allowed

– Prior gilteritinib or other FLT3 inhibitors

excluded

• Central laboratory-confirmed FLT3-ITD or

FLT3-TKD (D835/I836) by PCR

• ECOG performance status <2

• Normal liver, renal function

• QTcF <450 msec by central ECG reading

*Salvage chemotherapy regimen was selected prior to randomization

MEC (mitoxantrone, etoposide, and cytarabine)

FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF)

Low-dose cytarabine

Azacitidine

High intensity

(1–2 cycles)

Low intensity (given until disease progression or intolerance)

Perl et al. AACR 2019

Overall Survival (ITT Population: N=371)

Two-sided P-values were determined according to the log-rank test; the Kaplan-Meier method in combination with the Greenwood formula were used to determine overall survival and corresponding 95%

confidence intervals.

Abbreviations: CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival.

Median OS (95% CI)9.3 months (7.7, 10.7)

5.6 months (4.7, 7.3)

Gilteritinib 120 mg/day

Salvage chemotherapy

+ Censored

HR=0.637 (95% CI: 0.490, 0.830); P=0.0007

Perl et al. AACR 2019

37%

17%

CR/CRh Gilteritinib vs SC:

34.0% vs. 15.3%

What if the Patient has an IDH mutation?

Ivosedinib and enasedinib

effective alone and in

combination with HMA in

relapsed and de novo disease

Data on HMA/VEN in patients with

IDH mutations very encouraging

as well

Pollyea et al, ASH 2018

Mutation # CR/CRi %(N) Duration of response Overall Survival

(mo)

FLT3 18 72 (13) 11(6.5,NR) NR(8-NR)

IDH ½ 35 71(25) NR(6.8,NR) 24.4 (12.3-NR)

NPM1 23 91(21) NR(6.8, NR) NR (11-NR)

ATdapPted5fr3om DiNardo et al, Blood

2

03186 47(17) 5.6(1.2,9.4) 7.2(3.7-NR)

JAKARTA-2: Open-Label, Phase 2 Studyof Fedratinib

RUX

resistant

RUX

intolerant

Classification made by treating physician

Fedratinib

Once daily, starting dose 400 mg

Consecutive 4-week cycles

• Permitted dose adjustments = 200-600 mg/day

• Dose up-titration permitted if <50%reduction in

spleen volume by palpation to ECO6

• Dose-titration permitted in event of toxicity

• Patients who continued to benefit clinically could

remain on study until the occurrence of disease

progression or unacceptable toxicity

• Aged ≥18 years

• Intermediate-2 or high-risk status

– Primary MF

– Post–PVMF

– Post–ETMF

• Platelet count ≥50 x 109/L

• Received RUXfor ≥14 days

• Discontinued RUX≥14 days prior to

starting fedratinib

Harrison CN et al. Lancet Haematol. 2017;4:e317-e324.

6

JAKARTA: SPLEEN VOLUME AND SYMPTOMRESPONSES

• Among all patients, SVRR was significantly higher with fedratinib 400 mg/day vs. placebo (47% vs. 1%, respectively; P<0.0001)

• Symptom RR was also significantly improved with fedratinib overall

• There was no statistically significant difference in SVRR or symptom RR between BLplatelet count subgroups within the fedratinib 400 mg treatment arm

Statistical comparisons between BL platelet count subgroups should be interpreted with caution due to small sample sizes.

BL, baseline; ITT, intention-to-treat; NE, not estimable; RR, response rate; SVRR, spleen volume response rate.

BL Platelet Count50 to <100 × 109/L

BL Platelet Count≥100 × 109/L

JAKARTA

Placebo

n = 77

SVRR: 1.3%[95%CI 0%, 4%]

Symptom RR (n=65):

10.8%

[95%CI 3%, 18%]

Placebo

n = 18

SVRR: 0%[95%CI NE]

Symptom RR (n=16):

0%

[95%CI NE]

Fedratinib 400 mg

n = 14

SVRR: 35.7%[95%CI 11%, 61%]

Symptom RR (n=13):

30.8%

[95%CI 6%, 56%]

Fedratinib 400 mg

n = 82

SVRR: 48.8%[95%CI 38%, 60%]

Symptom RR (n=76):

42.1%

[95%CI 31%, 53%]

Fedratinib Is Effective in Patients With MFPreviously Treated WithRuxolitinib: Results From JAKARTA-2

Fedratinib, approved in August 2019, produced a 55%rate of ≥35%SVRand a 26%rate of ≥50%TSS reduction at wk24

-60

-40

-20

0

20

40

100

80

60

120

60

40

20

0

-20

-40

-60

-80

-100

Resistant Intolerant Other

Spleen

Harrison CN et al. Lancet Haematol. 2017;4:e317-e324.

Symptoms

Ch

an

ge

inS

ple

enV

olu

me

at

EC

OG

Rel

ati

ve

toB

ase

lin

e,%

Ch

an

ge

inM

S-S

AF

at

EC

OG

Rel

ati

ve

to

Ba

seli

ne,

%