A Herculean Task Emerging Therapies 2016 Ruemu E Birhiray MD CEO Indy Hematology Education Inc Partner Hematology Oncology of Indiana PC herculean adj 1 requiring tremendous effort strength etc ID: 919121
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Slide1
The Impending Death of Cancer:A Herculean TaskEmerging Therapies 2016
Ruemu E. Birhiray, MDCEO, Indy Hematology Education, IncPartner, Hematology Oncology of Indiana, PC
Slide2herculean
adj 1 requiring tremendous effort, strength, etc. a herculean task 2
sometimes cap resembling Hercules in strength, courage, etc.
Slide3Can·cer
[ˈ
kansər]
DEFINITION
astronomy
a constellation
(the Crab), said to represent a crab crushed under the foot of Hercules
.
It is most noted for the globular star cluster of
Praesepe
(the Beehive cluster).
astrology
the fourth sign of the zodiac, which the sun enters at the northern summer solstice (about June 21
).
medical
the disease caused by an uncontrolled division of abnormal cells in a part of the body:
a malignant growth or tumor resulting from the division of abnormal cells:
synonyms
: malignant growth · cancerous growth ·
tumor
· [more]
malignancy
·
carcinoma
·
sarcoma
·
melanoma
·
lymphoma
·
myeloma
Slide4Hydra
A monstrous serpent with nine heads, the hydra attacked with poisonous venom. Nor was this beast easy prey, for one of the nine heads was immortal and therefore indestructible.
Slide5HYDRA: The Nine Headed MonsterA: NINE HEADED APPROACH:1.
Naked monoclonal antibodies: Rituxan and Obinotuzumab2.
Anti PD1/PDl-1 antibodies: Nivolumab (Optivo) and
Pembrolizumab (Keytruda)3. Immunotoxins
: Brentuzimab vedotin
(
Adcetris
)
4.
Tyrosine inhibitors
:
Cell signal interference (
Gleevec
,
Imbruvica, Zydelig)5. Bi-specific antibodies: Blinatumumab6. Immunomodulating drugs (iMIDS): Revlimid, Pomolyst, Thalidomide7. Proteosome inhibitors: Cell “garbage disposal inhibitors” (Velcade, Kyprolis, Ninlaro)8. Epigenetic targeting drugs: targeting external modifications to DNA that turn genes “on” or “off” (vorinostat, romidepsin , panabinostat, vidaza)9. CART-T cells: T cells re-engineered with viruses to target cancer associated proteins (antigens)B: THE ROCK: Chemotherapy: anti DNA toxinsBendamustine, CHOP, Cytarabine, Idarubicin etc
Slide6Slide7Slide8RATIFY (MIDOSTAURIN) TRIAL: Most Significant Advance in AML in 30 years !
FLT3 mutations present in 25% pts with AML, a poor prognostic indicator, with higher incidence of relapse
FLT3 inhibitor midostaurin: Active against ITD-mutated leukemic cell lines
Current study investigated midostaurin added to standard chemotherapy in FLT3-mutated AML
23% improvement in relapse
Slide9Acute LeukemiaCLARA: 20% improvement in relapse riskClofarabine plus
Ara-C consolidation in intermediate and high risk AMLAPL: Arsenic Trioxide consolidation; safer and less relapse compared with Ara-C chemo
Slide10APL 2006: Arsenic trioxide plus idarubicin
Evaluate roles of ATO and ATRA plus idarubicin instead of cytarabine plus idarubicin
in consolidation for standard-risk APLMedian follow-up: 55 mos
Deaths, n: AraC, 6; ATO, 7; ATRA, 5.
RESULTS
All 3 regimens associated with high CR rates with few relapses in pts with standard-risk APL
5-yr CIR, % (n):
AraC
3.89 (4);
ATO 0 (0);
ATRA 7.41 (7);
P
= .03
Deaths, n:
AraC, 6; ATO, 7; ATRA, 5.ATO + idarubicin regimen significantly reduced relapse rates vs those attained with non-ATO regimens Ades L, et al. ASH 2015. Abstract 451Mos Post-CR
Cumulative Incidence of Relapse
0.00
0.05
0.10
0.15
0.20
0.25
0
20
40
60
80
ARA C
+ Ida arm
ATO + Ida
arm
ATRA
+ Ida arm
Slide11AML: Elderly PatientsFrontline
Venetoclax + HMAs in Elderly Pts With AML[1]
Anti-death protein BCL-2 inhibitor venetoclax Combination of
venetoclax with decitabine or azacitidine
tolerable, similar safety profile in both treatment arms High overall response rate, (CR, CRi, and PR) - 76%. The CR and CRi
rates were both 35%.
Pracinostat
+
Azacitidine
in Elderly Pts With Newly Diagnosed AML
[2]
Inhibitor of DNA unfolding protein: HDAC inhibitor
pracinostat
combined with
azacitidinePreviously untreated AML, unsuitable for intensive chemotherapy, intermediate- or high-risk cytogenetics (N = 50)Complte response: 42%1. DiNardo C, et al. ASH 2015. Abstract 327.2. Garcia-Manero G, et al. ASH 2015. Abstract 453.
Slide12Frontline Mini-HCVD + Inotuzumab in Older ALL Patients(1)
1.Jabbour E, et al. ASH 2015. Abstract 83.
2. Park JH, et al. ASH 2015. Abstract 682.
Inotuzumab
ozogamicin humanized
ant-CD22 monoclonal antibody linked with chemotherapy
calicheamicin
targeting leukemia cells, and released into cell, inducing cell death
S
tudy
evaluated safety and efficacy of reduced-dose HCVD +
inotuzumab
as frontline therapy in older adult pts with
ALL
Complete response: 80%19-28z CAR T Cells in R/R B-Cell ALL(2)Engineered T cells targeting CD19 molecule on leukemia cells, used in relapsed or refractory B-cell ALLHigh complete response rate (82%), often without detectable disease with molecular studies associated with superior survival.Efficacy/safety of CART cells similar in patients treated with/without prior allogeniec stem cell tranmsplantation
Slide13Blinatumomab in ALL
Blinatumomab: Immune match marker – brings immune cells to match cancer cells and kill cancer cells
Targets T cells to CD19+ B cells – expressed on B cell Acute lymphoblastic leukemia
ALCANTARA: Blinatumomab in Philadelphia Chromosome Positive ALL
(1)Adults relapses
andf
refarcatory
Acute lymphoblastic
leukemia
; failed targeted drugs (N = 45)
Complete response rate: 36%
Response to therapy was independent of T315l mutation
(
drug resistant mutation)100% of responders with ABL-kinase domain mutations had complete MRD responseMedian survival: 7.1 mosBlinatumomab in MRD-Positive BCP ALL(2)80% of MRD-positive BCP ALL pts achieved complete MRD response on blinatumomab therapyAchieving complete (vs incomplete) MRD response was associated with improved outcomesOS: 38.9 vs 12.5 mos; P = .002RFS: 23.6 vs 5.7 mos; P = .003DOR: NR vs 17.2 mos; P = .04967% of pts in CR following
blinatumomab
were able to receive
allo
-SCT
1
.
Martinelli
G, et al. ASH 2015. Abstract 679.
2.
Gökbuget
N, et al. ASH 2015. Abstract 680
Slide14GRAALL-R: Rituximab in ALL
Multicenter, randomized, phase III study from 2005-2014[1]CD20 expressed in 30% to 40% of B-cell precursor ALL pts, associated with worse outcomes
R
ituximab
added to chemotherapy demonstrated clinical benefit versus chemotherapy alone in adult patients with CD20+, Ph- BCP-ALLImproved event free survival: 65
vs
52%
Prolonged overall survival in patients not receiving
allo
-transplant after first complete remission
Well-tolerated safety profile in the
rituximab
group
vs
standard chemo aloneFurther study required to determine optimal rituximab dosing1. Maury S, et al. ASH 2015. Abstract 1. CD20+ Ph- tx-naïve BCP-ALL pts 18-59 yrs of age with ≥ 20% CD20+ blasts(N = 220)Standard Chemo + RituximabIV 375 mg/m2 16-18 infusions(n = 105)
Standard Chemo w/out
Rituximab
(n = 104)
Slide15Chronic Myeloid LeukemiaPONATINIB
Observational study of pooled data of TKI inhibitor ponatinib Ponatinib achieved significantly longer survival in patients with T315I+ Chronic Phase-CML compared with
allo-transplant Survival was similar for ponatinib compared with
allo-transplant in AP-CMLIn BP-CML and treatment-naïve Ph+ ALL, survival was longer for pts receiving allo
-transplantRadotinib
vs
Imatinib
in CML
In phase III trial of 2 doses of
radotinib
vs
imatinib in (Asian) pts with newly diagnosed chronic-phase CMLRadotinib associated with significantly higher molecular response rate Safety profiles different, with relatively low incidence of severe side-effectsHigher grade 3/4 laboratory abnormalities with radotinib1. Nicolini FE, et al. ASH 2015. Abstract 480. 2. Kwak J-Y, et al. ASH 2015. Abstract 476.
Slide16Myeloma: Proteosome Inhibition
SWOG S0777: TRIPLE THRAPY in untreated MyelomaVelcade plus Revlimide/
dex (VRd) induction in untreated MM without a planned immediate ASCT after induction
Significantly longer progression free survival and overall survival, Deeper responses, Acceptable safety profileENDEAVOR: Kd
vs
Vd
in Relapsed/Refractory Myeloma
Higher dose
Kyprolis
: Improved progression free survival and response rate
For pts with 1 prior line, median PFS: 22.2
mos
with
Kd
vs 10.1 mos with Vd; ORR: 82% for Kd vs 66% for Vd. For pts with ≥ 2 prior lines, median PFS: 14.9 mos with Kd vs 8.4 mos with Vd; ORR: 72% for Kd vs 60% for VdTOURMALINE-MM1: Ixazomib plus RD in Relapsed/Refractory MyelomaRandomized, double-blind, placebo-controlled, phase III trial: IRd resulted in fast/durable responses35% improvement in progression free survival
vs
Rd alone (20.7 mo vs. 14.6 mo)
Significantly prolonged progression free survival
vs
placebo in high risk patients with del(17p) mutation
Significantly improved time to
preogression
and response rates
vs
placebo
Ixazomib
plus Rd has tolerable safety profile with limited additional toxicity over Rd alone
Durie
B, et al. ASH 2015. Abstract 25
.
Berenson J, et al. ASH 2015. Abstract 373
Slide17Relapsed/Refractory MyelomaARRAY-520-216
(1): Filanesib:
novel, selective, orally active, inhibitor of Kinesin Spindle Protein (KSP), a protein that plays an essential role in mitotic spindle formation
Randomized, open-label, multicenter phase II trial, with Kyprolis
+ filanesib
PFS with
kyprolis
+
filanesib
: 2.8
mos
vs
8.5
mos with high vs low AAGPhase I/II CHAMPION-1(2): Weekly Carfilzomib + Dex in Relapsedf/Refractory MyelomaORR: 77%; 63% in velcade-refractory ptstwice-weekly 20 mg/m2 and 36 mg/m2Tolerable safety profileRates of grade ≥ 3 AEs and discontinuations similar or lower than historic twice-weekly dosing1.Zonder JA, et al. ASH 2015. Abstract 728. 2. Berenson J, et al. ASH 2015. Abstract 373.
Slide18ASCT in Myeloma: IFM/DCFI 2009
Parameter
RVD
(n = 350)
Transplantation
(n = 350)
Death, n
48
54
Cause of death, n (%)
Myeloma
Toxicity
Secondary primary malignancies
Other
40 (83)
4 (8)
1 (2)
3 (6)
35 (65)
9* (16)
6 (11)
4 (7)
4-yr survival, %
83
81
HR (95% CI);
P
value
1.2 (0.7-1.8); NS
*Includes transplant-related death, n = 5.
Attal
M, et al. ASH 2015. Abstract 391.
Triplet-regimen
RVD with and without ASCT for frontline
management
ASCT
superior to
RVD in pts with
untreated MM
is associated with:
31% reduced risk of progression or death (P < .001)
Improved TTP and rate of MRD negativity
Similar, low rate of
mortality
Slide19Myeloma ImmunotherapyDaratumumab
plus Len/Dex 81% ORR in relapsed/refractoryMyelomaDaratumumab plus
Pom/Dex shows active in heavily pretreated R/R MM: 71% ORR; 67% ORR in pts double-refractory to PI/IMiD
ELOQUENT-2: 3-yr follow-up, pts receiving elotuzumab
had 27% reduction in risk of progression or death vs Revlimid
/
dex
alone
BCMA-Targeted CAR T
cells
active -
sCR
in pt with a chemo-resistant MM.
PD-1/PD-L-1 INHIBITION IN MYELOMA:
Pembrolizumab in combination with len/dex: ORR - 76% Pembrolizumab in combination with pomalidomide/ dexamethasone shows promising activity in heavily pretreated relapsed/refractory MM: ORR - 60%
Slide20Follicular Lymphoma: Frontline Ibrutinib Plus Rituximab - Response
Current study evaluates chemotherapy-free combination ibrutinib plus
rituximab as frontline therapyORR of 82% (49 of 60); CR of 30%Median follow-up: 13.8 mos
with a median time to best response of 2.7 mosMedian duration of
ibrutinib treatment: 12.55 mos
Fowler NH, et al. ASH 2015. Abstract 470.
-100
-50
0
50
100
Improvement From Baseline SPD (Max %)
CR
PR
N = 60
*
*Response recorded in database is SD; unresolved query
SD
Slide21Follicular Lymphoma: GADOLINEfficacy and safety of
Obinutuzumab + Bendamustine
followed by Obinutuzumab
maintenance therapy in Rituximab
-refractory Indolent NHL
Investigator-assessed median PFS O-B
vs
B: 29.2
vs
14.0
mos
, respectively; HR: 0.52 (95% CI: 0.39-0.70;
P
< .0001)
No significant OS difference observed in interim analysisNo unanticipated adverse events reportedSehn LH, et al. ASCO 2015. Abstract LBA8502. .
0
0.2
0.4
0.6
0.8
1.0
Median follow-up:
21 mos
O + B
B
Censored
0
6
12
18
24
30
36
42
48
54
Mos
14.9
Probability of PFS
IRF-Assessed PFS
Events, n (%)
Median PFS,
mos
(95% CI)
Stratified HR (95% CI)
Log-rank
P
value
O + B (n = 194)
71 (37)
NR (22.5-NR)
B (n = 202)
104 (51)
14.9 (12.8-16.6)
0.55 (0.40-0.74)
.0001
Slide22Idelalisib ± Bendamustine
/Rituximab in Relapsed/Refractory CLL Study 115
Bendamustine + rituximab is an established regimen for frontline and R/R CLL treatment
Current study evaluated the combination of idelalisib and BR in R/R CLL: Results
Decreased risk of disease progression and deathExtended progression free survivalIncreased overall survivalAdvantage consistent across patient subgroups, regardless of high-risk prognostic factors such as TP53/del(17p), IGHV mutation status, and refractory disease
Zelenetz
AD, et al. ASH 2015. Abstract LBA-5.
Slide23Study 115: PFS
Zelenetz
AD, et al. ASH 2015. Abstract LBA-5.
IDELA + BR
Placebo + BR
Median PFS,
mos
23.1
11.1
HR (95% CI)
0.33 (0.24-0.45)
P
< .0001
Pts
a
t risk, n
(events)
IDELA + BR
207 (0)
154 (25)
74 (51)
27 (61)
6 (63)
1 (64)
Placebo + BR
209 (0)
145 (46)
36 (111)
11 (126)
1 (131)
0 (132)
Median follow-up time: 12 mos
100
80
60
40
20
0
PFS (%)
0
6
12
18
24
30
Mos
IDELA + BR
Placebo + BR
Slide24Study 115: OS
Zelenetz AD, et al. ASH 2015. Abstract LBA-5.
Pts at risk, n
(events)
IDELA + BR
207 (0)
181 (14)
104 (27)
52 (30)
13
(33)
1 (34)
Placebo + BR
209 (0)
180 (20)
93 (35)
33 (47)
8 (51)
0 (51)
IDELA +
BR
Placebo +BR
Median OS,
mos
NR
NR
HR (95% CI)
0.55 (0.36, 0.86)
P
= .008 (stratified) or .023 (unstratified)
100
80
60
40
20
0
Survival (%)
0
6
12
18
24
30
Mos
IDELA + BR
Placebo + BR
Slide25HELIOS: iBRRandomized, placebo-controlled phase III trial of
ibrutinib in combination with BR in pts with previously treated CLL/SLL
PFS benefit in all subgroups analyzed, including bulky disease, IgVH mutation status, no. prior therapies, presence of del11q
OS results confounded by crossover of 90 (31%) pts in placebo arm to ibrutinib
arm after PD
Chanan
-Khan AAA, et al. ASCO 2015. Abstract LBA7005.
100
80
60
40
20
0
PFS (%)
32
0
4
8
16
20
24
28
12
Mos
Placebo + BR
(
mPFS
– 13.3
mos
)
Ibrutinib
+ BR
(
mPFS
– NR)
100
80
60
40
20
0
OS (%)
32
0
4
8
16
20
24
28
12
Mos
Placebo + BR
Ibrutinib + BR
PFS
OS
HR (95% CI): 0.203 (0.150-0.276)
P
< .0001
Median OS NR in either arm
HR (95% CI): 0.628 (0.385-1.024)
P
= .0598
Risk of death reduced by 37% with
ibrutinib
despite crossover of 31% of patients on placebo arm
No unexpected toxicities reported with the combination of
ibrutinib
plus BR
Slide26Relapsed/Refractory CLLVenetoclax
and Rituximab in Refractory or Relapsed CLL(1)
Venetoclax + rituximab
highly activeOverall response rate: 86% with 47% complete responseNo detectable residual disease (MRD) in bone marrow of 55% of pts, and all MRD-negative pts maintained response at time of reporting
11 pts stopped venetoclax after achieving MRD negativity or CRNo MRD-negative pts progressed after stopping therapy
Phase I/II Trial of
Acalabrutinib
(ACP-196) for Relapsed/Refractory CLL
(2)
First-in-human study of second-generation BTK inhibitor
acalabrutinib
.
No major bleeding or
atrial
fibrillation reported in this studyAt median follow-up of 14.3 mos:Overall response: 95%Overall response in patients with del(17p) 100%Best responses over timeMa S, et al. ASH 2015. Abstract 830. 2. Byrd JC, et al. ASH 2015. Abstract 831
Slide27Hodgkin’s Lymphoma: Check Point InhibitorsKEYNOTE-013: PEMBROLIZUMAB
(1)Pembrolizumab after brentuximab
vedotin failure is safe and active in cHL
Response rate: 65%Response rate in transplant failure subgroup: 73%Response rate in the transplant ineligibility subgroup: 44%
Durattion of response ≥ 24 wks: 71%Pembrolizumab treatment increases circulating numbers of T and NK cells,
upregulates
TCR/IFN-
γ
signaling
Nivolumab
in R/R
cHL
: Phase I Dose Expansion Cohort
(2)
At a median follow-up of 101 wks, most patients have ongoing response1.Armand P, et al. ASH 2015. Abstract 584.2. Ansell S, et al. ASH 2015. Abstract 583.
Slide28PACE-MDS: Phase II Study in MDS(1)
Inhibition of erythroid precursor maturation by excessive Smad2/3 signaling via the TGF-β pathway
leads to anemiaLuspatercept (ACE-536): TGF-
β ligand trap that suppresses Smad2/3 activationHematologic improvement and reduced transfusion in pts with lower-risk MDS
Of 22 pts transfused prior to study, 11 (50%) achieved RBC-transfusion independence for ≥ 8 wksSustained Hb
increases, prolonged transfusion independence seen with treatment up to 1 yr, safe, well tolerated
Imetelstat
in RARS and RARS-T
(2)
Imetelstat
: Potent telomerase inhibitor of malignant progenitor cells with a high level of telomerase activity
Imetelstat
clinically active and safe in with RARS/RARS-T
Of 8 patients who were transfusion dependent at baseline, 3 achieved transfusion independence on study
Giagounidis A, et al. ASH 2015. Abstract 92.Tefferi A, et al. ASH 2015. Abstract 55.
Slide29Myelofibrosis
PRM-151: a recombinant human PTX-2(1)PTX-2 regulates tissue repair by preventing and reversing fibrosis, PTX-2 levels are low in pts with MF
13 pts completed 72 wks of treatment with PRM-151, well tolerated with few side effectsReductions in BM fibrosis observed at wk 12 and sustained through wk 72
Hemoglobin level increased with decreased need for RBC transfusionsPlatelet counts increased with a decreased need for platelet transfusions62% improved symptom score reduction of > 50% and 2 pts with > 50% reduction in
splenomegalyDanish COMBI Trial
(2)
:
Combination of
ruxolitinib
and interferon active in PV or
hyperproliferative
MF, including pts who failed IFN-
α
2 alone
63% of pts achieved a complete response; most by week 2 and all within 3 monthsSignificant symptom burden reduction by 3 mos (P = .007)Treatment regimen generally well tolerated 1. Verstovsek S, et al. ASH 2015. Abstract 56. 2. Mikkelsen SU, et al. ASH 2015. Abstract 824.
Slide30Waldenstrom’s
Macroglobulinemia
IMO-8400: Oligonucleotide
antagonist of endosomal TLRs 7, 8 and 9 amplified by MYD88 L265P mutation (90% of WM) well tolerated and active in
Denintuzumab
Mafodotin
in B-Lineage Non-Hodgkin Lymphoma
Anti-CD19 immunotoxin, Phase I trial
38% - Overall response rate,
23% - Complete response rate ,15% - Partial response
22% - Stable disease, 24% - Progressive disease
Slide31Hercules, Hydra and CancerHercules lured hydra from the safety of its den by shooting flaming arrows at it. The monster however wound one of its coils around Hercules' foot.
With his club, Hercules attacked the many heads of the hydra, but as soon as he smashed one head, two more would burst forth in its place! To make matters worse, the hydra had a friend of its own: a huge crab (CANCER) began biting the trapped foot of Hercules.
Slide32Hercules, Hydra, Cancer and IolausHercules called on
Iolaus his nephew and servant to help him out.Each time Hercules bashed one of the hydra's heads, Iolaus held a torch to the headless tendons of the neck. The flames prevented the growth of replacement heads.
Once he destroyed the eight mortal heads, Hercules chopped off the ninth, immortal head. This he buried and covered with a heavy rock. As for the rest of the hapless hydra, Hercules slit open the corpse and dipped his arrows in the venomous blood.
Slide33SAVE THIS DATE
!Meet the Experts 2017
March 3rd, 2017
Indianapolis Marriott® Downtown350 West Maryland Street,
Indianapolis, Indiana 46225