Upload
others
View
2
Download
0
Embed Size (px)
Citation preview
New drugs development in
lymphomas
Anastasios Stathis, MD
Phase I and Lymphoma Unit Oncology Institute of Southern Switzerland
Bellinzona
Jan 30, 2016
LyFE Forum of Excellence 2016What’s new in lymphoid neoplasias?
Leading new cancer cases and deaths-
2014 estimates USA
2014, American Cancer Society, Inc., Surveillance Research
IOSI LYMPHOID NEOPLASMS DATABASE 1980-2011[N=2035, Median follow-up: 9.8 years]
Traditional Treatment Strategies Are Based on
Histologic Subtypes
WHO classification > 50 distinct lymphoma histologies
Current Regimens in LymphomaRecycling old drugs
Disease Front-Line Regimen Salvage RegimenDLBCL RCHOP R-ICE
R-ESHAPR-DHAP
T-Cell NHL CHOP ICEESHAPDHAP
MCL RCHOPR-HyperCVAD
cHL ABVD ICEESHAPDHAPGND, IGEV
Early 1970s 2002 2010
CHOP RCHOP RCHOPABVD ABVD ABVD
Rappaport Working Formulation REAL WHO
Drugs registered for lymphomas1995-2010
1995 2000 2005 2010
Rituximab
Bortezomib
Vorinostat
Romidepsin
Ofatumumab
Alemtuzumab
Ibritumomab
Tositumomab
Stathis A. and Ghielmini M., Ann Oncol. 2012 Sep;23 Suppl 10:x92-8.
The Lymphomas
Improvement in Survival
Coiffier B, et al. NEJM 2002
OS (N = 399)
Su
rviv
al P
rob
ab
ilit
y
Yrs
0
0.
2
0.
4
0.
6
0.
8
1
0 1 3 5 7 82 4 6
CHOPR-CHOP
P = .0004
Fisher RI, et al. J Clin Oncol. 2005.
DLBCL FL
Explosion of new cancer therapeutics
>800 agents in
clinical trials in
2009
143% increase
from a decade ago
LoRusso PM et al. Clin Cancer Res 2010:16:1710-1718
Emerging therapeutic options in
relapsed/refractory NHL
Adapted from M.P. Chao. Cancer Manag Res. 2013; 5: 251–269
NativeT cell
Malignant B Cell
PD1
PD-L1PD-L2
MHC I/II
TCRCD3
BiTEEngineered
T Cell
Tumor vaccinesCytokines
Immune checkpointinhibitors
TCR
CAR
Batlevi C, Matsuki E, et al: Nature Rev Clin Oncol 2015
Therapeutic strategies to overcome immune
tolerance to cancer
Breakthrough lymphoma therapies2010-2015 FDA approved
Year Drug Type Target Indication
2011 Brentuximab Vedotin ADC CD30 R/R HL and ALCL
2013 Lenalidomide Small molecule Multiple 3d line, MCL
2013 Obinutuzumab MoAb CD20 1st line CLL with Chl
2013/2014
Ibrutinib Small molecule BTK 2nd line CLL and MCL
2014 Idelalisib Small molecule PI3Kδ R CLL with Rituximab, 3d line FL/SLL
ADC: antibody drug conjugate; MoAb: monoclonal antibody; R/R: relapsed/refarctory; HL: Hodgkin lymphoma. ALCL: anaplastic large cell lymphoma; MCL: mantle cell lymphoma; CLL: chronic lymphocytic leukemia; Chl: chlorambucil; FL: follicular lymphoma; SLL: small lymphocytic lymphoma
� Development of active, non-toxic drugs
� Incorporation of new drugs in standard treatments
� Define long-term toxicities especially in indolent
lymphomas
� Predictive biomarkers of response for rationale
drug development
New drug development for lymphomas:Open questions in 2016
Structure of human CD20 molecule
• B cell-specific tetra-transmembrane protein localized to microvilli and constitutively associated with membrane rafts
• no dissociation or internalization upon antibody binding
• role in B cell function not fully clear (regulator or component of a calcium channel), it forms homo-oligomers that physically associate with the BCR
Targeting CD20: Old target new drugs
GA101 (Obinutuzumab)
Glycoengineered, Type II Anti-CD20 mAb
FDA approved (Nov 2013) 1st line CLL with Chlorambucil
Type IIanti-CD20 mAb1,2 Glycoengineered
Fc region1
Increaseddirect cell death1
Increased ADCC1
1Mossner E et al. Blood. 2010;115(22):4393-402; 2Niederfellner G et al. Blood. 2011;118:358–67.mAb, monoclonal antibody.
Decreased complement dependent cytotoxicity
• CDC1-3
• ADCC1-3
• Apoptosis1-3
1Bello C, Sotomayor EM. Hematology Am Soc Hematol Educ Program; 2007: 233–242; 2Glennie MJ, et al. Mol Immunol 2007; 44(16): 3823–3837;3Jazirehi AR, Bonavida B. Oncogene 2005; 24(13): 2121–2143
1Bello C, Sotomayor EM. Hematology Am Soc Hematol Educ Program; 2007: 233–242; 2Glennie MJ, et al. Mol Immunol 2007; 44(16): 3823–3837;3Jazirehi AR, Bonavida B. Oncogene 2005; 24(13): 2121–2143
ADCC=antibody-dependent cellular cytotoxicity; CDC=complement-dependent cytotoxicity; MAC=membrane attack complex
ADCC=antibody-dependent cellular cytotoxicity; CDC=complement-dependent cytotoxicity; MAC=membrane attack complex
C1qC1q
mAbmAb
CD20 CD20
B cellMACMAC
MacrophageMacrophage
Anti-CD20 mAbs mechanism of action
1Cragg MS, et al. Curr Dir Autoimmun 2005; 8: 140–174; 2Glennie MJ, et al. Mol Immunol 2007; 44(16): 3823–3837; 3Teeling JL, et al. Blood 2004; 104(6): 1793–1800
Type I Type II
CD20 clustering in B-cell membrane
++ -
Induction of CDC ++ +
Induction of ADCC ++ ++
Induction of apoptosis + ++
Differences between type I and type II anti-CD20 mAbs1-3Differences between type I and type II anti-CD20 mAbs1-3
– = no activity; + = some activity; ++ = significant activity– = no activity; + = some activity; ++ = significant activity
Type IType I
Type IIType II
mAb=monoclonal antibody;CDC=complement-dependent cytotoxicity; ADCC=antibody-dependent cellular cytotoxicity
mAb=monoclonal antibody;CDC=complement-dependent cytotoxicity; ADCC=antibody-dependent cellular cytotoxicity
Anti-CD20 mAbs: two types
Ove
rall
Sur
viva
l in
the
Inte
ntio
n-to
-Tre
at P
opul
ati
on
Obinutuzumab plus Chlorambucil in patients
with CLL and coexisting conditions
G-Clb vs Clb HR 0.41 (95% CI, 0.23-0.74)P=0.002
R-Clb vs Clb HR 0.66 (95% CI, 0.39-1.11)P=0.11
G-Clb vs R-Clb HR 0.66 (95% CI, 0.41-1.06)P=0.08
Goede V et al. N Engl J Med 2014;370:1101-1110.
GADOLIN: Study design (NCT01059630)
G-B
B
Rituximab-refractory CD20+ iNHL
(incl FL, MZL and SLL)
(N=413)
G-maintenanceCR/ PR/ SD
R1:1
Obinutuzumab 1000 mg i.v. Days 1, 8 and 15 Cycle 1; Day 1 Cycle 2–6 (28 day cycles)Bendamustine 90 mg/m2/day i.v. Days 1 and 2 Cycles 1–6 (28 day cycles)
Obinutuzumab 1000 mg i.v. every 2 months for 2 years or until progression
Bendamustine120 mg/m2/day Days 1 and 2 Cycles 1–6 (28 day cycles)
Stratification factors:•NHL subtype (FL vs other) •Prior therapies (≤2 vs >2)•Refractory type (R-mono vs R-chemo)•Geographic region
• International, randomized, open-label study
• Primary endpoint: PFS as assessed by an Independent Radiology Facility (IRF)
• Response monitored by CT scan post-induction, then every 3 months for 2 years, then every 6 months
Cheson et al 13-ICML, Abstract 123
GADOLIN primary outcome: IRF-assessed PFS
Time (months)
Pro
babi
lity
of P
FS
Median F-up: 21 mos
1.0
0.8
0.6
0.4
0.2
0.0
IRF, independent radiology facility; HR, hazard ratio; CI, confidence interval; NR, not reached
0 6 12 18 24 30 36 42 48 54 mos
Cheson et al 13-ICML, Abstract 123
11.718.5
9.09.010.19.5
58.0 50.8
11.2 12.2
0
20
40
60
80
100
G-B
n=188
B
n=189
Pati
en
ts (%
)
GADOLIN: Response to therapy
69.263.0
* Patients ongoing in induction therapy are excluded from analysis. Patients with end of induction response assessment performed >60 days after last induction dose shown as missing.
** Best overall response excludes ongoing patients who have not yet reached the first response assessment. IRF, independent radiology facility
End-of-induction response (IRF)
5.7 7.6
4.7 4.110.9 11.7
62.0 59.4
16.7 17.3
0
20
40
60
80
100
G-B
n=192**
B
n=197**
Pa
tie
nts
(%)
CR
PR
SD
PD
NE/missing78.7 76.7
Best overall response to 12 months (IRF)
• 19 patients still in induction (G-B, n=6; B, n=13)*
Cheson et al 13-ICML, Abstract 123
No difference in PFS in head to head comparison with rituximab in
indolent lymphomas: final results of the GAUSS study
Sehn LH et al, J Clin Oncol. 2015 Oct 20;33(30):3467-74
The GOYA Study
Stratification• Number of planned CHOP cycles (6 or 8)• IPI score• Region of study conduct
IPI, International Prognostic Index.
GA101 + CHOP
Rituximab + CHOP
Previously untreatedDLBCL
1:1
GA101•1000 mg on days 1, 8, and 15 of cycle 1; day 1 of cycles 2–8, every 21 daysRituximab•375 mg/m2 on day 1 of cycles 1–8,every 21 days
• Phase III, open-label, multicenter, randomized
• Sites choose between use of 6 or 8 cycles of CHOP-21
1400 patients
The era of ADCs?
MMAE – microtubule-disrupting agent
Apoptosis
G2/M cell
cycle arrest
ADC binds to CD30
MMAE disrupts
microtubule network
ADC–CD30 complex internalized/ traffics to
lysosome
MMAE is released
Adapted from Ansell SM. Expert Opin Investig Drugs 2011;20:99–105 and Younes A, et al. N Engl J Med 2010;363:1812–21.
protease-cleavable linker
anti-CD30 monoclonal antibody
ADC, antibody–drug conjugate; MMAE, monomethyl auristatin E.
Brentuximab vedotin ADC
Brentuximab Vedotin (Adcetris)
Anti-CD30 conjugated to an antitubulin agent
Response rate 75% (34% CR)
Pivotal Phase II study in relapsed or refractory
HL post-ASCT
Younes A et al, J Clin Oncol. 2012
Response rate 86% (57% CR)
Pivotal Phase II study in relapsed or refractory
systemic ALCL (sALCL)
Pro B et al, J Clin Oncol. 2012
� Median observation 3 yrs:-mOS 40.5 mos-mPFS 9.3 mos
� 34 CR pts: -3-yr OS 73%-3-yr PFS 58%
� 16 CR pts progression-free at a median of 53.3 mos (range 29-56.2 mos)
� 12 CR pts progression-free without allogeneic transplant
Durable remissions in a significant proportion
of R/R HL patients
Gopal AK et al. Blood 2014
Brentuximab Vedotin consolidation after ASCT
in HL: the AETHERA trial
Craig H Moskowitz, The Lancet, 2015
HR for PFS 0·57, 95% CI 0·40–0·81 (p=0·0013). Median PFS 42·9 months (95% CI 30·4–42·9) vs 24·1 months (11·5–not estimable)
ADCs in development for B-cell NHL
Drug Target Format Stage of development
Inotuzumab Ozogamicin
(Pfizer)
CD22 Conjugated to calicheamicin
Combination with R-chemo,
Temsirolimus
SAR3419(Sanofi)
CD19 Conjugated to DM4 Combination with Rituximab
DCDT2980S(Roche)
CD22 Conjugated to MMAE
Combination with Rituximab
DCDT2980S(Roche)
CD79b Conjugated to MMAE
Combination with Rituximab
IMGN529 (Immunogen)
CD37 Conjugated to DM1 Phase I ongoing
Tumor cell
Effector cellAntigen
DM1
IMGN529
Fc Receptor
Complement
Apoptosis/growth inhibition by
direct signaling
Antibody-dependentcellular cytotoxicity
(ADCC)
Complement-dependent cytotoxicity
(CDC)
Delivery of cytotoxic agent (DM1)
IMGN529 is an anti-CD37 immunotoxin. Multiple mechanisms of action: apoptosis, CDC, ADCC, and cytotoxicity by maytansinoid delivery
CD37
IMGN529 compound profile and
mechanism of action
A Phase I, Multi-center, Open-label study of
IMGN529 in relapsed or refractory B-cell NHL
Stathis A, et al. ASH 2014, abstr 1760
Tumors exploit pathways that evade immune
destruction including endogenous immune checkpoints
Mellman I, Nature, 2011
MR Green et al,Blood 2010; 116:3268
DJ Andorsky et al, Clin Cancer Res 2011; 17:4232
BJ Chen et al, Clin Cancer Res 2013; 19:3462
RA Wilcox et al, Blood 2009;114:2149
J Liu et al, Blood 2007;110(1):296
Pre-clinical rationale for PD-1/PD-L1 blockade
Ansell SM et al. N Engl J Med. 2014 Dec 6. [Epub] DOI: 10.1056/NEJMoa1411087
RR 87%, CR 17%
PD-1 Blockade with Nivolumab in Relapsed
or Refractory Hodgkin’s Lymphoma
*Patient became PET negative and was therefore declared to be in complete remission.Analysis cut-off date: November 17, 2014.
*
Moskowitz et al, ASH 2014, abstr. 290
Pembrolizumab: RR 66% , CR 21%
Nivolumab Pembrolizumab
Related AE 78% 55%
Grade 3 AE 22% 10%
PancreatitisGI inflammation
ColitisPneumonitis
Axillary painHypoxia
Joint swellingPneumonitis
Safety profile similar to that in solid tumours
Toxicity
Armand et al, ASH 2014, abstr. 289
Moskowitz et al, ASH 2014, abstr. 290
Anti-PD1 in R/R HL studies
Baseline Characteristics
CharacteristicHodgkin
Lymphoma(n=23)
B-cell NHL
(n=31)
T-cellNHL
(n=23)
MultipleMyeloma
(n=27)
Histology, nNS HL: 22MC HL: 1
Follicular: 11DLBCL: 10PMBL: 2Other: 8(MCL, SLL, MZL)
MF: 13PTCL: 5Other: 5
MM: 27
Prior auto transplant, n (%)Prior brentuximab vedotin, n (%)
18 (78)18 (78)
4 (14)3 (10)
2 (9)6 (26)
15 (56)0 (0)
Prior therapies, median (range) 5 (2–15) 3 (1–16) 4 (1–9) 4 (1–12)
Nivolumab updated phase I results
Timmerman J et al, abstr 10; ICML 2018
Tumor Type #pts
ORR CR PR SD
Hodgkin Lymphoma 23 20 (87) 6 (26) 14 (61) 3 (13)
B-Cell Non-Hodgkin Lymphoma 31 8 (26) 3 (10) 5 (16) 16 (52)
Diffuse Large B-Cell 11 4 (36) 2 (18) 2 (18) 3 (27)
Follicular 10 4 (40) 1 (10) 3 (30) 6 (60)
Mantle Cell 4 0 0 0 3 (75)
Primary Mediastinal B-Cell 2 0 0 0 2 (100)
Other B-NHL (SLL n=3, MZL n=1) 4 0 0 0 2 (50)
T-Cell Non-Hodgkin Lymphoma 23 4 (17) 0 4 (17) 10 (43)
CTCL/MF 13 2 (15) 0 2 (15) 9 (69)
Peripheral T-Cell 5 2 (40) 0 2 (40) 0
Other T-NHL 5 0 0 0 1 (20)
Multiple Myeloma 27 1 (4) 1 (4) 0 17 (63)
Best response
Nivolumab updated phase I results
Timmerman J et al, abstr 10; ICML 2018
Targets for the development of small
moleculesKinase inhibitors
B-cell receptor (BCR)
PI3K/AKT/MTOR
JAK/STAT
RAS/RAF/MEK
Cell cycle
Immunomodulators
Microenvironment
Epigenetic modulators
HDAC
BRD
EZH2
Proteasome inhibitors
NFKb
Bcl2 inhibitors
Apoptosis
Ibrutinib
• Ibrutinib was designed to
specifically target and
selectively inhibit BTK
• BTK is a key mediator of at
least three critical B-cell pro-
survival mechanisms
occurring in parallel:
– regulation of apoptosis
– cell adhesion
– cell migration and homing
Phase I study (N=56)
RR DLBCL 28%
FL 38%
MCL 77%
CLL/SLL 79%
Durable responses with median PFS of 13.6 months
Advani et al., J Clin Oncol, 2013
Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma
ML, Wang et al NEJM, 2013
Ibrutinib + R-CHOP
A phase Ib study in CD20 positive NHL
Younes A, abstr 69, ICML-12, Lugano 2013
• n=32 CD20 positive treatment naïve pts (23 DLBCL, 5 MCL, 4 FL)
• MTD 560mg + standard RCHOP
• Toxicities: hematologic
420 mgn = 4
ORR 100% (CR 67%, PR 33%)
280 mgn = 6
560 mgn = 5
PR
CR
Num
ber
of P
atie
nts
1
DLBCL
DLBCL
DLBCL
MCL
MCL
MCL
FL
DLBCL
MCL
DLBCL
DLBCL
FL
FL DLBCL
MCL
Assessment performed at end of cycle 3; disease evaluations not complete
Staudt, 12-ICML, Hematol Oncol 2013. 31(suppl 1): 26-28
Responses to BTK-inhibitor ibrutinib are much
higher in ABC- DLBCL than GCB-DLBCL
ABC-DLBCL GCB-DLBCL
OR: 5%OR: 41%
Genetic lesions can partially predict
the response to the BTK-inhibitor ibrutinib
CD79B
MYD88
CARD11
mut.
wt
wt
wt
wt
wt
mut.
mut.
wt
wt
mut.
wt
wt
wt
mut.
Staudt, 12-ICML, Hematol Oncol 2013. 31(suppl 1): 26-28
Idelalisib: a highly selective PI3Kδ inhibitor
Lannutti B J et al. Blood 2011
PI3Kδ Inhibition by Idelalisib in Patientswith Relapsed Indolent Lymphoma
Gopal et al NEJM, 2014
ActivatesT, NK andNKT cells
NK and Tcell-
mediatedtumorkilling
Increasesantigen
presenting properties of tumor
cells
Arrestscell
cycle
Inducestumor
suppressorgenes
Tumorcell
apoptosis
Activatescaspases
Disrupts stromal cell
support
Reduces Tumorburden
Enhances Immunological
synapse formation
Lenalidomide mechanism of action
Rituximab, bendamustine and lenalidomide in
patients with aggressive B-cell lymphoma not eligible
for anthracycline-based therapy or intensive salvage
regimen. A phase II trial
Felicitas Hitz, Emanuele Zucca, Thomas Pabst, Natalie Fischer, Anne Cairoli, Panagiotis Samaras, Clemens Caspar, Nicolas Mach, Fatime Krasniqi, Adrian Schmidt, Christian Rothermundt, Milica Enoiu, Katrin Eckhardt, Simona Berardi Vilei, Stephanie Rondeau, Ulrich Mey
Hitz F et al, ICML 2015
Felicitas Hitz – June 17, 201551
Overall Response Rate
61%n=25
Pro
port
ion
of p
atie
nts
(%)
77%n=10
54%n=15
Felicitas Hitz – June 17, 201552
Overall follow-up time, median (range): 25.9 (0.2-37.9) months
Secondary Endpoints
Overall survivalmedian [95% CI]: 14.4 [4.9-21.6]
months
Time-to-event endpointMedian [95% CI] in
months
Progression-free survival4.8 [2.4-6.7]
Event-free survival 3.7 [1.8-5.2]
Response duration (n=25) 6.8 [3.4-12.3]
Time to progression 6.4 [2.4-8.6]
Overall survival 14.4 [4.9-21.6]
Rituximab-Bendamustine-Lenalidomide
• LBR is a very active regimen in different
lymphoprolipherative diseases
• The combination is very toxic if the drugs are given at full
dose
• A safe schedule seems to be:
Bendamustine 70 mg/m2 d1+2
Rituximab 375 mg/m2 d1
Lenalidomide 10 mg/d d1-14 q28d
• This regimen, although active, needs to be compared to
standard regimens in randomised trials
New drug combinations ICML 2015
Author Abstr Drug Target AEs RR
Mehta-Shah 016 Romidepsin
+Lenalidomide
HDAC+
Immunomodulator
ANC, PLT 53% TCL,
44% BCL
Barr 042 Entospletinib
+Idelalisib
SYK+PI3Kδ Pneumonitis in
20% of pts
29% NHL
Phillips 079 INCB040093
+ INCB039110
PI3Kδ+JAK1 Fatigue,
headache
28/75 (60%
HL)
Nastoupil 106 UBLITUXIMAB,
TGR-1202,
AND IBRUTINIB
CD20, PI3Kδ, BTK Diarrhea 9/13 NHL
Dunleavy 136 TEDDI-R BTK, CD20, CHEMO No DLTs 7/10 PCNSL
after
Ibrutinib
De Vos 147 Venetoclax+RB bcl2 Nausea,
anemia, PLT
66%, 74%
in FL
TGR-1202 (PI3ki) + Ublituximab (anti-CD20) + Ibrutinib (BTKi):
Phase-1 study
BEST PERCENT CHANGE FROM BASELINE IN DISEASE BURDEN
CRPRPRPR
PRPRPR
* * * * * * * * **(4.5) (2.5) (3.5) (7) (9.5) (4.5) (7) (8) (7) (9.5)
CRPRPRPR
PRPRPR
PRPR
* On Study
(X) Months On Study
• ORR, 86% with 76% reduction in nodal disease at first assessment in responders
• Well tolerated (neutropenia grade 3-4 in 6%)
L. Nastoupil , et al. Hematol Oncol. 2015;33: Supp 1. Abs 106
Venetoclax + Rituximab & Bendamustineearly and long-lasting responses with tolerable safety profile
MZLDLBCL FL
DLBCL ,
n=11FL, n=21 MZL, n=3
ORR 5 (45%) 15 (71%) 3 (100%)
CR 1 (9%) 6 (29%) 1 (33%)
Grade 3/4 AEs
(in ≥ 3 pts)
n (%)
Total
N=35
Lymphopenia 13 (34)
Neutropenia 11 (31)
Leukopenia 7 (20)
Thrombopenia 7 (20)
Anemia 6 (17)
Best Percent Change from Baseline in Nodal Size
S. De Vos et al. Hematol Oncol. 2015;33: Supp 1. Abs 147
Pathway Drug Target % Response rate in different histologies
DLBCL FL MCL SLL/CLL T-Cell HL
PI3K/AKT/mTOR
Everolimus mTOR 30% 50% 32% 18% 63% 53%
Temsirolimus mTOR 36% 56% 38% 10% - -
CALI-101 PI3K 0% 55% 67% 30% - -
B Cell Receptor (BCR)
Fostamtinib Syk 22% 10% 11% 55% 0% -
PCI32765 Btk 17% 23% 69% 67% - -
Modern drug development: not histology but
molecular characteristics?
Younes A & Berry D. Nature Rev Clin Oncol 2012
0%0%3%5%10%10%15%17%22%24%28%32%33%35%
0% 20% 40% 60% 80% 100%
Mapatumumab
YM155
SGN40
CMC544
Fostambinib
Lenalidomide
SAR3419
We are moving towards cell-of-origin
as a guide to therapy
Non-GCB type
• NF-kB activated
• BCR signalling
• TLR/IRAK signalling
• Bortezomib
• Ibrutinib
• Fostamatinib
• Lenalidomide
GCB type
• Epigenetic regulators mutant/lost
• EZH2, CREBBP
• ? EPOCH, DHAP
• ? GSK 126
• ? EPZ 6438
� Advances in preclinical research have supported the
development of a high number of new drugs
� Significant clinical activity observed in relapsed/refractory
patients and 5 drugs approved for different lymphomas
� Combination regimens are currently being tested and results
are awaited
� Molecular predictive biomarkers of efficacy are needed to
better select patients
In conclusion