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ESMO SUMMIT AFRICA 2019
Follicular LYMPHOMA
Christian Buske, M.D.
University Hospital Ulm, CCC Ulm, Germany
CONFLICT OF INTEREST DISCLOSURE
Prof. Buske
Research Grants: Roche, Janssen, Bayer
Honoraria: Roche, Janssen, Bayer, Pfizer, Celltrion, Hexal, Abbvie
Waldenström J Acta Medica Scandinaviva 1944
• About 25% of all lymphomas
• Median age 60–65 years
• 85% advanced stage III/IV
• Indolent clinical course
(median survival 15–20 years)
• In relapse still sensitive to therapy
The Non-Hodgkin's Lymphoma Classification Project. Blood 1997;89:3909–3918; Armitage et al., J Clin Oncol 1998;16:2780–2795.
Follicular Lymphoma
Follicular lymphoma –diagnostics
Dreyling et al., 2016
Follicular lymphoma –diagnostics – why?
Dreyling et al., 2016
Su
rviv
al p
rob
ab
ility
36%
37%
27%
Low risk (0-1 adverse factor)
Intermediate risk (2 factors)
Poor risk (> 3 adverse factors)
Parameter Adverse factor RR 95% CI
Age ≥60y 2.38 2.04 – 2.78
Ann Arbor stage III – IV 2.00 1.56 – 2.58
Hemoglobin <12 g/dL 1.55 1.30 – 1.88
Serum LDH level >ULN 1.50 1.27 – 1.77
Number of nodal sites >4 1.39 1.18 – 1.64Solal-Celigny Blood 2004; 104(5):1258-65
FLIPI in follicular lymphoma (n=1795)
Buske et al., Blood 2006 108:1504-1508
The FLIPI for GLSG patients receiving
1st line R-CHOP
Jurinovic et al., Blood 2016 Aug 25;128(8):1112-20
Clinicogenetic risk model: “m7-FLIPI“
Pro
ba
bili
ty
Pro
ba
bili
ty
Jurinovic et al., Blood 2016 Aug 25;128(8):1112-20
Failure free survival Overall survival
GLSG training cohort
Jurinovic et al., Blood 2016 Aug 25;128(8):1112-20
Reclassifying risk groups
Follicular lymphoma –
Low versus high burden?
ESMO
GUIDELINES FL
Dreyling et al., 2016Dreyling et al., 2016
ESMO
GUIDELINES FL
Dreyling et al., 2016Dreyling et al., 2016
ESMO
GUIDELINES FL
Dreyling et al., 2016
Rituximab
Induction Maintenance
Immunochemotherapy
RITC
onsolid
ation
Diagnosis Diagnostic Work-up (CT etc.)
Watch & Wait
Development of Symptoms
Start of therapy
Personal communication
Therapeutic Algorithms
Rituximab
Induction Maintenance
Immunochemotherapy
RITC
onsolid
ation
Diagnosis Diagnostic Work-up (CT etc.)
Watch & Wait
Development of Symptoms
Start of therapy
Personal communication
Therapeutic Algorithms
Follicular Lymphoma
When should we start to
treat?
An Intergroup Randomised Trial of
Rituximab vs a Watch & Wait Approach
in Patients with Advanced Stage, Asymptomatic,
non-Bulky Follicular Lymphoma
Kirit M Ardeshna, Paul Smith, Wendi Qian, June Warden, Lindsey Stevens,
Christopher FE Pocock, Fiona Miall, David Cunningham, John Davies, Andrew Jack
Jan Walewski,, A. Burhan Ferhanoglu, Ken Bradstock and David C Linch
Ardeshna et al., Lancet Oncol. 2014 Apr;15(4):424-35
Rx4
R
A
N
D
O
M
I
S
A
T
I
O
N
ARM A
Watch and Wait
ARM B
Rituximab Induction
ARM C
Rituximab Induction
& maintenance
Continued
follow up
Progressive disease requiring
therapy stops protocol treatment
Clinic visits
Ardeshna et al., Lancet Oncol. 2014 Apr;15(4):424-35
Proportion
of patients
with
no new
treatment
initiated
19 19219 8483 187
Events TotalsW+W R4 R4 + M
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Years from randomisation0 1 2 3 4 5
% not requiring Rx at 3yr
W+W=48%
R4=80%
R4+RM=91%
Time to Initiation of New Therapy –Median follow-up 32 months
HR (Rituximab vs W+W) = 0.37, 95%CI = 0.25, 0.56, p<0.001
HR (Rituximab + M vs W+W) = 0.20, 95% CI = 0.13, 0.29, p <0.001
HR (Rituximab + M vs Rituximab) = 0.57, 95% CI = 0.29, 1.12, p =0.10 Ardeshna et al., Lancet Oncol. 2014 Apr;15(4):424-35
8 1924 849 187
Events TotalsW+W R4 R4 + M
% of
patients
alive
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Years from randomisation0 1 2 3 4 5
Overall survival
3yr OS=95%
HR (Rituximab vs W+W) = 0.63, 95%CI = 0.21, 1.92, p=0.42
HR (Rituximab + M vs W+W) = 0.84, 95%CI = 0.32, 2.18, p=0.72
HR (Rituximab + M vs Rituximab) = 1.21, 95%CI = 0.37, 3.97, p=0.75 Ardeshna et al., Lancet Oncol. 2014 Apr;15(4):424-35
ESMO Guidelines – Follicular Lymphoma
Dreyling et al., Ann Oncol (2016) 27 (suppl 5): v83-v90
If we have to start treatment
– what should we offer the
patient?
Rituximab
Induction Maintenance
Immunochemotherapy
RITC
onsolid
ation
Diagnosis Diagnostic Work-up (CT etc.)
Watch & Wait
Development of Symptoms
Start of therapy
Personal communication
Therapeutic Algorithms
Rituximab-Chemotherapy is still standard in the
first line and salvage treatment in
follicular lymphoma
Summary
Rituximab-Chemotherapy is still standard in the
first line and salvage treatment in
follicular lymphoma
??
Summary
Obinutuzumab-based induction and
maintenance prolongs progression-free
survival (PFS) in patients with previously
untreated follicular lymphoma: primary results
of the randomized Phase III GALLIUM study
Robert Marcus,1 Andrew Davies,2 Kiyoshi Ando,3 Wolfram Klapper,4 Stephen Opat,5 Carolyn Owen,6
Elizabeth Phillips,7 Randeep Sangha,8 Rudolf Schlag,9 John F Seymour,10 William Townsend,7
Marek Trněný,11Michael Wenger,12 Günter Fingerle-Rowson,13 Kaspar Rufibach,13
Tom Moore,13 Michael Herold,14 Wolfgang Hiddemann15
1Kings College Hospital, London, United Kingdom; 2Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom; 3Tokai
University School of Medicine, Isehara, Kanagawa, Japan; 4University of Kiel, Kiel, Germany; 5Monash Health and Monash University, Melbourne,
Australia; 6Foothills Medical Centre and Tom Baker Cancer Centre, Calgary, AB, Canada; 7Cancer Research UK and UCL Cancer Trials Centre, London,
United Kingdom; 8Cross Cancer Institute, Edmonton, AB, Canada; 9Gemeinschaftspraxis Dr. Rudolf Schlag/Dr. Björn Schöttker, Würzburg, Germany; 10Peter MacCallum Cancer Centre, Melbourne, Australia; 11Charles University, Prague, Czech Republic; 12Genentech Inc, South San Francisco, CA, USA;
13F. Hoffmann-La Roche Ltd, Basel, Switzerland; 14HELIOS-Klinikum, Erfurt, Germany; 15Ludwig-Maximilians-University, Munich, Germany
Study design
International, open-label, randomized Phase III study
*FL and MZL pts were randomized separately; stratification factors: chemotherapy, FLIPI (FL) or IPI (MZL) risk group,
geographic region; †CHOP q3w × 6 cycles, CVP q3w × 8 cycles, bendamustine q4w × 6 cycles; choice by site (FL) or by pt
(MZL); ‡Pts with SD at EOI were followed for PD for up to 2 years; §Confirmatory endpoint
Primary endpoint Secondary and other endpoints
• PFS (INV-assessed in FL) • PFS (IRC-assessed)§
• OS, EFS, DFS, DoR, TTNT
• CR/ORR at EOI (+/− FDG-PET)
• Safety
Previously untreated CD20-
positive iNHL
• Age ≥18 years
• FL (grade 1–3a) or
splenic/nodal/extranodal MZL
• Stage III/IV or stage II bulky
disease (≥7cm) requiring treatment
• ECOG PS 0–2
• Target FL enrolment: 1200
G-chemo
G 1000mg IV on D1, D8, D15 of C1
and D1 of C2–8 (q3w) or C2–6 (q4w)
plus CHOP, CVP, or bendamustine†
R-chemo
R 375mg/m2 IV on D1 of C1–8 (q3w)
or C1–6 (q4w) plus CHOP, CVP,
or bendamustine†
G
G 1000mg IV
q2mo for 2 years or until PD
R
R 375mg/m2 IV
q2mo for 2 years or until PD
Induction Maintenance
Randomized
1:1*
CR or
PR‡
at EOI
visit
Marcus et al. ASH 2016 abstract 6
Response rates at end of induction (FL)*
CT (by investigator)
% (n); 95% CI R-chemo, n=601 G-chemo, n=601
ORR 86.9% (522); 83.9, 89.5 88.5% (532); 85.7, 91.0
CR 23.8% (143); 20.4, 27.4 19.5% (117); 16.4, 22.9
PR 63.1% (379) 69.1% (415)
SD 1.3% (8) 0.5% (3)
PD 4.0% (24) 2.3% (14)
Not evaluable / missing 3.5% (21) / 4.3% (26) 4.0% (24) / 4.7% (28)
Marcus et al. ASH 2016 abstract 6
*INV-assessed using the Revised Response Criteria for Malignant Lymphoma (Cheson BD, et al. J Clin Oncol 2007)
INV, investigator
INV-assessed PFS (FL; primary endpoint)
R-chemo,
n=601
G-chemo,
n=601
Pts with event,
n (%)
144
(24.0)
101
(16.8)
3-yr PFS,
% (95% CI)
73.3
(68.8, 77.2)
80.0
(75.9, 83.6)
HR (95% CI),
p-value*
0.66 (0.51, 0.85),
p=0.0012
Median follow-up: 34.5 months
0.8
0.6
0.4
0.2
0
1.0
Pro
babili
ty
R-chemo (N=601)
G-chemo (N=601)
+
Time (months)
12 18 24 30 36 42 48 5460
No. of patients at risk
R-chemo
G-chemo
505
536
463
502
378
405
266
278
160
168
68
75
10
13
562
570
601
601
0
0
Censored
Marcus et al. ASH 2016 abstract 6*Stratified analysis; stratification factors: chemotherapy regimen, FLIPI risk group, geographic region
TTNT (FL)
Median follow-up: 34.5 months
0.8
0.6
0.4
0.2
0
1.0
Pro
babili
ty
+
Time (months)
12 18 24 30 36 42 48 6060 54
No. of patients at risk
R-chemo
G-chemo525
551
503
539
475
519
352
385
231
249
131
145
47
51
565
574
601
601
2
0
0
0
Censored
R-chemo (N=601)
G-chemo (N=601)
R-chemo,
n=601
G-chemo,
n=601
Pts with event,
n (%)
111
(18.5)
80
(13.3)
3-yr TTNT,
% (95% CI)
81.2
(77.6, 84.2)
87.1
(84.0, 89.6)
HR (95% CI),
p-value*
0.68 (0.51, 0.91),
p=0.0094
Marcus et al. ASH 2016 abstract 6*Stratified analysis; stratification factors: chemotherapy regimen, FLIPI risk group, geographic region
OS (FL)
R-chemo,
n=601
G-chemo,
n=601
Pts with event,
n (%)
46
(7.7)
35
(5.8)
3-yr OS,
% (95% CI)
92.1
(89.5, 94.1)
94.0
(91.6, 95.7)
HR (95% CI),
p-value*
0.75 (0.49, 1.17),
p=0.21
Marcus et al. ASH 2016 abstract 6
Median follow-up: 34.5 months
*Stratified analysis; stratification factors: chemotherapy regimen, FLIPI risk group, geographic region
Pts at risk, n
R-chemo
G-chemo
588
584
566
573
527
549
399
416
265
271
160
161
58
55
2549
563
12 18 24 30 36 42 48 546 60
0.8
0.6
0.4
0.2
0
1.0
Pro
ba
bili
ty
0
R-chemo (N=601)
G-chemo (N=601)
Censored+
601
601
Time (months)
Bendamustine CHOP CVP
HR (95% CI)† 0.63 (0.46, 0.88)
3-yr PFS84.1% G-B vs
76.4% R-B
HR (95% CI)† 0.72 (0.48, 1.10)
3-yr PFS80.6% G-CHOP vs
75.6% R-CHOP
HR (95% CI)† 0.79 (0.42, 1.47)
3-yr PFS71.3% G-CVP vs
64.2% R-CVP
341
345
285
305
250
276
163
179
52
61
1.0
0.8
0.6
0.4
0.2
0
Pro
ba
bil
ity
0 12 24 36 48 60Time (months)
203
196
179
174
152
153
84
84
20
18 1
1.0
0.8
0.6
0.4
0.2
0P
rob
ab
ilit
y0 12 24 36 48 60
Time (months)57
60
41
56
36
49
20
28
5
6
1.0
0.8
0.6
0.4
0.2
0
Pro
ba
bil
ity
0 12 24 36 48 60Time (months)
R-chemo (n=341)
G-chemo (n=345)
R-chemo (n=203)
G-chemo (n=196)
R-chemo (n=57)
G-chemo (n=60)
Hiddemann W, et al. Hematol Oncol, 35(S2): 117–119 (ICML 2017)
GALLIUM in FL: INV-assessed PFS by
chemotherapy
Safety summary (FL)
*As MedDRA preferred term; †All events in MedDRA System Organ Class ‘Infections and Infestations’; ‡Any AE occurring during
or within 24h of infusion of G or R and considered drug-related; §Standardized MedDRA query for malignant or unspecified tumors
starting 6 mo after treatment start; ¶Ig levels were measured during screening, at EOI and end of maintenance and during follow-
up; **Includes patient who died after clinical cut-off date from AE starting before cut-off date; ††n=472; ‡‡n=462
% (n)
R-chemo
(n=597)
G-chemo
(n=595)
Any AE 98.3% (587) 99.5% (592)
Grade ≥3 AEs (≥5% in either arm) 67.8% (405) 74.6% (444)
Neutropenia 37.9% (226) 43.9% (261)
Leucopenia 8.4% (50) 8.6% (51)
Febrile neutropenia 4.9% (29) 6.9% (41)
IRRs* 3.7% (22) 6.7% (40)
Thrombocytopenia 2.7% (16) 6.1% (36)
Grade ≥3 AEs of special interest by category (selected)
Infections† 15.6% (93) 20.0% (119)
IRRs‡ 6.7% (40) 12.4% (74)
Second neoplasms§ 2.7% (16) 4.7% (28)
SAEs 39.9% (238) 46.1% (274)
AEs causing treatment discontinuation 14.2% (85) 16.3% (97)
Grade 5 (fatal) AEs 3.4% (20) 4.0% (24)**
Median (range) change from baseline in IgG levels at end of induction,
g/l¶-1.46 (-16.4–9.1)†† -1.50 (-22.3–6.5) ‡‡
Marcus et al. ASH 2016 abstract 6
Grade 5 (fatal) AEs by treatment (FL)*
Marcus et al. ASH 2016 abstract 6
Marcus et al. ASH 2016 abstract 6
Low T-cell count at baseline
R-benda,
n=341
G-benda,
n=345
R-CHOP,
n=203
G-CHOP,
n=196
R-CVP,
n=57
G-CVP,
n=60
CD3+/CD4+ cell count of ≤200/mm3 36 (12.5%) 36 (11.4%) 12 (7.2%) 9 (5.1%) 2 (4.4%) 4 (7.4%)
Bendamustine
CD
3+ C
D4+
(ce
lls/µ
l)
Mo
30
Mo
36
Mo
18
EO
I
C4
/C5
C1
/C2
BL
Mo
30
Mo
36
Mo
18
EO
I
C4
/C5
C1
/C2
BL
Mo
30
Mo
36
Mo
18
EO
I
C4
/C5
C1
/C2
BL Horizontal grey lines =
upper and lower limit of
normal
Mo
30
Mo
36
Mo
18
Mo
30
Mo
36
Mo
18
EO
I
C4
/C5
C1
/C2
BL
Mo
30
Mo
36
Mo
18
EO
I
C4
/C5
C1
/C2
BL
Mo
30
Mo
36
Mo
18
EO
I
C4
/C5
C1
/C2
BL
Mo
30
Mo
36
Mo
18
CD
3+ C
D4+
(ce
lls/µ
l)
CHOP CVP
Bendamustine CHOP CVP
CD3 + CD4+
Visit
Visit
C4
/C5
C1
/C2
BL
CD3 + CD8+
T-cell counts over time
RELEVANCE: Phase III Efficacy and Safety Study of Lenalidomide Plus Rituximab (R2) vs Rituximab Plus Chemotherapy (R-chemo), Followed by Rituximab,
in Previously Untreated Follicular Lymphoma
Franck Morschhauser, MD;1* Nathan H. Fowler, MD2* (*co-primary authors); Pierre Feugier, MD;3 Reda Bouabdallah, MD;4 Hervé Tilly, MD;5 M. Lia Palomba, MD;6
Christophe Fruchart, MD;7 Edward N. Libby, MD;8 Rene-Olivier Casasnovas, MD;9 Ian Flinn, MD;10 Corinne Haioun, MD;11 Hervé Maisonneuve, MD;12 Loic Ysebaert, MD;13
Nancy Bartlett, MD;14 Kamal Bouabdallah, MD;15 Pauline Brice, MD;16 Vincent Ribrag, MD;17 Nicolas Daguindau, MD;18 Steven Le Gouill, MD;19 Gian Matteo Pica, MD;20
Alejandro Martin Garcia-Sancho, MD, PhD;21 Armando López Guillermo, MD;22 Jean-François Larouche, MD;23 Kiyoshi Ando, MD, PhD;24 Maria Gomes da Silva, MD, PhD;25 Marc Andre, MD;26 Pierre Zachée, MD;27 Laurie H. Sehn, MD;28 Kensei Tobinai, MD;29 Guillaume Cartron, MD, PhD;30 David Liu, MD, PhD;31 Jianming Wang, PhD;31
Luc Xerri, MD, PhD;32 and Gilles A. Salles, MD, PhD;33 on behalf of the RELEVANCE Trial Investigators
1Centre Hospitalier Universitaire Régional de Lille, Unité GRITA, Department d’ Hematologie, Lille, France; 2The University of Texas MD Anderson Cancer Center, Department of Lymphoma and Myeloma, Houston, TX, USA; 3Centre Hospitalier Universitaire Régional de Nancy, Service d'Hématologie, Vandoeuvre les Nancy, France; 4Institut Paoli Calmettes, Department d’ Hematologie, Marseille, France; 5Centre Henri Becquerel, Department d’ Hematologie, Rouen, France; 6Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, NY, USA; 7Institut d'Hématologie de Basse Normandie, Caen, France; 8University of Washington, Department of Medicine, Seattle, WA, USA; 9CHU
Le Bocage Service d'Hématologie Clinique, Dijon, France; 10Sarah Cannon Research Institute, Nashville, TN, USA; 11Hôpital Henri Mondor Unité Hémopathies Lymphoïdes, Creteil, France; 12CHD Vendée Service d'Onco-Hématologie, Cedex, France; 13IUCT Oncopole Service d'Hématologie, Cedex, France; 14Washington University School of Medicine, Siteman Cancer Center Hematology Labs, St. Louis, Missouri, USA; 15Hôpital Haut Lévêque - Centre François
Magendie Service d'Hématologie Clinique et Thérapie Cellulaire, Cedex, France; 16Hôpital Saint Louis Service d'Onco-Hématologie, Cedex, France ; 17Gustave Roussy Cancer, Cedex, France; 18Centre Hospitalier Annecy Genevois Service d'Hématologie, Cedex, France; 19CHU de Nantes - Hôtel Dieu Service d'Hématologie Clinique, Nantes, France ; 20CH Métropole Savoie Service Hématologie, Chambery, France; 21Hospital Universitario de Salamanca and IBSAL,
CIBERONC, Department of Hematology, Salamanca, Spain; 22Hospital Clinic de Barcelona, Department of Hematology, Barcelona, Spain; 23CHU de Québec, Hôpital de l’Enfant-Jésus, Québec, Canada; 24Tokai University Hospital, Department of Hematology and Oncology, Kanagawa, Japan; 25Instituto Português de Oncologia Lisboa Francisco Gentil (IPOLFG) Departamento de Hematologia, Lisboa, Portugal; 26CHU UCL Namur, Hematology Department,
Yvoir, Belgium; 27ZNA Stuivenberg, Department of Hematology, Antwer, Belgium; 28British Columbia Cancer Centre for Lymphoid Cancer, University of British Columbia, Vancouver, Canada; 29Department of Hematology, National Cancer Center Hospital, Tokyo, Japan; 30Department of Hematology, CHU Montpellier, University of Montpellier, Montpellier,France; 31Celgene Corporation, Summit, NJ, USA; 32Departement de Bio-pathologie, Institut Paoli-
Calmettes, Marseilles, France; and 33Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, University of Lyon, Pierre-Benite, France
RELEVANCE: Study Design
NCT01476787; NCT01650701; EUDRA 2011-002792-42. *Per central (IRC) review by 1999 IWG with CT.
1. Salles et al. Lancet. 2011;377:42-51. 2. Brice et al. J Clin Oncol. 1997;15:1110-1117. 3. Shi et al. J Clin Oncol. 2017;35:552-560
Co-primary endpoints (superiority)*
• CR/CRu at 120 weeks
• PFS
R2 R2 Rituximab
R-chemo(R-CHOP, R-B,
R-CVP)
RituximabStratification•FLIPI score (0-1 vs 2 vs 3-5)•Age (> 60 vs ≤ 60 years)•Lesion size (> 6 vs ≤ 6 cm)
Treatment Period 1(~6 months)
Treatment Period 2(~1 year)
Treatment Period 3(~1 year)
Total Treatment Duration: 120 weeks
1:1
n = 513
n = 517
Previously untreated patients with advanced FL
requiring treatment per GELF1,2 (N = 1030)
• Selection of CR/CRu at 120 weeks was based on FLASH analysis and identification of CR30 as a surrogate endpoint for PFS3
RELEVANCE: Dosing Schedule
Treatment Period
R2 Arm R-Chemo Arm
1 (~6
months)
• Lenalidomide*: 20 mg/d, d2-22/28
• Rituximab: 375 mg/m2/wk cycle 1; day 1 cycles 2-6
Investigator/patient choice prior to randomization • R-CHOP (72%) 6 cycles + 2 cycles R only• R-B (23%) 6 cycles• R-CVP (5%) 8 cycles• Note: Rituximab dose 375 mg/m2 d1 of each cycle
2(~1 year)
• Lenalidomide: 20 or 10 mg/d (if CR or latest after 12 months) at 6, 9 or 12 cycles
• Rituximab: 375 mg/m2 q8wk
• Rituximab†: 375 mg/m2 q8wk
3(~1 year)
• Rituximab†: 375 mg/m2 q8wk • Rituximab†: 375 mg/m2 q8wk
*Lenalidomide was given at 10 mg/d if creatinine clearance was ≥30 to <60 mL/min. †Rituximab was continued in responders after initial combination treatment.
RELEVANCE: Baseline Characteristics (ITT)
Characteristics, n (%) R2 (n = 513) R-chemo (n = 517)
Median age, years (range) 59 (30-89) 59 (23-83)
Age > 70 years 80 (16) 78 (15)
Male 251 (49) 251 (49)
ECOG PS
0 341 (66) 345 (67)
1 157 (31) 157 (30)
2 13 (3) 14 (3)
Not evaluated 2 (< 1) 1 (< 1)
Ann Arbor stageI/II 30 (6) 40 (8)
III/IV 483 (94) 477 (92)
Bulky disease (> 7 cm) 218 (42) 199 (38)
FL grade*1 or 2 437 (85) 443 (86)
3a 65 (13) 63 (12)
FLIPI score
Low risk (0-1) 77 (15) 76 (15)
Intermediate risk (2) 183 (36) 191 (37)
High risk (3-5) 253 (49) 250 (48)
Lactate dehydrogenase (> ULN) 156 (30) 137 (26)
B-symptoms - yes 141 (27) 134 (26)Data cut-off 31May2017. *FL grade was unspecified or not FL grade 1-3a for 11 patients in each arm. ECOG PS, Eastern Cooperative Oncology Group performance status; FLIPI, FL International Prognostic Index; ULN, upper limit of normal.
RELEVANCE: Response by IRC (ITT)
R2
(n = 513)R-chemo(n = 517)
Co-Primary Endpoint: CR/CRu at 120 weeks Best CR/CRu Best ORR
48% 53%
0%
20%
40%
60%
80%
100%
Re
sp
on
se
, % 59%
67%
0%
20%
40%
60%
80%
100%
Re
sp
on
se
, %
84%89%
0%
20%
40%
60%
80%
100%
Re
sp
on
se
, %
R2
(n = 513)R-chemo(n = 517)
R2
(n = 513)R-chemo(n = 517)
P = 0.13
3-year DOR was 77% for R2 vs 74% R-chemo (IRC)
Investigator results were consistent with IRC
Data cut-off 31May2017.
RELEVANCE: Interim PFS By IRC
Data cut-off 31May2017.
• At a median follow-up of 37.9 months, interim PFS was similar in both arms
R2
(n = 513)
R-chemo
(n = 517)
Events, n (%) 119 (23) 111 (21)
3-year PFS (95% CI) 77% (72%-80%) 78% (74%-82%)
HR (95% CI) 1.10 (0.85-1.43)P value 0.48
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
PF
S P
rob
abil
ity
(IR
C)
R2
R-chemo
Months from Randomization0 6 12 18 24 30 36 42 48 54 60 66
513 435 409 393 364 282 174 107 49 0R2
Number of Patients at Risk
517 474 446 417 387 287 175 109 51 1 0R-chemo1314
Co-Primary Endpoint: Interim PFS (~50% events)
RELEVANCE: Prespecified Subgroup Analysis of Interim PFS (IRC)
R2, n/N R-chemo, n/N HR (95% CI)
Overall 119/513 115/517 1.10 (0.85-1.43)
Age
≤ 60 58/281 55/282 1.15 (0.79-1.66)
> 60 61/232 56/235 1.06 (0.74-1.53)
Sex
Male 61/251 59/251 1.02 (0.71-1.46)Female 58/262 52/266 1.23 (0.85-1.79)
Disease stage
I/II 6/30 5/40 2.23 (0.66-7.55)
III/IV 113/483 106/477 1.06 (0.82-1.39)
Longest diameter of the longest node
≤ 6 cm 62/253 58/271 1.19 (0.83-1.71)
> 6 cm 57/260 53/246 1.04 (0.71-1.51)
FLIPI score
0-1 14/77 9/76 2.06 (0.88-4.80)
2 37/183 35/191 1.12 (0.70-1.78)
3-5 68/253 67/250 1.00 (0.72-1.41)
Country
Ex-North America 93/384 92/379 1.03 (0.77-1.38)
North America 26/129 19/138 1.53 (0.84-2.76)
0.1 0.2 0.5 1 2 5 10
Favors R2 Favors R-chemo
Post-hoc analysis showed no differences between R2 and the three R-chemo regimens
Data cut-off 31May2017.
RELEVANCE: Overall Survival (Immature; ITT)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
OS
Pro
bab
ilit
y
R2
R-chemo
Months from Randomization
0 6 12 18 24 30 36 42 48 54 60 66
513 499 491 486 479 459 312 194 105 0R2
Number of Patients at Risk
517 496 487 481 470 453 298 193 115 2 0R-chemo
24
32
R2
(n = 513)
R-chemo
(n = 517)
Events, n (%) 38 (7) 31 (6)
3-year OS (95% CI) 94% (91%-96%) 94% (91%-96%)
HR (95% CI) 1.16 (0.72-1.86)
• At a median follow-up of 37.9 months, OS was similar in both arms
Data cut-off 31May2017.
RELEVANCE: Treatment-Emergent Adverse Events
Data cut-off 31May2017. Includes any-grade TEAEs (≥15%) and select AEs of interest as assessed per NCI CTCAE v4.03.
*Hematologic AEs were based on laboratory tests; all anemia events were grade 1. Cutaneous reactions included preferred terms from skin and subcutaneous tissue disorders
(including rash), gastrointestinal disorders, general disorders and administration site conditions, infections and infestations, and reproductive system and breast disorders.
TEAEs for R2 (n = 507), % TEAEs for R-chemo (n = 503), %
Grade 3/4Any grade
020406080100
Any event
Neutropenia*
Anemia*
Thrombocytopenia*
Nausea
Constipation
Fatigue
Asthenia
Cutaneous reactions*
- Rash
Diarrhea
Vomiting
Bronchitis
Peripheral neuropathy
Pyrexia
Cough
Back pain
Abdominal pain
Pruritus
Alopecia
Febrile neutropenia
Tumor flare reaction
Tumor lysis syndrome
TEAEs, %
0 20 40 60 80 100
TEAEs, %
What to do now? A formally negative
Study, but………..
The optimist says the glass is half full;
for the pessimist, the glass is half
empty.
-- Ibrutinib?
Ibrutinib Plus Rituximab in Treatment-Naïve Patients with Follicular Lymphoma: Results from a Multicenter,
Phase 2 Study
Nathan H. Fowler, MD1, Loretta Nastoupil, MD1, Sven De Vos, MD, PhD2, Mark Knapp, MD3, Ian W. Flinn, MD, PhD4, Robert Chen, MD5, Ranjana H. Advani, MD6,
Sumeet Bhatia, MD7, Peter Martin, MD8, Raul Mena, MD9, Samuel Suzuki, MS, MBA10, Darrin M. Beaupre, MD, PhD10, Jutta K. Neuenburg, MD, PhD10, M. Lia Palomba, MD11
1University of Texas MD Anderson Cancer Center, Houston, TX; 2David Geffen School of Medicine at UCLA, Los Angeles, CA; 3Mid Ohio Oncology/Hematology, Inc., Columbus, OH; 4Sarah Cannon Research Institute, Nashville, TN; 5City
of Hope National Medical Center, Duarte, CA; 6Stanford University School of Medicine, Stanford, CA; 7Community Health Network, Indianapolis, IN; 8Weill Cornell Medical College, New York, NY; 9Providence Saint Joseph Medical Center/Disney
Family Cancer Center, Burbank, CA; 10Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA; 11Memorial Sloan Kettering Cancer Center, New York, NY
Fowler et al., ASH 2016; abstract 1804
Study Schema
until disease
progression or
unacceptable
toxicity
Data from Arm 1 presentedArm 1: Main Study (N=60)
rituximab 375 mg/m2
IV q week × 4
Imaging every 12 weeks for 72 weeks, then every 24 weeks
12 weeks 24 weeks 36 weeks
Arm 2: Exploratory Arm (N=20)
2 monthlead-in
Imaging at 8 weeks, then every 12 weeks for 68 weeks (6x), and then every 24 weeks
20 weeks 32 weeks
until disease
progression or
unacceptable
toxicity
rituximab 375 mg/m2
IV q week × 4
8 weeks
ibrutinib 560 mg PO continuously
ibrutinib 560 mg PO continuously
Fowler et al., ASH 2016; abstract 1804
• Median time on study (range):
22 months (5.8-27.6)
• Median treatment duration (range):
20 months (0.8, 27.6)
• Median time to best response (range):
2.7 months (1.1, 16.5)
• Median time to initial response (range):
2.8 months (1.1, 19.0)
Best Response – Arm 1 (n=60)
Fowler et al., ASH 2016; abstract 1804
ALTERNATIVE
A prospective multicenter Phase 2
Study of the Chemotherapy-free
Combination of the Bruton's Tyrosine
Kinase Inhibitor, PCI-32765
(Ibrutinib) in Combination with
Obinutuzumab (GA 101) in Patients with
Previously Untreated Follicular
Lymphoma (FL) and a High Tumor Burden
TREATMENT
6 cycles
Ibrutinib 560mg +
Obinutuzumab 1000mg
MAINTENANCE TREATMENT
Ibrutinib 560mg/d
+ Obinutuzumab 1000mg
q8w
(for 2 years)
MRD-BASED MAINTENANCE
1 year additional
Ibrutinib treatment for
patients remaining
MRD-positive after
maintenance
TIMELINE
First patient in:
Apr 2016
End of recruitment May
2017
Primary Endpoint May
2018
End of follow up
Dec. 2022
Primary Endpoint: 1-year PFS
End of induction (n=97)
ORR: 90% (CR 5% / PR 85%)
SD: 5%
PD: 5%
After 1 year (n=95)
ORR: 77% (CR 13% / PR 64%)
SD: 3%
PD: 17%
Death: 3%
HypothesisHypothesis
PFS similar to R-
CHEMO?
ESMO
GUIDELINES FL
Some progess,
But still a lot of
chemotherapy!
Dreyling et al., 2016
ESMO
GUIDELINES FL
Dreyling et al., 2016
Relapsed FL
GADOLIN: Study Design
iNHL, indolent non-Hodgkins lymphoma; G-B, obinutuzumab plus bendamustine; G, obinutuzumab
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
Bendamustine
120 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
• 81% (n=321) of 396 iNHL pts enrolled had FL
• Response monitored by CT scan post-induction, then every 3 months for 2 years, then every 6 months
(modified Cheson criteria 2007)
Sehn et al, J Clin Oncol 33, 2015 (suppl; abstr LBA8502)
GADOLIN: Patient characteristics
79.9 82.2
13.9 9.4
6.2 7.9
0.5
0
20
40
60
80
100
G-B(n=194)
B(n=202)
Lymphoma subtype
WM
SLL
MZL
FL
19.6 22.3
80.4 77.7
0
20
40
60
80
100
G-B(n=194)
B(n=202)
Rituximab-refractory type
R-chemotherapycombination*
R-monotherapy
FL, follicular lymphoma; MZL, marginal zone lymphoma including extranodal, nodal and splenic;
SLL, small lymphocytic lymphoma; WM, Waldenström macroglobulinemia
Pa
tie
nts
(%
)
Pa
tie
nts
(%
)
* Including patients who relapsed during R-maintenance
within or after 6 months after R-chemotherapy induction
Sehn et al, J Clin Oncol 33, 2015 (suppl; abstr LBA8502)
GADOLIN: AEs
AE, adverse event; SAE, serious adverse event
98.5
38.118.0 49.5
67.0
6.2
98.0
32.815.7 41.4
62.1
6.1
0
20
40
60
80
100
Pat
ien
ts (
%)
G-B (n=194)
B (n=198)
≥1 AEs ≥1 SAEs ≥1 AEs leading to
withdrawal of any
treatment
≥1 AEs leading to
dose modification≥1 grade
3–4 AEs
AE leading to
death
Sehn et al, J Clin Oncol 33, 2015 (suppl; abstr LBA8502)
GADOLIN: Serious adverse events
* Multiple occurrences of same SAE in an individual were only counted once
** SAEs with ≥2.5% incidence
*** SAEs occurring during or within 24 hours after an infusion and considered to be
related to any study drug
* Multiple occurrences of same SAE in an individual were only counted once
SAE, n (%)*
G-B
(n=194)
B
(n=198)
Febrile neutropenia 8 (4.1) 6 (3.0)
Neutropenia 6 (3.1) 1 (0.5)
Thrombocytopenia 4 (2.1) 0
Anemia 3 (1.5) 3 (1.5)
Leukopenia 0 1 (0.5)
SAEs, n (%)*
G-B
(n=194)
B
(n=198)
IRR*** 8 (4.1) 3 (1.5)
Sepsis 6 (3.1) 7 (3.5)
Pneumonia 5 (2.6) 10 (5.1)
Pyrexia 5 (2.6) 3 (1.5)
Sehn et al, J Clin Oncol 33, 2015 (suppl; abstr LBA8502)
Hematological AEs Non-hematological AEs**
IRR, infusion related reaction
11.7 18.59.0
9.010.19.5
58.0 50.8
11.2 12.2
0
20
40
60
80
100
G-Bn=188
Bn=189
Pati
en
ts (%
)
GADOLIN: Response
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 7.64.7 4.1
10.9 11.7
62.0 59.4
16.7 17.3
0
20
40
60
80
100
G-Bn=192**
Bn=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)*
Sehn et al, J Clin Oncol 33, 2015 (suppl; abstr LBA8502)
GADOLIN: Primary endpoint PFS (IRC)
IRC, independent review committee
Time from randomisation (months)
Median PFS not reached
Median PFS 14·9 months
HR 0·55 [95% CI 0·40–0·74]; p=0·0001
Sehn et al, Lancet Oncol. 2016 Aug;17(8):1081-93
GADOLIN: PFS according to subgroups
Subgroup
Total
n
G-B (n=194) B (n=202) Hazard ratio
(95%CI)n Events n Events
Follicular lymphomaYesNo
32175
15539
5417
16636
9014
0.49 (0.35–0.68)0.94 (0.46–1.90)
No. of prior therapies≤2>2
31284
15440
5120
15844
8321
0.49 (0.34–0.69)0.80 (0.43–1.48)
Refractory typeRituximab + chemotherapyRituximab monotherapy
31383
15638
5714
15745
8222
0.55 (0.39–0.77)0.55 (0.28–1.08)
SexMaleFemale
228168
11084
4130
11884
5747
0.58 (0.39–0.87)0.52 (0.33–0.83)
Bulky disease at BLYes (>6 cm)No (≤6 cm)
136257
66128
2744
70129
3767
0.63 (0.38–1.04)0.51 (0.35–0.75)
B symptoms at BLYesNo
58335
30163
1259
28172
1687
0.57 (0.27–1.22)0.55 (0.40–0.77)
Double refractory statusYesNo
31185
14747
5516
16438
8717
0.56 (0.40–0.78)0.55 (0.28–1.10)
0.05 0.1 0.2 0.5 1 2 5 10 20
Favors
G-B
Favors
B
Hazard ratio (95%CI)
Sehn et al, J Clin Oncol 33, 2015 (suppl; abstr LBA8502)
GADOLIN:
PFS according to “Rituximab-refractory type”
Subgroup
Total
n
G-B (n=194) B (n=202) Hazard ratio
(95%CI)n Events n Events
IRF-assessed
Refractory to
R-mono
R-chemo induction
R-maintenance after
(R)chemo induction
83
162
146
38
76
76
14
29
28
45
86
70
22
42
39
0.55 (0.28–1.08)
0.59 (0.36–0.95)
0.57 (0.35–0.93)
Investigator-assessed
Refractory to
R-mono
R-chemo induction
R-maintenance after
(R)chemo induction
83
162
146
38
76
76
12
33
31
45
86
70
23
48
43
0.49 (0.24–0.98)
0.57 (0.37–0.89)
0.56 (0.35–0.89)
0.05 0.1 0.2 0.5 1 2 5 10 20
Favors
G-B
Favors
B
Hazard ratio (95%CI)
Sehn et al, J Clin Oncol 33, 2015 (suppl; abstr LBA8502)
No. of patients at risk
B
G-B
0.8
0.6
0.4
0.2
0
1.0
Pro
ba
bili
ty
137
141
122
129
103
111
84
90
65
71
49
56
159
147
171
164
Months12 18 24 30 36 42 48 6660
B (n=171)
G-B (n=164)
Censored+
54
32
38
7
12
60
13
20
0
0
Kaplan-Meier Plot OS for FL pts
Data Cut P-value C.I. HR
Sept `14 0,20 0,43-1,19 0,71
May `15 0,04 0,39-0,98 0,62
April `16 0,0061 0,39-0,86 0,58
GADOLIN FL: OS – April 2016
1. Cheson BD et al. ASH 2016; Abstract 615, oral presentation. * Der OS-Vorteil ist zum jetzigen Zeitpunkt noch nicht quantifizierbar, da der Median hier noch
nicht erreicht ist. Allerdings weisen die Daten der aktuellen Zwischenauswertung von GADOLIN darauf hin, dass der OS-Vorteil bei mindestens 3,2 Jahren liegt.
https://www.g-ba.de/informationen/nutzenbewertung/131/#tab/beschluesse.
Gopal et al., NEJM 2014;370:1008-18
Study Design and Patient Characteristics
Study 101-09 (Phase 2)
N=125
Continuous therapy
Idelalisib 150 mg BID
Week 0 48
Long-term Follow-upStudy 101-09
Therapy maintained until progression
Baseline Patient Characteristics N=125
Male/female, n (%) 80/45 (64/36)
Median age, y (range) 64 (33–87)
Disease type, n (%)
FL 72 (58)
SLL 28 (22)
MZL 15 (12)
LPL/WM 10 (8)
Lactate dehydrogenase >ULN, n (%) 38 (30)
Bulky disease [>7 cm], n (%) 33 (26)
Neutropenia [ANC <1500 cells/μL], n
(%)
17 (14)
Anemia [Hb <10 g/dL], n (%) 19 (15)
Thrombocytopenia [platelets
<75,000/μL], n (%)
10 (8)
Prior Therapy Exposure at Baseline N=125
Median prior regimens, n (range) 4 (2–12)
Prior therapy, n (%)
Rituximab 125 (100)
Alkylating agent 125 (100)
Bendamustine 81 (65)
Anthracycline 80 (64)
Purine analog 42 (33)
Stem-cell transplantation 14 (11)
Median time from last regimen to study entry, mo 3.9
‡
Gopal et al., NEJM 2014;370:1008-18
Overall Response Rate and By Disease Subgroups
Study 101-09 (Phase 2)
June 2013
Complete Response Stable Disease Progressive Disease Not evaluablePartial Response Minor Response
June 2014
n=2
47%
n=59
33%
n=41
57%
Overall
Response
n=71/125
(95% CI:
47.6–65.6)
50%
n=63
34%
n=42
10%n=12
6%n=7
1%n=1*
2%n=22%
8%n=10
1%n=1*
58%
Overall
Response
n=72/125
(95% CI:
48.4–66.4)
8%n=10
*LPL/WM patient.
0% 20% 40% 60% 80% 100%
FLn=72
56% (43–67)
ORR, % (95% CI)
14%n=10
42%n=30
32%n=23
8%n=11
SLLn=28
MZLn=15
LPL/WMn=10
61% (41–79)
47% (21–73)
80% (44–98)
57%
n=16
40%n=6
70%n=7
10%n=1
36%
n=10
47%n=7
10%n=1
10%n=1
4%
n=1
1%n=1
4%
n=1
7%n=1
7%n=1
CompleteResponse
StableDisease
ProgressiveDisease
Notevaluable
PartialResponse
MinorResponse
Overall Response Rate By Disease Subgroups: 2014
‡
Gopal et al., NEJM 2014;370:1008-18
Adverse Events
Study 101-09 (Phase 2)
AE Occurring in >15%, n (%) Any Grade Grade ≥3
Diarrhea/colitis 63 (50) 24 (19)
Cough 40 (32) 0
Nausea 39 (31) 2 (2)
Fatigue 38 (30) 2 (2)
Pyrexia 38 (30) 4 (3)
Dyspnea 23 (18) 6 (5)
Decreased appetite 23 (18) 1 (1)
Abdominal pain 21 (17) 3 (2)
Upper respiratory infection 21 (17) 0
Vomiting 20 (16) 3 (2)
Decreased weight 19 (15) 0
Hematologic Lab
Abnormalities
Patients, n (%)
Any Grade
Baseline On Study Baseline On Study
Neutrophils decreased 29 (23) 71 (57) 7 (6) 35 (28)
Hb decreased 64 (51) 41 (33) 1 (1) 3 (2)
Platelets decreased 43 (34) 36 (29) 4 (3) 10 (8)
‡
Gopal et al., NEJM 2014;370:1008-18
Adverse events (cont’d)
71
AE, n (%) Any Grade Grade ≥3
Diarrhea/colitis 18 (42) 7 (16)
Pyrexia 11 (26) 2 (5)
Cough 9 (21) 0
Pneumonia 7 (16) 6 (14)
Upper respiratory infection 7 (16) 0
Nausea 6 (14) 0
Dyspnea 5 (12) 3 (7)
Vomiting 4 (9) 3 (7)
Adverse Events Occurring >1 year Idelalisib Exposure, n=43
Study 101-09 (Phase 2) ‡
• Grade ≥3 was reversible with drug interruption• 15 of 18 patients with Grade ≥3 were rechallenged
• 11 (73%) did not have recurrence of Grade ≥3• 4 (27% had recurrence
ALT/AST Elevations
Patients, n (%) Grades 1-2 Grade 3 Grade 4
ALT/AST elevation 45 (36) 15 (10) 3 (2)
Gopal et al., NEJM 2014;370:1008-18
Relapsed FL – New developments?
ABSTRACT 445
AUGMENT: A Phase III Randomized Study of Lenalidomide Plus Rituximab (R2) vs Rituximab/Placebo in Patients With
Relapsed/Refractory Indolent Non-Hodgkin Lymphoma
John P. Leonard,1 Marek Trneny,2 Koji Izutsu,3 Nathan H. Fowler,4 Xiaonan Hong,5 Jun Zhu,6 Huilai Zhang7 Fritz Offner,8 Adriana Scheliga,9
Grzegorz Nowakowski,10 Antonio Pinto,11 Francesca Re,12 Laura Maria Fogliatto,13 Phillip Scheinberg,14 Ian Flinn,15 Claudia Moreira,16
David Liu,17 Stacey Kalambakas,17 Chengqing Wu,17 Pierre Fustier,18 and John G Gribben,19
on behalf of the AUGMENT study investigators
1Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; 2Charles University Hospital, Prague, Czech Republic ; 3National Cancer Center Hospital, Tokyo, Japan; 4The University of Texas MD Anderson Cancer Center, Houston, TX; 5Fudan University Shanghai Cancer Center, Shanghai, China; 6Beijing Cancer Hospital, Beijing, China; 7Tianjin Medical University
Cancer Institute and Hospital, Tianjin, China; 8UZ Gent, Gent, Belgium; 9INCA Instituto Nacional De Câncer, Rio de Janeiro, Brazil; 10Mayo Clinic, Rochester, MN; 11Istituto Nazionale Per Lo Studio E La
Cura Dei Tumori Fondazione Giovanni Pascale, Napoli, Italy; 12Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; 13Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil; 14 Division of Hematology, Hospital A Beneficência Portuguesa, São Paulo, Brazil; 15SCRI Tennessee Oncology Nashville, Nashville, TN; 16Instituto Português de Oncologia Do Porto Francisco Gentil Epe,
Porto, Portugal; 17Celgene Corporation, Summit, NJ; 18Celgene Corporation, Boudry, Switzerland; 19Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom
STUDY DESIGN: RANDOMIZED DOUBLE BLIND PHASE III TRIAL
• Primary endpoint: PFS by IRC (2007 IWG criteria w/o PET)
Stratification
• Prior rituximab (yes vs no)
• Time since last therapy (≤ 2 vs > 2 y)
• Histology (FL vs MZL)
Key eligibility criteria
• MZL or FL (grades 1-3a) in need of
treatment
• ≥ 1 prior chemotherapy, immunotherapy
or chemoimmunotherapy
• Not rituximab refractory
R-lenalidomide (R2)Rituximab: 375 mg/m2 d1, 8, 15, 22 of cycle 1; d1 of cycles 2-5
Lenalidomide: 20 mg/d*, d1-21/28 (12 cycles)
R-placeboRituximab: 375 mg/m2 d1, 8, 15, 22 of cycle 1; d1 of cycles 2-5
Placebo: matched capsules (12 cycles)
≤ 12 cycles or until PD, relapse, or intolerability
1:1
Relapsed/refractory
FL and MZL
(N = 358)*10 mg if CrCl between 30 to 59 mL/min.
5-year follow-up
for OS, SPMs,
subsequent
treatment, and
histological
transformations
• Prophylactic anticoagulation / antiplatelet Rx recommended for at risk patients
• Growth factor use was allowed per ASCO/ESMO guidelines1,2
NCT01938001
1. Crawford et al. Ann Oncol. 2010;21 Suppl 5:248-251. 2. Smith et al. J Clin Oncol. 2015;33:3199-3212.
SAFETY (AEs IN ≥ 10% OF PATIENTS FOR EITHER GROUP IN THE SAFETY POPULATION)
*Febrile neutropenia occurred in 5 patients (3%) and 1 patient (1%) in the lenalidomide-rituximab and placebo-rituximab groups, respectively. Infections included all preferred terms in infection and infestation system organ class (SOC). Cutaneous reactions included preferred terms from skin and subcutaneous disorders SOC, gastrointestinal disorders SOC, infection and infestation SOC , and general disorders and administration site conditions SOC that are consistent with skin toxicities. Data cutoff June 22, 2018.
PRIMARY ENDPOINT: PROGRESSION-FREE SURVIVAL (ITT, IRC)
Median PFS
R2
(n = 178)
R-placebo
(n = 180) HR (95% CI) P Value
By IRC, mo (95% CI) 39.4 (22.9-NE) 14.1 (11.4-16.7) 0.46 (0.34-0.62) < 0.0001
By investigator, mo (95% CI) 25.3 (21.2-NE) 14.3 (12.4-17.7) 0.51 (0.38-0.69) < 0.0001
PFS by IRC*
Median follow up: 28.3 months
*Censoring rules based on FDA guidance.
Data cutoff June 22, 2018.
Data cutoff June 22, 2018.
PRESPECIFIED SUBGROUP PFS ANALYSIS (IRC, ITT)
OVERALL SURVIVAL IN PATIENTS WITH FL (PRESPECIFIED SUBGROUP ANALYSIS)
• 35 total deaths (11 R2, 24 R-placebo)
• 2-year OS was 95% (95% CI, 90%-98%) for R2 and 86% (95% CI, 79%-91%) for R-placebo
Median follow up: 28.3 months
Data cutoff June 22, 2018.
Abstract no.: 617
Phase 2 Study of Venetoclax plus Rituximab
or Randomized Venetoclax plus
Bendamustine + Rituximab (BR) versus BR in
Patients with Relapsed/ Refractory Follicular
Lymphoma: CONTRALTO Study- Interim Data
Pier Luigi Zinzani1, Max S. Topp2, Sam L.S. Yuen3, Chiara Rusconi4, Isabelle Fleury5,
Barbara Pro6, Giuseppe Gritti7, Michael Crump8, Wanling Hsu9, Elizabeth Punnoose9,
James Hilger9, Mehrdad Mobasher9, Wolfgang Hiddemann10
1. Institute of Hematology “L. e A. Seragnoli”, University of Bologna, Bologna, Italy; 2. Medizinische Klinik und Poliklinik
II, Universitatsklinikum Wurzburg, Germany; 3. Department of Haematology, Calvary Mater Newcastle, NSW Australia;
4. Division of Hematology, Niguarda Hospital, Milan, Italy; 5. Department of Hematology, Maisonneuve-Rosemont
Hospital and University of Montreal, Montreal, Canada; 6. Robert H. Lurie Comprehensive Cancer Center Chicago, Il,
USA; 7. Ospedale Papa Giovanni XXIII, Hematology and BMT Unit, Bergamo, Italy; 8. Princess Margaret Cancer
Centre, University of Toronto, Toronto, Canada; 9. Genentech, Inc., South San Francisco, CA, USA; 10. Department of
Internal Medicine III, Klinikum der Universitat Munchen, Munich, Germany
Zinzani et al. ASH 2016. Abstract 617
CONTRALTO Phase 2 Study Design
VEN + R and randomized VEN + BR vs BR alone in patients
with R/R FL, Grade 1–3a
Chemotherapy Free(N = 50)
ARM A
VEN+R
Chemotherapy Containing(N = 100)
R 1:1a
ARM C
BR
Key inclusion criteria
Age ≥18 yrs
Confirmed R/R FL (Gr 1–3a)
Treated with ≥1 line of prior therapy for FL
Adequate marrow, coagulation, renal, and hepatic function
No history of bendamustine-refractory disease
No CNS lymphoma
Primary Endpoint
PET-CR rate by IRC at end of induction (Cheson 2014)
Secondary Endpoints
CR rate (PET and CT) by investigator at end of induction and 1 year
ORR
PFS
Safety
Chemo vs. No ChemoInvestigator’s Discretion
a Stratified: DOR to prior tx (≤12m vs. >12m) Disease burden (high vs. low)
ARM B
VEN+BR
Safety run-in (N=9)
600 mg VEN+BR
12.4mb 6.3mb 6.2mb
b median months on study so far (ongoing) Zinzani et al. ASH 2016. Abstract 617
0 2 4 6 8 10 12 14 16 18 20
Dosing Schedule by Arm and Time on Study (Ongoing)
MonthsBlue circles represent the median, and the lines are for the associated range
*R administered on Days 1, 8, 15 and 22.
28-day cycles
Rituxumab D1 of period indicated
Bendamustine D1 + D2 of period indicated
Venetoclax Daily over period indicated 800 mg daily
375 mg/m2
Arm A: VEN + R
Arm B: VEN + BR
Arm C: BR
VEN 800 mg (daily)
VEN 800 mg (daily)
*
TLS mitigation on day 1
• hydration
• allopurinol or rasburicase
• mandatory hospitalization for
pts with bulk and high ALC
BR end
(Arm B+C)
VEN end (Arm A+B)
R end (Arm A)
90 mg/m2
Zinzani et al. ASH 2016. Abstract 617
VEN + BR vs. BR: Safety
All AE > 18%, n (%)
Arm B
VEN + BR
(N=49)
Arm C
BR
(N=50)
Neutropenia 36 (73) 19 (38)
Nausea 32 (65) 22 (44)
Thrombocytopenia 29 (59) 9 (18)
Diarrhea 24 (49) 9 (18)
Vomiting 23 (47) 13 (26)
Fatigue 22 (45) 14 (28)
Anemia 17 (35) 6 (12)
Constipation 10 (20) 17 (34)
Pyrexia 10 (20) 9 (18)
Decreased Appetite 10 (20) 5 (10)
Hypokalemia 10 (20) 4 (8)
Cough 8 (16) 11 (22)
G3–4 AE > 10%, n (%)
Neutropenia 30 (61) 15 (30)
Thrombocytopenia 22 (45) 3 (6)
Anemia 7 (14) 1 (2)
Febrile Neutropenia 6 (12) 3 (6)
Lab tumor lysis syndrome was seen in 3 pts (VEN +
BR) and was manageable
3 deaths on these arms
• VEN + BR: 1 pneumonia
• BR: 1 PD and 1 hypoxia
Pts with adverse events leading to stopping drug:
• VEN + BR: 16 pts (33%) stopped at least 1 drug
• VEN: 12 pts (24%)
• B: 10 pts (20%)
• R: 7 pts (14%)
• BR
• 1 pt stopped BR due to hypoxia
Zinzani et al. ASH 2016. Abstract 617
VEN + R: Efficacy
Response rates by PET-CT by
investigator at 6-month (primary),1 n (%)VEN + R
(N=53)
VEN + R
Refractory
(N=40)
VEN + R
Non Refractory
(N=13)
ORR 16 (30) 11 (28) 5 (38)
CMR 7 (13) 5 (13) 2 (15)
PMR 9 (17) 6 (15) 3 (23)
No metabolic response 2 (4) 3 (8) 0
Progressive disease 24 (45) 19 (48) 5 (38)
Response data unavailable 11 (21) 8 (20) 3 (23)
Best response2 by PET-CT or CT by investigator, n (%)
ORR 20 (38) 13 (33) 7 (54)
CR 11 (21) 9 (23) 2 (15)
PR 9(17) 4 (10) 5 (38)
Stable disease 8 (15) 6 (15) 2 (15)
Progressive disease 18 (34) 16 (40) 2 (15)
Response data unavailable 7 (13) 5 (13) 2 (15)1 Primary responses evaluated 6-8 weeks after: C6D1 or date of drug discontinuation (whichever was earlier)2 Best responses evaluated from randomization to the end of the study. CT used if PET was unavailable. Zinzani et al. ASH 2016. Abstract 617
VEN + BR vs. BR: Efficacy
1 Primary responses evaluated 6-8 weeks after: C6D1 or date of drug discontinuation (whichever was earlier)2 Best responses evaluated from randomization to the end of the study. CT used if PET was unavailable.
Response rates by PET-CT by
investigator at 6-month (primary),1 n (%)
Arm B
VEN + BR
(N=51)
Arm C
BR
(N=51)
ORR 38 (75) 39 (77)
CMR 32 (63) 31 (61)
PMR 6 (12) 8 (16)
No metabolic response 0 0
Progressive disease 2 (4) 6 (12)
Response data unavailable 11 (22) 6 (12)
Best response2 by PET-CT or CT by investigator, n (%)
ORR 46 (90) 45 (88)
CR 36 (71) 34 (67)
PR 10 (20) 11 (22)
Stable disease 1 (2) 0
Progressive disease 1 (2) 4 (8)
Response data unavailable 3 (6) 2 (4)
Zinzani et al. ASH 2016. Abstract 617
ESMO
GUIDELINES FL
Dreyling et al., 2016
Relapsed FL
Follicular Lymphoma
We can – at least for a subgroup of patients,
by extending remission beyond
the individual lifespan
Event-Free
Survival
Overall
Survival
Cure
Initial
Response
(CR, PR)
Vielen DankMANY THANKS!