EHA 2016 | CLL3001 HELIOS | Fraser G, et al.
Ibrutinib Plus Bendamustine and Rituximab in Previously Treated CLL/SLL: 2-Year Follow-up
Including MRD From the HELIOS Study
Graeme Fraser,1 Paula Cramer,2 Fatih Demirkan,3 Rodrigo Santucci Silva,4 Sebastian Grosicki,5 Ann Janssens,6 Jiri Mayer,7 Marie-Sarah Dilhuydy,8 Halyna Pylypenko,9 Javier Loscertales,10
Andre Goy,11 Abraham Avigdor,12 Simon Rule,13 Charles Phelps,14 Michelle Mahler,14 Mariya Salman,14 Angela Howes,15 and Michael Hallek16
1Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada; 2Department I of Internal Medicine and German CLL Study Group, University of Cologne, Cologne, Germany; 3Division of Hematology, Dokuz Eylul University, Izmir, Turkey; 4IEP São Lucas / Hemomed Oncologia e Hematologia, São Paulo, Brazil; 5Department of Cancer Prevention, Faculty of Public Health, Silesian Medical University, Katowice, Poland; 6Universitaire Ziekenhuizen
Leuven, Leuven, Belgium; 7Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic; 8Hopital Haut Leveque, Bordeaux, Pessac, France; 9Department of Hematology, Cherkassy Regional Oncological Center, Cherkassy, Ukraine;
10Hematology Department, Hospital Universitario La Princesa, IIS-IP, Madrid, Spain; 11John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA; 12Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer and Sackler
School of Medicine, University of Tel-Aviv, Tel-Aviv, Israel; 13Department of Haematology, Derriford Hospital, Plymouth, UK; 14Janssen Research & Development, Raritan, NJ, USA; 15Janssen Research & Development, High Wycombe, UK; 16Department I of Internal Medicine,
Center of Integrated Oncology, University of Cologne and Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany.
EHA 2016 | CLL3001 HELIOS | Fraser G, et al.
Methods: HELIOS Study Design
2
Patients with
previously treated CLL/SLL
Excluding patients
with del17p
Ibrutinib + BR (N = 289) BRb (maximum of 6 cycles)
Oral ibrutinib 420 mg once daily starting on Cycle 1, Day 2
Placebo + BR (N = 289) BRb (maximum of 6 cycles)
Oral placebo once daily starting on Cycle 1, Day 2
Ibrutinib (treat to PD or unacceptable toxicity)
R A
N D
O M
I Z
E
Placebo (treat to PD or unacceptable toxicity)
Crossover to ibrutinib 420 mg once daily after
IRC-confirmed PD
First patient crossed over in May 2014
1:1a
Enrollment dates: Sep 2012 – Jan 2014
Primary end point: IRC-assessed PFSc
Secondary end points: IRC-assessed ORR, OS, rate of MRD negative response, safety
aStratified by purine analogue refractory status (failure to respond or relapse in ≤ 12 months) and prior lines of therapy (1 line vs > 1 line). bSimilar dosing to Fischer K, et al. J Clin Oncol. 2011;29:3559-3566. cAccording to 2008 iwCLL criteria (Hallek M, et al. Blood. 2008;111:5446-5456).
Initial data report: Mar 2015 2-year update: Oct 2015
IRC, independent review committee; MRD, minimal residual disease; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival.
EHA 2016 | CLL3001 HELIOS | Fraser G, et al. 3
Response:
– CT scans were performed at baseline, then every 12 weeks for 2 years, then every 6 months until progression
– Long-term follow-up assessments of PFS and response are based on investigator assessment
– PFS2 was defined as the period from randomization to PD following the next line of treatment (including crossover to ibrutinib for patients originally on placebo + BR arm), or death
MRD status:
– Blinded central review with 8-color flow; MRD-negative defined as < 1 CLL cell per 10,000 leukocytes (< 0.01%)
– When patients achieved clinical complete response (CR), bone marrow aspirate was evaluated for MRD
– If patients had a confirmed clinical CR, follow-up for MRD status was evaluated by peripheral blood every 12 weeks
Methods: Assessments
EHA 2016 | CLL3001 HELIOS | Fraser G, et al.
Results: Patient Disposition (Oct 2015)
4
Intent-to-Treat Population Ibrutinib + BR
(N = 289) Placebo + BR
(N = 289) Median time on study, months (95% CI)a,b 25.7 (24.4-26.6) 25.4 (24.3-26.1)
Disposition during study treatment phase, n (%)
Did not receive study drug 2 (0.7) 2 (0.7)
Ongoing 186 (64.4) 0
Discontinued 101 (34.9) 287 (99.3)
Primary reason for discontinuation during study treatment phase, n (%)c
AE 45 (15.6) 34 (11.8)
Death 10 (3.5) 9 (3.1)
Lost to follow-up 1 (0.3) 1 (0.3)
PD or relapse 21 (7.3) 148 (51.2)
Investigator or sponsor decision 6 (2.1) 81 (28.0)
Withdrawal of consent 20 (6.9) 16 (5.5)
Disposition during follow-up phase, n (%)
In study treatment phase 186 (64.4) 0
In follow-up phase 48 (16.6) 213 (73.7)
Crossover to ibrutinib, n (%) 142 (49.1)
Death during crossover period 10 (3.5)
AE, adverse event; CI, confidence interval.
aTime from randomization to death or last known alive date. bBased on Kaplan-Meier estimates. The reverse Kaplan-Meier method was used to estimate the median time on study, with patients who died being censored at death date. cIncludes patients who did not receive study medication.
EHA 2016 | CLL3001 HELIOS | Fraser G, et al.
Results: PFS in the Intent-to-Treat Population
5
Median follow-up, 25.4 months Investigator-assessed
Median follow-up, 17 months IRC-assessed1
Ibrutinib + BR
Placebo + BR
0 4 8 12 16 20 24 28 32
Months
0
20
40
60
80
100
PFS
(%
)
Placebo + BR
289
289
264
259
247
234
200
117
127
59
52
17
5
3
0
0
0
0
Patients at risk
Ibrutinib + BR
Ibrutinib + BR Placebo + BR
Median PFS (months) NR 13.3
HR 0.203
95% CI 0.15-0.28
Log-rank p value < 0.0001
Ibrutinib + BR Placebo + BR
Median PFS (months) NR 14.2
HR 0.199
95% CI 0.15-0.26
Log-rank p value < 0.0001
Ibrutinib + BR
Placebo + BR
0 4 8 12 16 20 24 28 36 32
Months
0
20
40
60
80
100
PFS
(%
)
Placebo + BR
289
289
268
260
256
237
241
166
227
125
174
65
117
31
47
10
6
1
0
0
Patients at risk
Ibrutinib + BR
1. Chanan-Khan A, et al. Lancet Oncol. 2016;17:200-211.
HR, hazard ratio; NR, not reached.
EHA 2016 | CLL3001 HELIOS | Fraser G, et al.
Results: PFS Following Subsequent Lines of Therapy (PFS2) in the Intent-to-Treat Population
6
Ibrutinib + BR
Placebo + BR
0 4 8 12 16 20 24 32 40 36 28
Months
0
20
40
60
80
100 P
FS (
%)
Placebo + BR 289 289
269 265
258 245
245 230
232 216
178 178
120 100
50 41
6 8
0 0
0 0
Patients at risk:
Ibrutinib + BR
Ibrutinib + BR Placebo + BR
Median PFS2 (months) NR NR HR 0.622 95% CI 0.42-0.92 Log-rank p value 0.0162
EHA 2016 | CLL3001 HELIOS | Fraser G, et al.
Results: OS in the Intent-to-Treat Population
Median follow-up, 25.4 months
7
Median follow-up, 17 months1
Ibrutinib + BR
Placebo + BR
0 4 8 12 16 20 24 28 40
Months
0
20
40
60
80
100
OS
(%)
Placebo + BR
289
289
273
273
261
255
255
244
244
234
233
219
147
138
74
71
0
0
36
0
2
32
14
21
Patients at risk
Ibrutinib + BR
Ibrutinib + BR
Placebo + BR
0 4 8 12 16 20 24 28 32
Months
0
20
40
60
80
100
OS
(%)
Placebo + BR
289
289
273
273
261
255
250
237
147
138
73
70
8
16
0
0
0
0
Patients at risk
Ibrutinib + BR
1. Chanan-Khan A, et al. Lancet Oncol. 2016;17:200-211.
HR 0.628 (95% CI, 0.39–1.02) HR 0.670 (95% CI, 0.44–1.02)
EHA 2016 | CLL3001 HELIOS | Fraser G, et al. 8
CR/CRi (Investigator-Assessed)
MRD-Negative (Central Laboratory)
Ibrutinib + BR Placebo + BR Ibrutinib + BR Placebo + BR
Median follow-up, 17 months1 21.4% 5.9% 12.8%
(n = 37) 4.8%
(n = 14)
Median follow-up, 25.4 months 33.9% 7.3% 18.0%
(n = 52) 4.8%
(n = 14)
Results: Increased Depth of Response
Median time to CR/CRi was 11.14 months (95% CI, 10.2-12.1) for ibrutinib + BR and 11.07 months (95% CI, 8.4-11.7) for placebo + BR
Median time to MRD-negative response was 12.91 months (95% CI, 10.5-14.5) for ibrutinib + BR and 10.63 months (95% CI, 8.2-13.8) for placebo + BR
Among the patients who achieved MRD-negative disease, 23 of the 52 in the ibrutinib + BR arm and 7 of the 14 in the placebo + BR arm were confirmed using bone marrow samples; the remainder for both arms were confirmed with peripheral blood samples
CRi, CR with incomplete bone marrow recovery.
1. Chanan-Khan A, et al. Lancet Oncol. 2016;17:200-211.
EHA 2016 | CLL3001 HELIOS | Fraser G, et al.
Results: MRD-Negative Response Over Time
0.7
4.2
7.6
11.1
12.8
15.9
17.3 18.0
0.3
2.4 3.5
4.5 4.5 4.8 4.8 4.8
0
2
4
6
8
10
12
14
16
18
20
3 6 9 12 15 21 27
Ibrutinib + BR
Placebo + BR
9
End of induction
Months following induction
Pat
ien
ts w
ith
MR
D-n
egat
ive
resp
on
se (
%)
MRD-negative response continues to increase over time for patients treated with ibrutinib + BR
As of Mar 2016, 60 patients (20.7%) demonstrated an MRD-negative response
EHA 2016 | CLL3001 HELIOS | Fraser G, et al.
Results: PFS by MRD Status (Oct 2015)
10
0 4 8 12 16 20 24 28 36 32
Months
0
20
40
60
80
100
PFS
(%
)
52 52 52 51 50 45 33 10 2 0
72 72 71 70 70 53 32 14 2 0
19 19 19 19 18 14 12 7 0 0
8 8 8 8 8 6 4 2 1 0
14 35 5 5 1 1 1 0 0 0
103 103 101 101 80 55 35 14 1 0
MRD ≥ 0.01% to < 1%
MRD ≥ 1% to < 10%
MRD ≥ 10%
MRD never tested responder nonresponder
Patients at risk
MRD < 0.01%
Among patients who exhibited an MRD-negative response (< 0.01%), those on ibrutinib + BR have not yet reached the median PFS, compared with a median PFS of 22.1 months (95% CI, 13.9 to not estimable) for placebo + BR
0 4 8 12 16 20 24 28 36 32
Months
0
20
40
60
80
100
PFS
(%
)
14 14 14 13 11 7 3 0 0 0
MRD ≥ 0.01% to < 1% 24 24 24 24 21 13 6 4 1 0
MRD ≥ 1% to < 10% 15 15 15 13 12 7 4 1 0 0
MRD ≥ 10% 9 9 9 8 6 3 2 1 0 0
66 95 48 19 10 4 2 0 0 0
132 132 127 89 65 31 14 4 0 0
MRD never tested responder nonresponder
Patients at risk
MRD < 0.01%
MRD ≥ 1% to < 10% MRD ≥ 10% MRD never tested responder MRD never tested nonresponder MRD ≥ 0.01% to < 1%
Ibrutinib + BR Placebo + BR
MRD < 0.01%
EHA 2016 | CLL3001 HELIOS | Fraser G, et al.
Results: PFS by MRD Status (Oct 2015)
11
0 4 8 12 16 20 24 28 36 32
Months
0
20
40
60
80
100
PFS
(%
)
52 52 52 51 50 45 33 10 2 0
72 72 71 70 70 53 32 14 2 0
19 19 19 19 18 14 12 7 0 0
8 8 8 8 8 6 4 2 1 0
14 35 5 5 1 1 1 0 0 0
103 103 101 101 80 55 35 14 1 0
MRD ≥ 0.01% to < 1%
MRD ≥ 1% to < 10%
MRD ≥ 10%
MRD never tested responder nonresponder
Patients at risk
MRD < 0.01%
Among patients who exhibited an MRD-negative response (< 0.01%), those on ibrutinib + BR have not yet reached the median PFS, compared with a median PFS of 22.1 months (95% CI, 13.9 to not estimable) for placebo + BR
0 4 8 12 16 20 24 28 36 32
Months
0
20
40
60
80
100
PFS
(%
)
14 14 14 13 11 7 3 0 0 0
MRD ≥ 0.01% to < 1% 24 24 24 24 21 13 6 4 1 0
MRD ≥ 1% to < 10% 15 15 15 13 12 7 4 1 0 0
MRD ≥ 10% 9 9 9 8 6 3 2 1 0 0
66 95 48 19 10 4 2 0 0 0
132 132 127 89 65 31 14 4 0 0
MRD never tested responder nonresponder
Patients at risk
MRD < 0.01%
MRD ≥ 1% to < 10% MRD ≥ 10% MRD never tested responder MRD never tested nonresponder MRD ≥ 0.01% to < 1%
Ibrutinib + BR Placebo + BR
MRD < 0.01%
Among patients who exhibited a MRD-negative response (< 0.01%), those on
ibrutinib + BR have not yet reached the median PFS, compared with a median
PFS of 22.1 months (95% CI, 13.9-NE) for placebo + BR
EHA 2016 | CLL3001 HELIOS | Fraser G, et al.
Results: Safety
Intent-to-Treat Population, n (%) Ibrutinib + BR
(N = 287) Placebo + BR
(N = 287)
Treatment-emergent AEs 281 (97.9) 279 (97.2)
Grade ≥ 3 250 (87.1) 231 (80.5)
Drug-related 243 (84.7) 228 (79.4)
Treatment-emergent serious AEs 159 (55.4) 127 (44.3)
Grade ≥ 3 140 (48.8) 108 (37.6)
Drug-related 90 (31.4) 64 (22.3)
Treatment-emergent AEs leading to treatment discontinuation 44 (15.3) 33 (11.5)
Treatment-emergent AEs with outcome of deatha 24 (8.4) 19 (6.6)
12
Overall, incidence of individual AEs remained similar in the update analysis compared with the original analysis
Most common grade 3-4 AEs were neutropenia and thrombocytopenia; similar in both arms
Any grade diarrhea was slightly higher with ibrutinib + BR (37%) than with placebo + BR (24%)
Incidence of bleeding events, infection, and myalgia decreased over time
– There were no new major bleeding events.
aMay include deaths that occurred more than 30 days after last dose with the treatment-emergent AE as the reason for death.
EHA 2016 | CLL3001 HELIOS | Fraser G, et al.
0
10
20
30
40
50
0-3 3-6 6-9 9-12 12-15 15-18 18-21 21-24 > 24
0
10
20
30
40
50
0-3 3-6 6-9 9-12 12-15 15-18 18-21 21-24 > 24
0
10
20
30
40
50
0-3 3-6 6-9 9-12 12-15 15-18 18-21 21-24 > 24
0
20
40
60
80
100
120
0-3 3-6 6-9 9-12 12-15 15-18 18-21 21-24 > 24
Results: Safety Over Time
13
Nu
mb
er o
f P
atie
nts
Nu
mb
er o
f P
atie
nts
Nu
mb
er o
f P
atie
nts
Nu
mb
er o
f P
atie
nts
Patients at risk Ibrutinib + BR 287 263 245 230 216 203 196 181 120
Placebo + BR 287 261 243 208 164 123 81 39 23
Patients at risk Ibrutinib + BR 287 263 245 230 216 203 196 181 120
Placebo + BR 287 261 243 208 164 123 81 39 23
Months Months
Patients at risk Ibrutinib + BR 287 263 245 230 216 203 196 181 120
Placebo + BR 287 261 243 208 164 123 81 39 23
Months Patients at risk Ibrutinib + BR 287 263 245 230 216 203 196 181 120
Placebo + BR 287 261 243 208 164 123 81 39 23
Months
Incidence of AEs of interest generally decreases over time
Infection Bleeding
Atrial Fibrillation Myalgia
Ibrutinib + BR Placebo + BR
Ibrutinib + BR Placebo + BR
Ibrutinib + BR Placebo + BR
Ibrutinib + BR Placebo + BR
EHA 2016 | CLL3001 HELIOS | Fraser G, et al. 14
With continued ibrutinib treatment, the rate and depth of response further improve; rates of CR/CRi and MRD-negative response increase over time
At each residual disease level measured (< 0.01% through ≥ 10%) ibrutinib + BR showed a more sustained PFS than placebo + BR
The safety profile with continued follow-up was consistent with the original analysis
These 2-year follow-up data demonstrate continued superiority for ibrutinib + BR compared with placebo + BR, with significantly longer PFS and PFS2 and higher ORR and MRD-negative responses, further confirming the important role of ibrutinib in patients with previously treated CLL/SLL
Conclusions
JC 9Y
EHA 2016 | CLL3001 HELIOS | Fraser G, et al. 15
The authors would like to thank:
– The patients and their families, without whose support this trial would not have been possible
– The global study investigators
Acknowledgments
EHA 2016 | CLL3001 HELIOS | Fraser G, et al.
Europe
Belgium: A Janssens, F Offner, E Van den Neste, A Van Hoof
Czech Republic: J Mayer, J Novak, M Trneny
France: G Cartron, C Dartigeas, M Dilhuydy, D Ghez, C Haioun, V Leblond,
G Salles
Germany: C Balser, P Cramer, P Dreger, J Durig, M Eckart, B Heinrich,
T Illmer, K Jentsch-Ullrich, M Pfreundschuh, J Schetelig, R Schlag, U Soling,
S Stilgenbauer
Greece: A Anagnostopoulos, A Dimopoulos, P Panagiotidis, E Vrakidou
Israel: O Bairey, D Ben Yehuda, A Braester, R Fineman, Y Herishanu,
A Nagler, R Ruchlemer, T Tadmor
Poland: S Grosicki, W Homenda, W Jurczak, A Pluta, D Woszczyk
Portugal: A Espirito Santo, R Luis, J Raposo, C Viveiros
Russian Federation: J Alexeeva, Y Dunaev, M Golubeva, N Khuageva,
A Loginov, I Lysenko, E Osmanov, V Pavlov, A Pristupa, A Proydakov,
V Rossiev, I Samarina, O Samoilova, O Serduk, T Shneider, D Udovitsa,
S Voloshin
Spain: J Gayoso, M Gonzalez, E Gonzalez Barca, J Hernandez Rivas,
I Jarque, J Loscertales
Sweden: C Karlsson, M Sender
Turkey: M Aktan, O Arslan, F Demirkan, B Ferhanoglu, L Kaynar,
N Sayinalp, F Vaural, M Yagci
Ukraine: I Dyagil, P Kaplan, Z Masliak, H Oliynyk, T Popovska, H Pylypenko,
G Rekhtman
United Kingdom: C Dearden, N Morley, P Moss, S Rule
North America
Canada: S Assouline, I Bence-Bruckler, R Buckstein, G Fraser, L Larratt,
L Minuk, D Villa
United States of America: A Angevine, N Bartlett, D Bixby, P Caimi,
A Chanan-Khan, M Craig, A Forero-Torres, S Ganguly, A Goy, L Heffner,
R Hermann, F Lansigan, J Leis, J Letzer, B Link, D Liu, K McCaul, E McGuire,
W Skinner, A Starodub, R Stuart, M Thirman, N Tirumali, J Yang
Latin America
Argentina: M Pavlovsky, D Riveros
Brazil: R Da Silva, M Romeo, A Scheliga
Colombia: L Salazar
Mexico: D Gomez, E Ramirez
Asia
South Korea: C Jung
HELIOS Study Investigators
16