Ibrutinib Plus Bendamustine and Rituximab in Previously ... · EHA 2016 | CLL3001 HELIOS | Fraser G, et al. 3 Response: –CT scans were performed at baseline, then every 12 weeks

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.


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


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.


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


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.


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


Median PFS2 (months) NR NR HR 0.622 95% CI 0.42-0.92 Log-rank p value 0.0162


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


HR 0.628 (95% CI, 0.39–1.02) HR 0.670 (95% CI, 0.44–1.02)


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.



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


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


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%


MRD < 0.01%


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%


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


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%


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


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.


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


Placebo + BR 287 261 243 208 164 123 81 39 23

Months Months


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






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


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


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

Documents

Ibrutinib Plus Bendamustine and Rituximab in Previously ... · EHA 2016 | CLL3001 HELIOS | Fraser G, et al. 3 Response: –CT scans were performed at baseline, then every 12 weeks