Lymphome, CLL - InVOinvo.maxit4u.de/wp-content/uploads/2019/02/Neues... · OS: HR 0.66, P=0.024 • A+CHP has a comparable safety profile to CHOP • ECHELON-2 is first prospective

MJR

Mathias Rummel

Alexander Burchardt

Med. Klinik IV – Hämatologie

Klinikum der Justus-Liebig-Universität Gießen

Lymphome, CLL

MJR

ASH 2018: CLL and NHL

PTCL / PMBCL / MCL

Brentuximab + CHP vs CHOP (ECHELON-2) Horwith et al.

Pembrolizumab in r/r PMBCL (KEYNOTE) Armand et al.

B-R + R-Cytarabin + APBSCT in MCL Merryman et al.

CLL

Ibrutinib vs Ibrutinib-Rituximab vs B-R in elderly CLL Woyach et al.

Ibrutinib + Rituximab vs FC-R in young CLL Shanafelt et al.

Ibrutinib + Venetoclax in relapsed / refractory CLL Hillmen et al.

Indolent NHL

R2 vs R + Placebo (AUGMENT) Leonard et al.

Ibrutinib + Obinutuzumab 1st-line (GLSG) Schmidt et al.

DLBCL

4 x R-CHOP + 2xR vs 6 x R-CHOP favorable (FLYER) Poeschel et al.

R-CHOP +/- Ibrutinib in Non-GCB (PHOENIX) Younes et al.

The Phase 3 ECHELON-2 Trial:

Results of a Randomized, Double-Blind,

Active-Controlled Study of

Brentuximab Vedotin and CHP (A+CHP) vs CHOP

in Previously Untreated Subjects with

CD30-Expressing Peripheral T-Cell Lymphomas (PTCL)

Steven Horwitz, Owen A O’Connor, Barbara Pro, Tim Illidge, Michelle Fanale, Ranjana Advani,

Nancy L Bartlett, Jacob Haaber Christensen, Franck Morschhauser, Eva Domingo-Domenech,

Giuseppe Rossi, Won Seog Kim, Tatyana Feldman, Anne Lennard, David Belada, Árpád Illés,

Kensei Tobinai, Kunihiro Tsukasaki, Su-Peng Yeh, Andrei Shustov, Andreas Hüttmann, Kerry J

Savage, Sam Yuen, Swaminathan Iyer, Pier Luigi Zinzani, Zhaowei Hua, Meredith Little,

Shangbang Rao, Joseph Woolery, Thomas Manley, Lorenz Trümper

American Society of Hematology Annual Meeting; San Diego, California, December 1-4, 2018, Abstract #997

ECHELON-2 Study Design (NCT01777152)

Key Eligibility Criteria

• Age ≥18 years

• CD30-expression (≥10% cells)

• Previously-untreated PTCL:

o Systemic ALCL (sALCL)*

including ALK(+) sALCL with IPI ≥2,

ALK(-) sALCL

o PTCL-NOS, AITL, ATLL, EATL,

HSTCL

Stratification Factors

• IPI score (0-1 vs. 2-3 vs. 4-5)

• Histologic subtype (ALK-positive

sALCL vs. all other histologies)

R

(1:1)

N=226

N=226

EOT

PET

A+CHP

(A) brentuximab vedotin 1.8 mg/kg +

(C) cyclophosphamide 750 mg/m2 +

(H) doxorubicin 50 mg/m2 +

(P) prednisone 100 mg (Days 1-5)

+ placebo vincristine

Q3W for 6 to 8 cycles

CHOP

(C) cyclophosphamide 750 mg/m2 +

(H) doxorubicin 50 mg/m2 +

(O) vincristine 1.4 mg/m2 +

(P) prednisone 100 mg (Days 1-5)

+ placebo brentuximab vedotin

Q3W for 6 to 8 cycles

*targeting 75% (±5%) ALCL per EU

regulatory commitment

AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large-cell lymphoma; ALK, anaplastic lymphoma kinase ATLL, adult T-cell leukaemia/lymphoma; EATL, enteropathy-associated T-cell lymphoma; EOT, end of treatment; GCSF, granulocyte-colony stimulating factor; HSTCL, hepatosplenic T-cell lymphoma; IPI, international prognostic index

Per investigator discretion:

GCSF primary prophylaxis, consolidative RT and SCT

Progression-free Survival (ECHELON-2)

3-yr PFS

57% 44%

Events HR (95% CI) P

A+CHP 95 (42%) 0.71 (0.54, 0.93)

0.011 CHOP 124 (55%)

Median PFS (95% CI)

48.2 mo (35.2, NE) 20.8 mo (12.7, 47.6)

Median Follow-up 36.2 months

Overall Survival (ECHELON-2)

Deaths HR (95% CI) P

A+CHP 51 (23%) 0.66 (0.46, 0.95)

0.0244 CHOP 73 (32%)

Horwitz et al. ASH 2018 Abstract #997

Treatment-Emergent Peripheral Neuropathy

Peripheral Neuropathy (PN)*

*The SMQ includes the preferred terms of peripheral sensory neuropathy, paraesthesia, peripheral motor neuropathy, muscular weakness, peripheral sensorimotor neuro-

pathy, hypoaesthesia, dysaesthesia, areflexia, burning sensation, peroneal nerve palsy, polyneuropathy, autonomic neuropathy, gait disturbance, muscle atrophy, and neuralgia.

Subjects, n (%)

A+CHP

(N=223)

CHOP

(N=226)

Treatment-emergent PN, n 117 124

Resolution† of all PN events 58 (50) 79 (64)

Improvement of PN events 14 (12) 15 (12)

Ongoing PN events at last

follow-up 61 (52) 45 (36)

Grade 1 44 (38) 32 (26)

Grade 2 15 (13) 12 (10)

Grade 3 2 (2) 1 (1)

†Resolution was defined as resolved/recovered with or without sequelae; or return

to baseline or lower severity as of the latest assessment for pre-existing events


Summary and Conclusions

• A+CHP provided significant and clinically meaningful improvement in PFS and OS

versus CHOP for frontline treatment of CD30-expressing PTCL

◦ PFS: HR 0.71, P=0.011; 3-year PFS, 57%

◦ OS: HR 0.66, P=0.024

• A+CHP has a comparable safety profile to CHOP

• ECHELON-2 is first prospective trial in PTCL to show OS benefit over CHOP

• FDA approved brentuximab vedotin in combination with CHP for adults with previously

untreated sALCL or other CD30-expressing PTCL, including AITL and PTCL-NOS.


Pembrolizumab in Patients With Relapsed or Refractory PMBCL Data from the KEYNOTE-013 and

KEYNOTE-170 Studies

1Dana-Farber Cancer Institute, Boston, MA, USA; 2Pirogov National Medical Surgical Center, Moscow, Russia; 3Hôpital Saint-Louis, Paris, France; 4Hôpital Haut-Levêque, Pessac, France; 5N.N Blokhin Russian Cancer Research Center, Moscow, Russia; 6Ankara University Medical School, Ankara, Turkey; 7Clinica Alemana de Santiago, Santiago, Chile; 8Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil; 9Hospital Clínico de Salamanca, Salamanca, Spain; 10Maria Sklodowska-Curie Institute Oncology Center, Warszawa, Poland; 11Anadolu Medical Center, Gebze, Turkey; 12Institut Gustave Roussy, Paris, France; 13The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; 14Hospital Israelita Albert Einstein, Sao Paulo, Brazil; 15Universite Claude Bernard Lyon, Lyon, France;16University of Pennsylvania, Philadelphia, PA, USA;17City of Hope, Duarte, CA, USA; 18Brigham & Women’s Hospital, Boston, MA, USA; 19Merck & Co., Inc., Kenilworth, NJ, USA; 20Institute of Hematology “Seràgnoli” University of Bologna, Bologna, Italy

Philippe Armand1*; Scott Rodig1*; Vladimir Melnichenko2; Catherine Thieblemont3; Kamal Bouabdallah4; Gayane Tumyan5; Muhit Özcan6; Sergio Portino7; Laura Fogliatto8; D. Caballero Barrigon9; Jan Walewski10; Zafer Gulbas11; Vincent Ribrag12; Beth Christian13; Guilherme Fleury Perini14; Gilles Salles15; Jakub Svoboda16, Jasmine Zain17; Sanjay Patel18; Pei-Hsuan Chen1; Azra H. Ligon18; Jing Ouyang1; Donna Neuberg1; Robert Redd1; Arkendu Chatterjee19; Robert Orlowski19; Arun Balakumaran19; Margaret Shipp1; Pier Luigi Zinzani20 *Co-lead authors

Treatment of R/R PMBCL is an important clinical need

PMBCL may be sensitive to PD-1 blockade

• Often affects young patients

• Frequent activation of NFkB and JAK/STAT

• Amplification/translocation of 9p24

• PD-L1 and PD-L2 overexpression

• High PD-L2 expression on tumor cells

Primary Mediastinal B-Cell Lymphoma (PMBCL)

• Aggressive B-cell NHL

• Good outcomes with 1L therapy

• Poor outcomes in R/R disease

Primary endpoint: ORR

Secondary endpoints: DOR, PFS, OS

Patients

Richter syndrome

PMBCL cohort

(N=53) •Age ≥18 years

•Diagnosis of rrPMBCL

•Failed/ineligible auto-

SCT

•Failure of ≥2 prior rx

Pembrolizumab

200 mg Q3W

Response assessment:

PET/CT scan at Wk 12

then Q12W

IWG 2007 criteria

Treatment up to

2 years or until

unacceptable toxicity,

disease progression,

or patient/physician

withdrawal decision

NCT02576990

Phase 2 KEYNOTE-170 Design

Characteristic, n (%) KEYNOTE-013 N = 21

KEYNOTE-170 N = 53

Median age, years (range) 31 (22-62) 33 (20-61)

Female, n (%) 14 (67) 30 (57)

Prior transplant, n (%) 8 (38) 14 (26)

Prior lines of therapy

(median, range) 3 (2-9) 3 (2-8)

Prior radiation, n (%) 15 (71) 17 (32)

Prior rituximab, n 21 (100) 53 (100)

Data cutoff: April 4, 2018 (KN013); April 13, 2018 (KN170).

Baseline Characteristics


BICR, blinded independent central review; *Patients with insufficient data for assessment of response.

Response, n (%) KEYNOTE-013

N = 21 KEYNOTE-170

N = 53

Overall response 10 (48) 24 (45)

Complete response 7 (33) 7 (13)

Partial response 3 (14) 17 (32)

Stable disease 5 (24) 5 (9)

Progressive disease 4 (19) 12 (23)

Non-evaluable/No assessment* 2 (10) 12 (23)

Efficacy: Best Response (BICR)

Duration of Response


NR, not reached.

N at risk

KEYNOTE-013

KEYNOTE-170

9 8 7 6 6 6 6 5 3 2 2 1 1 0 10

20 15 11 8 5 2 1 0 0 24 0 0 0 0 0

Time, months

Re

sp

on

se

, %

3 6 9 12 15 18 21 24 27 30 33 36 39 42 0 0

10

20

30

40

50

60

70

80

90

100 12-month DOR Median

78% NR (1.9+-39.8+)

76% NR (1.1+-22.0+)

KEYNOTE-013

KEYNOTE-170

• Pembrolizumab yields frequent and durable responses

in heavily pre-treated patients with rrPMBCL

– Median DOR not reached with median follow-up of 29.1 mo (KEYNOTE-013) and

12.5 mo (KEYNOTE-170)

– At least 50% of pts alive at 1 year in both studies

– Very durable CRs

• Manageable safety profile

• Biomarker conclusions

• Data provided basis for US FDA accelerated approval of

pembrolizumab in patients with rrPMBCL on June 13, 2018

Conclusions

American Society of Hematology Annual Conference

Reid Merryman1, Natasha Edwin2, Robert Redd3, Jad Bsat1, Matthew Chase1, Ann LaCasce1,

Arnold Freedman1, Caron Jacobson1, David Fisher1, Samuel Ng1, Jennifer Crombie1, Austin Kim1,

Oreofe Odejide1, Matthew Davids1, Jennifer R Brown1, Heather Jacene5, Natasha Edwin2, Amanda

Cashen2, Nancy Bartlett2, Neha Mehta-Shah2, and Armin Ghobadi2, Brad Kahl2, Philippe Armand1,

Robin Joyce6, Eric Jacobsen1

1Department of Medical Oncology, Dana-Farber Cancer Institute 2Division of Hematology and Oncology, Washington University in St. Louis 3Department of Biostatistics, Dana-Farber Cancer Institute 5Department of Radiology, Dana-Farber Cancer Institute 6Department of Medical Oncology, Beth Israel-Deaconess Medical Center

RB x 3 RC x 3

RB RB RC RC

Cohort 3: WUSTL phase II trial (2016-2018)

Cohort 1: Dana-Farber phase II trial (2012-2014)

Cohort 2: Dana-Farber off-trial (2014-2018)

Autologous stem

cell transplantation

RB RB RC

RB

• Rituximab – 375 mg/m2, day 1

• Bendamustine – 90 mg/m2, days 1-2

RC

• Rituximab – 375 mg/m2, day 1

• Cytarabine – 3 gm/m2 BID days 1-2* *Dose reductions (2 gm/m2, 1.5 gm/m2, or

1 gm/m2) for each of the following: age >60,

creatinine > 1.5, pre-existing neurotoxicity.

Patient characteristics

Total DFCI trial DFCI off-

trial

WUSTL

trial

Patients N=86 N=23 N=49 N=14

Age 57 (30-72) 57 (42-69) 57 (30-72) 59 (38-65)

Sex (male) 62 (72%) 15 (65%) 34 (69%) 13 (93%)

Stage

1

2

3

4

1 (1%)

2 (2%)

10 (12%)

73 (85%)

0 (0%)

0 (0%)

3 (13%)

20 (87%)

0 (0%)

2 (4%)

7 (14%)

40 (82%)

1 (7%)

0 (0%)

0 (0%)

13 (93%)

ECOG PS

0-1

2

83 (97%)

3 (3%)

22 (96%)

1 (4%)

49 (100%)

0 (0%)

12 (86%)

2 (14%)

Treatment

center

Academic

Community

69 (80%)

17 (20%)

23 (100%)

0 (0%)

32 (65%)

17 (35%)

14 (100%)

0 (0%)

Progression-free

survival

3

years

85% (74-92%)

5

years

80% (66-89%)

Overall survival

3

years

92% (81-97%)

5

years

85% (62-95%)

*

*

*

* p<0.05 p<0.05 *

MJR


PTCL / PMBCL / MCL




CLL




Indolent NHL



DLBCL



Ibrutinib alone or in combination with rituximab produces superior progression free survival (PFS) compared with bendamustine plus rituximab in

untreated older patients with CLL: Results of Alliance North American

Intergroup Study A041202

Jennifer A. Woyach, Amy S. Ruppert, Nyla Heerema, Weiqiang Zhao, Allison M Booth, Wei Ding, Nancy L. Bartlett, Danielle M Brander, Paul M Barr, Kerry A Rogers, Sameer Parikh, Steven Coutre, Arti Hurria, Gerard

Lozanski, Sreenivasa Nattam, Richard A. Larson, Harry Erba, Mark Litzow, Carolyn Owen, James Atkins, Jeremy Abramson, Rich Little, Scott E. Smith, Richard M. Stone, Sumithra Mandrekar, John C. Byrd

Schema

Stratify*

R A N D O M I Z E

Bendamustine 90mg/m2 days 1&2 of each 28 day cycle + Rituximab 375 mg/m2 day 0 cycle 1, then 500 mg/m2 day 1 cycles 2-6

Ibrutinib 420mg daily until disease progression

Stratification •High risk vs intermediate risk Rai Stage •Presence vs absence of del(11q22.3) or del(17p13.1) on FISH performed locally •< 20% vs ≥ 20% Zap-70 methylation of CpG 3 performed centrally

Ibrutinib 420mg daily until disease progression + Rituximab 375 mg/m2 weekly for 4 weeks starting cycle 2 day 1, then day 1 of cycles 3-6

Untreated patients age ≥ 65 who meet IWCLL criteria for CLL treatment

Documented progression

Patient Characteristics Characteristic Total

N=547 BR

N=183 Ibrutinib

N=182 IR

N=182

Age (years), median (range)

71 (65-89) 70 (65-86) 71 (65-89) 71 (65-86)

Male, % 67 65 68 69

ECOG 0-1, % 97 95 97 99

White blood cell count x103/µL, median (range)

82 (4-518) 92 (7-518) 79 (6-438) 70 (4-481)

FISH Characteristics, %

Del (17p) 6 8 5 6

Del (11q) 19 18 19 21

TP53 mutation, % 10 9 9 12

Complex Karyotype, % 29 27 24 36

Zap-70 Unmethylated, %

53 52 53 53

IGVH unmutated*, % 61 58 63 61 *N= 360 total

Primary Endpoint: Progression Free Survival Eligible Patient Population

Arm C (IR)Arm B (I)

Arm A (BR)

% A

live a

nd

Pro

gre

ssio

n-F

ree

0 6 12 18 24 30 36 42 48 52

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36 42 48 52

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

Censor

32/170Arm C (IR)

34/178Arm B (I)

68/176Arm A (BR)

Events/TotalArm

Patients-at-Risk176 140 129 122 103 88 57 26 11 0178 165 154 147 136 120 78 45 22 0170 159 145 138 132 115 74 40 20 0

Pairwise Comparisons

I vs BR: Hazard Ratio 0.39 95% CI: 0.26-0.58

(1-sided P-value <0.001)

IR vs BR: Hazard Ratio 0.38 95% CI: 0.25-0.59

(1-sided P-value <0.001)

IR vs I: Hazard Ratio 1.00 95% CI: 0.62-1.62

(1-sided P-value 0.49)

Arm N 24 Month Estimate

BR 176 74% (95% CI: 66-80%)

I 178 87% (95% CI: 81-92%)

IR 170 88% (95% CI: 81-92%)

Arm C (IR)Arm B (I)

Arm A (BR)

% A

live a

nd

Pro

gressio

n-F

ree

0 6 12 18 24 30 36 42 48 52

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36 42 48 52

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

Censor

14/86Arm C (IR)

20/86Arm B (I)

23/87Arm A (BR)

Events/TotalArm

Patients-at-Risk87 75 70 68 60 52 33 15 7 086 80 74 69 64 56 35 20 9 086 79 70 70 65 59 37 18 6 0 Arm C (IR)

Arm B (I)Arm A (BR)

% A

live a

nd

Pro

gressio

n-F

ree

0 6 12 18 24 30 36 42 48 52

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36 42 48 52

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

Censor

6/45Arm C (IR)

7/45Arm B (I)

12/52Arm A (BR)

Events/TotalArm

Patients-at-Risk52 47 42 42 38 34 22 10 7 045 41 38 36 33 31 18 13 6 045 41 38 36 35 32 18 10 7 0

IGVH Mutated

Zap-70 Methylated

IGVH mutated & Zap-70 methylated Subgroups PFS Intention-to-Treat Patient Population


BR 52 87% (95% CI: 74-94%)

I 45 86% (95% CI: 72-94%)

IR 45 88% (95% CI: 73-95%)

Arm C (IR)Arm B (I)

Arm A (BR)

% A

live

0 6 12 18 24 30 36 42 48 52

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36 42 48 52

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

Censor

22/182Arm C (IR)

24/182Arm B (I)

20/183Arm A (BR)

Events/TotalArm

Patients-at-Risk183 166 163 160 153 143 98 53 23 1182 175 166 161 156 146 100 62 26 1182 172 169 165 161 147 100 55 24 1

Overall Survival Intention-to-Treat Patient Population

Median Follow-up: 38 months


BR 183 95% (95% CI: 91-98%)

I 183 90% (95% CI: 85-94%)

IR 182 94% (95% CI: 89-97%)

Grade 3, 4, or 5 Adverse Events During treatment or follow-up (excluding crossover)

Adverse Event BR N=176

Ibrutinib N=180

IR N=181

P-value

All Hematologic -- no. (%) 107 (61) 74 (41) 70 (38) <0.001

Anemia 22 (13) 21 (12) 11 (6) 0.09

Neutropenia 71 (40) 27 (15) 39 (22) <0.001

Thrombocytopenia 26 (15) 12 (7) 9 (5) 0.008

All Non-hematologic -- no. (%) 111 (63) 133 (74) 134 (74) 0.04

Bleeding 0 (0) 3 (2) 5 (3) 0.46

Infections 26 (15) 37 (21) 37 (20) 0.62

Febrile neutropenia 13 (7) 3 (2) 1 (1) <0.001

Atrial fibrillation 5 (3) 17 (9) 10 (6) 0.05

Hypertension 25 (14) 53 (29) 61 (34) <0.001

Unexplained/unwitnessed

death 2 (1) 7 (4) 4 (2) 0.24

• Deaths during active treatment + 30 days: 2 (1%), 13 (7%), 13 (7%) • Deaths during active treatment + 30 days, up to 6 cycles: 2 (1%), 3 (2%), 6 (3%)

Conclusions

• Ibrutinib or ibrutinib plus rituximab significantly prolongs PFS

compared with BR in the frontline setting for older CLL patients

• Rituximab does not improve PFS over ibrutinib alone

• BTK inhibition with ibrutinib is not without significant toxicity in

older patients, so close monitoring is still warranted

• Strategies to discontinue therapy are of great interest

• Clinical trials for this patient population are still of high clinical

interest

Ibrutinib-based therapy vs. standard FCR chemoimmunotherapy

in Untreated Younger Patients with CLL

Fazit: Ibrutinib-based therapy vs. FCR in untreated young CLL

MJR


PTCL / PMBCL / MCL




CLL




Indolent NHL



DLBCL



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 John G Gribben,19 on behalf of AUGMENT 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)

NCT01938001

1. Crawford et al. Ann Oncol. 2010;21 Suppl 5:248-251. 2. Smith et al. J Clin Oncol. 2015;33:3199-3212.

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-placebo Rituximab: 375 mg/m2 d1, 8, 15, 22 of cycle 1; d1 of cycles 2-5

Placebo: matched capsules (12 cycles) 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

≤ 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

PRIOR TREATMENT HISTORY (ITT POPULATION)

*Refractory defined as no response or progressive disease < 6 months after last dose.

Most common prior last regimens were R-CHOP (R2 37%, R-placebo 38%), combination chemotherapy (R2 33%, R-placebo 31%,) and rituximab monotherapy (R2 21%, R-placebo 23%)

Data cutoff June 22, 2018.

Characteristic, n (%) R2

(n = 178) R-placebo

(n = 180)

Number of prior systemic antilymphoma regimens

1 102 (57) 97 (54)

2 31 (17) 42 (23)

≥ 3 45 (25) 41 (23)

Prior rituximab treatment 152 (85) 150 (83)

Prior rituximab-containing chemotherapy 130 (73) 129 (72)

≤ 2 y since last antilymphoma therapy 89 (50) 92 (51)

Relapse ≤ 2 y of initial diagnosis 56 (31) 61 (34)

≤ 2 y of initial therapy 66 (37) 75 (42)

Refractory to last regimen* 30 (17) 26 (14)

SAFETY (AEs IN ≥ 10% OF PATIENTS FOR EITHER GROUP IN THE SAFETY POPULATION)

TEAEs for R2 (n = 176) TEAEs for R-placebo (n = 180)

Grade 3/4

Any grade

Adverse Events, % *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.

≥ 10%

difference

PRIMARY ENDPOINT: PROGRESSION-FREE SURVIVAL (ITT, IRC)

*Censoring rules based on FDA guidance.


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

Median follow up: 28.3 months

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

CONCLUSIONS

• AUGMENT met its primary endpoint as R2 demonstrated statistically

significant and clinically relevant superiority over R-placebo for the

primary endpoint of PFS

– PFS advantage in prespecified subgroups, except MZL, was consistent with

overall population

– Overall survival advantage for R2 in the follicular lymphoma subgroup

R2 represents an important new treatment option in patients

with previously treated indolent NHL

.

Schmidt et al, ASH 2018

Ibrutinib + Obinutuzumab in untreated Follicular Lymphoma

MJR


PTCL / PMBCL / MCL




CLL




Indolent NHL



DLBCL



Viola Poeschel1, Gerhard Held1, Marita Ziepert2, Bettina Altmann2, Mathias Witzens-Harig3, Harald Holte4, Lorenz Thurner1, Andreas Viardot5, Peter Borchmann6, Lothar Kanz7, Ulrich Keller8, Christian Schmidt9, Rolf Mahlberg10, Bernd Metzner11, Reinhard Marks12, Heinz-Gert Hoeffkes13, Konstantinos Christofyllakis1, Josif Amam1, Christian Berdel14, Stephan Stilgenbauer1, Norbert Schmitz15, Lorenz Truemper16, Niels Murawski1,

Markus Löffler2, Michael Pfreundschuh1

1Department of hematology, oncology and rheumatology, Saarland University Medical School, Homburg / Saar, Germany; 2Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; 3Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; 4Oslo University Hospital, Oslo, Norway; 5Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany; 6Department of Haematology and Oncology, University Hospital of Cologne, Cologne, Germany; 7University Hospital of Tuebingen, Tuebingen, Germany; 8Klinikum rechts der Isar der TU München, Munich, Germany; 9Department of Medicine III, University Hospital, Munich, Germany; 10Klinikum Mutterhaus der Borromaerinnen, Trier, Germany; 11Klinikum Oldenburg, Oldenburg, Germany; 12Department of Hematology and Oncology, University Medical Center, Freiburg, Germany; 13Klinikum Fulda Tumorklinik, Fulda, Germany; 14Department of radiooncology, Saarland University Medical School, Homburg / Saar, Germany; 15Medizinische Klinik A, University Hospital Münster, Münster, Germany; 16Georg August University, Goettingen, Germany

Excellent outcome of young patients (18-60 years) with favourable-prognosis diffuse large B cell lymphoma (DLBCL) treated with 4 cycles CHOP plus 6 applications of rituximab:

Results of the 592 patients of the FLYER trial of the DSHNHL/GLA.

supported by:

FLYER: Study Design

d 22 d 43 d 64 d 85 d 106 d 1

CHOP

R

R

• Front-line treatment of aggressive B-cell lymphoma • 18-60 years, stage I/II, aaIPI = 0, no bulk (max. diameter < 7.5 cm)

CHOP

R

CHOP

R

CHOP

R R

CHOP

R

CHOP

R

CHOP

R

CHOP

R

CHOP

R

CHOP

R

R

Demographics Total (n = 588) 6 x R-CHOP (n = 295) 4 x R-CHOP (n = 293) p-value

Female 234 (40 %) 116 (39 %) 118 (40 %) 0.814

Age, median (range) 48 (18,60) 47 (19, 60) 49 (18,60) 0.438

LDH > UNV 0 (0 %) 0 (0 %) 0 (0 %) -

ECOG > 1 0 (0 %) 0 (0 %) 0 (0 %) -

Stage I

II

III/IV

346 (59 %)

236 (40 %)

6 (1 %)

172 (58%)

119 (40 %)

4 (1 %)

174 (59 %)

117 (40 %)

2 (1 %)

0.953

aaIPI 0 1

582 (99 %)

6 (1 %)

291 (99 %)

4 (1 %)

291 (99 %)

2 (1 %) 0.686

Extralymph. involvement

191 (32 %) 96 (32 %) 95 (32 %) 0.975

Bulky disease 2 (0.3 %) 1 (0.3 %) 1 (0.3 %) 1.000

B-symptoms 36 (6 %) 9 (3 %) 27 (9 %) 0.002

Response Rates

6 x R-CHOP-21 (n = 295) 4 x R-CHOP-21 + 2 x R (n = 293)

At 36 months:

6 x R-CHOP-21 94% (95% CI: 91 %; 97 %) (n = 295)

4 x R-CHOP-21 + 2 x R 96 %, (95 % CI: 94 %; 99 %) (n = 293)

Median follow-up: 66 months

Primary Endpoint: PFS

Overall Survival (OS)

At 36 months:

6 x R-CHOP-21 98% (95% CI: 96 %; 99 %) (n = 295)

4 x R-CHOP-21 + 2 x R 99 % (95 % CI: 98 %; 100 %) (n = 293)

Median follow-up: 67 months

Total Number of Hematological Adverse Events

* - *** Blood counts in between chemotherapy cycles were only available in 69 % cycles resp. 73% cycles

Nu

mb

er o

f d

ocu

men

ted

eve

nts

Total Number of non-Hematological Adverse Events

6x R-CHOP-21

(n=295)

4 x R-CHOP-21 + 2 x R (n = 293)

any grade grade 3-4 any grade grade 3-4

All 1295 70 835 46

Paresthesia 370 14 227 12

Nausea 319 12 195 6

Infection 156 23 98 20

Vomiting 117 7 56 1

Mucositis 105 3 68 1

Overall reduction of non-hem AEs by approx a third

Conclusion • PFS and OS with 4 cycles of R-CHOP + 2 x R is

non-inferior to the previous standard 6 x R-CHOP in younger patients with favourable prognosis aggressive B-NHL (aaIPI=0, no bulk)

• AEs with 4 cycles were reduced by about a third, which means a significant benefit for patients

• Relapse pattern is similar in both arms

A Global, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Ibrutinib Plus Rituximab, Cyclophosphamide, Doxorubicin,

Vincristine, and Prednisone in Patients With Previously Untreated Non-Germinal Center B-Cell-Like

Diffuse Large B-Cell Lymphoma

Anas Younes,1 Laurie H Sehn,2 Peter Johnson,3 Pier Luigi Zinzani,4 Xiaonan Hong,5 Jun Zhu,6 Olga Samoilova,7 Cheolwon Suh,8 Itaru Matsumura,9 Andres Lopez-Hernandez,10

Ulrich Dührsen,11 Catherine Thieblemont,12 Jodi Carey,13 Grace Liu,14 S. Martin Shreeve,15 Steven Sun,14 Jessica Vermeulen,16 Louis Staudt,17

and Wyndham Wilson,18 on behalf of the PHOENIX investigators 1

1Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2BC Cancer Centre for Lymphoid Cancer, Vancouver, BC, Canada; 3Cancer Research UK Clinical Centre, University of Southampton, Southampton, UK; 4Institute of Hematology, “Seràgnoli” University of Bologna, Bologna, Italy;

5Fudan University Shanghai Cancer Center, Shanghai, China; 6Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China; 7Regional Clinical Hospital, Nizhniy Novgorod, Russian Federation; 8Department of Oncology, Asan Medical Center, University of Ulsan

College of Medicine, Seoul, Republic of Korea; 9Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osakasayama, Japan; 10Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain; 11Department of Hematology, University

Hospital Essen, Essen, Germany; 12APHP, Hôpital Saint-Louis, Hemato-Oncology, Paris, France; Diderot University, Sorbonne Paris-Cité, Paris, France; 13Janssen R&D, Spring House, PA, USA; 14Janssen Research & Development, Raritan, NJ, USA; 15Janssen Research & Development, San

Diego, CA, USA; 16Janssen Research & Development, LLC, Leiden, The Netherlands; 17Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

18National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

American Society of Hematology 60th Annual Meeting and Exposition, Younes A, et al. Abstract 784.

Key eligibility criteria

Untreated non-GCB DLBCL – Determined by Hans-based IHC at a

central laboratory

– Retrospectively analyzed for ABC subtype using GEP

Stage II to IV measureable disease

R-IPI ≥ 1

ECOG performance status ≤ 2

End points

Primary end point: EFS† in ITT (non-GCB) and ABC subgroup

Secondary end points: PFS, CR rate, OS, safety

– Response assessed per Revised Response Criteria for Malignant Lymphoma1

Study Design: Double-Blind, Placebo-Controlled Study

Ran

do

miz

ea

R-CHOP (6-8 cycles*) + placebo

R-CHOP (6-8 cycles*) + 560 mg ibrutinib

aStratified by R-IPI, region, and number of prespecified treatment cycles (6 vs 8 cycles). Prophylactic antibiotics and G-CSF were not mandated but were permitted at the investigator’s discretion per local or other standard guidelines

N = 838

1:1 *As prespecified by site

†EFS: time from randomization to PD, relapse from CR, initiation of subsequent disease-specific therapy for PET-positive or biopsy-proven residual disease after ≥ 6 cycles of R-CHOP, or any-cause death.

1. Cheson BD, et al. J Clin Oncol. 2007;25:579-586.


Months

0

EFS

by

inve

stig

ato

r as

sess

me

nt

(%)

100

90

80

70

60

50

40

30

20

10

0

Patients at risk Ibrutinib + R-CHOP Placebo + R-CHOP

419 374 336 316 300 291 276 233 179 120 63 25 3 0 419 390 341 316 297 286 277 244 184 118 60 33 5 0

4 8 12 16 20 24 28 32 36 40 44 48 52

Hazard ratio (95% CI): 0.934 (0.726-1.200) p value: 0.5906

ITT (n = 838)

Primary End Point: EFS in the ITT and ABC Population

Ibrutinib + R-CHOP Placebo + R-CHOP

Months

0

EFS

by

inve

stig

ato

r as

sess

me

nt

(%)

100

90

80

70

60

50

40

30

20

10

0

Patients at risk Ibrutinib + R-CHOP Placebo + R-CHOP

4 8 12 16 20 24 28 32 36 40 44 48 52

285 256 225 211 197 191 181 149 111 77 39 15 2 0 282 260 225 212 196 188 183 160 125 78 41 25 3 0

Hazard ratio (95% CI): 0.949 (0.704-1.279) p value: 0.7311

ABC (n = 567)

Overall response (89.3% vs 93.1%) and CR rates (67.3% vs 68.0%) were similar in the ibrutinib + R-CHOP and placebo + R-CHOP arms in the ITT population

CNS progression was observed: 10 (2.4%) vs 16 (3.8%) patients in the ibrutinib + R-CHOP and placebo + R-CHOP arms


EFS and OS in Patients < 60 Years

EFS (n = 342) OS (n = 342)

Months

0

EFS

by

inve

stig

ato

r as

sess

me

nt

(%)

100

90

80

70

60

50

40

30

20

10

0

4 8 12 16 20 24 28 32 36 40 44 48 52

156 146 133 125 121 117 113 93 72 44 27 13 2 0

186 177 148 137 132 127 120 104 78 52 24 16 3 0

Hazard ratio (95% CI): 0.579 (0.380-0.881)

Months

0

Du

rati

on

of

OS

(%)

100

90

80

70

60

50

40

30

20

10

0

Patients at risk

Ibrutinib + R-CHOP

Placebo + R-CHOP

4 8 12 16 20 24 28 32 36 40 44 48 52

156 151 145 142 138 137 134 125 96 62 39 18 3 0

186 181 173 161 153 148 145 130 101 70 38 21 5 0

Hazard ratio (95% CI): 0.330 (0.162-0.673)

Patients at risk

Ibrutinib + R-CHOP

Placebo + R-CHOP

δ 12.3%

δ 11.1%

Ibrutinib + R-CHOP improved EFS and OS vs placebo + R-CHOP in patients < 60 years of age Subgroup analyses showed that EFS benefit was consistent across most subgroups for baseline factors A similar trend with age was seen in patients with the ABC subtype (HR [95% CI]: 0.532 [0.307-0.922] for EFS;

HR [95% CI]: 0.345 [0.138-0.862] for OS) More patients on the placebo + R-CHOP arm received subsequent antilymphoma therapy (25.2% vs 33.5%)



Treatment-Emergent SAEs,* Overall Population

*Occurring in ≥ 2% patients in any treatment group.

0 20 40 60

Thrombocytopenia

Pyrexia

Atrial fibrillation

Lung infection

Diarrhea

Anemia

Neutropenia

Pneumonia

Febrile neutropenia

Serious AEs

SAEs overall population

Patients (%)

Placebo + R-CHOP

Ibrutinib + R-CHOP

TEAE types were consistent with those expected for ibrutinib and R-CHOP Prophylactic G-CSF was used in 66% vs 64% patients in the ibrutinib + R-CHOP and placebo + R-CHOP arms

─ 56.5% vs 56.2% in patients < 60 years ─ 71.8% vs 70.0% in patients ≥ 60 years


AE Rate by Age (Cumulative) in the Ibrutinib + R-CHOP vs Placebo + R-CHOP Group

Serious AEs TEAEs leading to treatment discontinuation


Rat

e o

f A

Es (

%)

Age

100

90

80

70

60

50

40

30

20

10 5 0

Age

100

90

80

70

60

50

40

30

20

10 5 0

AE rates were analyzed in cumulative age groups from < 53 to < 89 years Higher rates of SAEs and AEs leading to discontinuations were seen in older patients treated

with ibrutinib + R-CHOP


Safety Summary AEs and SAEs by Age < 60 and ≥ 60 Years

Patients (%)

0 10 20 30 40 50 60 70 80 90 100

< 60 years only

TEAEs leading to death

TEAEs leading to R-CHOP d/c

TEAEs leading to study drug d/c

Study drug–related SAEs

SAEs

Study drug–related TEAEs

Grade ≥ 3 TEAEs

TEAEs

Grade ≥ 3 SAEs

TEAEs leading to death

TEAEs leading to R-CHOP d/c

TEAEs leading to study drug d/c

Study drug–related SAEs

SAEs

Study drug–related TEAEs

Grade ≥ 3 TEAEs

TEAEs

Grade ≥ 3 SAEs

0 10 20 30 40 50 60 70 80 90 100

≥ 60 years only

Patients (%)

Ibrutinib + R-CHOP

Placebo + R-CHOP

AEs were similar across arms for both age groups TEAEs leading to dose reduction or treatment discontinuation primarily included febrile neutropenia and

peripheral neuropathy In patients ≥ 60 years, ibrutinib + R-CHOP was associated with

Higher SAEs Higher AEs leading to treatment discontinuation


In the ITT population, addition of ibrutinib to R-CHOP did not improve efficacy in

patients with untreated non-GCB DLBCL

The benefit-risk profile of ibrutinib + R-CHOP is dependent on age

– In patients < 60 years, ibrutinib + R-CHOP was associated with prolonged EFS, PFS,

and OS

In patients ≥ 60 years, addition of ibrutinib to R-CHOP increased rates of SAEs and

AEs leading to R-CHOP discontinuation, which compromised treatment exposure

and likely decreased efficacy

– In older patients, risk with the addition of ibrutinib to R-CHOP outweighs the benefit

Since the primary end point of the study was not met, this hypothesis-generating

finding requires confirmation in a prospective clinical trial

Conclusions

MJR


PTCL / PMBCL / MCL




CLL




Indolent NHL



DLBCL



Documents

Lymphome, CLL - InVOinvo.maxit4u.de/wp-content/uploads/2019/02/Neues... · OS: HR 0.66, P=0.024 • A+CHP has a comparable safety profile to CHOP • ECHELON-2 is first prospective