esmo summit africa 2019 · obinutuzumab-based induction and maintenance prolongs progression-free...

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?


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


Failure free survival Overall survival

GLSG training cohort


Reclassifying risk groups

Follicular lymphoma –

Low versus high burden?

ESMO

GUIDELINES FL

Dreyling et al., 2016Dreyling et al., 2016

ESMO

GUIDELINES FL


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


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


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)


*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)


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


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



*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) ‡‡


Grade 5 (fatal) AEs by treatment (FL)*



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


• 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


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


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


• 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)


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%

Secondary Endpoints

Secondary

endpoints

[email protected]

Continuous PFS

HypothesisHypothesis

PFS similar to R-

CHEMO?

ESMO

GUIDELINES FL

Some progess,

But still a lot of

chemotherapy!


ESMO

GUIDELINES FL


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


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


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)


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)*


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)


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)



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


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


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.


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


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


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


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)


ESMO

GUIDELINES FL


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!

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