PCYC-1125-Ca trial: Ibrutinib Plus Rituximab in Treatment-Naive Patients With Follicular Lymphoma

Nathan Fowler, Department of Lymphoma and Myeloma, The University

of Texas MD Anderson Cancer Center, Houston, TX

Follicular Lymphoma

Ibrutinib in FL

• Ibrutinib :phase 1, first-in-human, dose-escalation trial in patients with relapsed/refractory FL

overall response rate (ORR) 38%

Complete Response (CR) 20% --(Advani, JCO 2013).

Frontline Ibrutinib Plus Rituximab in FL: Study Design

• Multicenter phase II study of combination ibrutinib plus rituximab therapy in previously untreated FL pts

• Primary endpoint: ORR

• Secondary endpoints: DoR, PFS, OS, and safety

Treatment naive,

stage II, III, or IV FL

pts with at least

1 measurable lesion

≥ 2 cm; ECOG PS ≤

2

(N = 60)

Ibrutinib

560 mg PO QD +

Rituximab

375 mg/m2 IV weekly x 4

Continued

until

disease

progression

or toxicity

Frontline Ibrutinib Plus Rituximab in FL:

Response

ORR of 82% (49 of 60); CR of 30%

– Median follow-up: 13.8 mos with a median time to best response of 2.7 mos

– Median duration of ibrutinib treatment: 12.55 mos

Frontline Ibrutinib Plus Rituximab in FL: DoR and PFS

• At a median follow-up of 13.8 mos:• Median PFS not reached; 12-mo PFS rate of 86%

• Median OS not reached; 12-mo OS rate of 98%

100

90

80

70

60

50

40

30

20

10

0

Do

R (

%)

Mos From Initiation of Study Treatment0 123 6 9

Pts at

Risk, n: 49 45 34 9 0

100

90

80

70

60

50

40

30

20

10

0

PF

S (

%)

Mos From Initiation of Study Treatment0 123 6 9

Pts at

Risk, n: 60 56 53 41 12

15

1

Frontline Ibrutinib Plus Rituximab in FL: Additional Safety Outcomes

Characteristic, n (%) Ibrutinib + Rituximab

(N = 60)

Serious AEs (all in 1 pt each)

Any

Grade 3/4

10 (17)

9 (15)

Bleeding events 19 (32)

Atrial fibrillation 3 (5)

Secondary malignancies 4 (7)

Discontinued ibrutinib due to toxicity/intercurrent illness 9 (15)

Dose reduction of ibrutinib (560 mg to 420 mg) due to

toxicity4 (7)

Frontline Ibrutinib Plus Rituximab in FL: Conclusions

“Ibrutinib addition to rituximab in treatment-naive FL pts is highly active with 82% ORR and 30% CR”

“Combination chemotherapy-free treatment well tolerated with few grade 3/4 serious Aes”

PYRAMID: Frontline R-CHOP ± Bortezomib in Non-GCB DLBCL

Leonard et al, Weill Cornell Medical College, New York, NY

PYRAMID: Background

In retrospective analyses, non-GCB DLBCL pts display less favorable outcomes with R-CHOP chemotherapy than those with GCB DLBCL

Non-GCB DLBCL dependent on NF-κB pathways

Randomized phase II study in non-GCB DLBCL pts investigates efficacy and safety of frontline R-CHOP vs R-CHOP + bortezomib[8]

Meyer PN, et al. J Clin Oncol. 2011;29:200-207./Davis RE, et al. J Exp Med. 2001;194:1861-1874./Ngo VN, et al. Nature.

2006;441;106-110.

PYRAMID: Study Design• Prospective randomized, open-label phase II study

• Primary endpoint: PFS

• Secondary endpoints: OS, ORR, CR, toxicity• Evaluated response, disease progression by CT and FDG-PET at end of cycles 2 and 6• Follow-up scans every 3 mos until disease progression

Treatment-naive,

centrally confirmed

non-GCB DLBCL by

Hans IHC method with

measurable disease,

ECOG PS 0-2

(N = 183)

Bortezomib 1.3 mg/m2 IV Days 1, 4 +

R-CHOP* 21 days x 6 cycles

(n = 92)

R-CHOP* 21 days x 6 cycles

(n = 91)

PYRAMID: Baseline Characteristics

CharacteristicVR-CHOP

(n = 92)

R-CHOP

(n = 91)

Median age, yrs (range)

Age > 65 yrs, %

65 (20-83)

46

62 (24-85)

44

Male, % 49 58

IPI risk group, %

Low

Low/intermediate

High/intermediate

High

28

27

34

11

24

25

38

12

ECOG PS, %

0

1

2

59

40

1

44

44

12

LDH > ULN, % 54 55

PYRAMID: Drug Exposure and Response

• 85% VR-CHOP and 86% R-CHOP pts completed ≥ 6 treatment cycles• Median relative dose intensity: > 98% in both arms for all drugs

• Median duration of follow-up: 34 mos in both arms

Characteristic, %VR-CHOP

(n = 90)

R-CHOP

(n = 86)

CR 56 49

CR/PR 96 98

Negative FDG-PET at EOT visit 59 53

PYRAMID: Survival Outcomes

Outcome, %VR-CHOP

(n = 92)

R-CHOP

(n = 91)HR (95% CI) P Value

2-yr PFS rate 82 780.73

(0.43-1.24).611

2-yr PFS rate by IPI risk group

Low and Low/Intermediate 89 (n = 51) 90 (n = 45)0.85

(0.35-2.10).958

Intermediate/High and

High72 (n = 41) 65 (n = 46)

0.67

(0.34-1.29).606

2-yr OS rate 93 880.75

(0.38-1.45).763

PYRAMID: Safety

• Any grade AE in ≥ 25% pts in either arm

• Hematologic: neutropenia, thrombocytopenia,‡ anemia

• Non-hematologic: fatigue,§ nausea,§

peripheral neuropathy,‡ alopecia,§

constipation, insomnia, diarrhea, peripheral edema,‡ decreased appetite

• Grade ≥ 3 AEs in ≥ 10% pts in either arm

• Hematologic: neutropenia, thrombocytopenia,‡ anemia,‡

decreased WBC, leukopenia,§

decreased platelet count, febrile neutropenia

• Nonhematologic: hypokalemia

Event, %VR-CHOP

(n = 101)

R-CHOP

(n = 100)

Any AE

Grade ≥ 3

99

79

100

71

Drug-related AE

Grade ≥ 3

95

68

88

55

Serious AE 34 31

AEs leading to

discontinuation6 4

Death < 1* 1†

PYRAMID: Conclusions

“Similar survival outcomes with VR-CHOP and R-CHOP in treatment-naive pts with non-GCB DLBCL”

S1106: R-Bendamustine vs R-HyperCVADInduction Therapy Followed by ASCT in MCL

S1106: Background

• Best treatment for MCL still undefined

• R-hyperCVAD effective; but combination with high-dose cytarabine and methotrexate important

–ASCT possible after short course of R-hyperCVAD

• In a phase III trial, R-bendamustine demonstrated greater efficacy than R-CHOP

Romaguera JE, et al. J Clin Oncol. 2005;23:7013-7023. 2. Khouri IF, et al. J Clin Oncol. 1998;16:3803-3809. 3. Till BG, et al. Leuk Lymphoma.

2008;49:1062-1073. 4. Rummel MJ, et al. Lancet. 2013;38:1203-1210. 5. Dreyling M, et al. Blood. 2005;105:2677-2684. 6.

S1106: Study Design

• Randomized phase II US Intergroup trial

• Primary endpoint: 2-yr PFS rate

• Secondary endpoints: ORR, OS, toxicity, prognostic value of MRD monitoring

Adult pts 18-65 yrs of age

with untreated stage III,

IV, or bulky stage II MCL;

CD19+ or CD20+;

cyclin D1 IHC or t(11;14);

2-dimensional

measurable disease,

adequate organ function

(N = 52)

R-Bendamustine

4 cycles

(n = 35)

R-HyperCVAD

Cycle 1

R-MTX/Cytarabine

Cycle 2

(n = 17)

R-HyperCVAD

Cycle 3

Stem cell collection

R-MTX/Cytarabine

Cycle 4

R-Bendamustine

2 cycles

R-Cyclophosphamide

1 cycle

Stem cell collection

Stratified by MIPI Restaging:* ≥ PR Restaging: age

< 61 yrs: CBV,

BEAM, or

TBI/VP16/Cy

61-65 yrs:

CBV or BEAM

*< PR off study.

S1106: Baseline Characteristics

CharacteristicR-Bendamustine

(n = 35)

R-HyperCVAD

(n = 17)P Value

Age, yrs 57 (33-64) 59 (44-66) .23

Male, n (%) 32 (91) 9 (53) .003

ECOG PS, n (%)

0

1

26 (74)

9 (26)

11 (65)

6 (35)

.52

Disease stage, n (%)

III

IV

3 (8.5)

32 (91.4)

1 (5.9)

16 (94.1)

1.00

Bulky disease, n (%) 3 (8) 1 (6) 1.00

B symptoms, n (%) 10 (29) 6 (35) .75

Bone marrow involvement, n (%) 30 (86) 14 (82) 1.00

Extranodal involvement, n (%) 32 (91) 15 (88) 1.00Elevated LDH, n (%) 9 (26) 5 (29) 1.00

MIPI score, n (%)

Intermediate/high risk

Low risk

13 (37)

22 (63)

6 (35)

11 (65)

1.00

S1106: Outcomes

Outcome, n = 52 evaluable ptsR-Bendamustine

(n = 35)

R-HyperCVAD

(n = 17)

Median follow-up, mos (range) 27.3 (1.0-39.5) 34 (10.0-41.0)

Response, %

ORR

CR

PR

Inadequate

82.9

40

43

17

94.1

35

59

6

Survival, %

2-yr PFS

2-yr OS

81

87

82

88

S1106: Induction Phase Grade 3/4 AEsEvent, %

R-Bendamustine(n = 35)

R-HyperCVAD(n = 17)

Thrombocytopenia 17 71

Neutropenia Febrile neutropenia

3414

6529

Anemia 8.6 59

Hypokalemia 5.7 29

Hypophosphatemia 2.9 24

Hyperglycemia 0 12

Increased ALT 0 5.9

Increased AST 0 5.9

Catheter infection 2.9 5.9

Dehydration 0 5.9

Diarrhea 0 5.9

Epistaxis 0 5.9

Nausea 0 5.9

Rash 2.9 5.9

Syncope 0 5.9

S1106: Progression-Free Survival

100

80

60

40

20

00 12 24 36 48

Months After Registration

%

R-Bendamustine

R-HCVAD

Failed

8

4

At Risk

35

17

2-year

Estimate

81%

82%

S1106: Overall Survival

100

80

60

40

20

00 12 24 36 48

Months After Registration

%

R-Bendamustine

R-HCVAD

Failed

4

2

At Risk

35

17

2-year

Estimate

87%

88%

S1106: Conclusions

“R-bendamustine exhibited similar response rates, 2-yr PFS, and 2-yr OS compared with R-hyperCVAD”

• R-bendamustine:–2-yr PFS rate of 81%

–89% MRD-negative rate on paired samples

–Exhibited less hematologic and marrow toxicity than R-hyperCVAD

Chen R, et al. ASH 2015. Abstract 518.

Bendamustine Treatment in Refractory or Relapsed T Cell Lymphomas: A Retrospective

Multicenter Study

Reboursiere et al, CHU, Caen, France

Background

• Peripheral T-cell lymphoma :aggressive disease with poor outcome.

• First line therapies are usually unsatisfactory with frequent need for second-line therapies.

• Median progression free survival (PFS) and overall survival (OS) for relapse PTCL patients are very short with few available therapeutic options.

• Bendamustine has been shown to be active in phase 1 studies.

Study Method

• median age was 64y (range 28-89)

• Histology : AILT=63, PTCL-NOS =44), ALCL=13, NK/TCL (n=3), mycosis fungoides (MF=7), subcutaneous panniculitis-like-TCL (n=2), hepato-splenic-TCL (n=1) and others (n=9).

• The majority of patients (96%, n=130) had stage-disseminated disease and 72% (n=102) of them had extranodal localisations.

• The median number of chemotherapy lines prior to bendamustine was 2 (range 0-8). Seven patients (5%) had SCT and 16 autoSCT (11%)

• The median duration of response prior to bendamustine 4.3m and 50% of patients had refractory disease.

Result

• Overall, they received a median of 2 cycles (range 1-8) with a median dose of 90mg/m2 (range 50-150).

• The best overall response rate (ORR) was 32% ,complete response of 24% (CR=34). The median DoR was 3.3 months (1-39).

• For AITL patients, ORR was 52% (33/63) with CR of 41%, whereas it was 18% (8/44) with 11% of CR,

“Bendamustine as single agent must be considered as a therapeutic option for relapsed or refractory PTCL, particularly in patients with AITL”