Methods Results Conclusions References ... - MorphoSys AG

L-MIND: MOR208 combined with lenalidomide (LEN) in patients with relapsed or refractory diffuse large B-cell lymphoma (R-R DLBCL) – a single-arm phase II study Kami J. Maddocks, Eva González Barca, Wojciech Jurczak, Anna Marina Liberati, Johannes Duell, Zsolt Nagy, Tomáš Papajík, Marc Andre, Nagesh Kalakonda, Martin H. Dreyling, Pier Luigi Zinzani, Sumeet Vijay Ambarkhane, Johannes Weirather, Gilles A. Salles 1

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Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH; 2Department of Hematology, Institut Catalá d‘Oncología, Hospital Duran i Reynals, IDIBELL, Barcelona, Spain; 3Department of Hematology, Jagiellonian University, Kraków, Poland; 4SC Oncoematologia, Azienda Ospedaliera Santa Maria, Terni, Italy; 5Medizinische Klinik und Poliklinik II, UniversityHospital of Würzburg, Würzburg, Germany; 6 First Department of Internal Medicine, Semmelweis University, Budapest, Hungary; 7Department of Hemato-Oncology, Palacký University Olomouc and the University Hospital Olomouc, Olomouc, Czech Republic; 8Université catholique de Louvain, CHU UCL Namur, Department of Hematology, Yvoir, Belgium; 9Department of Haematology, Royal Liverpool University Hospital, Liverpool, United Kingdom; 10University Hospital of LMU, Munich, Germany; 11 Institute of Hematology “L. e A. Seràgnoli”, University of Bologna, Bologna, Italy; 12MorphoSys AG, Planegg, Germany; 13Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Service d‘Hématologie, Pierre Bénite, France 1

ASCO June 2–6, 2017: Abstract 7514 • CD19 is broadly and homogeneously expressed across different B-cell malignancies including DLBCL, and enhances B-cell receptor (BCR) signaling and tumor cell proliferation.1,2 • MOR208 is an Fc-engineered, humanized, monoclonal antibody that targets CD19 on tumor cells leading to natural killer (NK) cell-mediated antibody-dependent cellmediated cytotoxicity, macrophage-mediated antibody-dependent cell-mediated phagocytosis and direct cytotoxicity (Figure 1).

O

NH2

O

NH

Methods

O

activation

ADCC

Affinity matured CD19 binding site ► Direct tumor cell killing

Natural killer cell

Patients

Engineered Fc portion ► Enhanced ADCC ► Enhanced ADCP

• Patients must have an ECOG performance status of 0–2 and adequate bone marrow, hepatic and renal function.

• The enrollment of 80 patients is planned; recruitment is ongoing.

Cycle 1-3

Direct cytotoxicity ADCP

• LEN, which belongs to a class of immunomodulating agents (immunomodulatory drugs [IMiDs®]), has both antiproliferative and antiangiogenic activities, stimulating the activity of effector cells such as NK cells.5 • LEN has been shown to have single agent activity in patients with R-R DLBCL, as indicated by a recently reported overall response rate of 27.5%, including a complete response rate of 9.8%.6 • We present preliminary efficacy and safety data from an ongoing phase II study of MOR208 combined with LEN in patients with R-R DLBCL.

Objectives Primary

• To determine the activity of MOR208 combined with LEN in relation to objective response rate (complete responses + partial responses) in adult patients with R-R DLBCL.

Ann-Arbor

III-IV

26 (59)

ECOG PS

0-1

41 (93)

Prior lines

LDH level

Patients with R-R DLBCL:

20 (46)

Poor (3-5)

21 (48)

MOR208

MOR208

12 mg/kg IV Days 1, 8, 15, 22*

12 mg/kg IV Days 1, 15

1

22 (50)

≥2

18 (41) 4 (9)

Elevated

25 (57)

Not elevated

16 (36)

Refractory to last prior line

Prior ASCT

3 (7)

Yes

12 (27)

No

20 (46)

Currently unknown

12 (27)

Yes

16 (36)

No

18 (41)

Currently unknown

10 (23)

Yes

2 (5)

No

40 (91)

Currently unknown

2 (5)

Relapse ≤12 months

8 (18)

Relapse >12 months

25 (57)

Currently unknown

11 (25)

Data are n (%) unless otherwise stated. ASCT, autologous stem cell transplant; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; serum LDH levels of >220 U/L were considered to be elevated; R-IPI, revised international prognostic index.

Additional antibody treatment phase

Disease control (≥SD)

MOR208 12 mg/kg IV Days 1, 15

Survival follow-up

• As of March 06, 2017, a total of 44 patients had been enrolled in the study of which 34 qualified for efficacy assessment; the study is ongoing. • 10 patients did not have a post-baseline response assessment and were ongoing. • Baseline characteristics are shown in Table 1.

Table 3. Frequency of patients with LEN dose reductions, n (%) N=44

CR CR CR CR PR SD PR

CR PR

PR

CR PR

PR PD

SD PR CR

PD PR

60

PD PD

Ongoing patients

NE

N=34

PD PD NE NE NE

2

4

6

8

10

12

Time on Study (months)

Table 2. Most common TEAEs, n (%) N=44 Any grade*

Grade ≥3

Grade 4

Neutropenia

16 (36)

14 (32)

5 (11)

Anemia

11 (25)

2 (5)

0

Thrombocytopenia

8 (18)

4 (9)

0

Leukopenia

6 (14)

4 (9)

0

Rashes

9 (20)

3 (7)

0

Pyrexia

7 (16)

1 (2)

0

Diarrhea

7 (16)

0

0

Asthenia

6 (14)

0

0

Pneumonia

5 (11)

4 (9)

1 (2)

Bronchitis

5 (11)

1 (2)

1 (2)

Nausea

5 (11)

0

0

Cough

4 (9)

1 (2)

0

Cramps

4 (9)

1 (2)

0

Urinary tract infection

4 (9)

0

0

Hematological

Non-Hematological 40

ORR: 56% 20

CR: 32% (n=11)

0 Five patients were not evaluable due to: adverse events (n=2), withdrawal of consent (n=1), non-compliance (n=1), or death (n=1) before any postbaseline response assessment. CR, complete response; NE, not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.

Reduction to 15 mg/day

3 (7) 8 (18)

• The preliminary objective response rate was 56% with a complete response rate of 32%.

NE

• As of now no unexpected toxicities were observed compared to the known toxicity profiles of lenalidomide or MOR208 monotherapy.

PR: 24% (n=8)

9 (20)

• MOR208 in combination with LEN showed encouraging preliminary activity in patients with R-R DLBCL, ineligible for transplantation, with a poor prognosis, and a median age of 73 years.

• The median time to response, or to complete response were 1.8 months and 3.4 months, respectively (Figure 4).

SD: 12% (n=4)

Reduction to 20 mg/day

Conclusions

SD

• Treatment-related serious adverse events occurred in six patients (pneumonia, febrile neutropenia, agranulocytosis, bronchitis, tumor flare, pyrexia; all six patients recovered).

PD/NE: 32% (n=11)

12 (27)

CR

• With a median follow-up of 5.6 months, 16 out of 19 responses are ongoing.

100

Reductions (in total)

PR

• Treatment-emergent adverse events of any grade, grade ≥3 and grade 4 are shown in Table 2.

n=34

24 (55)

Currently unknown

• An additional 12% of patient benefited from therapy with stable disease.

Figure 3. Response rate

No reduction

SD

Safety

80

• This is a report of preliminary efficacy (investigator assessed, according to the revised response criteria based on the guidelines of International Working Group, reported by Cheson et al.) – and safety data.

CR

CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.

25 mg PO Days 1-21

Results

PR

• The objective response rate was 56% with a complete response rate of 32% (Figure 3).

Lenalidomide

*An additional loading dose was administered on day 4 of cycle 1. Safety data from the first six patients were evaluated in a safety run-in to determine the starting dose of LEN for the remainder of study. ASCT, autologous stem cell transplant; EOT, end of treatment; HDCT, high-dose chemotherapy; IV, intravenous; PO, per os; R-R DLBCL, relapsed or refractory diffuse large B-cell lymphoma; SD, stable disease.

LEN dose reductions

CR

3 (7)

Preliminary efficacy analysis

Cycle 4 -12

•h  ave received 1-3 prior regimens • a re not eligible for HDCT and ASCT

Intermediate (1-2)

Currently unknown Refractory to rituximab

SD

3 (7)

Currently unknown

• Phase II, single-arm, open-label, multicenter study (NCT02399085; Figure 2).

MOR208

• Previous phase I and phase II study results have shown MOR208 to be safe and well tolerated with a potential clinical benefit for patients with R-R non-Hodgkin’s lymphomas, including DLBCL with an overall response rate of 26%, including a complete response rate of 6%.3,4

24 / 20

First relapse post-diagnosis

Figure 2. Study design and dosing scheme

ADCC, antibody-dependent cell-mediated cytotoxicity, ADCP, antibody-dependent cell-mediated phagocytosis.

Female / Male

• No infusion-related reactions were reported for MOR208.

CR

73 (47–82)

Sex

Key exclusion criteria

Tumor cell

Macrophage

Median (range)

Currently unknown

Study design CD19

Age, years

Key inclusion criteria

• Patients with a primary refractory DLBCL, a history of “double/triple hit” DLBCL and, those with central nervous system lymphoma involvement, are excluded.

antiproliferative

n (%) N=44

R-IPI

• Patients with grade 3b follicular lymphoma, or histological transformation from indolent lymphoma into DLBCL with subsequent relapse are also eligible.

Lenalidomide

Characteristic

2

• Patients aged ≥18 years with histologically confirmed relapsed and/or refractory DLBCL, who have received at least one but not more than three previous systemic regimens of which one therapy line must have included a CD20-targeted therapy (e.g., rituximab), and who are not candidates for high-dose chemotherapy are eligible.

Figure 1. MOR208 and LEN modes of action

N

• To determine progression-free survival, duration of response, overall survival, safety, peripheral B-, T- and NK cell counts and gene expression profiling analysis for cell of origin subtyping.

Infusion tolerability

Figure 4. Time on study and best response

Table 1. Baseline characteristics

Best Overall Response (%)

Introduction

Best Overall Response

Secondary

*Most commonly reported TEAEs occurring in ≥7% of patients. TEAEs, treatment-emergent adverse events.

• MOR208 in combination with LEN was well tolerated, only 27% patients required a reduction of LEN dose due to toxicity. • Accrual and follow-up of patients (including continued study treatment) is ongoing, as are cell of origin and other subgroup analyses.

References 1. Olejniczak SH, et al., Immunol Invest. 2006;35(1):93-114. 2. Poe JC, et al. J Immunol 2012;189:2318-25. 3. Woyach JA, et al. Blood 2014;124:3553-60. 4. Jurczak W, et al. Blood 2016;128:623. 5. Kritharis A, et al. Blood 2015; 125:2471-2476. 6. Czuczman MS, et al. Clin Cancer Res 2017. [Epub ahead of print] 7. Cheson BD, et al. J Clin Oncol 2007;25:579-86.

Acknowledgments This study was sponsored by MorphoSys AG. Medical writing support was provided by Jim Heighway PhD, Cancer Communications and Consultancy Ltd (Knutsford, UK) and Manuel Krinner; both were funded by MorphoSys AG.

Disclosures Disclosures in relation to MorphoSys AG: WJ, consulting/advisory role; research funding; SVA, JW, employment; other authors had no conflict of interest to disclose in relation to MorphoSys AG.

Correspondence [email protected] Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO® and Kami Maddocks, MD.