ASCO June 2–6, 2017: Abstract 7514

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 studyKami J. Maddocks,1 Eva González Barca,2 Wojciech Jurczak,3 Anna Marina Liberati,4 Johannes Duell,5 Zsolt Nagy,6 Tomáš Papajík,7 Marc Andre,8 Nagesh Kalakonda,9 Martin H. Dreyling,10 Pier Luigi Zinzani,11 Sumeet Vijay Ambarkhane,12 Johannes Weirather,12 Gilles A. Salles13

1Division 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; 6First 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; 11Institute 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

Secondary

• 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.

MethodsPatients

Key inclusion criteria

• 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.

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

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

Key exclusion criteria

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

Study design

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

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

Figure 2. Study design and dosing scheme

* 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.

Results

• 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.

• 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 1. Baseline characteristicsCharacteristic n (%) N=44Age, years Median (range) 73 (47–82) Sex Female / Male 24 / 20Ann-Arbor III-IV 26 (59)ECOG PS 0-1 41 (93)

2 3 (7)R-IPI Intermediate (1-2) 20 (46)

Poor (3-5) 21 (48)Currently unknown 3 (7)

Prior lines 1 22 (50)≥ 2 18 (41)Currently unknown 4 (9)

LDH level Elevated 25 (57)Not elevated 16 (36)Currently unknown 3 (7)

Refractory to rituximab Yes 12 (27)No 20 (46)Currently unknown 12 (27)

Refractory to last prior line Yes 16 (36)No 18 (41)Currently unknown 10 (23)

Prior ASCT Yes 2 (5)No 40 (91)Currently unknown 2 (5)

First relapse post-diagnosis 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.

Preliminary efficacy analysis

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

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

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

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

Figure 3. Response rate

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 post- baseline response assessment. CR, complete response; NE, not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.

Best

Ove

rall

Resp

onse

(%)

0

20

40

60

80

100

CR: 32%(n=11)

PD/NE: 32%(n=11)

PR: 24%(n=8)

ORR: 56%

SD: 12%(n=4)

n=34

Figure 4. Time on study and best response

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

Safety

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

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

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

Table 2. Most common TEAEs, n (%) N=44Any grade* Grade ≥3 Grade 4

HematologicalNeutropenia 16 (36) 14 (32) 5 (11)Anemia 11 (25) 2 (5) 0Thrombocytopenia 8 (18) 4 (9) 0Leukopenia 6 (14) 4 (9) 0

Non-HematologicalRashes 9 (20) 3 (7) 0Pyrexia 7 (16) 1 (2) 0Diarrhea 7 (16) 0 0Asthenia 6 (14) 0 0Pneumonia 5 (11) 4 (9) 1 (2)Bronchitis 5 (11) 1 (2) 1 (2)Nausea 5 (11) 0 0Cough 4 (9) 1 (2) 0Cramps 4 (9) 1 (2) 0Urinary tract infection 4 (9) 0 0

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

Infusion tolerability

• No infusion-related reactions were reported for MOR208.

LEN dose reductions

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

No reduction 24 (55)

Reductions (in total) 12 (27)

Reduction to 20 mg/day 9 (20)

Reduction to 15 mg/day 3 (7)

Currently unknown 8 (18)

Conclusions

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

• 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.

References1. 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.

AcknowledgmentsThis 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.

DisclosuresDisclosures 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.

CorrespondenceKami.Maddocks@osumc.edu

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Time on Study (months)

Best

Ove

rall

Resp

onse

PD

PD

NE

NE

PD

NE

PD

NE

PD

PD

NE

2 4 6 8 10 12

SD

SD

PR

PR

CR

SD

SD

PR

PR

PR

PR

PR

PR

CR

PR

CR

CR

CR

CR

CR

CR

CR

CR

SDPRCR

Ongoing patients

N=34

ADCP

ADCC

CD19

Macrophage

Natural killer cell

Tumor cell

Engineered Fc portion► Enhanced ADCC► Enhanced ADCP

Direct cytotoxicity

MOR208

A�nity matured CD19 binding site► Direct tumor cell killing

NH2

NHN

O

O

O

Lenalidomide

antiproliferative

activation

Introduction• 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 cell- mediated cytotoxicity, macrophage-mediated antibody-dependent cell-mediated phagocytosis and direct cytotoxicity (Figure 1).

Figure 1. MOR208 and LEN modes of action

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

• 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 lym-phomas, including DLBCL with an overall response rate of 26%, including a complete response rate of 6%.3,4

• 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.

ObjectivesPrimary

• 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.

Patients with R-R DLBCL:

• have received 1-3 prior regimens

• are not eligible for HDCT and ASCT

Additional antibody treatment

phase

Survival follow-up

Disease control (≥SD)

Cycle 1-3 Cycle 4 -12

MOR20812 mg/kg IV Days 1, 15

Lenalidomide25 mg PO Days 1-21

MOR20812 mg/kg IV

Days 1, 8, 15, 22*

MOR20812 mg/kg IV Days 1, 15