ASH December 2010 Efficacy Analysis from Phase I Study of Lorvotuzumab (IMGN901) Used as Monotherapy in Patients with Heavily Pre-Treated CD56-Positive Multiple Myeloma Abstract # 1962 Chanan-Khan, A.1, Wolf, J.2, Garcia, J.3, Gharibo, M.4, Jagannath, S. 5, Manfredi, D.1 , Sher, T. 1, Martin, C.6, Weitman, S.7*, O’Leary, J.8*, Zildjian, S.8*, Bulger, E.8*, and Vescio, R.6 Roswell Park Cancer Institute, Buffalo, NY1; Medical Center of University of California San Francisco, San Francisco, CA2; Hospital Privado de Cordoba, Cordoba, Argentina3; Cancer Institute of New Jersey, New Brunswick, NJ4; St. Vincent’s Comprehensive Cancer Center, New York, NY5; Cedars-Sinai Samuel Oschin Cancer Center, Los Angeles, CA6; The University of Texas Health Science Center at San Antonio, San Antonio, TX7; ImmunoGen, Inc., Waltham, MA8;

Background Objectives Results Continued

• Lorvotuzumab mertansine (IMGN901) is a novel antibody-drug Primary Table 3: Treatment-Related Adverse Events Experienced by >10% of Patientsa Figure 3 : Treatment Duration (n=37) conjugate (ADC) composed of a CD56-targeting antibody with the • To determine the dose-limiting toxicity (DLT) and maximum tolerated dose maytansinoid, DM1, attached via a disulfide linker. (MTD), and the recommended phase II dose of single agent lorvotuzumab Lorvotuzumab mertansine dose (mg/m2) • CD56 is a neural cell adhesion molecule (NCAM) with surface mertansine. 40 60 75 90 112 140 Total Treatment Duration in Cycles expression in approximately 70% of multiple myeloma cases. Other Secondary n=3 n=3 n=3 n=3 n=19 n=6 n=37 tumor types expressing CD56 include small cell lung cancer, Merkel cell • To determine the qualitative and quantitative toxicities of single agent MR PR All MR carcinoma, and neuroendocrine tumors. lorvotuzumab mertansine. Preferred Term All Gr Gr 3 All Gr Gr 3 All Gr Gr 3 All Gr Gr 3 All Gr Gr 3 All Gr Gr 3 Grades Grade 3 PR • In preclinical xenograft models, lorvotuzumab mertansine has • To evaluate the pharmacokinetics of single agent lorvotuzumab mertansine. Headache 1 2 5 4 12 demonstrated potent anti-tumor activity as monotherapy and in • To evaluate overall objective response rate and duration of response (DOR). MR * Fatigue 6 5 2 11 2 combination in several models of human malignancy including multiple • To assess time to progression, progression free survival and overall survival. myeloma. Neuropathyb 1 1 6 2 2 10 2 MR • In clinical trials assessing alternative dosing schedules, lorvotuzumab Methods AST increased 1 3 2 1 7 mertansine has been found to have an acceptable safety profile and has Constipation 1 2 3 6 demonstrated activity signals in a variety of CD56+ tumor types. Trial Design Diarrhea 5 1 6 • Reported here is the safety and activity of lorvotuzumab mertansine 37 Patients • Phase I multi-center, dose escalation study with 3+3 design. Nausea 1 2 2 5 when administered as single agent therapy to patients with CD56- • The MTD defined as the highest dose at which no more than 1/6 patients Anorexia 1 2 2 5 postiive multiple myeloma. experienced a DLT in cycle 1. • Once MTD was declared, up to 40 patients are to be enrolled (expansion Paraesthesia 4 1 5 Figure 1: Lorvotuzumab Mertansine Structure and Routes of phase). Asthenia 1 2 1 1 4 1 Intracellular Activation • Responses are assessed using the European Blood and Bone Marrow ALT increased 1 1 2 4 Transplantation (EMBT) criteria. Blood Uric Acid 0 102030405055 85 linker DM1 Treatment Scheme Increased 1 1 2 4 O Lorvotuzumab Number of Weeks S S CH3 Humanized IgG1 antibody • Lorvotuzumab mertansine is administered as an intravenous (IV) infusion Myalgia 1 2 1 4 LorvotuzumabhuN901 HN NO • 40 60 75 90 112 140 O CH3 once weekly for two weeks every three weeks. 2 H3C O Conjugated to DM1 Dose Limiting Criteria a. Patients who experienced the same coded event more than once are counted only once under that coded event. (Dose Cohort mg/m ) CH3 O b. Neuropathy includes sensory neuropathy and peripheral neuropathy. Cl N O • Derivative of maytansine • Any of the following that are at least possibly related to lorvotuzumab CH3 • Antimitotic – inhibits tubulin Minimal Response (MR) H3CO mertansine: There were no treatment-related Grade 4 adverse events (AE). The grade 3 treatment-related AEs that are not included in CH3 O polymerization • Grade 4 neutropenia ≥ 5 days. this table (experienced by less than 10% of patients) are neutropenia (1 patient at 112 mg/m2), areflexia (1 patient at 140 Partial Response (PR) O Attached to antibody via a * Patient ongoing at time of data cut off. N • • Grade 3 or greater febrile neutropenia or Grade 4 thrombocytopenia. 2 2 H CO HO H mg/m ) and renal failure (1 patient at 140 mg/m ). Renal failure and fatigue were deemed the dose-limiting toxicities. CH 3 disulfide linker 3 • Grade 3 or 4 non-hematological toxicity (excluding alopecia or sub- n optimally treated nausea, vomiting or diarrhea). Figure 4: Case Descriptions n ~ 3.5 (DM1 is ~ 1.8% by weight of Mab) • Any other lorvotuzumab mertansine-related toxicity deemed dose limiting. Eligibility Case Description: Patient 0226 Monoclonal Protein (0232) Case Description: Patient 0244 Major Inclusion Criteria 5 450 • 62 year old female with stage III relapsed multiple myeloma with • 57 year old male with stage III relapsed/refractory multiple myeloma Bind to antigen • Diagnosed of multiple myeloma (CD56-positive) based on standard criteria. 400 multiple bone lesions. 4 on cell surface Internalization • Age ≥ 18 years and ECOG performance status of 0-2. 350 with multiple bone lesions. via endocytosis • One prior treatment with bortezomib, doxorubicin and 300 • Multiple radiation therapies and 6 prior lines of (most • Standard oncology phase I laboratory inclusion criteria. 3 Disulfide thalidomide (partial response). Progressed 3 months later. 250 recent treatment with cyclophosphamide). Progressive disease cleavage Major Exclusion Criteria 2 2 200 Tubulin • Treatment at 140 mg/m . The patient received 26 cycles of within 8 months of last therapy. DM1 • Significant residual neurological or cardiac toxicity from prior therapy. 150 Serum g/dL 2 Traffic to lorvotuzumab mertansine, and achieved partial response 1 100 Urine mg/24hr • Treatment at 112 mg/m . The patient has received 6 cycles of Lysosome • History of significant underlying cardiac disorders. Lysine-LINK-DM1 DM1 (duration of response 13 months) with a reduction of serum M 50 treatment and has achieved minimal response with a 42% reduction Disulfide • History of multiple sclerosis or other demyelinating disease or any CNS injury 0 0 Cleavage Tubulin component of 52%. in serum M component. Cancer Cell with residual neurological deficit. Jul-09 Oct-09 Jan-10 May-10 Aug-10 Degradation of • Patient decision to discontinue treatment. • Patient remains active on study. MAb in lysosome • Previous sensitivity to therapy. Bystander Serum Urine Cancer Cell • Prior malignancy within the last 3 years. Monoclonal Protein (0226) Monoclonal Protein (0244) Erickson et al, 2006 5 450 5 450 Results 400 Case Description: Patient 0232 400 4 350 • 51 year old male with stage III relapsed multiple myeloma with bone and 4 350 Lorvotuzumab mertansine binds with high affinity to CD56 expressed on the 300 soft tissue lesions. 300 surface of tumor cells. The conjugate is then internalized. Inside the cell, Table 1: Cohort Size (n=37) 3 250 3 250 • One prior treatment with bortezomib, doxorubicin and thalidomide DM1 is released by cleavage of the disulfide linker. The DM1 disrupts tubulin 2 200 2 200 Dose (mg/m2) 40 60 75 90 112 140 Total 150 (partial response). Progressed ~10 months later. 150

polymerization and microtubule assembly. Serum g/dL Serum g/dL 100 Urine mg/24hr 2 100 1 • Treatment at 112 mg/m . The patient received 10 cycles of lorvotuzumab 1 mg/24hr Urine Patients (n) 33 3 319637 50 50 Figure 2: Dose Response of Lorvotuzumab Mertansine in Myeloma mertansine, and achieved partial response with a 46% decrease in 0 0 0 0 Xenograft Models serum M component. Table 2: Patient Demographics and Disease Characteristics (n=37) Jun-08 Dec-08 Jul-09 Jan-10 Aug-10 May-10 Jul-10 Aug-10 Sep-10 Oct-10 • Investigator decision to discontinue treatment due to a slight decrease in response and increase in neuropathy (grade 2). NCI-H929 MOLP-8 Median Age, years (range) 61 (39-85) Serum Urine Serum Urine 2000 2000 ) 3 ) 3 Gender, n (%) 1500 1500 Table 4: Pharmacokinetics (n=37) Conclusions Male 21 (57) • The MTD has been identified as 112 mg/m2 and is being explored for activity in a less 1000 1000 Female 16 (43) Dose 40 60 75 90 112 140 heavily pretreated patient population (6 or fewer prior treatments) in the expansion phase. (mg/m2) ECOG Performance Status at Screening, n (%) • Preliminary pharmacokinetic data suggests that exposure and maximum plasma 500 500 Plasma Exposure (AUC) observed 0 23 (62) concentration of lorvotuzumab mertansine increase with increasing dose. Elimination half life MeanTumor Volume (mm

Mean tumor volume (mm Number 4000 remains similar at all dose levels. 0 0 3 3 3 3 19 6 20 40 60 80 100 120 15 25 35 45 55 65 1 13 (35) patients (n) • Lorvotuzumab mertansine was generally well tolerated in this heavily pretreated population Days after Tumor Inoculation Days after Tumor Inoculation 2 1 (3) of patients. There was no clinically significant myelosuppression. Mild-to-moderate PBS PBS 3000 headache, fatigue and neuropathy were the most commonly reported treatment-related IMGN901, 7 mg/kg qw x2 IMGN901, 7 mg/kg qw x2 Race, n (%) Cmax 32.8 ± 53.3 ± 42.9 ± 49.3 ± 55.1 ± 81.5 ± IMGN901, 13 mg/kg qw x2 IMGN901, 13 mg/kg qw x2 adverse events. IMGN901, 26 mg/kg qw x2 (ug/mL) 11.3 12.8 6.0 10.9 13.1 18.9 IMGN901, 26 mg/kg qw x2 g*hr/mL) Caucasian 34 (92) μ • Objective responses and clinically significant stable disease (SD) has been observed among

( 2000 )

CB17 SCID mice bearing established NCI-H929 or MOLP-8 multiple myeloma ∞ the 37 patients treated in the study. 3 Black/African American 2 (5) 16.7 ± 18.3 ± 17.1 ± 16.5 ± 21.3 ± 23.7 ± (0- xenografts (~100 mm tumor volume) were treated with lorvotuzumab mertansine at t (h) • 6 objective responses. doses of 7, 13 and 26 mg/kg (based on antibody concentration) weekly for 2 weeks. 1/2 5.2 1.5 5.1 0.8 7.1 2.6 1000

Other (Indian) 1 (3) AUC • 2 patients have had partial response (PR), with response duration of 5 and 13 months. Lorvotuzumab mertansine was active against NCI-H929 xenografts at the lowest Prior Chemotherapy, n (%) AUC 791 ± 1406 ± 1012 1202 ± 1503 2289 ± • 4 patients have had minimal response (MR), with response duration of 2 (still active dose tested (7 mg/kg), with complete tumor regression (CR) in 1 of 6 mice, and 0 1 prior regimen 5 (13.5) on study), 3, 9 and 9 months. highly active at the 13 and 26 mg/kg doses, with all mice achieving CRs and (h.ug/mL) 406 317 ±50 326 ± 700 656 40 60 75 90 112 140 • 15 patients with stable disease (SD) greater than 3 months, including those with remaining tumor-free until the end of the study (day 113 post tumor inoculation). 2-5 prior regimens 11 (29.5) 2 Dose (mg/m ) objective responses. Lorvotuzumab mertansine was also highly active against MOLP-8 xenografts at CL 63.9 ± 44.4 ± 74.2 ± 78.3 ± 88.7 ± 66.5 ± 6+ prior regimens 21 (57) • 10 patients have had treatment on lorvotuzumab mertansine longer than prior therapy. the 13 and 26 mg/kg dose levels, with CRs in 1 of 5 mice at both doses, and (mL/h/m2) 40.3 9.4 3.7 18.8 39.1 22.8 Treatment Duration > 3 months partial tumor regressions (PR) in 1 of 5 and 4 of 5 mice, respectively. • The study remains open to enrollment for patients with CD56-positive multiple myeloma. Prior Radiation Therapy, n (%) Treatment Duration < 3 months R. Lutz et al., AACR Annual Meeting, Los Angeles, CA (2007). • Based on promising preclinical combination data and preliminary single-agent clinical None 20 (54) 2 1295 1118 ± 2106 1718 ± 2277 1971 ± activity, a study to assess lorvotuzumab mertansine, used in combination with lenalidomide Disclosures Vss (mL/m ) 1 prior radiation therapy 11 (30) ± 739 248 ± 164 392 ± 833 424 and dexamethasone has been initiated (ASH 2010 abstract #1934: Phase I Study of Authors without * have no disclosures Lorvotuzumab Mertansine (IMGN901) Used in Combination with Lenalidomide and ≥ 2 prior radiation therapy 6 (16) 2 2 * Disclosure of employee of ImmunoGen, Inc. All values are mean ± SD calculated from Cycle 1, Dose 1; except for 1 patient each at 60 mg/m and 112 mg/m are cycle Dexamethasone in Patients with CD56-Positive Multiple Myeloma: A Preliminary Safety and Stem Cell Transplant, n (%) 5, dose 1 Efficacy Analysis of the Combination). The authors would like to acknowledge the significant contribution of: Robert Mastico* Robin Guild* Kathleen Whiteman* Yes 14 (38) • The elimination half life is approximately 1 day at the MTD or higher. • No correlation between exposure and duration of treatment (comparing patients on treatment for greater than or The authors would like to especially thank the patients who have consented to be included in Data cut off is of October 26, 2010. No 23 (62) less than 3 months) was noted. this study, as well as their families. Data presented in this poster is based upon preliminary unaudited data.