Study Rationale. Reference: Chanan-Khan, A., et al., ASH 2010, Abstract#1962. Reference: Whiteman, K., et al, AACR, 2009, Abstract#2799

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1 Phase I Study of Lorvotuzumab Mertansine (LM) in Combination with Lenalidomide and Dexamethasone in Patients with CD56-Positive Relapsed or Relapsed/Refractory Multiple Myeloma (MM) Jesus Berdeja 1, Francisco Hernandez-Ilizaliturri 2, Asher Chanan-Khan 3, Manish Patel 4, Kevin R. Kelly 5, Robin Guild 6, Christina Carrigan 6, Sharron Ladd 6, Mary Murphy 6 Kelli L. Running 6, James J. O Leary 6, Sikander Ailawadhi 7 Sarah Cannon Research Institute, Nashville, TN 1 ; Roswell Park Cancer Institute, Buffalo, NY 2, Mayo Clinic, Jacksonville, FL 3, Florida Cancer Specialists, Sarasota, FL 4, Cancer Therapy and Research Center, San Antonio, TX 5, ImmunoGen, Inc., Waltham, MA 6, University of Southern California, Los Angeles, CA 7 Publication# 728

2 Study Rationale Despite development of new treatments for MM, all patients eventually relapse Lorvotuzumab mertansine (LM) An antibody-drug conjugate (ADC) designed to deliver a potent tubulinacting agent specifically to CD56-expressing cancer cells CD56 is expressed on 78% of MM cases, but not normal plasma cells CD56 is also expressed on a variety of other hematological and solid tumors >300 patients with CD56+ MM or solid tumors have been treated with LM LM has demonstrated encouraging single-agent activity and tolerability in Phase I testing Reference: Chanan-Khan, A., et al., ASH 2010, Abstract#1962 In preclinical evaluation, LM in combination with lenalidomide/dexamethasone (len/dex) was found to be significantly more effective than len/dex alone Reference: Whiteman, K., et al, AACR, 2009, Abstract#2799 2

3 Lorvotuzumab Mertansine (LM) Developed by ImmunoGen for treatment of CD56+ malignancies Potent cytotoxic agent, DM1, attached to CD56-targeting antibody using engineered linker Same cytotoxic agent as in T-DM1 How LM is designed to work 1 LM travels through bloodstream 2 LM binds to CD56 on cancer cells 3 LM is internalized with target 4 DM1 is released from LM in lysosomes 5 Released DM1 disrupts tubulin formation 6 Apoptosis 3

4 LM Demonstrates Single-Agent Activity Against Refractory MM Dose-finding trial (N = 37) LM administered Day 1, Day 8 of 21 day cycle LM doses evaluated 40 to 140 mg/m 2 MTD was 112 mg/m 2 Patient population Relapsed or relapsed/refractory CD56+ MM 57% had 6 or more prior chemotherapy regimens LM single agent activity all dose levels 41% of patients had clinical benefit (patients with PR/MR or SD > 3 months) LM single agent tolerability Generally well tolerated in these heavily pre-treated patients Most common treatment related adverse events consisted of Grade 1 and Grade 2 headache, fatigue and neuropathy Neuropathy reported in 10 patients (27%); mostly Grade 1/2 No clinically significant myelosuppression Reference: Chanan-Khan, A., et al., ASH 2010, Abstract#1962 4

5 Trial Design and Treatment Regimen Day 1 LM IV Dex (40 mg PO) Day 8 LM IV Dex (40 mg PO) Day 15 LM IV Dex (40 mg PO) Day 22 Dex (40 mg PO) week 1 week 2 week 3 week 4 Lenalidomide daily x 21 (25 mg) Phase 1, multicenter, standard 3+3 dose-escalation study in patients with relapsed or relapsed/refractory CD56+ MM (1 Cycle = 28 days) Dose-finding phase: Determine MTD, using standard DLT criteria 75 mg/m 2, 90 mg/m 2, 112 mg/m 2 Dose-expansion phase : PK, safety and preliminary efficacy Responses assessed using the IMWG Criteria References: Durie et al. Leukemia 2006; 20 (10): 1-7; Rajkumar et al. Blood 2011; 117 (18):

6 Key Eligibility Criteria INCLUSION: CD56-positive, relapsed or relapsed/refractory MM Patients may have received prior lenalidomide > 1 prior therapy; no upper limit Dose expansion: for patients receiving prior lenalidomide, the last full dose must be > 6 mos prior to C1D1 (4 weeks for maintenance lenalidomide) The patients must have achieved a response of > SD to lenalidomide The patients must have tolerated prior lenalidomide Standard oncology phase 1 laboratory inclusion criteria Must agree to follow the RevAssist Program EXCLUSION > Grade 1 peripheral neuropathy at baseline History of MS or other demyelinating disease, or any CNS injury with residual neurological deficit History of DVT or PE within 6 months of C1D1 or serious cardiac issues Previous hypersensitivity to monoclonal antibody therapy, lenalidomide or other thalidomide derivatives 6

7 Patient Population 1 (N=44) Demography Median age (range) 62.5 (37-81) n (%) Males 22 (50.0) Females 22 (50.0) ECOG n (%) ECOG (97.7) ECOG 2 1 (2.9) Baseline Characteristics n (%) Relapsed 28 (63.6) Relapsed/refractory 16 (36.4) Known mutations r/t poor outcome t(4,14), del(13q), 17p 13 (29.6) 1 Data cut off: 16 Nov 2012 (represents monitored and unmonitored data). 7

8 Patient Prior Treatment (N=44) Prior Systemic Treatment n (%) > 3 prior regimens 20 (45.5) 2 prior regimens 9 (20.5) 1 prior regimens 15 (34.1) Median (range) 2 (1 10) Prior Treatments Received n (%) Bortezomib 40 (90.9) IMiDs: Lenalidomide Thalidomide 33 (75.0) 26 (59.1) 20 (45.5) Alkylating agents 28 (63.6) Anthracyclines 18 (40.9) Radiation Therapy 16 (36.4) ASCT 19 (43.2) 8

9 Dose Exploration LM dose escalation Started at 75 mg/m 2 Escalated to 90 mg/m 2, 112 mg/m 2 There were no Cycle 1 DLTs Grade 3 peripheral neuropathy seen at higher doses beyond cycle 1 Majority (72.7%) of patients had Grade 1 peripheral neuropathy at study entry LM demonstrated clinical activity at all dose levels 75 mg/m 2 selected for expansion phase 9

10 Best Response on Study (IMWG Criteria 1 ) All Dose Levels N (%) Evaluable Patients 2 Lenalidomide Naïve Received Prior Lenalidomide (Including Len Refractory) Relapsed & Refractory 3 to Last Regimen Total N 39 (100.0) 2 16 (41.0) 23 (58.9) 12 (30.8) Overall Response (>PR) Clinical Response (>MR) 22 (56.4) 14 (87.5) 8 (34.8) 6 (50.0) 25 (64.1) 14 (87.5) 11 (47.8) 6 (50.0) scr 1 (2.6) 1 (6.2) 0 0 VGPR 11 (28.2) 8 (50.0) 3 (13.0) 3 (25.0) PR 10(25.6) 5 (31.3) 5 (21.7) 3 (25.0) MR 3 (7.7) 0 3 (13.0) 0 SD 12 (30.8) 2 (12.5) 10 (43.5) 5 (41.7) PD 2 (5.1) 0 2 (8.7) 1 (8.3) 1 Durie et al. Leukemia. 2006; Rajkumar et al. Blood, Response evaluable patients received at least one dose of drug and 1 post-dose tumor assessment 3 Relapsed and refractory myeloma: disease that is nonresponsive while on salvage therapy, or progresses within 60 days of last therapy in patients who have achieved > minimal response (MR) previously 10

11 Efficacy Seen in Len-Naïve as Well as Poor Prognostic Subgroups LM demonstrated clinical activity at all dose levels Objective response (> PR) was observed in 87.5% lenalidomide naïve patients 1 scr, 8 VGPR, 5 PR, 2 SD Clinical response (> MR) was observed in 4/5 lenalidomiderefractory patients 1 VGPR, 1 PR, 2 MR, 1 SD Clinical response (> MR) was observed in 9/13 patients (69.2%) with known poor prognostic mutations 4 VGPR, 4 PR, 1 MR, 4 SD The two patients who had 17p- had a VGPR 11

12 Time to progression and clinical response at 75mg/m Days 337 Days TTP=7.7months 34 Patients ClinResp (>MR) =58.6% Days on Study 12

13 Most Common (> 15%) AEs r/t the Study Regimen - 75 mg/m 2 N = 34 n (%) Peripheral Neuropathy 1,2 19 (55.9) Fatigue 14 (41.2) Neutropenia 2 11 (32.4) Thrombocytopenia 2 11 (32.4) Nausea 10 (29.4) Diarrhea 9 (26.5) Anorexia 8 (23.5) Muscle Spasms 7 (20.6) Anemia 6 (17.6) Asthenia 6 (17.6) 1 At baseline, 73.5% of patients at the 75 mg/kg dose level had Grade 1 neuropathy 2 Results for similar preferred terms have been combined 13

14 All Grade 3/4 AEs r/t the Study Regimen - 75mg/m 2 N = 34 Grade 3 n (%) Grade 4 n (%) Neutropenia 3 (8.8) 1 (2.9) Thrombocytopenia 1 (2.9) 1 (2.9) Hyperuricemia 0 1 (2.9) Peripheral neuropathy 3 (8.8) 0 Pneumonia 3 (8.8) 0 Tumor lysis syndrome 2 (5.9) 0 Fatigue 1 (2.9) 0 Sepsis 1 (2.9) 0 ALT increased 1 (2.9) 0 Creatinine increased 1 (2.9) 0 Hemoglobin decreased 1 (2.9) 0 Lipase increased 1 (2.9) 0 Neutrophils decreased 1 (2.9) 0 Acute renal failure 1 (2.9) 0 14

15 Pharmacokinetic and Immune Response Summary The PK parameters for LM for patients treated in combination with lenalidomide and dexamethasone in the expansion cohort (LM 75 mg/m 2 ) were generally similar to those observed previously at this dose in the single agent trial. The PK parameters for lenalidomide and dexamethasone in combination with LM at 75 mg/m 2 were similar to published reports References: Chen et al. Journal of Clin Pharmacol 2007; 47: ; O Sullivan et al. Biol Psychiatry 1997;41: , and Rose, Journal of Pharmacokinetics and Biopharmaceutics 1981;9(1): Pharmacokinetic Assessment no evidence of drug-drug interaction Immunogenicity Assays for the detection of humoral immune response against the antibody component (HAHA) and DM1 component (HADA) of LM were negative. 15

16 Summary and Conclusions LM in combination with lenalidomide/dexamethasone is feasible and active in patients with relapsed or relapsed/refractory, CD56+ MM, including patients previously treated with IMiDs and/or bortezomib Clinical response of 64.1% ( VGPR of 30.8% ) observed across all dose levels At 75 mg/m 2, 58.6% of patients achieved a response of MR or better In lenalidomide-naïve patients, a response of PR or better was seen in 87.5% Time to onset of first response generally observed by end of cycle 2 Best response typically observed by end of cycle 4 Median TTP at 75 mg/m 2 was 231 days (7.7 months) Safety profile manageable with IMGN901 at 75 mg/m 2 Most common adverse events with LM/len/dex regimen consist of Grade 1 and 2 peripheral neuropathy, fatigue, neutropenia, nausea and diarrhea These results support continued evaluation of LM in relapsed/refractory MM 16

17 Acknowledgements Sikander Ailawadhi, MD University of California, Los Angeles Francisco Hernandez-Ilizaliturri, MD Roswell Park Cancer Institute Asher Chanan-Khan, MD - Mayo Clinic, Jacksonville, FLA Manish Patel, MD Florida Cancer Center Kevin R. Kelly, MD - Florida Cancer Specialists Elber Camacho, MD Comprehensive Cancer Center of the Desert Adam Cohen, MD Fox Chase Cancer Center Cristina Gasparetto, MD Duke University Medical Center Ruben Niesvizky, MD - Weill Cornell Medical College Thank you to the Patients and their Families 17