Vadastuximab Talirine + Hypomethylating Agents Active and Well Tolerated in Untreated Older Patients With AML New Findings in Hematology: Independent Conference Coverage of ASH 2016*; December 3-6, 2016; San Diego, California *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. AML, acute myeloid leukemia. This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

Frontline Vadastuximab Talirine + HMA in Older Pts With AML: Background Older pts with AML have limited treatment options due to higher-risk disease biology and lower tolerance of chemotherapy HMAs may be used but offer suboptimal remission and survival rates[1,2] Vadastuximab talirine (SGN-CD33A): CD33-targeted ADC Anti-CD33 antibody linked to toxic PBD dimer Dose-dependent single-agent activity in AML shown in phase I study[3] Preclinical evidence suggests efficacy may be enhanced by HMA priming to increase surface CD33 expression and incorporation of PBD dimer into DNA[4] Current phase I combination cohort study evaluated safety, tolerability, pharmacokinetics, and antileukemic activity of vadastuximab talirine plus HMA in higher-risk pts with untreated CD33+ AML[5] ADC, antibody–drug conjugate; AML, acute myeloid leukemia; HMA, hypomethylating agents; PBD, pyrrolobenzodiazepine. 1. Dombret H, et al. Blood. 2015;126:291-299. 2. Kantarjian HM, et al. J Clin Oncol. 2012;30:2670-2677. 3. Stein AS, et al. ASH 2015. Abstract 324. 4. Sutherland MSK, et al. ASH 2015. Abstract 3785. 5. Fathi AT, et al. ASH 2016. Abstract 591. Slide credit: clinicaloptions.com

If clinical benefit, continue until recurrence Frontline Vadastuximab Talirine + HMA in Older Pts With AML: Study Design Open-label, phase I combination cohort study Previously untreated CD33+ AML; aged ≥ 60 yrs; ECOG PS 0/1; declined intensive induction/consolidation therapy; no prior HMA (N = 53) Azacitadine 75 mg/m2 SQ/IV x 7 days or Decitabine 20 mg/m2 IV x 5 days + Vadastuximab talirine 10 µg/kg IV on last HMA day 4 x 4-wk cycles If clinical benefit, continue until recurrence Follow-up every 3 mos BM response assessment (IWG criteria) 3 times during treatment. Study objectives: Safety, tolerability Pharmacokinetics Antileukemic activity AML, acute myeloid leukemia; BM, bone marrow; ECOG, Eastern Cooperative Oncology Group; HMA, hypomethylating agents; IWG, International Working Group; PS, performance status. Slide credit: clinicaloptions.com Fathi AT, et al. ASH 2016. Abstract 591.

Frontline Vadastuximab Talirine + HMA in Older Pts With AML: Baseline Characteristics All Pts (N = 53) Pts, Secondary AML (n = 23) Median age, yrs (range) ≥ 75 yrs, % 75 (60-87) 55 77 (60-87) 70 Male, % 64 ECOG PS (0/1), % 21/79 22/78 MRC cytogenetic risk: intermediate/adverse, % 62/38 30/70 Wheatley risk,* % Good/standard Poor 13/28 -- 96 Underlying myelodysplasia, % 42 57 FLT3+, % 11 13 NPM+/FLT3-, % 8 BM blasts at enrollment, % (range) 52.5 (20-90) 46.8 (20-90) Median WBC at baseline, x 103/μL 2.1 (0.4-132) 2.0 (0.8-18.9) AML, acute myeloid leukemia; BM, bone marrow; ECOG, Eastern Cooperative Oncology Group; HMA, hypomethylating agents; MRC, Medical Research Council; PS, performance status; WBC, white blood cell. *Data not available, n = 2. Slide credit: clinicaloptions.com Fathi AT, et al. ASH 2016. Abstract 591.

Treatment-Emergent AE in ≥ 20% of Pts Frontline Vadastuximab Talirine + HMA in Older Pts With AML: Safety and Tolerability Treatment-Emergent AE in ≥ 20% of Pts High incidence of grade 3/4 cytopenias 39% (103/263) of pts with dose delays due to AEs, mainly cytopenias No treatment-related deaths or grade 4/5 bleeding events 30-day mortality: 2% 60-day mortality: 8% No DLTs, infusion-related reactions 15% (8/53) of pts received growth factor support Thrombocytopenia Febrile neutropenia Anemia Neutropenia 58 Hematologic 49 47 47 Fatigue Nausea Constipation Peripheral edema Decreased appetite Dyspnea Pyrexia Diarrhea Vomiting Dizziness Headache Hypotension 60 49 43 42 40 34 Grade 1/2 Grade 3 Grade 4 Grade unknown Nonhematologic 32 28 AE, adverse event; AML, acute myeloid leukemia; DLT, dose-limiting toxicity; HMA, hypomethylating agents; PS, performance status. 28 26 23 21 10 20 30 40 50 60 70 Pts (%) Slide credit: clinicaloptions.com Fathi AT, et al. ASH 2016. Abstract 591. Reproduced with permission.

Frontline Vadastuximab Talirine + HMA in Older Pts With AML: Pt Disposition Characteristic All Pts (N = 53) Pts still alive, n (%) 19 (36) Pts on treatment, n (%) 8 (15) Median duration of treatment, mos (range) 4.8 (0.5-26.5) Pts who discontinued treatment, n (%) Reason for discontinuation AE Relapse/recurrence Lack of response Other* 45 (83) 13 (25) 11 (21) 7 (13) 14 (26) Received non-HMA therapy post discontinuation, n (%) 10 (19) Received subsequent alloSCT, n (%) 2 (4) AE, adverse event; alloSCT, allogeneic stem cell transplantation; AML, acute myeloid leukemia; HMA, hypomethylating agents. *Investigator or pt choice (non-AE), other (non-AE), completed treatment. Slide credit: clinicaloptions.com Fathi AT, et al. ASH 2016. Abstract 591.

Frontline Vadastuximab Talirine + HMA in Older Pts With AML: Responses 50% of pts with response achieved MRD negativity by FCT 57% (13/23) of pts with CR 38% (5/13) of pts with CRi No correlation between response and baseline CD33 expression to date Outcome, % Evaluable Pts (n = 49) Secondary AML Pts‡ (n = 22) Pts with FLT3/ITD+ AML (n = 5) Pts Aged ≥ 75 Yrs (n = 26) Remission rate (CR + CRi) 73 77 100 65 CR 47 50 80 38 CRi (p)* 20 18 19 CRi (n)† 6 9 8 mLFS 2 5 4 ORR (CR+CRi+mLFS) 76 82 69 AML, acute myeloid leukemia; CRi, CR with incomplete blood count recovery; CRi (n), CR with incomplete neutrophil recovery; CRi (p), CR with incomplete platelet recovery; FCT, flow cytometry; HMA, hypomethylating agents; MDS, myelodysplastic syndromes; mLFS, morphologic leukemia-free state; MRD, minimal residual disease. *CR with ANC 1000/µL, incomplete platelet recovery. †CR with platelet 100,000/µL, incomplete ANC recovery. ‡Therapy-related AML or AML evolved from prior MDS or de novo AML with MDS-related cytogenetics. Slide credit: clinicaloptions.com Fathi AT, et al. ASH 2016. Abstract 591.

Frontline Vadastuximab Talirine + HMA in Older Pts With AML: OS by Age < 75 vs ≥ 75 Yrs Mos 2 4 6 8 10 12 14 1.0 0.8 0.6 0.4 0.2 Survival Rate 16 18 20 22 24 26 Aged < 75 yrs censored pts Aged ≥ 75 yrs censored pts Aged < 75 yrs Aged ≥ 75 yrs N 24 29 Events 18 20 Median, Mos 10.9 12.7 95% CI 8.7-13.0 6.0-15.6 AML, acute myeloid leukemia; HMA, hypomethylating agents. Slide credit: clinicaloptions.com Fathi AT, et al. ASH 2016. Abstract 591. Reproduced with permission.

Frontline Vadastuximab Talirine + HMA in Older Pts With AML: OS by Response and MRD Status OS by Response Status OS by MRD Status N 23 14 16 Events 15 8 15 Median, Mos 12.19 14.05 4.35 95% CI 9.7 to -- 6.0 to -- 1.9-9.5 N 19 18 16 Events 8 15 15 Median, Mos Evolving 11 404 95% CI 9.6-13.7 1.9-9.5 CR CRi Nonresponders MRD- CR/CRi MRD+ CR/CRi Nonresponders 1.0 1.0 0.8 0.8 0.6 0.6 Survival Rate Survival Rate 0.4 0.4 0.2 CR censored pts CRi censored pts Nonresponders censored pts 0.2 MRD- CR/CRi censored pts MRD+ CR/CRi censored pts Nonresponders censored pts CRi, CR with incomplete blood count recovery; EFS, event-free survival; MRD, minimal residual disease; RFS, relapse-free survival. 2 4 6 8 10 12 14 16 18 20 22 24 26 2 4 6 8 10 12 14 16 18 20 22 24 26 Mos Mos Median follow-up: 14.7 mos; median time to remission: 2.5 mos; median RFS: 9.1 mos; median EFS: 9.5 mos Slide credit: clinicaloptions.com Fathi AT, et al. ASH 2016. Abstract 591. Reproduced with permission.

Frontline Vadastuximab Talirine + HMA in Older Pts With AML: Conclusions Vadastuximab talirine + HMA shows promising activity and tolerability in a higher- risk population of older AML pts Safety profile, including myelosuppression, consistent with on-target effects 73% CR + CRi rate higher than expected for HMA alone Maintained in highest risk pt subsets: secondary AML (77%), pts aged ≥ 75 yrs (65%) Combination achieves deep responses, with 50% of responding pts achieving MRD-negative status MRD strong predictor of survival CASCADE phase III trial now enrolling to evaluate vadastuximab talirine + HMA vs HMA alone in older pts with newly diagnosed AML (NCT02785900) AML, acute myeloid leukemia; CRi, CR with incomplete blood count recovery; HMA, hypomethylating agents; MRD, minimal residual disease. Slide credit: clinicaloptions.com Fathi AT, et al. ASH 2016. Abstract 591.

Go Online for More CCO Coverage of ASH 2016! Short slideset summaries of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in: Leukemias Lymphomas/CLL Myeloma/plasma cell disorders MDS and myeloproliferative neoplasms clinicaloptions.com/oncology