1. 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.

2. 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: Kantarjian HM, et al. J Clin Oncol. 2012;30: Stein AS, et al. ASH Abstract Sutherland MSK, et al. ASH Abstract Fathi AT, et al. ASH Abstract 591.
Slide credit: clinicaloptions.com

3. 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 Abstract 591.

4. 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 ( )
2.0 ( )
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 Abstract 591.

5. 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 Abstract 591. Reproduced with permission.

6. 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 ( )
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 Abstract 591.

7. 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 Abstract 591.

8. 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
95% CI
AML, acute myeloid leukemia; HMA, hypomethylating agents.
Slide credit: clinicaloptions.com
Fathi AT, et al. ASH Abstract 591. Reproduced with permission.

9. Frontline Vadastuximab Talirine + HMA in Older Pts With AML: OS by Response and MRD Status
OS by Response Status
OS by MRD Status N
Events
Median, Mos
95% CI 9.7 to --
6.0 to -- N
Events
Median, Mos Evolving
95% CI 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 Abstract 591. Reproduced with permission.

10. 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 (NCT )
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 Abstract 591.

11. Go Online for More CCO Coverage of ASH 2016!
Short slideset summaries of all the key data
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Leukemias
Lymphomas/CLL
Myeloma/plasma cell disorders
MDS and myeloproliferative neoplasms
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