1. Addition of Vadastuximab Talirine to Induction Therapy for Newly Diagnosed AML: Phase Ib Dose-Escalation Trial
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.
This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

2. Vadastuximab Talirine in Newly Diagnosed AML: Background
7 + 3 has been standard induction therapy for newly diagnosed AML for ~ 30 yrs, with MRD-negative CR correlating with better survival[1,2]
~ 90% of AML cases express CD33[1]
Clinical benefit of adding CD33-targeted ADC gemtuzumab ozogamicin to for newly diagnosed AML shown in 2 phase III trials[3,4]
Vadastuximab talirine (SGN-CD33A): second-generation CD33-targeted ADC
Anti-CD33 antibody linked to pyrrolobenzodiazepine dimer
Phase I study showed promising activity of vadastuximab talirine in R/R AML[5]
Current phase Ib study examined safety, tolerability, and antileukemic activity of dose-escalated vadastuximab talirine plus induction therapy in adult pts younger than 65 yrs of age with newly diagnosed AML[1]
ADC, antibody–drug conjugate; AML, acute myeloid leukemia; MRD, minimal residual disease; R/R, relapsed/refractory.
1. Erba HP, et al. ASH Abstract Chen X, et al. J Clin Oncol. 2015;33: Castaigne S, et al. Lancet. 2012;379: Burnett AK, et al. J Clin Oncol. 2011;29: Stein AS, et al. ASH Abstract 324.
Slide credit: clinicaloptions.com

3. Vadastuximab Talirine in Newly Diagnosed AML: Study Design
Phase Ib dose escalation/expansion study
Treatment-naive AML pts aged yrs, including secondary AML,
but no APL
(N = 42)
Vadastuximab talirine* Days 1, 4 +
7 + 3 Induction
(cytarabine 100 mg/m2/day Days 1-7 +
daunorubicin 60 mg/m2/day Days 1-3)
28-day cycles
Follow-up
every 3 mos
*Vadastuximab talirine dosing: dose escalation/expansion from µg/kg to µg/kg per SMC.
MRD assessed by BM biopsy on Days 15, 28.
Study objectives
Safety, tolerability, estimate MTD
Antileukemic activity
Pharmacokinetics, immunogenicity
AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; BM, bone marrow; MRD, minimal residual disease; MTD, maximum tolerated dose; SMC, Safety Monitoring Committee.
Slide credit: clinicaloptions.com
Erba HP, et al. ASH Abstract 211.

4. Vadastuximab Talirine in Newly Diagnosed AML: Dose Escalation
Dose level 1: μg/kg on Days 1, 4
No protocol-defined DLTs
1 pt with delayed full count recovery
Dose escalation to intermediate dose per SMC: μg/kg on Days 1, 4
SMC established as MTD
Expansion at MTD (n = 38)
DLT criteria: lack of platelet (< 25,000/mm3) or ANC (< 500/mm3) recovery by Day 42 or grade ≥ 3 nonhematologic AEs
AE, adverse event; AML, acute myeloid leukemia; ANC, absolute neutrophil count; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; SMC, Study Monitoring Committee.
Slide credit: clinicaloptions.com
Erba HP, et al. ASH Abstract 211.

5. Vadastuximab Talirine in Newly Diagnosed AML: Baseline Characteristics
Pts (N = 42)
Median age, yrs (range)
45.5 (18-65)
Female, % 64
ECOG PS, % 1 50
Secondary AML, % 17
MRC cytogenetic risk classification,* %
Favorable
Intermediate
Adverse 12 36
NPM1-mutated AML, % 10
FLT-3–mutated AML, % 14
AML, acute myeloid leukemia; ECOG, Eastern Cooperative Oncology Group; MRC, Medical Research Council; PS, performance status.
*Missing MRC classification data, n = 1.
Slide credit: clinicaloptions.com
Erba HP, et al. ASH Abstract 211.

6. Vadastuximab Talirine in Newly Diagnosed AML: Survival
EFS by MRD
1.0
0.8
0.6
Proportion Achieving EFS
0.4
Events, n 2 3 10
Median EFS,
Mos NR
7.46
1.23 N 25 7 10
MRD- CR/CRi
MRD+ CR/CRi
Nonresponders
0.2
AML, acute myeloid leukemia; CRi, CR with incomplete blood count recovery; EFS, event-free survival; MRD, minimal residual disease; NR, not reached. 3 6 9 12 15 18
Mos
OS not reached
Slide credit: clinicaloptions.com
Erba HP, et al. ASH Abstract 211. Reproduced with permission.

7. Vadastuximab Talirine in Newly Diagnosed AML: Responses
94% (30/32) of pts achieved CRc (CR + CRi) with 1 cycle
78% (25/32) of pts in CRc were MRD negative
76% (19/25) of pts in CR were MRD negative
86% (6/7) of pts in CRi were MRD negative
Response, % CR
CRi*
CRc
(CR + CRi)
Evaluable pts (N = 42) 60 17 76
Cytogenetic risk by MRC
Favorable (n = 5)
Intermediate (n = 21)
Adverse (n = 15)
100 67 40 19 20 86
*All pts with CRi had CR with ANC ≥ 1000/uL, incomplete platelet recovery.
AML, acute myeloid leukemia; ANC, absolute neutrophil count; CRc, CR plus CR with incomplete blood count recovery; CRi, CR with incomplete blood count recovery; MRC, Medical Research Council; MRD, minimal residual disease.
Slide credit: clinicaloptions.com
Erba HP, et al. ASH Abstract 211.

8. Vadastuximab talirine + 7 + 3
Vadastuximab Talirine in Newly Diagnosed AML: Frontline Fit Data vs Historical Controls
Characteristics
Vadastuximab talirine
SWOG Eligible*
(n = 30)
± GO
SWOG 0106†
(N = 595)
Median age, yrs 45 48
Adverse cytogenetic risk, % 27 23
CRc rate (CR + CRi), % 80 75
CRc with 1 cycle, % 77 60
MRD-negative CRc, % 73
~ 54‡
AML, acute myeloid leukemia; CRc, CR plus CR with incomplete blood count recovery; CRi, CR with incomplete blood count recovery; GO, gemtuzumab ozogamicin; MRD, minimal residual disease.
*SWOG eligibility: 60 yrs of age or younger, de novo only. †Aggregate data from Othus M, et al. Leukemia. 2016;30:
‡Calculated MRD-negative rate.
Slide credit: clinicaloptions.com
Erba HP, et al. ASH Abstract 211.

9. Vadastuximab Talirine in Newly Diagnosed AML: Tolerability
MTD: μg/kg
On-target grade 4 myelosuppression was dose limiting
No infusion-related reactions, VOD/SOS, or significant hepatotoxicity
50% (21/42) of pts received alloSCT
2% 30-day mortality rate
Most common hematologic AEs: febrile neutropenia, thrombocytopenia, anemia (grades ≥ 3); most common non-hematologic AEs (grades 1/2) included nausea, diarrhea, constipation, decreased appetite, fatigue
alloSCT, allogeneic stem cell transplantation; AML, acute myeloid leukemia; MTD, maximum tolerated dose; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.
Slide credit: clinicaloptions.com
Erba HP, et al. ASH Abstract 211.

10. Vadastuximab Talirine in Newly Diagnosed AML: Conclusions
Acceptable safety, tolerability with vadastuximab talirine plus combination
MTD: μg/kg
Similar AE rate to alone
2% 30-day mortality rate
Deep, rapid remissions indicated with addition of vadastuximab talirine to 7 + 3
CRc: 76%
94% achieved CRc with 1 induction therapy cycle
78% of pts who reached CRc were also MRD negative
Upcoming randomized phase II trial of vadastuximab talirine plus vs alone
AE, adverse event; AML, acute myeloid leukemia; CRc, CR plus CR with incomplete blood count recovery; MRD, minimal residual disease; MTD, maximum tolerated dose.
Slide credit: clinicaloptions.com
Erba HP, et al. ASH Abstract 211.

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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