Does Chlorambucil Add to Obinutuzumab in the Treatment of the Unfit CLL Patient? NO Richard R. Furman, MD CLL Research Center

Obinutuzumab Type II humanized IgG1 Glycoengineered to have: Enhanced ADCC Modified elbow to increase PCD MOA No induction of migration to lipid rafts Stimulate direct cell death associated with: actin reorganization homotypic adhesion lysosomal mediated cell death

CLL 11: Obinutuzumab Pivotal Design Arm 1: chlorambucil x 6 cycles R A N CLL Patients: Untreated Unfit for chemo CIRS >6 CrCl 30-69 mL/min D Stage 1 O M Arm 2: obinutuzumab + chlorambucil x 6 cycles I Z A Stage 2 T I Arm 3: rituximab + chlorambucil x 6 cycles O N

CLL 11: G-Clb vs. Clb Progression Free Survival Goede V. NEJM 2014; 370:1101

CLL 11: G-Clb vs. Clb Overall Survival Goede V. NEJM 2014; 370:1101

R-Clb vs Clb + G-Clb vs Clb R-Clb + Clb G-Clb + Clb Goede V. NEJM 2014; 370:1101

Problem Lack single agent data as a comparator in untreated CLL patients Cannot rule out additive or synergistic effects Increased antibody dose provides greater efficacy Reduced tumor bulk provides greater efficacy

Obinutuzumab: Response by Tumor Burden in Relapsed / Refractory CLL (GAUGUIN) Cartron G. Blood. 2014; 124:2196.

CLL11: Progression Free Survival vs. Time to Next Treatment PFS: TTT:

Problem PFS for: clb = 11.1 months clb + rituximab = 16.3 months Lack single agent data as a comparator in untreated CLL patients Cannot rule out additive or synergistic effects Increased antibody dose provides greater efficacy Reduced tumor bulk provides greater efficacy PFS for: clb = 11.1 months clb + rituximab = 16.3 months clb + obinutuzumab = 26.7 months TTT for: clb = 14.8 months Clb + obinutuzmab = NR

Obinutuzumab in Untreated CLL: GAGE Trial GA101 1000 mg Days 1, 8, 15 of Cycle 1 Day 1 of Cycle 28, every 3 weeks GA101 2000 mg Previously untreated CLL (n=80) All patients required treatment by IWCLL criteria Randomized 1:1 Stratification factors: Tumor burden at baseline (high or low) Presence (high) or absence (low) of at least one nodal mass ≥ 5 cm in the baseline CT scan Rai Stage at baseline (I/II or III/IV)

GAGE Trial: Progression Free and Overall Survival 1000 mg (N=41) 2000 mg (N=39) Event, n (%) 13 (32) 10 (26) Progression 12 9 Death 1 Progression free survival (months) Median (95% CI) 21 (13, 28) 20 (19, NE) 18-month PFS, % 59% 83% P value = 0.07 Overall survival (months), median Not reached Flynn JM. ASCO 2014

Adverse Event in >5% of Patients   G-Clb % Clb % Neutropenia 41 18 Nausea 13 25 Anemia 12 10 Thrombocytopenia 15 8 Diarrhea 11 Fatigue 7 Pyrexia Constipation Asthenia Cough Headache Vomiting 5 Nasopharyngitis Bronchitis Anorexia 3 Pneumonia Dyspnea 2 Abdominal pain Rash Insomnia 4 Arthralgia Back pain Leukopenia Goede V. NEJM 2014; 370:1101

Adverse Event in >5% of Patients   G-Clb % Clb % Neutropenia 41 18 Nausea 13 25 Anemia 12 10 Thrombocytopenia 15 8 Diarrhea 11 Fatigue 7 Pyrexia Constipation Asthenia Cough Headache Vomiting 5 Nasopharyngitis Bronchitis Anorexia 3 Pneumonia Dyspnea 2 Abdominal pain Rash Insomnia 4 Arthralgia Back pain Leukopenia Goede V. NEJM 2014; 370:1101

CLL 11 vs GAGE CLL 11: PFS: clb = 11.1 months clb + rituximab = 16.3 months clb + obinutuzumab = 26.7 months TTT: clb = 14.8 monts clb + obinutuzumab = NR GAGE: PFS: obinutuzumab 1000 mg = 21 months obinutuzumab 2000 mg = 20 months TTT: ?

Risk of t-MN with FC vs F in Untreated CLL: E2997 Therapy FC F TOTAL N enrolled 141 137 278 t-MN 9 4 13 Additional Therapy: yes no 2 7 3 1 Crude Incidence 6.4% 2.9% 4.7% Cumulative Incidence (at 7 yrs) 8.2% 4.6% Smith, M. 2011. Blood; 118: 3525

Second Cancers: F vs. Clb CALGB 9011 509 patients 27 epithelial cancers Fludarabine: 9 chlorambucil: 11 F + C: 7

Summary: Does Obinutuzumab Need Chlorambucil Chlorambucil may aid obinutuzumab by reducing bulk. Unnecessary with higher doses of antibody Single agent obinutuzumab approaches combinatin PFS Greater toxicities with chlorambucil Have not looked at long-term toxicity of alkylator use