Does Chlorambucil Add to Obinutuzumab in the Treatment of the Unfit CLL Patient?
Richard R. Furman, MDCLL Research Center
NO
Obinutuzumab
• Type II humanized IgG1• Glycoengineered to have:
– Enhanced ADCC– Modified elbow to
increase PCD
• MOANo induction of migration to lipid raftsStimulate direct cell death associated with:
‐ actin reorganization‐ homotypic adhesion‐ lysosomal mediated cell death
CLL 11: Obinutuzumab Pivotal Design
CLL Patients:• Untreated• Unfit for chemo• CIRS >6• CrCl 30-69 mL/min
Arm 1:chlorambucil x 6 cycles
Arm 2:obinutuzumab + chlorambucil x 6 cycles
Arm 3:rituximab +chlorambucil x 6 cycles
Stage 1
Stage 2
RAN
OD
M
NOITAZI
CLL 11: G-Clb vs. ClbProgression Free Survival
Goede V. NEJM 2014; 370:1101
CLL 11: G-Clb vs. ClbOverall Survival
Goede V. NEJM 2014; 370:1101
R-Clb vs Clb + G-Clb vs Clb
Goede V. NEJM 2014; 370:1101
R-Clb + Clb G-Clb + Clb
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
• 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 monthsclb + rituximab = 16.3 monthsclb + obinutuzumab = 26.7 months
• TTT for: clb = 14.8 monthsClb + obinutuzmab = NR
Obinutuzumab in Untreated CLL:GAGE Trial
GA101 1000 mg
Days 1, 8, 15 of Cycle 1Day 1 of Cycle 28, every 3 weeks
GA101 2000 mgDays 1, 8, 15 of Cycle 1
Day 1 of Cycle 28, every 3 weeksPreviously untreated CLL
(n=80)
All patients required treatment by IWCLL criteria
Randomized1:1
Stratification factors:1. 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
2. Rai Stage at baseline (I/II or III/IV)
GAGE Trial: Progression Free andOverall Survival
Flynn JM. ASCO 2014
1000 mg (N=41) 2000 mg (N=39)Event, n (%) 13 (32) 10 (26)
Progression 12 9Death 1 1
Progression free survival (months)Median (95% CI) 21 (13, 28) 20 (19, NE)18-month PFS, % 59% 83%
P value = 0.07Overall survival (months), median Not reached Not reached
Adverse Event in >5% of Patients G-Clb % Clb %Neutropenia 41 18Nausea 13 25Anemia 12 10Thrombocytopenia 15 8Diarrhea 10 11Fatigue 7 10Pyrexia 10 7Constipation 7 10Asthenia 7 7Cough 10 7Headache 7 7Vomiting 5 12Nasopharyngitis 7 7Bronchitis 5 7Anorexia 3 8Pneumonia 5 3Dyspnea 2 7Abdominal pain 5 5Rash 3 3Insomnia 4 4Arthralgia 5 3Back pain 5 2Leukopenia 7 0
Goede V. NEJM 2014; 370:1101
Adverse Event in >5% of Patients G-Clb % Clb %Neutropenia 41 18Nausea 13 25Anemia 12 10Thrombocytopenia 15 8Diarrhea 10 11Fatigue 7 10Pyrexia 10 7Constipation 7 10Asthenia 7 7Cough 10 7Headache 7 7Vomiting 5 12Nasopharyngitis 7 7Bronchitis 5 7Anorexia 3 8Pneumonia 5 3Dyspnea 2 7Abdominal pain 5 5Rash 3 3Insomnia 4 4Arthralgia 5 3Back pain 5 2Leukopenia 7 0
Goede V. NEJM 2014; 370:1101
CLL 11 vs GAGE
• CLL 11:PFS: clb = 11.1 months
clb + rituximab = 16.3 monthsclb + obinutuzumab = 26.7 months
TTT: clb = 14.8 montsclb + obinutuzumab = NR
• GAGE:PFS: obinutuzumab 1000 mg = 21 months
obinutuzumab 2000 mg = 20 monthsTTT: ?
Risk of t-MN with FC vs F in Untreated CLL: E2997
Smith, M. 2011. Blood; 118: 3525
Therapy FC F TOTAL
N enrolled 141 137 278
t-MN 9 4 13
Additional Therapy: yesno
27
31
Crude Incidence 6.4% 2.9% 4.7%
Cumulative Incidence(at 7 yrs)
8.2% 4.6%
Second Cancers: F vs. ClbCALGB 9011
• 509 patients– 27 epithelial cancers
Fludarabine: 9chlorambucil: 11F + 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
