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