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

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