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1154
The Canadian Tositumomab and I Tositumomab (TST/I -TST) Experience:
Five Year Survival Data
131
131
Harold J. Olney1, Marni Freeman2, Joy Mangel3, Douglas Stewart4, Darrell White5,
Guylaine Gaudet6, Julia Elia-Pacitti2
Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada; 2 GlaxoSmithKline Inc., Mississauga, ON, Canada; 3
London Health Sciences Centre, London, ON, Canada; 4 University of Calgary and Tom Baker Cancer Centre, Calgary, AB, Canada; 5
QEII Health Sciences Centre, Halifax, NS, Canada; 6 Hôpital du Sacré-Coeur, Montreal, QC, Canada
1
Table 3) Summary of Serious Adverse Events (SAEs):
BACKGROUND
RESULTS
• Indolent Non-Hodgkin Lymphoma (NHL) is characterized by relapses and
remissions and tends to respond less to each successive line of therapy.1
Table
table 1 1) Summary of Baseline Patient Characteristics
• Radiotherapy use in NHL is generally limited to localized disease or palliation, being
more toxic as field size increases.
Characteristic
Patients
(n=93)
Patients (n=93)
Median age (range)
59 yrs (32-78)
Characteristic
Gender
• Immunotherapy against CD20 has revolutionized NHL treatment specifically
targeting B cells.
54 % males
ECOG Status
• Combining these two modalities as radioimmunotherapy (RIT) has been shown to
be highly active but remains to be fully characterized.2
• Mature survival data in this setting is very limited. The Canadian experience with 5
years follow-up can now provide some insights in this regard.
OBJECTIVES
0
1
2
55.9 %
37.6 %
6.5 %
Bone marrow involvement
25.8%
Histology
78.5%
16.1%
5.4%
Follicular Grade 1/2
Follicular Grade 3
Marginal Zone
Investigator Reported Nonfatal SAEs
4.9 yrs (0.8-22.7)
Median number of prior therapies (range)
5 (2-14)
Prior radiotherapy
25.8 %
Enrolled within 6months of last treatment
39.8 %
24%
Efficacy
• Describe long-term safety of TST/I131-TST
• Updated results from those presented at EHA 2010:
• Explore predictors of OS and PFS
– Study defined response rate at 6 months was 43.0% (95% CI 32.8-53.7); with
a 4.3% complete response rate.
PATIENTS AND METHODS
– In 80 evaluable patients (excluding those for whom a best response could not
be calculated, i.e. due to missing lesion measurements), response rate was
50% (38.6-61.4); with a 5.0% complete response rate.
• Median follow-up time: 48.6 months (4.1 years)
Study Design
Figure 2) Updated Duration of Response at 5 years
• Median duration of response was not reached (95% CI 31.7-IND)
• Phase II, single arm, open label study at 12 Canadian centres
• Enrollment took place from April 2004 to February 2007 and was limited to
patients with:
– Follicular (grade 1-3) or marginal zone CD20+ NHL
– ≥
2 prior courses of systemic treatment for NHL, including ≥ 1 course of
rituximab, and who responded to their most recent systemic treatment
– ≥ 1 bi-dimensionally, measurable lesion with two dimensions ≥20 mm
– ≤25% bone marrow involvement
– ECOG status 0-2
– Absolute granulocyte count ≥ 1.5 x 10 /L and a platelet count ≥ 100 x 10 /L
within 21 days prior to study entry without support of hematopoietic cytokines
or transfusion of blood products
– Adequate renal and hepatic function
– No evidence of circulating human anti-murine antibody (HAMA) at baseline and
within 48 hours before the therapeutic dose
Patients (n=93)
Any Grade
Median duration since diagnosis (range)
Subsequent treatment <6 months post prior rituximab
• To assess overall survival (OS) and progression free survival (PFS) at 5 years from
treatment with TST/I131-TST
• A total of 13 (14%) patients experienced ≥ 1 SAE (29 events in total)
– 46% (6/13) experienced ≥ 1 SAE (15 events in total) related to study medication during
on treatment period
• 4 additional SAEs were reported in 3 patients in the later periods of the study
– MDS: 2 cases (with 3 and 6 prior lines of therapy prior to TST/I131TST, and occurring
44.5 and 11.5 months following the start of therapy with TST/I131TST)
– Fatal sepsis (in one MDS patient)
– Left ventricular dysfunction
%
Related to
study
medication
Patients with any SAEs
14
6
Neutropenia
4
4
Myelodysplastic syndrome
2
2
Pyrexia
1
Anaemia
2
1
Anaphylactic reaction
1
1
Back pain
1
1
Bacterial sepsis
1
-
Candidiasis
1
-
Deep vein thrombosis
1
-
Febrile neutropenia
1
1
Gastrointestinal haemorrhage
1
-
Hydronephrosis
1
-
Infection
Left Ventricular Dysfunction
1
-
1
1
Obstructive airways disorder
1
1
Pain in extremity
1
1
Pancytopenia
1
1
Pulmonary oedema
1
-
Rash generalized
1
1
Renal failure
1
-
Respiratory failure
1
-
Sepsis
1
1
Small intestine obstruction
1
1
Viraema
1
-
1
Univariate and Multivariate Analysis
Cox Proportional Hazards Regression:
9
• Age, Sex, BMI, BSA, Stage of disease at first diagnosis, ECOG performance
status, Extranodal involvement, Bone marrow involvement, Years since diagnosis,
Bulky disease, Number of prior anti-cancer therapies, Hemoglobin level,
Lymphocyte count, Platelet count, LDH, Response after last Rituxan, Treatment
after last Rituxan, Prior Anthracycline, and Prior Fludarabine were all explored as
potential predictors of OS and PFS by univariate analysis
9
– No prior stem cell transplant or radioimmunotherapy
– No obstructive hydronephrosis
– No CNS disease
– No rapid relapse (1 yr) in radiation field of >35 cGY
– Informed consent according to each individual institutional review board
• Variables identified as significant in univariate analysis were evaluated using
α ≤ 0.05 as entry/exit criteria for inclusion in multivariate model
Duration
40
37
30
26
23
23
23
21
20
20
0
Table 4) O
verall Survival Multivariate Analysis:
Step-wise Model Building
Figure 3) U
pdated Progression Free and Overall Survival at
5 years
• Body Surface Area (<2.2), Bulky Disease (<5 cm) and Hemoglobin level (≥120g/L) were
identified as significant predictors of overall survival in the multivariate analysis
• Median progression free survival was 12.0 months (95% CI 7.7-17.5, range 1.2 months –
62.9 months)
Three study periods:
• On treatment: 26 weeks after dosimetric dose (15 scheduled visits)
• Median overall survival was 59.8 months (4.98 years) (95% CI 31.7-NR, range 1.2-62.9+
months)
• Short-term follow-up (STFU): from week 26, Q6 months until progression or
2 years from study entry
table 4
– there were 47 deaths, 40 due to progressive disease
•L
ong-term follow-up (LTFU): from STFU, Q6 months until 5 years from
study entry
Variable
Comparisons
BSA
<2.2 vs. ≥2.2 m2
0.357 (0.166, 0.771)
64% reduction
0.0087
<5 vs. ≥5 cm
0.341 (0.167, 0.696)
66% reduction
0.0031
≥ 120 vs. < 120 g/L
0.374 (0.197, 0.713)
63% reduction
0.0028
Bulky Disease
Hemoglobin Level
Treatment:
table 5
table 4
• Standard TST/I 131-TST treatment in an outpatient setting3 (Figure 1.)
Variable
Variable
BSA
BSA
Comparisons
Comparisons
<2.2 vs. ≥2.2 m2
<2.2 vs. ≥2.2 m2
HazardRatio&ConfidenceInterval
HazardRatio&ConfidenceInterval
HazardRatio&ConfidenceInterval
0.457 (0.241, 0.868)
0.357
(0.166,
0.771)
54%
reduction
64%(0.207,
reduction
0.410
0.808)
Table 5) P
rogression-Free Survival Multivariate Analysis:
Bulky Disease Step-wise Model
<10 vs. ≥10
cm
Building
Bulky Disease
<5 vs. ≥5 cm
0.341
(0.167,
0.696)
59%
reduction
66%
reduction
0.495
(0.277,
0.885)
Number
of Prior
Anti-Cancer
P-Value
P-Value
P-Value
0.0166
0.0087
0.0101
0.0031
of Prior Anti-Cancer
<4 vs. Disease
≥ 4 therapies
0.0177
•Number
Body Surface
Area (<2.2), Bulky
(<10 cm),
Therapies
Hemoglobin
Level and LDH (< upper
≥ 120 vs.
< 120
g/L
0.374
(0.197,
0.713)
0.0028of
Therapies
51%
reduction
(<4 therapies)
limit
of normal)
were identified
as significant
predictors
63%(0.295,
reduction
PFS in the multivariate analysis
LDH
<ULN vs. ≥ ULN
0.485
0.797)
0.0043
Figure 1) Tositumomab and Iodine I 131 Tositumomab
Treatment Regimen
52% reduction
table 5
Dosimetric Dose
Whole Body Counts
Therapeutic Dose
Calculates total body
residence time
Patient-specific dosing
Determines individual
total body clearance
2 infusions:
• 450 mg TST then
• 35mg TST labeled
with 5 mCi I 131
D-1
3 Gamma Camera Counts:
• Day 0
• Day 2, 3 or 4
• Day 6 or 7
a
2 infusions:
• 450 mg TST then
• 35mg TST labeled with an
individualized I 131 dose to
deliver 75 cGyb
D0
D7 - D14
Thyroprotection: Day – 1 to 14 days post therapeutic dose
Individual dose designed to minimize bone marrow toxicity and maximize clinical response
b
Decreased to 65 cGy for patients with platelet counts of 100 to < 150x109/L
a
D21 - D28
70
45
66
35
62
29
57
28
51
26
48
25
47
23
46
23
26
13
• Overall response (OR) rate
• Overall survival (OS)
• Complete response (CR) rate
• Quality of Life (QoL)
• Duration of response
• Safety
• Progression-free survival (PFS)
– ITT population: all patients registered in the study (N=93)
– Safety population: all patients who received at least one dose of study
medication (N=93)
<2.2 vs. ≥2.2 m2
0.457 (0.241, 0.868)
54% reduction
0.0166
Bulky Disease
<10 vs. ≥10 cm
0.410 (0.207, 0.808)
59% reduction
0.0101
<4 vs. ≥ 4 therapies
0.495 (0.277, 0.885)
51% reduction
0.0177
<ULN vs. ≥ ULN
0.485 (0.295, 0.797)
52% reduction
0.0043
• Serious Adverse Events were documented in all three study periods.
CONCLUSIONS
• Treatment with TST/I 131-TST was associated with durable
responses (median not reached at 5 years) as well as prolonged OS
and PFS in indolent NHL patients with prior rituximab therapy
• A total of 91 (98%) patients experienced ≥1 AE
– 74% (67/91) experienced ≥1 AE related to study medication
• A total of 31 (33%) patients experienced Grade 3 or 4 AEs
• The five most common AEs were fatigue (49%), nausea (43%), cough (31%),
haedache (23%), diarrhea (20%), mostly mild to moderate
• There were no unexpected toxicities in this heavily pretreated
(median of 5 prior therapies) large cohort of patients
• Predictors of outcome included:
– tumour bulk,
– BSA,
Table 2) Hematologic Laboratory Evaluations to 26 weeks
– hemoglobin,
• As expected hematologic toxicities were common however they were delayed compared
to conventional salvage therapies (median nadirs at 5-8 weeks post treatment)
– LDH,
– prior number of therapies.
• Overall survival, duration of response, and PFS: Kaplan−Meier techniques
• Predictors of OS and PFS: explored using Cox proportional hazards regression
P-Value
• Adverse Events were collected during on treatment period.
Statistical Analysis
BSA
Number of Prior Anti-Cancer
Therapies
HazardRatio&ConfidenceInterval
Safety
• Median TSH remained normal; nine (9.7%) patients had 2 consecutive TSH
measurement above local upper limit of normal
• Efficacy analysis: Intent to Treat (ITT) population
Comparisons
LDH
Most Common Non-Hematologic Adverse Events (AEs)
to 26 weeks
Study Endpoints
0
Variable
Patients (n=93)
Laboratory Parameter
Any Toxicity
n (%)
Grade 4 Toxicity
n (%)
Nadir
Mean (range)
Hemoglobin (g/L)
71 (78)
2 (2)
110.0 (47.0-153.0)
8.1
Neutrophils (109/L)
73 (80)
16 (18)
1.23 (0.0-8.4)
7.6
Platelets (109/L)
84 (92)
10 (11)
73.0 (8.0-300.0)
6.3
• Multivariate model: developed with step-wise selection procedure (α ≤ 0.05)
Median time to nadir
(weeks)
REFERENCES
DISCLOSURES
ACKNOWLEDGEMENTS
1) Horning SJ. Semin Oncol 1993; 20(suppl 5): 75-88
Olney: Consultancy GlaxoSmithKline.
• The authors wish to thank the patients and their families and the clinical investigators participating
2) Vose JM. Oncologist 2004; 9(2): 160-172
Freeman: Employment GlaxoSmithKline.
3) Wahl RL, et al. J Nucl Med 1998; 39(suppl):14S-20S
Mangel: No relevant disclosures.
in the 393229/032 study
• The authors thank Thierry Horner (Clinical Development, Oncology R&D, GlaxoSmithKline) for
Stewart: No relevant disclosures.
his editorial support and insightful comments, and Tina Haller (Statcon Consulting Services) for
White: No relevant disclosures
analysis and programming support
Gaudet: No relevant disclosures.
Elia-Pacitti: Employment GlaxoSmithKline
• This study was sponsored by GlaxoSmithKline, Mississauga, ON, Canada
Presented at the 17th Congress of The European Hematology Association, Amsterdam, The Netherlands, June 14-17, 2012