ASCO 2010:
Highlights from the Annual Clinical
Meeting
Gynecologic Cancer
Sidney A. Scudder, MD
Professor of Medicine
U.C. Davis Cancer Center
Acknowledgments
• Conference Directors:
– Helen Chew, MD, FACP
– Primo Lara, Jr., MD
• Multiple authors for sending me
material to pilfer for this talk
– Robert Coleman, MD
– Bradley Monk, MD
– Wui-Jin Koh, MD
GOG-0218: Schema
Arm
Carboplatin (C) AUC 6
Front-line:
Epithelial OV, PP or
FT cancer
• Stage III optimal
(macroscopic)
• Stage III
suboptimal
• Stage IV
n=1800 (planned)
Paclitaxel (P) 175
R
A
N
D
O
M
I
Z
E
mg/m2
I
Placebo
Carboplatin (C) AUC 6
1:1:1
Paclitaxel (P) 175 mg/m2
BEV 15 mg/kg
II
Placebo
Carboplatin (C) AUC 6
Stratification variables:
• GOG performance status (PS)
• Stage/debulking status
Paclitaxel (P) 175 mg/m2
III
BEV 15 mg/kg
Cytotoxic (6
cycles)
Maintenance
(16 cycles)
15 months
3
GOG-0218: Statistical Design for the
Primary Endpoint
• Planned sample size of 1800
– Based on 90% power to detect PFS hazard ratio (HR)
0.77
• Median PFS shift: 14.0 months (historical)  18.2 months
• Primary analyses
– Compare investigator-assessed PFS for each BEV arm
vs control
• Protocol defined: RECIST, global clinical deterioration, or CA125 (Gynecologic Cancer Intergroup criteria1)
• Per regulatory mandate: RECIST or global clinical
deterioration, censoring for CA-125 (Gynecologic Cancer
Intergroup criteria)
4
1. Rustin et al. J Natl Cancer Inst 2004
GOG-0218: Study Conduct
•
1873 patients enrolled from 336 sites in four countries
(US, Canada, South Korea, Japan), October 2005–June 2009
•
Key protocol amendments
– Inclusion of optimally debulked (macroscopic residual disease) patients (August 2007;
478 patients enrolled)
– Primary endpoint changed to PFS (October 2008; 1298 patients enrolled)
•
Final data analysis triggered by pre-specified number of events in the control
arm (data locked February 5, 2010)
•
Analyses
– Efficacy population: n=1873 (intent to treat, all randomized patients)
– Safety population: n=1816 (all randomized patients who received any study treatment
during cycle 2 or later)
•
Median follow-up: 17.4 months (range 0.0–50.7 months)
5
GOG-0218: Baseline Surgical
Pathologic Characteristics
Arm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV  BEV
(n=623)
III optimal (macroscopic)
218 (35)
205 (33)
216 (35)
III suboptimal
254 (41)
256 (41)
242 (39)
IV
153 (25)
164 (26)
165 (27)
543 (87)
523 (84)
525 (84)
Endometrioid
20 (3)
15 (2)
25 (4)
Clear cell
11 (2)
23 (4)
18 (3)
Mucinous
8 (1)
Characteristic, n (%)
Stage/residual size
Histology
Serous
5 (<1)
8 (1)
Tumor grade
3a
412 (66)
435 (70)
430 (69)
2
94 (15)
77 (12)
92 (15)
1
33 (5)
28 (4)
16 (3)
Not specified/pending
86 (14)
85 (14)
85 (14)
Percentages may not total 100% due to rounding or categorization
aGrade 3 includes all clear cell tumors
6
GOG-0218: Patient Disposition
Characteristic
Median (range) number BEV/placebo cycles
Patients on study treatment at time of data
lock (Feb 5, 2010), n (%)
Arm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV  BEV
(n=623)
11 (0–22a)
12 (0–22a)
14 (0–21)
86 (14)
82 (13)
117 (19)
100 (16)
104 (17)
148 (24)
299 (48)
264 (42)
164 (26)
Adverse events
69 (11)
86 (14)
94 (15)
Cycles 1–6
57 (9)
73 (12)
59 (9)
Cycle ≥7
12 (2)
13 (2)
35 (6)
Completed regimen, n (%)
Discontinued study treatment, n (%)
Disease progression
Deaths
8 (1)
7 (1)
13 (2)
Patient refusal
44 (7)
55 (9)
50 (8)
Other
19 (3)
27 (4)
37 (6)
aOne
patient in each group received BEV/placebo in cycle 1
Percentages may not total 100% due to rounding or categorization
7
GOG-0218: Select Adverse Events
Onset between cycle 2 and 30 days after date of last treatment
GI eventsa (grade ≥2)
Arm I
CP
(n=601)
7 (1.2)
Arm II
CP + BEV
(n=607)
17 (2.8)
Hypertension (grade ≥3)
10 (1.7)b
36 (5.9)b
4 (0.7)
4 (0.7)
55 (9.2)b
73 (12.0)b
Adverse event (grade when limited), n (%)
Proteinuria (grade ≥3)
Pain (grade ≥3)
Neutropenia (grade ≥4)
Arm III
CP + BEV  BEV
(n=608)
16 (2.6)
63 (10.4)b
10 (1.6)
83 (13.7)b
347 (57.7)
384 (63.3)
385 (63.3)
Febrile neutropenia
21 (3.5)
30 (4.9)
26 (4.3)
Venous thromboembolic event
35 (5.8)
32 (5.3)
41 (6.7)
Arterial thromboembolic event
5 (0.8)
4 (0.7)
4 (0.7)
CNS bleeding
0
0
2 (0.3)
Non-CNS bleeding (grade ≥3)
5 (0.8)
8 (1.3)
13 (2.1)
RPLS
0
1 (0.2)
1 (0.2)
RPLS = reversible posterior leukoencephalopathy syndrome
aPerforation/fistula/necrosis/leak
8
bp<0.05
GOG-0218: Select Adverse Events by Treatment Phase
Select adverse events, n
(grade when limited)
Patients, n
Cycles, n
Treatment phasea
Arm I
CP
(n=601)
2906
Arm II
CP + BEV
(n=483)
4059
(n=607)
2911
Arm III
CP + BEV  BEV
(n=457)
4204
(n=608)
2891
(n=464)
4677
Cytotoxic Maintenance Cytotoxic Maintenance Cytotoxic Maintenance
(cycles 2–6) (cycles ≥7) (cycles 2–6) (cycles ≥7) (cycles 2–6) (cycles ≥7)
GI eventsb (grade ≥2)
6
1
16
1
15
1
Hypertension (grade ≥3)
3
7
24
12
25
38
Proteinuria (grade ≥3)
2
2
4
0
0
10
28
23
42
31
46
37
345
2
382
2
385
0
Febrile neutropenia
21
0
30
0
26
0
Venous thromboembolic event
26
9
27
5
27
14
Arterial thromboembolic event
4
1
1
3
3
1
CNS bleeding
0
0
0
0
0
2
Non-CNS bleeding (grade ≥3)
3
2
8
0
10
3
RPLS
0
0
1
0
0
1
Pain (grade ≥3)
Neutropenia (grade ≥4)
aOnset
within 30 days of last treatment
bPerforation/fistula/necrosis/leak
GOG-0218: Investigator-Assessed PFS
Proportion surviving progression free
1.0
0.9
Patients with event, n (%)
0.8
Arm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV  BEV
(n=623)
423
(67.7)
418
(66.9)
360
(57.8)
10.3
11.2
14.1
0.908
(0.759–1.040)
0.717
(0.625–0.824)
0.080*
<0.0001*
Median PFS, months
0.7
Stratified analysis HR
(95% CI)
0.6
One-sided p-value (log rank)
0.5
0.4
0.3
0.2
CP (Arm I)
+ BEV (Arm II)
0.1
+ BEV → BEV maintenance (Arm III)
0
0
12
24
Months since randomization
36
*p-value boundary = 0.0116
GOG-0218: Subgroup Analyses of PFS
CP + BEV  BEV (Arm III) vs CP (Arm I)
Hazard ratio
Stage 3 optimal (n=434)
0.618
Stage 3 suboptimal (n=496)
0.763
Stage 4 (n=318)
0.698
PS 0 (n=616)
0.710
PS 1/2 (n=632)
0.690
Age <60 years (n=629)
0.680
Age 60–69 years (n=409)
0.763
Age 70 years (n=210)
0.678
Experimental arm
(CP + BEV  BEV;
Arm III) better
0.33
0.5 0.67
Control arm
(CP; Arm I) better
1.0
1.5
Treatment hazard ratio
2.0
3.0
GOG-0218: Ramifications of Using
CA-125 as Determinant of Progression
Protocol-defined
PFS analysis
CA-125-censored
PFS analysis
Median PFS, months
CP (Arm I)
10.3
12.0
CP + BEV  BEV (Arm III)
14.1
18.0
Absolute difference in median
PFS (months)
3.8
6.0
Hazard ratio
0.717
0.645
Censored for CA-125, %
CP (Arm I)
0
20
CP + BEV  BEV (Arm III)
0
29
GOG-0218: Mean Patient-Reported
TOI (QOL) Score During Chemotherapy
Mean TOI score
112
100
90
80
70
60
50
40
30
20
10
0
CP (Arm I)
Randomization
CP + BEV  BEV (Arm III)
Pre-cycle 4
Pre-cycle 7
TOI = Trial Outcome Index of the Functional Assessment of Cancer TherapyOvary (FACT-O TOI): FACT-G [Physical Well-Being (7 items), Functional Well
Being (7 items)] and the Ovarian Cancer Subscale (12 item)
GOG-0218: Overall Survival (OS)
Outcome
Deaths, n (%)
1-year survival, %
Arm I
CP
(n=625)
Arm II
CP + BEV
Arm III
CP + BEV  BEV
(n=625)
(n=623)
156
(25.0)
150
(24.0)
138
(22.2)
90.6
90.4
91.3
• Events observed in 24% of patients at time of data lock
• After primary endpoint changed from OS to PFS
– Unblinding to treatment assignment allowed at time of disease progression
GOG-0218: Overall Survival Analysis
At time of final PFS analysis (January 2010)
Patients with events, n (%)
1.0
Median OS, months
0.9
Stratified analysis
HR (95% CI)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV 
BEV
(n=623)
156 (25.0)
150 (24.0)
138 (22.2)
39.3
38.7
39.7
1.036
0.915
(0.827–1.297) (0.727–1.152)
One-sided p-value
0.8
Proportion surviving
Arm I
CP
(n=625)
0.361
0.252
0.7
0.6
0.5
0.4
0.3
0.2
CP (Arm I)
+ BEV (Arm II)
0.1
+ BEV → BEV maintenance (Arm III)
0
0
12
24
Months since randomization
36
48
15
GOG-0218: Conclusions
•
GOG-0218 met the primary objective in the front-line treatment of advanced
ovarian (epithelial OV, PP and FT) cancer
– PFS with CP + BEV (Arm II) not statistically superior to CP (Arm I) alone
– PFS with CP + BEV  BEV maintenance (Arm III) statistically superior to
alone
CP (Arm I)
•
Interpretation of survival analysis limited
•
Treatment regimen was generally well tolerated; adverse events (including GI
perforation) similar to previous BEV studies
•
No decrement in quality of life during chemotherapy phase
•
BEV - first molecular targeted and first anti-angiogenic agent to demonstrate
benefit in this population
– CP + BEV  BEV maintenance is an option for front line therapy
Patient Populations in Front-Line
Ovarian Cancer Phase IIIPoorTrials*
prognosis
GOG1111
GOG-02182
ICON5/
GOG1823
66
66%
%
34%
25%
50%
35%
GOG1584
25%
65%
37%
GOG1725
63%
Stage I
OVO 106 7%
74%
JGOG NOVEL7
18%
ICON72
18%
GOG1788
Stage IV
Stage III (subopt)
Stage III
(optimal, macro)
Stage III
(optimal, micro)
Stage II
100%
20%
30%
Stage IV, CCR
52%
Stage III CCR
32%
50%
100%
*Based on data available from publications, except ICON7 and
GOG-0218 CCR=complete clinical response
Better
prognosis
1. McGuire et al. N Engl J Med. 1996;334:1–6; 2. Data on file. Genentech, Inc.
3. Bookman et al. J Clin Oncol. 2009;27:1419–25. 4. Ozols et al. J Clin Oncol. 2003;21:3194–3200.
5. Armstrong et al. N Engl J Med. 2006;354:34–43. 6. Piccart et al. J Natl Cancer Inst. 2000;92:699–708.
7. Katsumata et al. Lancet. 2009;374:1331–1338. 8. Markman et al. Gynecol Oncol. 2009;114:195–198
ICON7: Study Design
Carboplatin
AUC 6*
Paclitaxel 175
mg/m2
Front-line EOC,
PP or FT cancer
• Stage I-IIA (Gr 3
or CC)
• Stage IIB/C
• Stage III
• Stage IV
n=1520 (planned)
Stratification variables:
• Stage/surgery
• Time since surgery
• GCIG group
*
*
Carboplatin
AUC 6*
Paclitaxel 175
mg/m2
Bevacizumab 7.5 mg/kg
Primary
endpoints:
PFS
Secondary
endpoints: OS,
RR, safety, QOL,
costeffectiveness,
translational
No IRC present
12 months
*Might vary based on GCIG group
**Omit cycle 1 bevacizumab if <4 weeks from surgery
ICON7: Statistics
• Primary objective
– PFS
• HR=0.78, median PFS of 18 months in control
• Secondary objective
– OS
• HR=0.81, median OS of 43 months in control (results in
late 2012)
AURELIA (GINECO)
Platinumresistant
OC, PP, FTC, (PFI
<6 months)
Prior
bevacizumab
allowed
n=332
Chemotherapy
to progression
Chemotherapy
to progression
Bevacizumab 10 mg/kg
q2w* to progression
P
R
0
G
R
E
S
S
I
O
N
Physician’s
choice: SOC
or
bevacizumab
15 mg/kg q3w
SOC
Primary endpoint:
PFS
Stratification variables:
• Chemotherapy regimen
• Previous anti-angiogenic
Secondary
therapy
endpoints:
• PFI <3 vs 3–6 months
Chemotherapy options (physician’s choice): ORR, PFIbio, OS, QoL,
safety
• Weekly paclitaxel 80 mg/m2
• Topotecan (4 mg/m2 d1, 8, 15 OR 1.25 mg/m2 d1–
5 q3w)
• Pegylated liposomal doxorubicin 40 mg/m2 d1 q4w
*15 mg/kg q3w if combined with topotecan q3w
OCEANS
Platinumsensitive,
recurrent
OC, PP, FTC
No prior
bevacizumab
n=480
Stratification variables:
•Time to recurrence
•Cytoreductive surgery
Carboplatin
AUC 4
Gemcitabine 1000
mg/m2 d1/8
Placebo to progression
Carboplatin
AUC 4
Gemcitabine 1000
mg/m2 d1/8
Primary endpoint:
PFS
Secondary
endpoints:
ORR, OS, DR, safety
Exploratory
endpoints:
IRC, CA 125
response, ascites
Bevacizumab 15 mg/kg to progression
IRC present
GOG 213
Carboplatin
AUC 5
Paclitaxel 175
mg/m2
Platinumsensitive,
recurrent
OC, PP, FTC
Prior
bevacizumab
allowed
Surgical
candidate?
No
R
Carboplatin
AUC 5
Yes
n=660
R
Paclitaxel 175 mg/m2
Surgery
No
Surgery
Stratification variable:
• Time to recurrence
Bevacizumab 15 mg/kg to progression
Primary endpoints: OS (secondary
cytoreduction), OS (bevacizumab)
Secondary endpoints: PFS, hypersensitivity,
QOL, translational
No IRC present
mEOC
Carboplatin AUC 5–
6 q3w
Paclitaxel 175 mg/m2
Chemonaive
mucinous
epithelial ovarian
cancer
FIGO stage II–IV
or recurrent
stage I
n=332
R
R
A
N
D
O
O
M
M
I
I
Z
ZE
E
Oxaliplatin 130 mg/m2
q3w
Capecitabine 850
mg/m2 bid
Carboplatin AUC 5–
6 q3w
Paclitaxel 175 mg/m2
Bevacizumab 15 mg/kg q3w
Oxaliplatin 130 mg/m2
q3w
Capecitabine 850
mg/m2 bid
Bevacizumab 15 mg/kg q3w
18 cycles
Developmental Therapeutics
• Phase III updates
–
–
–
–
MITO-2
TCON
OVA-301
CALYPSO
• NKTR-102
• Folate:
– EC-145
• Angiogenesis:
– AMG-386
• PARP
Phase III Study: MITO-2
Pignata, ASCO 2009, LBA5508
Ovarian cancer
- Stage IC-IV
- Age ≤ 75
- PS: 0-2
- Iº Endpoint: PFS
R
A
N
D
O
M
I
Z
E
Paclitaxel 175 mg/m2
Carboplatin AUC 5
Every 3 weeks
Relapse
PLD 30 mg/m2
Carboplatin AUC 5
Every 4 weeks
Opened: 1/2003
Closed: 11/2007
N = 820 (needed 632 events for HR: 0.8, b=0.2)
Phase III Study: MITO-2
Characteristic
Paclitaxel/Carb PLD/Carb
o
o
P
≥ 6 cycles of therapy
86%
80%
ORR (measurable)
N = 290
59%
57%
0.70
CR (non-target only)
N = 182
33%
29%
0.64
Normalization (CA-125
only)
N = 168
83%
86%
0.56
Pignata, ASCO 2010, LBA5508
Phase III Study: MITO-2
Characteristic
Paclitaxel/Carbo
PLD/Carbo
P
Anemia (All Grades)
59%
68%
<0.05
Thrombocytopenia (All Gr)
19%
48%
<0.05
Alopecia
63%
14%
<0.05
PPE (All Grades)
6%
20%
<0.05
PPE (Gr 3-4)
0%
2%
<0.05
Stomatitis
9%
20%
<0.05
Diarrhea
13%
16%
<0.05
Neurotoxicity (All Grades)
47%
15%
<0.05
Pignata, ASCO 2010, LBA5508
MITO-2: PLD/Carbo vs. Pac/Carbo
• Patients (n=820):
– Age: 57 (21-77)
– Stage III (60%) and Stage IV (22%)
– Median follow-up: 40.2 mos
• Events: 556 progression (313 deaths)
Pignata ASCO 2010 LBA5033
Progression-free survival
0.6
0.8
st, 2009
Date cut-off for analysis: December 31Median
PFS
Patients
Events
Months (95% CI)
Standard
410
282
16.8 (15.2 - 19.4)
Experimental
410
274
19.0 (16.3 - 24.0)
0.2
0.4
Hazard Ratio 0.95 (0.81 – 1.13)
Log-rank test p = 0.58
0.0
Probability of progression-free survival
1.0
MITO-2: PLD/Carbo vs. Pac/Carbo
0
Patients at risk
Standard
Experimental
6
12
18
24
30
36
42
48
54
60
66
72
72
70
52
52
30
32
14
18
7
12
4
5
Months
410
410
361
349
269
262
191
215
159
177
125
135
89
98
Pignata ASCO 2010 LBA5033
Phase III trial of induction
gemcitabine (G) or paclitaxel (T) plus
carboplatin (C) followed by elective T
consolidation in advanced ovarian
cancer (OC): Final safety and efficacy
report - TCON trial.
M.G. Teneriello, et al. ASCO 2010LBA 5008
Patient Disposition – TCON trial
Enrolled
(N = 919)
Patients randomly assigned
(n = 916)
Excluded
(n = 3)
Not meeting inclusion criteria
(NA)
Other
(NA)
Excluded (clerical errors)
85)
Allocated to GC
Received GC
Withdrew
Discontinued
Patient request
Toxicity
Physician request
Death
>5 week therapy delay
Progressive disease
Other
Unknown
Received CO-T
(n = 417)
(n = 411)
(n = 6)
Allocated to TC
Received TC
Withdrew
(n = 414)
(n = 409)
(n = 5)
Discontinued
Patient request
Toxicity
Physician request
Death
>5 week therapy delay
Progressive disease
Other
Unknown
(n = 165)
(n = 58)
(n = 26)
(n = 20)
(n = 6)
(n = 5)
(n = 5)
(n = 33)
(n = 12)
Received CO-G
78)
(n = 77)
Received Tcon
(n =169)
Received Tcon
(n =
(n = 148)
(n = 39)
(n = 37)
(n = 11)
(n = 8)
(n = 7)
(n = 6)
(n = 19)
(n = 6)
(n =
(n =183)
Abbreviations: N, number of patients enrolled; n, number of patients in
group; NA, not available.
Progression-Free Survival (ITT)
1.0
Survival Probability
0.9
PFS
 GC (N=417)
 TC (N=414)
Patients censored, n (%)
122 (29.3)
134 (32.4)
Median, months (95% CI)
20.0 (17.9, 22.2)
22.2 (19.0, 25.7)
P-value
0.8
0.7
0.199
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
5
10
15 20
25 30
35 40 45
50 55
60 65
70 75 80
Survival Time (months)
Abbreviations: CI, confidence interval; ITT, intent-to-treat.
M.G. Teneriello, et al. ASCO 2010LBA 5008
OVA301
Recurrent EOC
• One prior regimen
• Evaluable and measurable disease
• Platinum-sensitive (⅔) and resistant
(⅓)
R
PLD 30 mg/m2 +
Trabectadin 1.1mg/m2
Every 21 days
PLD 50 mg/m2
Every 28days
Accrual Goal: 650 patients (4/07: 672)
Primary endpoint: PFS
Other endpoints: OS, RR, Safety
Monk, J et al J Clin Oncol. 2010 Jun 1. [Epub ahead of print]
Translational Research
• Pharmacokinetics
• Pharmacogenomics
• Pharmacoeconomics
• Quality of Life
• Circulating tumor cells
OVA-301: 6-12 Month
Cohort
PFS:
Overall Survival:
Poveda, ASCO 2010 ; abstr 5012
Time to Subsequent Platinum
Induction
Poveda, ASCO 2010 ; abstr 5012
Phase III Study: CALYPSO
Ovarian cancer
-Platinum Sensitive
ROC,FTC, PPC
- Age > 18
- PS: 0-2
- Iº Endpoint: PFS
-1st Relapse
R
A
N
D
O
M
I
Z
E
Paclitaxel 175 mg/m2
Carboplatin AUC
Every 3 weeks x 6
Relapse
PLD 30 mg/m2
Carboplatin AUC 5
Every 4 weeks x 6
Opened: 1/2003
Closed: 11/2007
N = 820 (needed 632 events for HR: 0.8, b=0.2)
Pujade-Lauraine E, JCO, 28:3323, 2010
Intermediate Sensitive:
6-12 mo
ESGO 2009
CD
CP
Median PFS, mo
9.4
8.8
HR (95% CI)
0.73 (0.58,
0.90)
Log-rank P-value
(superiority)
0.004
P-value (noninferiority)
<0.001
CALYPSO:PFS
Pujade-Lauraine E et al. JCO 2010;28:3323-3329
©2010 by American Society of Clinical Oncology
Intermediate Sensitive:
6-12 mo
Median PFS,
mo
CD
CP
9.4
8.8
HR (95% CI)
0.73 (0.58,
0.90)
Log-rank Pvalue
(superiority)
0.004
P-value (noninferiority)
<0.001
ESGO 2009
CALYPSO trial -Comparison of Toxicity
Between Elderly (≥ 70 yrs) and Younger
Patients
• No difference in hematological toxicity and febrile neutropenia rate
• C-PLD is not associated with a clinically significant higher cardiac
toxicity
• More allergic carboplatin reactions in younger patients (13.9% versus
5.8%, p=0.005)
• More grade ≥2 sensory neuropathy in elderly (24.4% versus 15.5%,
p=0.007)
Kurtz J ASCO 2010; abstr 5031
Developmental Therapeutics
• Phase III updates
–
–
–
–
MITO-2
TCON
OVA-301
CALYPSO
• NKTR-102
• Folate:
– EC-145
• Angiogenesis:
– AMG-386
• PARP
Phase 2 Study of NKTR-102 in Women with
Platinum-Resistant/
Refractory Ovarian Cancer
Ignace Vergote et al
J Clin Oncol 28:7s, 2010 (suppl; abstr 5013)
Study 08-PIR-04 Design: Two-Stage
Platinum
resistant/
refractory
ovarian
cancer
(N=70)
NKTR-102
145 mg/m2 q14d
NKTR-102
145 mg/m2 q21d
Stage 1
N=20 /
regime
n
Stage 2
N=15 /
regimen
Primary Endpoint:
Objective Response
Rate
(RECIST evaluation
every 6 weeks)
Statistical Hypotheses: 2-stage design (with power of 0.85 for a RR of
20% and with alpha of 0.03 for RR of 5%
Stage 1: If ≥ 1 patient responds, that treatment regimen proceeds to the
next stage
Stage 2: An additional 15 are patients enrolled
If ≥ 5 patients respond out of 35 patients (Stage 1 and Stage 2 combined),
the drug has met the efficacy threshold.
Ignace Vergote et al J Clin Oncol 28:7s, 2010 (suppl; abstr 5013)
NKTR-102: Topoisomerase I inhibitor
(irinotecan)-polymer conjugate
Irinotecan has
high C-max
Plasma SN-38 Conc (ng/mL)
10
No exposure of
drug to tumor
cells
SN-38 from
irinotecan
1
0.1
0
3
6
Time (weeks)
9
12
NKTR-102: Topoisomerase I inhibitor
(irinotecan)-polymer conjugate
• NKTR-102 extends half-life of active metabolite to ~50 days (normally ~2 days)
• Continuous long-term exposure with markedly reduced peak concentration
Plasma SN-38 Conc (ng/mL)
10
SN-38 from
NKTR-102
NKTR-102
blunted C-max
SN-38 from
irinotecan
1
Continuous exposure of drug to tumor cells
0.1
0
3
6
9
12
Time (weeks)
Ignace Vergote et al J Clin Oncol 28:7s, 2010 (suppl; abstr 5013)
Demographics
NKTR-102
145 mg/m2 q14d
(N = 36)
NKTR-102
145 mg/m2 q21d
(N = 35)
Total
(N = 71)
Platinum-Free Interval
<1 month (refractory)
1-3 months (resistant)
3-6 months (resistant)
> 6 months (platinum sensitive)**
39%
17%
39%
6%*
57%
20%
20%
3%*
48%
18%
30%
4%*
Previous Platinum Regimens
1
2
3
4+
33%
44%
17%
6%
31%
40%
14%
14%
32%
42%
16%
10%
3
3
3
44%
11%
39%
97%
49%
14%
46%
94%
47%
13%
42%
96%
*
Prior Lines of Therapy (median)
Prior PLD
Prior bevacizumab
Prior gemcitabine
Prior taxane
*
From date of last dose of platinum to progression
**These patients not included in following efficacy tables
Objective Response Rates
(Platinum Resistant / Refractory Patients)
NKTR-102
145 mg/m2 q14d
NKTR-102
145 mg/m2 q21d
Confirmed + Unconfirmed
Confirmed
33
8 (24%)
7 (21%)
31
9 (29%)
7 (23%)
Confirmed + Unconfirmed
Confirmed
34
14 (41%)
10 (29%)
34
14 (41%)
13 (38%)
Confirmed
29
11 (38%)
29
11 (38%)
33
17 (52%)
31
14 (45%)
RECIST
N (evaluable)
GCIG
N (evaluable)
CA-125
N (evaluable)
Clinical Benefit (CR+PR+[SD≥3 months])
N (evaluable)
Confirmed RECIST
Ignace Vergote et al J Clin Oncol 28:7s, 2010 (suppl; abstr 5013)
Maximum Decline by RECIST or CA-125
(Confirmed Responses)
100
80
Platinum Resistant / Refractory Patients
q14d and q21d patients combined
60
40
20% Increase (RECIST)
20
0
-20
30% Decrease (RECIST)
-40
-60
-80
-100
100
80
q14d and q21d patients combined
60
40
50% Increase (CA125)
20
0
-20
-40
-60
50% Decrease (CA125)
-80
-100
Ignace Vergote et al J Clin Oncol 28:7s, 2010 (suppl; abstr 5013)
NKTR-102 Safety Profile: All Patients
Most Common* Drug-related
Grade 3 and 4 AEs
*>5% overall
NKTR-102
145 mg/m2 q14d
(N = 36)
NKTR-102
145 mg/m2 q21d
(N = 35)
Grade 3
Grade 4
Grade 3
Grade 4
Diarrhea
25%
0%
14%
0%
Dehydration
22%
0%
6%
0%
Hypokalemia
17%
3%
9%
0%
Fatigue
6%
0%
14%
0%
Nausea
14%
0%
3%
0%
Vomiting
11%
0%
3%
0%
Abdominal pain
6%
0%
6%
0%
Hyponatremia
8%
0%
3%
0%
Neutropenia
6%
0%
6%
3%
Two NKTR-102 related deaths:
q14d: acute renal failure
q21d: neutropenic sepsis
Targeting the Folate Receptor
• Farletuzumab
– Humanized MoAb to FR-a
– Induces CMC and ADCC
– Blocks Lyn Kinase-(P)
• ASCO 2008
– Phase I: #5517
– Phase II: #5000
White, #5001
Farletuzumab: Phase II
EOC in first relapse
Platinum-sensitive (>6 mos)
Increased CA125;
Measurable or CA125
Needing chemotherapy
Symptoms
Increased CA125;
Measurable or CA125
No symptoms of disease
N = 28
Arm A:
Single agent Farletuzumab
Until progression or symptoms
N = 26
N = 21
Arm B:
Front-line Chemo regimen
Farletuzumab (6 cycles)
N=?
Arm C
Maintenance Farletuzumab
Farletuzumab: Phase II
Response: CA125 criteria
• 44 evaluable
– 89% normalized CA125
– 34 still on study
• 9/44 (21%) CR2 > CR1
Response: RECIST
PFI1 < 12m PFI1 > 12m
CR/PR
64%
71%
CR/PR/SD 100%
90%
CA-125
Normalized 92%
84%
White, #5001
Utilizing the Folate Receptor: EC145
• Folate-Vinca conjugate
• Relevant for imaging
targeting and therapy
Reddy JA, et al. Cancer Res. 2007;67:4434-4442.
EC145: Novel Folate Receptor Targeted
Therapeutic
• Randomized Phase II, Platinum-resistant ovarian
• Prior therapy: no more than 2 priors
• Regimen:
– PLD 50 mg/m2 IBW q 28 days
– PLD 50 mg/m2 IBW q 28 days + EC145 2.5 mg weeks 1 and 3 (cycle: 28 days)
• Toxicity similar in both arms: total AEs, SAEs, TETs
Arm
PFS
HR
P
PLD
11.7 wks
-
-
PLD+EC145
24.0 wks
0.497
0.014
Naumann W, et al. ASCO 2010. Abstract LBA5012b.
EC145 Survival Outcomes
Naumann W, et al. ASCO 2010. Abstract LBA5012b.
J Clin Oncol 28:7s, 2010 (suppl; abstr 5000)
J Clin Oncol 28:7s, 2010 (suppl; abstr 5000)
J Clin Oncol 28:7s, 2010 (suppl; abstr 5000)
J Clin Oncol 28:7s, 2010 (suppl; abstr 5000)
Mechanism for enhanced toxicity by inhibition of PARP
Biochemical Society Transactions
www.biochemsoctrans.org
(2004) 32, 959-961
Biochem. Soc. Trans.
Response rate - Olaparib
N=57; 39 BRCA1 & 18 BRCA2
Olaparib
400 mg bid
100 mg bid
Patients
RECIST ORR
33
33%
24
12.5%
Toxicity
Nausea
Fatigue
Anemia
Leukopenia
Grade 1&2
44%
35%
14%
Grade 3
7%
5%
M. W. Audeh, et al. ASCO 2009
PARP inhibitors in clinical trials
Agent
Company
Strategy
AG014699
KU59436
Pfizer
AstraZenecaKudos
Abbott
BiPar
Combination
Single
IV
Oral
Single
Single
Combinations
Combination
Oral
IV
Single agent
combination
Combination
Oral
ABT-888
BSI-201
INO-1001
MK
InotekGenentech
Merck
GPI 21016
MGI Pharma
Administration
IV
Oral
Adapted Ratnam K, Low JA Clin Cancer Res 2007;13: 1383-1388
www.clinicaltrials.gov
ASCO 2010 Abstract 5041
J. Ang, et al.
Preliminary experience with the use of
chemotherapy following treatment with
olaparib, a poly(ADP-ribose) polymerase
inhibitor, in patients with BRCA1/2-deficient
ovarian cancer.
Response to chemotherapy after PARP
inhibitor - Olaparib
Previous chemotherapies
Platinum/taxane resistance
Median time from start olaparib to chemotherapy
3 lines
>60%
8.7 months
Patients treated with chemotherapy post olaparib
23
RECIST/GCIC ORR with platinum/taxane reinduction
54%
ONLY PTS RECEIVING PLATINUM OR TAXANE RESPONDED
AGAIN
Ang J et al ASCO 2010 Abstract 5041
Can we define tumors that will respond to
PARP inhibitors? A phase II correlative study
of olaparib in advanced serous ovarian
cancer and triple-negative breast cancer
J Clin Oncol 28:7s, 2010 (suppl; abstr 3002)
Karen Gelmon1, Hal Hirte2, André Robidoux3, Katia Tonkin4, Marc
Tischkowitz5, Ken Swenerton1, David Huntsman1, James
Carmichael6, Euan Macpherson6, Amit Oza7
1British
Columbia Cancer Agency, Vancouver, Canada
2Juravinski Cancer Centre, Hamilton, Canada
3Centre Hospitalier de l'Universite de Montreal-Hotel-Dieu, Montreal, Canada
4University of Alberta Cross Cancer Institute, Edmonton, Canada
5Jewish General Hospital, Montreal, Canada
6AstraZeneca, Macclesfield, UK
7Princess Margaret Hospital, Toronto, Canada
Study no: D010C00020
Objective Response Rate (ORR)
Actual BRCA Mutation Status
Ovarian
Breast
Evaluable for RECIST Response
BRCA
Non-BRCA
95%
95%
ORR %
ORR %
confidence
confidence
(x/n)
(x/n)
interval* (%)
interval (%)
41.2
23.9
21.6, 64.0
13.9, 37.9
(7/17)
(11/46)
0
(0/8)
0, 32.4
0
(0/15)
0, 20.4
Gelmon K et al J Clin Oncol 28:7s, 2010 (suppl; abstr 3002)
*Confidence intervals were calculated using the Wilson Score method
A Randomized Phase III Study Comparing
Concurrent Gemcitabine (Gem) plus Cisplatin
(Cis) and Radiation
Followed by Adjuvant Gem plus Cis
versus
Concurrent Cis and Radiation
in Patients with Stage IIB to IVA Carcinoma of the
Cervix
Alfonso Dueñas-González, Juan José Zarbá, Juan Carlos Alcedo,
Pittayapoom Pattarunataporn, Semir Beslija, Firuza Patel, Luis
Casanova, Helen Barraclough, Mauro Orlando
Study Design
Randomization
Stratified by:
stage;
tumor size;
investigator
site;
radiation
equipment
(Co60 or
LinAc);
age
N=515
patients
Chemoradiation
Arm A
N=259
BCT
Adjuvant Chemotherapy
30-35 Gy
(low or
IM DR)
Arm A
mg/m2
cisplatin 40
+
gemcitabine 125 mg/m2
weekly for 6 weeks
REST
2 cycles of:
cisplatin 50 mg/m2 (day 1) +
gemcitabine 1 g/m2 (days 1 and 8)
given q3 weeks
pelvic EBRT 50.4 Gy 1.8
Gy/day in 5.4 weeks
30-35 Gy
(low or
IM DR)
Arm B
N=256
cisplatin 40 mg/m2
weekly for 6 weeks
pelvic EBRT 50.4 Gy 1.8
Gy/day in 5.4 weeks
Week 0
Weeks 1 to 6
Week 7 Weeks 8 to 9
Weeks 10 to 15
Duenas-Gonzalez et al, ASCO 2009
Patient baseline characteristics
(Duenas-Gonzalez, 2009)
Arm A
N=259
Arm B
N=256
Overall
N=515
p-value
Age, years
Median (range)
45.0 (22 – 68)
46.0 (18 – 70)
46.0 (18 – 70)
0.377 (t)
Karnofsky Performance Status
Median (range)
90.0 (80 – 100)
90.0 (70 – 100)
90.0 (70 – 100)
0.734 (t)
Pathological Diagnosis, n (%)
Adenocarcinoma
Non-adenocarcinoma
17 (6.6)
242 (93.4)
15 (5.9)
241 (94.1)
32 (6.2)
483 (93.8)
0.856 (e)
Stage of Disease, n (%)
IIB
IIIA
IIIB
IVA
160 (61.8)
1 (0.4)
94 (36.3)
4 (1.5)
156 (60.9)
1 (0.4)
94 (36.7)
5 (2.0)
316 (61.4)
2 (0.4)
188 (36.5)
9 (1.7)
0.973 (e)
6.00 (2.0 – 20.0)
5.90 (2.8 – 11.0)
6.00 (2.0 – 20.0)
0.494 (t)
12.00 (7.9 – 15.8)
12.05 (8.5 – 15.9)
12.00 (7.9 – 15.9)
0.893 (t)
Characteristic
Maximum Diameter of the Largest Lesion, cm
Median (range)
Hemoglobin at Baseline, g/dL
Median (range)
Country, n (%)
Bosnia
Pakistan
Thailand
Argentina
Panama
Peru
India
Mexico
33
27
34
17
31
29
60
28
(12.7)
(10.4)
(13.1)
(6.6)
(12.0)
(11.2)
(23.2)
(10.8)
28
29
33
18
30
31
56
31
(10.9)
(11.3)
(12.9)
(7.0)
(11.7)
(12.1)
(21.9)
(12.1)
61
56
67
35
61
60
116
59
(11.8)
(10.9)
(13.0)
(6.8)
(11.8)
(11.7)
(22.5)
(11.5)
0.997 (e)
Abbreviations: N = total number of patients; n = number of patients per category. P-values determined by (e) Fisher’s exact test or (t) t test.
Enrolment: 10 sites, 8 countries (May ‘02 to March ’04) follow-up completed April ’08.
Progression-Free Survival at 3 Years
(Duenas-Gonzalez et al, ASCO 2009)
1.0
0.9
0.8
Gem/cis/rad
Cis/rad
0.7
0.6
PFS probability 0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
36
42
48
54
60
months
Abbreviations: CI = confidence interval; cis = cisplatin; Gem = gemcitabine; PFS = progression-free survival; Rad = radiation.
PFS at 3 years: 74.4% in Gem/cis/rad versus 65.0% in Cis/rad (p=0.029)
Overall Survival (Duenas-Gonzalez et al, ASCO 2009)
1.0
0.9
0.8
Gem/cis/rad
0.7
Cis/rad
0.6
OS probability 0.5
0.4
0.3
Log-rank p = 0.022
Hazard ratio = 0.68
95% CI = 0.49-0.95
0.2
0.1
0.0
0
6
12
18
24
30
36
42
48
54
60
66
months
Abbreviations: CI = confidence interval; cis = cisplatin; Gem = gemcitabine; OS = overall survival; Rad = radiation.
•
OS was statistically superior for Gem/cis/rad over Cis/rad
•
OS at 3 years: 78.2% in Gem/cis/rad versus 69.1% in Cis/rad