Case 1: Frontline Therapy

Transcription

Case 1: Frontline Therapy
• A 67-year-old real estate agent presented to her PCP with
early satiety and abdominal bloating for 6 weeks
• Performance status = 0; no medical comorbidities with the
exception of mild hypertension
• Ultrasound revealed 6-8 cm bilateral adnexal masses with
moderate to large volume ascites
• Exploratory laparotomy with TAH / BSO, omentectomy,
peritoneal stripping, and partial small bowel resection with
primary reanastomosis was performed with optimal
cytoreduction
• Dx: poorly differentiated papillary serous adenocarcinoma
1
Case 2: Maintenance Therapy
• A 62-year-old woman with an unremarkable PMH and excellent
performance status presents to her gynecologist with
progressive abdominal symptoms and pelvic mass by exam
• CT scan reveals extensive mesenteric disease, multiple
peritoneal implants, and ascites
• Ultrasound-guided paracentesis revealed high-grade papillary
serous adenocarcinoma consistent with a müllerian primary
• Normal CEA, CA-125 = 8,433
• Treated with 3 cycles of neoadjuvant paclitaxel + carboplatin
with good clinical response and CA-125 level falling to 89
• Undergoes an optimal interval cytoreduction (5 mm residuum)
• Receives 3 additional cycles of carboplatin + paclitaxel and
achieves a complete clinical remission by exam, CA-125 = 10,
and CT scan
• She expresses concern about the high risk for recurrence
2
Case 3: Late Recurrence
• A 40-year-old patient presented with stage IIIC serous
ovarian cancer and was optimally cytoreduced and
treated with IP paclitaxel and cisplatin
• Family hx: maternal aunt with ovarian cancer and 2
maternal cousins with premenopausal breast cancer
• CA-125 was initially 456 U/mL and nadir was 11 U/mL
after 6 cycles
• Had grade 1 neuropathy that has resolved; PS = 0
• 24 months later her CA-125 = 118 U/mL and CT
revealed small volume pelvic disease
3
Case 4: Early Recurrence
• A 59-year-old florist presented with abdominal pain, bloating, and a
pelvic mass. CA-125 was 1020 IU/mL
• After an optimal cytoreduced (5 mm residuum) she randomized to Arm
III of GOG-218 (paclitaxel and carboplatin 6 cycles with concurrent
bevacizumab followed by maintenance bevacizumab)
• Before starting maintenance bevacizumab she had a negative CA-125
and imaging (achieved complete clinical response)
• Regimen was tolerated well except grade 1 neuropathy (mild
numbness in her fingers and toes)
• 5 months into maintenance bevacizumab she experienced abdominal
pain and swelling develops
• CA-125 has risen to 70 IU/mL and a CT scan reveals ascites and
multiple pelvic masses causing intermittent moderate nausea and
early satiety
4
Case 5: Treatment Toxicity
• A 66-year-old woman with stage IIIC serous
ovarian cancer recently underwent TAH /
BSO and omentectomy resulting in
suboptimal cytoreduction with small volume
residual
• PMH:
– HTN treated with lisinopril, current BP 140/88
– DVT 20 years ago after elective cholecystectomy
– PS = 1
• Surgical wound healing well and patient is
without current complaint
5
CaseMat Home
•
•
•
•
•
•
•
•
Introduction
Patient Case 1: Frontline
Patient Case 2: Maintenance
Patient Case 3: Late recurrence
Patient Case 4: Early recurrence
Patient Case 5: Toxicity assessment
Novel agents / developmental therapeutics
Conclusion
6
Ovarian Cancer
• 2nd most common gynecologic malignancy
with the highest mortality
– Estimated 21,880 new cases diagnosed in 2010
• Almost 75% of cases present with advanced
stage disease
– Risk of relapse in advanced stage disease is as
high as 70%
• No effective early diagnostic test available
• The incidence increases with advancing age
7
American Cancer Society. Cancer Facts & Figures. 2010. Atlanta: American Cancer Society; 2010.
Gynecologic Cancer Comparisons
Estimated New Cancer
Cases
Ovarian
Uterine
Cervical
Other
14%
7%
51%
28%
Estimated Cancer
Deaths
Ovarian
Cervical
14%
Uterine
Other
6%
54%
26%
8
American Cancer Society. Cancer Facts & Figures. 2010. Atlanta: American Cancer Society; 2010.
Ovarian Cancer Staging
Stage
Description
Stage I
Confined to the Ovary
IA
Growth limited to one ovary, no ascites, capsule intact, no surface
tumor extension
IB
Same as IA but involves both ovaries
IC
IA or IB but with positive washings or ruptured capsule
Stage II
Extends to True Pelvis
IIA
Involves fallopian tube or uterus
IIB
Extension to other pelvic tissues
IIC
Either IIA or IIB but with positive washings or ruptured capsule
Stage III
Extends Beyond the True Pelvis
IIIA
Tumor limited to true pelvis but microscopic positive biopsy
outside the pelvis
IIIB
Abdominal implants up to 2 cm
IIIC
Positive lymph nodes or abdominal implants > 2 cm
Stage IV
Distant Disease
Incidence
Survival
20%
85%
5%
60%
58%
26%
17%
12%
9
Adapted from AJCC Cancer Staging Manual. 7th ed. New York, New York: Springer; 2010.
Ovarian Cancer Symptomatology
• Symptoms nonspecific and common
• No difference in symptom frequency for late vs early stage
Symptom(s)
Early Stage Late Stage
(n = 37)
(n = 118)
Odds Ratio
(95% CI)*
Unusual Bloating, Fullness, and
Pressure in the Abdomen / Pelvis
65%
71%
1.3 (0.61-2.9)
Unusual Abdominal or
Lower Back Pain
49%
52%
1.1 (0.54-2.4)
Frequent Urination, Urgency,
or Burning
35%
32%
0.87 (0.40-1.9)
Unusual Constipation
30%
21%
0.64 (0.28-1.5)
8%
22%
3.2 (0.96-10.7)
Unusual Diarrhea
27%
14%
0.42 (0.18-1.0)
Nausea
14%
11%
0.79 (0.26-2.4)
Unusual Lack of Appetite
*Late stage compared with early stage.
Goff BA, et al. J Am Med Assoc. 2004;291:2705-2712; Olson SH, et al. Obstet Gynecol. 2001;98(2):212-217.
10
Historic Treatment Paradigm
Diagnosis
Symptoms
Evaluation / Surveillance
Chemotherapy #1
Surgery / Staging
Progression Evaluation
+/- Maintenance
Chemo #2
Cure
Progression
Death
Chemo #3+
Supportive
Care
11
Secondary Response to Platinum
Cleveland Clinic Experience
• Retrospective review
• ≥ 2 platinum-based
recurrence regimens
administered
• 176 patients with 211
regimens reviewed
• TFI2 > TFI1 in 4 pts (3%)
• Length of TFI1 predictive of
upper limit of response
duration assuming same
or similar regimen
13
Markman M, et al. J Clin Oncol. 2004;22(15):3120-3125.
Chemotherapy Sensitivity
End of FrontLine Therapy
(Month 0)
6 Months
12 Months
Primary Treatment
Refractory
Chemo Resistant
Chemo Sensitive
“IntermediateSensitive”
“High-Sensitive”
14
CaseMat Home
•
•
•
•
•
•
•
•
Introduction
Conclusion
15
Frontline Treatment
16
Primary Approach to Systemic
Therapy: Landmark Phase III Studies
GOG-111
– Cisplatin /
cyclophosphamide vs
cisplatin / paclitaxel
0.9
– Firstline paclitaxel ↑
0.6
Paclitaxel / Cisplatin
Cyclophos / Cisplatin
0.8
0.7
Proport ion
PFS and OS in
advanced disease
OS
1.0
0.5
0.4
0.3
PFS
0.2
Paclitaxel / Cisplatin
0.1
Cyclophos / Cisplatin
0.0
0
6
12
18
24
30
36
42
48
Months After Entry into Study
17
McGuire WP, et al. N Engl J Med. 1996;334(1):1-6.
Primary Approach
to Systemic
.
GOG-158
1.0
Carboplatin / paclitaxel
OS
0.9
Cisplatin / paclitaxel
0.8
Proportion
0.7
0.6
0.5
PFS
0.4
0.3
0.2
Carboplatin / paclitaxel
0.1
Cisplatin / paclitaxel
0.0
0
12
24
36
Months
©2003 RF,
by American
of Clinical2003;21(17):3194-3200.
Oncology
Ozol
et al. JSociety
Clin Oncol.
48
60
18
Primary Approach to Systemic
• GOG-172
– Paclitaxel + IV cisplatin
vs paclitaxel + IP
cisplatin
– IP cisplatin ↑ OS in
optimally debulked
stage III disease
CDDP = cisplatin.
Armstrong DK, et al. N Engl J Med. 2006;354(1):34-43; Figure from GOG Intraperitoneal Chemotherapy Workshop, 2006.
Available at: http://www.gog.org/ipchemoed/ipchemoed.html. Accessed March 11, 2011.
19
GOG-172: Treatment Regimens
Every 21 Days
Regimen 1
Intravenous
6
D1: IV Paclitaxel 135 mg/m2/24h
D2: IV Cisplatin 75 mg/m2
D1
IV
D2
IV
Regimen 2
Intraperitoneal
D1
IV
D2
IP
D8
IP
D1: IV Paclitaxel 135 mg/m2/24h
D2: IP Cisplatin 100 mg/m2
D8: IP Paclitaxel 60 mg/m2
20
Armstrong DK, et al. N Engl J Med. 2006;354(11):34-43.
GOG-172: Survival Outcomes
Progression-Free Survival
1.0
1.0
Rx Group PF Failed Total
IV
50 160
210
IP
63 142
205
0.9
Proportion Progression-Free
Overall Survival
0.8
0.7
IV: 18 mos
IP: 24 mos
HR: 0.80, P = 0.05
0.6
0.5
0.9
0.8
0.7
0.6
IV: 50 mos
IP: 66 mos
HR: 0.75, P = 0.03
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0.0
0
12
24
36
Months on Study
48
60
Rx Group Alive Dead
IV
93
117
IP
117
88
Total
210
205
0.0
0
12
24
36
48
60
Months on Study
21
Armstrong DK, et al. N Engl J Med. 2006;354(11):34-43.
GOG-172: Non-Hematologic Toxicity
and Number of Courses Completed
Grade 3 / 4
Adverse Events
IV
Gastrointestinal
Event
24%
100
46%
90
2%
Fatigue
4%
1%
7%
18%
11%
% Completed
70
7%
27%
74
60
59
50
40
9%
19%
47
4
5
42
20
0
8
0
Neurologic Event
52
30
10
Metabolic Event
92
80
Renal or
Genitourinary
Event
Pain
IP
1
2
3
IP Courses
6
22
Armstrong DK, et al. N Engl J Med. 2006;354(11):34-43; Walker JL, et al. Gynecol Oncol. 2006;100(1):27-32.
GOG-172: PFS Estimate by Total
Cycles Administered
1.0
IP for 6 cycles superior to
combination of IV/IP for 6 cycles
0.9
PFS Probability
0.8
No difference between routes if
1-2 or 3-5 cycles received
0.7
0.6
0.5
0.4
0.3
0.2
GOG 172-IP = 6
GOG 172-IP = 3-5
GOG 172-IP < 3
GOG 172-IV = 6
0.1
0.0
0
6
12
18
24
30
36
42
48
54
60
66
72
Months on Study
23
Tewari D, et al. J Clin Oncol. 2008;26(18S). Abstract 5549.
GOG-172: Association of Survival
With Reduced BRCA1 Expression
• Archival tissue from 393 patients analyzed
• Median follow-up 86 months
BRCA1 Expression
Median OS (mo)
IP Arm
IV Arm
High (n = 204)
58
50
Low (n = 189)
84
48
Hazard ratio (95% CI)
0.689 (0.474-1.0)
1.299 (0.935-1.818)
24
Lesnock J, et al. Gynecol Oncol. 2010;116(3 suppl 1). Abstract 4.
Moving the Bar: Primary Therapy
• Dose-dense therapy
• Biologics: anti-angiogenesis
• Intraperitoneal chemotherapy
25
Dose-Dense Paclitaxel
Ovarian Epithelial,
PP, FT
FIGO Stage II-IV
DOSE DENSE
Paclitaxel 80 mg/m2 over 1 hr day 1, 8, 15
Carboplatin AUC 6 day 1
q3w × 6-9 cycles
Dose density: 80 mg/m2/wk
n = 312
R
Stratification:
CONVENTIONAL
Paclitaxel 180 mg/m2 over 3 hr day 1
Carboplatin AUC 6 day 1
q3w × 6-9 cycles
Dose density: 60 mg/m2/wk
n = 319
Residual disease: ≤ 1 cm, > 1 cm
• FIGO stage II vs III vs IV
• Histology: clear cell / mucinous vs serous / other
•
26
Katsumata N, et al. Lancet. 2009;374(9698):1351-1363.
Dose Dense: Survival Outcomes
Progression-Free Survival
100
HR 0.714 (95% CI 0.58-0.88)
P = 0.001
80
80
Patients surviving (%)
Patients Surviving Progression-Free (%)
100
Overall Survival
60
40
20
Events Med PFS
160 28.0 mo
200 17.2 mo
Dose dense
Conventional
0
60
HR 0.75 (95% CI 0.57-0.98)
P = 0.03
40
20
Dose dense
Conventional
Events 3-yr OS
96 72.1%
124 65.1%
0
0
6
12
18
24
30
36
42
48
Months From Randomization
0
6
12 18 24 30 36 42 48 54 60 66
27
Dose-Dense Therapy is
Tougher to Maintain
Dose
Dense
76%
Conventional
P
67%
0.02
At least one dose reduction
48%
35%
< 0.001
Carbo dose intensity
77%
79%
NS
Paclitaxel dose intensity
85%
86%
NS
At least one cycle delay
28
GOG-218
Primary Adjuvant and Maintenance Therapy
RANDOMIZATION (n = 1873)
Cycles 1-6*
Cycles 7-22
Paclitaxel 175 mg/m2
Carboplatin AUC = 6.0
Placebo
q3wk
cycles
Placebo
cycles
2-62-6
Placebo q3w
16
Bevacizumab
15 15
mg/kg
q3wk
cycles
Bevacizumab
mg/kg
cycles
2-62-6
Placebo q3w
16
Bevacizumab
15 15
mg/kg
q3wk
cycles
Bevacizumab
mg/kg
cycles
2-62-6
Inclusion Criteria
• EOC, FT, or primary peritoneal CA
• Stage III with any gross
(macroscopic or palpable) residual
disease OR stage IV disease
Burger R, et al. J Clin Oncol. 2010;28(18S). LBA1.
Bevacizumab 15 mg/kg
q3w 16
15 months total treatment
Primary Endpoint: PFS
*3-week cycles.
29
GOG-218: Patient Characteristics
Arm I
CP
n = 625
Arm II
CP + BEV
n = 625
60
60
Arm III
CP + BEV →
BEV
n = 623
60
Suboptimally debulked stage III disease
41%
41%
39%
Stage IV disease
25%
26%
27%
11
(0-22)
12
(0-22)
14
(0-21)
On treatment at time of analysis
14%
13%
19%
Completed treatment regimen
16%
17%
24%
Experienced disease progression while
on treatment
48%
42%
26%
Median age (years)
Median number of cycles with bevacizumab or
placebo (range)
30
GOG-218 Investigator-Assessed PFS
Arm I
Arm II
Arm III
CP + PLA → PLA CP + BEV → PLA CP + BEV  BEV
(n = 625)
(n = 625)
(n = 623)
Median follow-up: 17.4 months
Proportion Surviving Progression-Free
1.0
Patients with event, n (%)
0.9
Median PFS, months
0.8
HR (stratified)
(95% CI)
0.7
One-sided log-rank P value
375(60)
405(67)
363(71)
10.4
11.5
13.9
0.864
0.726
(0.759-0.996) (0.627-0.840)
0.0218
< 0.0001*
0.6
0.5
*P
0.4
value boundary = 0.0116.
0.3
0.2
CP (arm I)
+ BEV (arm II)
0.1
+ BEV → BEV (arm III)
0
0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Months Since Randomization
31
GOG-218: Progression-Free Survival
1.0
0.9
Median PFS, months
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
Stratified analysis HR
(95% CI)
0.7
0.908
0.717
(0.759-1.040) (0.625-0.824)
One-sided P value (log rank)
0.080*
< 0.0001*
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
36
*P value boundary = 0.0116.
32
GOG-218: Overall Survival
1.0
0.9
Proportion Alive
0.8
0.7
0.6
0.5
0.4
Patients with
events, n (%)
0.3
Median, months
Arm I
CP
(n = 625)
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
HR*
(95% CI)
One-sided P value
0.2
0.1
1.036
0.915
(0.827-1.297) (0.727-1.152)
0.361
0.252
0
0
12
24
36
48
No at
risk
625/625/623
442/432/437
173/162/171
46/39/40
*Stratified analysis.
33
GOG 218: Toxicity Comparisons
Arm I (CP)
Arm II (CP + BEV)
Arm III (CP + BEV --> BEV)
P = NS;
P = 0.03 if combined bev arms
GI
Perforation/fistula
P < 0.036
Hemorrhage
P < 0.005
Hypertension
0
5
10
15
20
34
GOG-218: Prospective Analysis of
Gastrointestinal Perforation
• Overall incidence
in 1759 patients
Odds Ratio
14
12
Multivariate OR
– Placebo: 1.7%
– Concurrent
bevacizumab:
3.4%
– Concurrent +
maintenance
bevacizumab:
3.4%
16
10
8
6
4
2
0
IBD
LBR
SBR
Bev
Characteristic
IBD = inflammatory bowel disease, LBR = large bowel resection
SBR = small bowel resection, Bev = bevacizumab
35
Burger R, et al. Society of Gynecologic Oncologists 2011 Annual Meeting. Abstract 7.
ICON-7 First-Line Bevacizumab
RANDOMIZATION
N = 1520
Cycles 1-6*
Cycles 7-18*
Bevacizumab 7.5 mg/kg
q3w × 5-6†
Inclusion Criteria
• EOC, fallopian, or PPC
• Optimal or suboptimal cytoreduction
• Stage I-IV
q3w 12
12 months total
Randomization closed Feb 2009
*3-week cycles; †Begin cycle 2, bevacizumab can be
omitted from the first cycle if cytotoxic chemotherapy must be started
within 4 weeks of surgery.
36
Primary Investigator: T Perren. Available at: http://www.icon7trial.org/. Accessed February 22, 2011.
ICON-7: PFS Benefit
Proportion Alive Without Progression
From Date of Last CT or Last Clinical Follow-up, Whichever Was Later
1.00
Events, n (%)
CP
CPB 7.5+
392 (51)
367 (48)
17.3
19.0
Median, months
0.75
Log-rank test
P = 0.0041
HR (95% CI)
0.81 (0.70-0.94)
0.50
CP
duration
0.25
Number at risk
CP
CPB 7.5+
CPB7.5+
duration
0
0
3
6
9
764
764
723
748
693
715
556
647
12
15
18
Time (months)
464
585
307
399
216
263
21
24
27
30
143
144
91
73
50
36
25
19
37
Perren T, et al. ESMO 2010. Abstract LBA4. Available at: http://www.icon7trial.org/. Accessed February 22, 2011.
ICON-7: Preliminary Analysis of
Overall Survival
Proportion Surviving
1.00
0.75
0.50
Control
Research
130 (17)
111 (15)
P = 0.098
Log-rank test
0.25
Based on immature OS data
(241 of 715 required events,
16% of all patients) as
required by regulatory
authorities (approved by
IDMC and TSC)
0.81 (0.63-1.04)
Hazard ratio (95% CI)
1-year survival rate, %
Anti-VEGF after progression, n (%)
93
95
30 (4)
14 (2)
0
0
3
30
Number at risk
Control
764
741
Research
764
753
6
724
737
9
701
716
12
652
678
15
486
525
368
404
18
252
259
21
24
159
162
27
83
89
Time (months)
33
40
38
Perren T, et al. 35th ESMO Congress Milan, Italy. October 2010. Abstract LBA4.
38
ICON-7: Selected Adverse Events
(all grades)
45
40
Patients (%)
Control (n=753)
39.6
Research (n=745)
35
30
29.1 28.3
25.9
25
20
15
10
5
0
12.5
11.6
6.2
5.0
4.4
2.5
2.1
1.31.7 0.41.3
6.7
4.1
9.2
3.6
1.5
0.4 0.4 0
0
2.8
2.0
ATE = arterial thromboembolism; CHF = congestive heart failure;
RPLS = reversible posterior leukoencephalopathy syndrome; VTE = venous thromboembolism
39
Perren T, et al. ESMO 2010. Abstract LBA4. Available at: http://www.icon7trial.org/. Accessed February 22, 2011.
Key Differences Between
GOG-218 and ICON-7
Trial
Setting / Design
Patient
Population
Additional
Endpoint
GOG-218
• Double-blinded,
placebo-controlled
• Three-arm study
• Bev for 15 months
• Bev dose: 15 mg q3w
• Stage III (suboptimal)
• Stage III (optimal,
visual / palpable)
• Stage IV
• OS analysis (formal
testing at time of PFS)
• IRC
ICON-7
•
•
•
•
Open-label
Two-arm study
Bev for 12 months
Bev dose: 7.5 mg q3w
• Stage I or IIA (grade 3 /
clear cell histology)
• Stages IIB-IV (all)
• Defined final OS
analysis (end 2012)
• No IRC
40
Phase III GOG-252 Schema
Cycles 1-6*
Cycles 7-22*
IV Paclitaxel 80 mg/m2 days 1, 8,
and 15
IV Carboplatin AUC 6 day 1
q3w
RANDOMIZATION
N = 1100
Bevacizumab 15 mg/kg q3w†
and 15
IP Carboplatin AUC 6 day 1
q3w
IV Paclitaxel 135 mg/m2 day 1
IP Cisplatin 75 mg/m2 day 2
IP Paclitaxel 60 mg/m2 day 8
q3w
Bevacizumab 15 mg/kg q3w †
*Each cycle is 3 weeks; †Begin cycle 2.
Walker JL. Am Soc Clin Oncol Ed Book. 2009:308-312.
Primary endpoint: PFS
41
Case 1 Revisited: Frontline Therapy
• A 67-year-old real estate agent presented to her PCP with
early satiety and abdominal bloating for 6 weeks
• Performance status = 0; no medical comorbidities with the
exception of mild hypertension
• Ultrasound revealed 6-8 cm bilateral adnexal masses with
moderate to large volume ascites
• Exploratory laparotomy with TAH / BSO, omentectomy,
peritoneal stripping, and partial small bowel resection with
primary reanastomosis was performed with optimal
cytoreduction
• Dx: poorly differentiated papillary serous adenocarcinoma
42
CaseMat Home
•
•
•
•
•
•
•
•
Introduction
Conclusion
43
Maintenance Treatment
44
Historic Treatment Paradigm
Diagnosis
Symptoms
Evaluation / Surveillance
Chemotherapy #1
Surgery / Staging
Progression Evaluation Progression Death
+/- Maintenance
Chemo #2
Cure
Chemo #3+
Supportive
Care
What we know (maintenance):
• 50% of CRs recur
• 40% of PCRs recur
• Reassessment is experimental
45
Maintenance Therapy Scorecard
Maintenance Beneficial?
Strategy
No
Prolonged Initial Therapy
✓
Short Duration / Non-Cross Resistant
Chemotherapy
✓
High-Dose Chemotherapy
✓
Intraperitoneal P32
✓
Interferon-
✓
Anti-CA-125 Ab
✓
Biologic Agent (MMPI, bevacizumab*)
✓
Paclitaxel (6 months)
✓
Paclitaxel (1 year)
Yes
✓*
✓?
46
Maintenance Therapy: Phase III
Trial
N
Maintenance Arms
Median
PFS
Statistic
(months)
SWOG 9701 /
GOG 1781,2
MITO-013
AGO-OVAR /
GINECO4
AFTER-65
296
273
1308
200
Paclitaxel 175 mg/m2 × 3
vs
Paclitaxel 175 mg/m2 × 12
Observation
vs
Topotecan 1.5 mg IV
days 1-5 q3w × 4
Observation
vs
Topotecan 1.25 mg IV
days 1-5 q3w × 4
Observation
vs
q3w × 6
14
HR 0.68
22
P = 0.004
28.4
HR 1.18
18.2
P = 0.83
18.5
HR 0.97
18.2
P = 0.688
30
2-year OS:
90% vs 87%
P = NS
34
1Markman
M, et al. J Clin Oncol. 2003;21(13):2460-2465; 2Markman M, et al. Gynecol Oncol. 2009;114(2):195-198; 3DePlacido
S, et al. J Clin Oncol. 2004;22(13):2635-2642; 4Pfisterer J, et al. J Natl Cancer Inst. 2006;98(15):1036-1045; 5Pecorelli S, et al. J
Clin Oncol. 2009;27:4642-4648.
47
MITO-1
AGO / GINECO
EOC
Stage IC-IV
EOC
Stage IIB-IV
Carboplatin AUC 5
6 cycles
RANDOMIZE
(N = 1308)
CR or PR
Paclitaxel 175 mg/m2 Paclitaxel 175 mg/m2
Carboplatin AUC 5
Carboplatin AUC 5
6 cycles
6 cycles
RANDOMIZE
(N = 273)
Topotecan 1.5 mg/m2
Days 1-5
4 cycles
NFT
De Placido S, et al. J Clin Oncol. 2004:22:2635-2642.
Topotecan 1.25 mg/m2
Days 1-5
4 cycles
Pfisterer J, et al. J Natl Cancer Instit. 2006;98:1036-1045.
48
Randomized Maintenance Trials:
Topotecan
MITO-1
AGO / GINECO
PFS
PFS
Hazard Ratio 1.18 (0.86 - 1.63)
De Placido S, et al. J Clin Oncol. 2004:22:2635-2642.
Pfisterer J, et al. J Natl Cancer Instit. 2006;98:1036-1045.
49
Consolidation Therapy: GOG-178
EOC, Fallopian, PP
Stage III-IV
Prior chemo 5-6 cycles
Register 3-8 weeks
CCR
Neuropathy ≤ Gr II
N = 450 anticipated
Accrual closed 9/6/2001
N = 277, 222 with follow-up
54 Progression events
R
A
N
D
O
M
I
Z
E
Paclitaxel (3-hour)
175 mg/m2 q 28 d 3
Paclitaxel (3-hour)
175 mg/m2 q 28 d 12
End points
• PFS
• OS
50
Markman M, et al. Gynecol Oncol. 2009;114(2):195-198.
SWOG 9701 / GOG-178
Updated Progression-Free Survival
100%
Hazard ratio 0.68 (P = 0.004)
80%
At Risk Failed Median (mo)
Paclitaxel 12 courses 150
104
22
Paclitaxel 3 courses
146
120
14
60%
40%
20%
0%
0
24
48
72
96
Months After Registration
51
Overall Survival (%)
SWOG 9701 / GOG-178
Updated Overall Survival
100
Hazard ratio 0.88 (P = 0.34)
80
60
40
20
At Risk Deaths
76
88
0
0
24
Median (months)
53
48
48
72
96
52
GOG-178: Toxicity
Result
3-Mos
PFS
21
G4 Neut
9%
G3 Myalgia
0%
G2 Neuropathy 14%
G3 Neuropathy 1%
Adapted from Markman M, et al. Clin Adv Hem Onc. 2003.
12-Mos
P
28
4%
1%
18%
5%
0.0023
NS
NS
NS
NS
53
SWOG 9701 / GOG-178
Survival by CA-125
100%
At Risk
CA-125: 0 - 10 175
CA-125: >10 - 35 121
80%
Median
Death in Months
70
57
76
41
HR: 0.59, P = 0.03
60%
40%
20%
0%
0
24
Markman M, et al. J Clin Oncol.2006;24:1454.
48
72
96
54
Phase III Maintenance Trials:
AFTER-6
EOC, PP, FT cancer
• N = 200 over 7+ yrs
– Closed due to slow accrual
Paclitaxel & Carboplatin
cCR or pCR
– Looking for 15% increase in
absolute PFS
• Violations
– 14% of obs patients got treatment
– 22% of pac patients stopped early
Paclitaxel
175 mg/m2
q21d 6 mos
No Treatment
• Results
– Median f/u: 44 mos
– PFS: 34 vs 34.5 mos (NS)
N = 250 patients
PFS (Iº)
Survival & Toxicity (IIº)
endpoints
– OS (3 yr): 88% (obs) vs 78% (pac)
55
Pecorelli S, et al. J Clin Oncol. 2009;27:4642-4648.
GOG-218: Progression-Free Survival
1.0
0.9
Median PFS, months
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
Stratified analysis HR
(95% CI )
0.7
0.908
0.717
(0.759-1.040) (0.625-0.824)
One-sided P value (log rank)
0.080*
< 0.0001*
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
36
*P value boundary = 0.0116.
56
GOG-218: Overall Survival
1.0
0.9
Proportion alive
0.8
0.7
0.6
0.5
0.4
Patients with
events, n (%)
0.3
Median, months
Arm I
CP
(n = 625)
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
HR*
(95% CI )
One-sided P value
0.2
0.1
1.036
0.915
(0.827-1.297) (0.727-1.152)
0.361
0.252
0
0
No at
risk
625/625/623
12
24
36
Months since randomization
442/432/437
173/162/171
48
46/39/40
*Stratified analysis.
57
GOG-218 and ICON-7:
Restricted Means Estimate – Benefit During Exposure Only?
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
14 vs 17
3 months’ difference
Research Arm
0
6
20
18
16
14
12
10
8
6
4
Research Arm
2
0 0
6
12
18
24
30
36
GOG-218
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
30
13.3 vs 16.5
3 months’ difference
Research Arm
0
6
12
18
24
30
36
ICON-7 (III suboptimal and IV subgroup)
25
20
15
10
Research Arm
5
12
18
Time (months)
24
30
36
0
-5
0
6
12
18
24
30
36
Time (months)
-10
Burger R, et al. J Clin Oncol. 2010;28(18S). LBA1; Perren T, et al.
-15ESMO 2010. Abstract LBA4.
58
ICON-7 First-Line Bevacizumab
RANDOMIZATION
N = 1520
Cycles 1-6*
Cycles 7-18*
q3w × 5-6†
Inclusion Criteria
• EOC, fallopian, or PPC
• Optimal or suboptimal cytoreduction
• Stage I-IV
q3w 12
12 months total
Randomization closed Feb 2009
*3-week cycles; †Begin cycle 2, bevacizumab can be
omitted from the first cycle if cytotoxic chemotherapy must be started
within 4 weeks of surgery.
59
Primary Investigator: T Perren. Available at: http://www.icon7trial.org/. Accessed February 22, 2011.
Phase III GOG-252 Schema
Cycles 1-6*
Cycles 7-22*
and 15
IV Carboplatin AUC 6 day 1
q3w
RANDOMIZATION
N = 1100
and 15
IP Carboplatin AUC 6 day 1
q3w
IV Paclitaxel 135 mg/m2 day 1
IP Cisplatin 75 mg/m2 day 2
IP Paclitaxel 60 mg/m2 day 8
q3w
Bevacizumab 15 mg/kg q3w †
*Each cycle is 3 weeks; †Begin cycle 2.
Walker JL. Am Soc Clin Oncol Ed Book. 2009;308-312.
Primary endpoint: PFS
60
GOG Ovarian Strategy: 262
Paclitaxel 80 mg/m2 IV weekly
Carboplatin AUC 6 IV q3wk
Bevacizumab 15 mg/kg IV
(beginning cycle 2; optional*)
Suboptimal
(> 1 cm
Residual)
Paclitaxel 175 mg/m2 IV q3wk
Carboplatin AUC 6 IV q3wk
Bevacizumab 15 mg/kg IV
(beginning cycle 2; optional*)
Bevacizumab
q3wk
(If chosen)
Maintenance
to
Progression
*Patient chooses whether to receive bevacizumab prior to enrolling in study.
61
Available at: http://www.clinicaltrials.gov/ct2/show/NCT01167712. Accessed April 12, 2011
Maintenance Therapy Scorecard
Maintenance Beneficial?
Strategy
No
Prolonged Initial Therapy
✓
Short Duration / Non-Cross Resistant
Chemotherapy
✓
High-Dose Chemotherapy
✓
Intraperitoneal P32
✓
Interferon-
✓
Anti-CA-125 Ab
✓
Biologic Agent (MMPI, bevacizumab*)
✓
Paclitaxel (6 months)
✓
Paclitaxel (1 year)
Yes
✓*
✓?
62
Maintenance Trials: Ongoing
GOG-212
EOC, PP, FT cancer
• Bevacizumab
• Abagovomab
Paclitaxel
Carboplatin
• Erlotinib
• Sorafenib
• Pazopanib
Paclitaxel CTI-2103
No
12 mos
12 mos Treatment
• Intedanib (BIBF 1120)
N = 1550 patients
Survival primary endpoints
QOL endpoints
63
Case 2: Maintenance Therapy
• A 62-year-old woman with an unremarkable PMH and excellent
performance status presents to her gynecologist with
progressive abdominal symptoms and pelvic mass by exam
• CT scan reveals extensive mesenteric disease, multiple
peritoneal implants and ascites
• Ultrasound-guided paracentesis revealed high grade papillary
serous adenocarcinoma consistent with a müllerian primary
• Normal CEA, CA-125 = 8,433
• Treated with 3 cycles of neoadjuvant paclitaxel + carboplatin
with good clinical response and CA-125 level falling to 89
• Undergoes an optimal interval cytoreduction (5 mm residuum)
• Receives 3 additional cycles of carboplatin + paclitaxel and
achieves a complete clinical remission by exam, CA-125 = 10,
and CT scan
• She expresses concern about the high risk for recurrence
64
CaseMat Home
•
•
•
•
•
•
•
•
Introduction
Conclusion
65
Late Recurrence
66
1000
100
900
90
800
80
700
70
600
60
500
50
400
40
300
30
200
20
100
10
0-3 Prog 0-3 Non PD 3-12 mos 12-18 mos
Percentage
Days
Treatment-Free Interval and Survival
18+ mos
PFS (days)
90
176
174
275
339
OS (days)
217
375
375
657
957
Response
(%)
9
24
35
52
62
67
Pujade-Lauraine E, et al. Proc Am Soc Clin Oncol. 2002;21. Abstract 829.
Recurrent Ovarian Cancer: Options
A. Chemo
Single Agent
Combination
Non-Platinum
(novel agents)
Platinum
B. Surgery
C. Other (biologics, radiation, hormones …)
68
Secondary Cytoreductive Surgery
Goal of surgery: No gross residual disease
DFI
6-12 mos
12-30 mos
> 30 mos
Single Site
Suggest
SC
Suggest
SC
Suggest
SC
Multiple Sites:
No
Carcinomatosis
Carcinomatosis
Offer SC
Suggest
SC
Suggest
SC
No SC
Offer SC
Suggest
SC
DFI = disease-free interval; mos = months; SC = secondary cytoreduction.
69
Chi DS, et al. Cancer. 2006;106(9):1933-1939.
Phase III GOG-213
Recurrent Ovarian, PPT, or
FT Cancer; TFI ≥ 6 months
Surgical Candidate?
Yes
No
Randomize
Randomize
Surgery
No Surgery
Chemotherapy
Randomization
Inclusion Criteria
• EOC, fallopian, or peritoneal cancer
• One prior therapy, platinum-free interval
≥ 6 months
Carboplatin /
Paclitaxel
Carboplatin /
Paclitaxel /
Bevacizumab
Bevacizumab
Until
Progression
Primary Endpoint: OS
Available at: http://www.cancer.gov/clinicaltrials/GOG-0213; Coleman R. Clinical Ovarian Cancer. 2008;1(1):78-80.
70
AGO-OVAR DESKTOP III
A randomized trial evaluating cytoreductive surgery
in patients with platinum-sensitive recurrent ovarian cancer
Platinum-sensitive
recurrent cancer of the
ovaries, fallopian tubes, or
peritoneum
PFI > 6 mos
No prior chemotherapy
for this 1st relapse
Complete resection
seems feasible and positive
AGO score:
• PS ECOG 0
• No ascites > 500 mL
• Prior complete debulking
or initial FIGO I/II
(if data available)
R
A
N
D
O
M
I
Z
E
Cytoreductive
surgery
Platinum-based
chemotherapy*
recommended
No surgery
*Recommended platinum-based chemotherapy regimens:
- Carboplatin / paclitaxel
- Carboplatin / gemcitabine
- Carboplatin / pegylated liposomal doxorubicin
- or other platinum combinations in prospective trials
71
Available at: http://www.clinicaltrials.gov/ct2/show/NCT01166737. Accessed March 11, 2011.
Recurrence Regimens
NCCN Preferred Agents
Platinum-Sensitive
Combination*
Platinum-Sensitive
Single-Agent
Platinum-Resistant
Single-Agent
Targeted Therapy
Carboplatin /
Paclitaxel (cat 1)
Carboplatin
Docetaxel
Bevacizumab
Carboplatin / Weekly
Paclitaxel
Cisplatin
Oral etoposide
Carboplatin /
Docetaxel
Gemcitabine
Carboplatin /
Gemcitabine
Pegylated liposomal
doxorubicin
Cisplatin /
Gemcitabine
Weekly paclitaxel
Carboplatin /
Liposomal
doxorubicin
Topotecan
*Platinum-based combination therapy should be considered for platinum-sensitive recurrences.
NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer v.1.2011.
Available at: http://www.nccn.org/professionals/physician_gls/PDF/ovarian.pdf. Accessed October 7, 2010.
72
Selected Positive Phase III Trials
Recurrent Disease
Trial
ICON 4
AGOOVAR-2.5
OVA-301
CALYPSO
Year
2003
2006
2010
2010
Platinum
Sensitive
Sensitive
Sensitive
and
Resistant
Intervention
N
No Prior
Trt (%)
Med PFS
(mo)
OS (mo)
Platinum
410
57
9.0
24
Platinum +
Paclitaxel
392
57
12.0
29
Carboplatin
178
33
5.8
17.3
Carboplatin +
Gemcitabine
178
31
8.6
18
PLD
335
-
5.8
Trabectedin +
PLD
337
-
7.3
Carboplatin +
Paclitaxel
507
-
9.4
Carboplatin +
PLD
466
-
11.3
Sensitive
Data
maturing
Data
maturing
Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322; Parmar MK, et al. Lancet. 2003;361:2099-2106; Pfisterer J, et al. J Clin
Oncol. 2006;24:4699-4707; Monk BJ, et al. J Clin Oncol. 2010;28(19):3107-3114; Pujade-Lauraine E, et al. J Clin Oncol.
2010;28(20):3323-3329.
PLD = Pegylated liposomal doxorubicin.
73
Phase III CALYPSO
International Randomized GCIG Intergroup Study
Patients > 6 months
post first- or secondline platinum-based
therapy w / prior
taxane exposure
Paclitaxel 175 mg/m2 +
Carboplatin AUC 5
q3w 6
n = 507
PLD 30 mg/m2 +
Carboplatin AUC 5
q3-4w 6
n = 466
Secondary Endpoints: OS, safety, QOL
PLD = pegylated liposomal doxorubicin.
74
Pujade-Lauraine E, et al. J Clin Oncol. 2010;28(20):3323-3329.
Patient Characteristics and
Treatment Exposure
Carboplatin / PLD
n = 466
Carboplatin / Paclitaxel
n = 507
Stage III / IV
401 (86%)
427 (84%)
Previous Lines of Therapy
1
2
408 (88%)
58 (12%)
421 (83%)
87 (17%)
Treatment-Free Interval
6-12 m
> 12 m
162 (35%)
304 (65%)
182 (36%)
326 (64%)
Trial Treatment Exposure
Median Treatment Duration
(weeks)
Patients With ≥ 6 Cycles*
21
16
85%
77%
*P < 0.001.
75
Proportion not Progressing
Primary Endpoint PFS
Carbo / PLD
Carbo / Pac
11.3
9.4
Median PFS
(months)
1.0
0.8
C / PLD
HR (95% CI)
0.82 (0.72-0.94)
P Value
(non-Inferiority)*
< 0.001
0.6
C / Pac
0.4
0.2
0.0
0
Number at Risk
467
CD
CP
509
6
12
18
24
30
397
405
188
152
60
45
20
10
4
2
*P value superiority = 0.005.
76
Randomized Phase III Study Comparing PLD and
Trabectedin With PLD Alone in Subjects With
Advanced Relapsed Ovarian Cancer (OVA-301)
Advanced recurrent EOC
1 prior platinum-based tx
regimen
Evaluable / measurable dz
Platinum sensitive or
resistant
ECOG PS ≤ 2
Secondary Endpoints: OS, RR,
safety
Pegylated Liposomal
Doxorubicin
50 mg/m2 IV q4w
n = 335
Pegylated Liposomal
Doxorubicin
30 mg/m2 IV q4w
Trabectedin
1.1 mg/m2 q3w
n = 337
Translational Studies
PK, PD, QOL, pharmacoeconomics,
and circulating tumor cells
77
Monk B, et al. J Clin Oncol. 2010;28(19):3107-3114.
OVA-301: Primary and Secondary
Endpoints
30
28
PLD
PLD+T
PFS (mos)
19
20
HR: 0.79
P = 0.019
10
5.8
7.3
HR: 0.73
P = 0.017
7.5
HR: 0.95
P = 0.75
P = 0.008
9.2
15
10
3.7 4
5
20
% Response
25
25
15
30
5
0
0
ITT
ITT-PS
ITT-PR
RR
Data are for Independent Radiology Review
PS = platinum-sensitive, PR = platinum-resistant
ITT = intent-to-treat, RR = response rate
Monk B, et al. J Clin Oncol. 2010;28(19):3107-3114.
78
RANDOMIZATION N = 450
Ovarian Cancer Evaluation of
Bevacizumab and Safety (OCEANS)
Phase III Second-Line Bevacizumab Trial
Gemcitabine 1000 mg/m2 day 1 & 8
Carboplatin AUC = 4.0 day 1
Bevacizumab 15 mg/kg day 1 q3w 6
Bevacizumab
to 51 weeks
Gemcitabine 1000 mg/m2 day 1 & 8
Carboplatin AUC = 4.0 day 1
Placebo day 1 q3w 6
Placebo
to 51 weeks
Bevacizumab
to PD
Inclusion Criteria
• Documented ovarian, PP, or fallopian tube
carcinoma that has recurred
• No prior chemotherapy in the recurrent setting
(platinum sensitive)
79
Available at: http://clinicaltrials.gov/show/NCT00434642.
Summary
Recurrent Ovarian Cancer: Sensitive
Chemotherapy
Single-Agent Combination
Options
NonPlatinum
(novel agents)
Platinum
80
Case 3 Revisited: Late Recurrence
• A 40-year-old patient presented with stage IIIC serous
ovarian cancer and was optimally cytoreduced and
treated with IP paclitaxel and cisplatin
• Family hx: maternal aunt with ovarian cancer and 2
maternal cousins with premenopausal breast cancer
• CA-125 was initially 456 U/mL and nadir was 11 U/mL
after 6 cycles
• Had grade 1 neuropathy that has resolved; PS = 0
• 24 months later her CA-125 = 118 U/mL and CT
revealed small volume pelvic disease
81
Poly (ADP-Ribose) Polymerase
(PARP)
• Key regulator of DNA damage repair
– Involved in DNA base-excision repair
• Binds directly to DNA damage and produces
large branched chains of poly (ADP-ribose)
DNA damage
PARP
NAD+
nicotinamide
+ pADPr
82
Tutt A, et al. Lancet.2010;376(9737):235-244.
PARP Inhibitors
Suggested Mechanism of Action
Chemotherapy inflicts DNA
damage via adducts and
DNA cross-linking
PARP1
PARP
Inhibitor
PARP1
PARP1 Upregulation
Base-excision repair of
DNA damage
Inhibition of
PARP1
PARP1
Disables DNA
base-excision
repair
Replication
fork collapse
Double strand
DNA break
BRCA1
BRCA2
CELL SURVIVAL
CELL DEATH
83
O’Shaughnessy J, et al. J Clin Oncol. 2009;27(15S). Abstract 3.
Phase I Trial of the
PARP Inhibitor Olaparib
84
Fong PC, et al. N Engl J Med. 2009;361(2):123-134.
Expansion Cohort of
Phase I Olaparib Trial (200 mg BID)
Characteristic
BRCA1 mutation, n
BRCA2 mutation, n
Strong family history, n
Mean age, years (range)
41
8
1
52 (37-80)
Platinum status, n (%)
Sensitive
Resistant
Refractory
13 (26)
24 (48)
13 (26)
Number of prior therapies, n (%)
1
2
3
>4
5 (20)
11 (22)
11(22)
23 (46)
85
Fong PC, et al. J Clin Oncol. 2010;28(15):2512-2519.
Olaparib Phase I Expansion
Clinical Activity by RECIST + GCIG
Total
Platinum
Sensitive
Platinum
Resistant
Platinum
Refractory
50
13
24
13
Responders by
RECIST
14 (28%)
4 (46%)
8 (34%)
0 (0%)
Responders by
GCIG CA-125
17 (34%)
8 (62%)
7 (30%)
2 (15%)
Responders by
either RECIST or
GCIG criteria
20 (40%)
8 (62%)
10 (42%)
2 (15%)
SD (> 16 weeks)
3 (6%)
1 (7%)
1 (4%)
1 (8%)
28 (23-33)
28 (20-37)
28 (19-38)
Not
evaluable
Number of
evaluable patients
Median duration of
response in weeks
(95% CI)
86
Adverse Events > 8 % Incidence
Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%)
Lymphopenia
0
0
6
2
Anemia
0
6
8
0
Nausea
36
6
6
0
Vomiting
14
4
2
0
Diarrhea
4
2
2
0
Dyspepsia
6
10
0
0
Anorexia
12
4
0
0
Dysgeusia
8
2
0
0
Fatigue
8
32
4
0
Dizziness
4
2
2
0
87
Correlation of Platinum-Free Interval and Best Response
Platinum-Free Interval (months)
24
Sensitive
Resistant
Refractory
18
12
6
0
CR/PR
SD > 4mos
PD
88
Phase II Study of Olaparib of Patients
With BRCA1 or BRCA2 Mutation
• Two dosages tested in sequential cohorts of patients
with recurrent, measurable disease
• Primary endpoint: response rate
400 mg BID
n = 33
ORR = 33%
100 mg BID
n = 24
ORR = 13%
• Adverse events: nausea, fatigue, anemia
89
Audeh MW, et al. Lancet. 2010;376(9737):245-251.
Phase II Study of Olaparib vs PLD in
Patients With BRCA1 or BRCA2 Mutation
• BRCA1/2 germline
carriers with ovarian
cancer
• Progressive or
recurrent disease < 12
months after previous
platinum-based
chemotherapy
RANDOMIZATION
Open label
Planned N = 90
Primary objective: Compare efficacy (PFS) of 2 dose levels of olaparib
(OLA) with pegylated liposomal doxorubicin (PLD)
OLA
200 mg bid in
28-day cycles
OLA
400 mg bid in
28-day cycles
PLD 50 mg/m2 IV
every 4 weeks
PD or withdrawal
from treatment for
other reason
As above or max
lifetime cumulative
dose reached
Patients in PLD group were allowed to
cross over to
olaparib 400 mg bid on confirmed PD
90
Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710.
Proportion of Patients Progression-Free
Median PFS (80% CI)
1.0
OLA 200 mg
OLA 400 mg
0.9
0.8
6.5 (5.6-8.0) months
8.8 (6.3-9.2) months
PLD 50 mg/m2 7.1 (5.5-7.8) months
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
HR vs PLD (80% CI)
OLA 200 mg: 0.91 (0.60-1.39); P = 0.78
OLA 400 mg: 0.86 (0.56-1.30); P = 0.63
OLA 200 mg + 400 mg: 0.88 (0.62-1.28); P = 0.66
0
Number of patients at risk:
OLA 200 mg
32
OLA 400 mg
32
PLD
33
2
4
6
8
10
12
3
1
3
0
0
0
Time From Randomization (months)
24
28
25
21
21
18
13
17
15
8
12
8
91
RECIST
Response
OLA 400
PR
SD ≥ 4 mos
OLA 200
SD 2-4 mos
PLD
PD
0%
20%
40%
60%
80%
100%
> Grade 3 toxicities
OLA 200 (n = 32)
OLA 400 (n = 32)
PLD (n = 32)
Any (%)
34
38
69
Anemia (%)
6
13
0
Fatigue (%)
3
9
9
PPE syndrome (%)
0
0
34
Rash (%)
0
0
9
92
Selection of PARP Inhibitors in
Clinical Trials
Agent
Administration
AZD-2281 (olaparib)
Oral
ABT-888 (veliparib)
Oral
BSI-201 (iniparib)
IV
KU59436
Oral
AGO14699
IV
INO-1001
IV
MK4827
Oral
GPI 21016
Oral
93
Adapted Ratnam K, et al. Clin Cancer Res. 2007;13:1383-1388; http://www.clinicaltrials.gov.
CaseMat Home
•
•
•
•
•
•
•
•
Introduction
Conclusion
94
Early Recurrence
95
Recurrence Regimens
NCCN Preferred Agents
Platinum-Sensitive
Combination*
Platinum-Sensitive
Single-Agent
Platinum-Resistant
Single-Agent
Targeted Therapy
Carboplatin /
Paclitaxel (cat 1)
Carboplatin
Docetaxel
Bevacizumab
Carboplatin / Weekly
Paclitaxel
Cisplatin
Oral etoposide
Carboplatin /
Docetaxel
Gemcitabine
Carboplatin /
Gemcitabine
Pegylated liposomal
doxorubicin
Cisplatin /
Gemcitabine
Weekly paclitaxel
Carboplatin /
Liposomal
doxorubicin
Topotecan
*Platinum-based combination therapy should be considered for platinum-sensitive recurrences.
NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer v.1.2011.
Available at: http://www.nccn.org/professionals/physician_gls/PDF/ovarian.pdf. Accessed October 7, 2010.
96
Select Phase II / III
Single-Agent Trials
Author
N
Treatment
Median TTP
(Weeks)
Median OS
(Weeks)
ten Bokkel
Huinink et al
226
Topotecan
23
61
Paclitaxel
14
43
Bolus Paclitaxel
12
42
Weekly Paclitaxel
14
37
Oxaliplatin
12
42
Paclitaxel
14
37
PLD
16
60
Topotecan
17
57
PLD
16
56*
Gemcitabine
20
51*
Rosenberg et al
Piccart et al
Gordon et al
Ferrandina et al
208
86
474
153
*Statistically significant; P = 0.048.
ten Bokkel Huinink W, et al. Ann Onc. 2004;15(1):100-103; Rosenberg P, et al. Acta Oncol. 2002;41:419-424; Piccart MJ, et al. J
Clin Oncol. 2000;18(6):1193-1202; Gordon AN, et al. Gynecol Oncol. 2004;95(1):1-8; Ferrandina G, et al. J Clin Oncol.
2008;26:890-896.
97
GOG Single-Agent Trials
GOG
Resistant
Population
Treatment
Response
Rate
126-J
60
Docetaxel*
22%
126-N
48
Weekly paclitaxel*
21%
126-Q
51
Pemetrexed*
20%
126-M
50
Ixabepilone
14%
126-K
25
Oxaliplatin
4%
126-H
25
Topotecan (24H)
4%
126-L
57
Gemcitabine + paclitaxel
16%
126-R
51
Nab-paclitaxel*
23%
*After paclitaxel.
Rose P, et al. Gynecol Oncol. 2003;88:130-135; Markman M, et al. Gynecol Oncol. 2006;101:436-440; Miller DS, et al. J Clin
Oncol. 2009;27(16):2686-2691; Fracasso P, et al. J Clin Oncol. 2003;21(15):2856-2859; Markman M, et al. Gynecol Oncol.
1999;75:444-446; Brewer C, et al. Gynecol Oncol. 2006;103(2):446-450.
98
Phase II Single-Agent Bevacizumab
Recurrent Disease
Dose / schedule
Median age (Years)
Primary endpoint
Measurable disease
Prior regimens
Platinum DFI
1o Platinum DFI < 6 mo
% Prior regimens (1 / 2 / 3 / 4)
% GOG / ECOG PS (0 / 1 / 2)
GOG-170-D
Burger, et al.
N = 62
Cannistra, et al.*
N = 44
Bevacizumab
15 mg/kg q21d
Bevacizumab
15 mg/kg q21d
57 (18-79)
59.5 (31-87)
ORR + 6-month PFS
ORR
Yes (RECIST)
Yes (RECIST)
1-2
2-3
Non-specified
< 6 months
(1st- or 2nd-Line)
36%
84%
34 / 66 / 0 / 0
0 / 52 / 48 / 0
73 / 27 / 0
59 / 41 / 0
*Trial terminated prematurely due to incidence of GI perforation.
99
Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5167; Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186.
Phase II Single-Agent Bevacizumab
Efficacy and Safety
ORR
6-Month PFS
GOG 170-D
Burger, et al.
N = 62
Cannistra, et al.*
N = 44
13 (21%)
7 (15.9%)
40.3%
27.8%
≥ Grade 3 Toxicity
GI perforation
Thrombosis / embolism
HTN
-
5 (11.4%)
1 (1.6%)
4 (9.0%)
(Venous)
(3 Arterial 1 VTE)
6 (9.7%)
6 (13.6%)
-
1 (2.3%)
1 (1.6%)
-
-
3 (6.8%)
Cerebral ischemia
Proteinuria
Death suspected as related to
bevacizumab
*Trial terminated prematurely due to incidence of GI perforation.
100
Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5167; Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186.
GOG-170-D Progression-Free Survival
All Patients
Proportion Progression-Free
1.0
0.9
Treatment
PF Failed Total
Historical Controls* 2
330 332
Pts on GOG-170-D 14
48
62
0.8
0.7
0.6
P < 0.0001
0.5
0.4
0.3
0.2
0.1
0
0
12
Months on Study
24
*The historical controls arm is comprised on agents found to be inactive in the GOG-126 series and
does not represent active agents in this setting.
101
Burger RA, et al. J Clin Oncol. 2007;25:5165-5171.
Summary
Recurrent Ovarian Cancer: Resistant
Chemotherapy
Single-Agent Combination
Options
Non-Platinum
(novel agents)
Platinum
102
Case 4 Revisited: Early Recurrence
• A 59-year-old florist presented with abdominal pain, bloating, and a
pelvic mass. CA-125 was 1020 IU/mL
• After an optimal cytoreduced (5 mm residuum) she randomized to Arm
III of GOG-218 (paclitaxel and carboplatin 6 cycles with concurrent
bevacizumab followed by maintenance bevacizumab)
• Before starting maintenance bevacizumab she had a negative CA-125
and imaging (achieved complete clinical response)
• Regimen was tolerated well except grade 1 neuropathy (mild
numbness in her fingers and toes)
• 5 months into maintenance bevacizumab she experienced abdominal
pain and swelling develops
• CA-125 has risen to 70 IU/mL and a CT scan reveals ascites and
multiple pelvic masses causing intermittent moderate nausea and
early satiety
103
CaseMat Home
•
•
•
•
•
•
•
•
Introduction
Conclusion
104
Toxicity Assessment
105
Summary of Adverse Events in
Early Randomized Trials
Gordon 2001
PLD
Topo
ICON 4 2003
P
P+Pac
Pfisterer 2006
C
C+G
Sensory Neuropathy
(grade 2-4)
NR
NR
1%
20%
5%
5%
Alopecia
16%
49%
25%
86%
2%
14%
Neutropenia
(grade 3/4)
12%
77%
NR
NR
12%
70%
Thrombocytopenia
(grade 3/4)
1%
34%
NR
NR
11%
35%
Hematologic
(grade 3/4)
NR
NR
46%
29%
NR
NR
PPE
(grade 3/4)
23%
0%
NR
NR
NR
NR
Gordon AN, et al. J Clin Oncol. 2001;19(14):3312-3322; Parmar MK, et al. Lancet. 2003;361(9375):2099-2106; Pfisterer J,
et al. J Clin Oncol. 2006;24(29):4699-4707.
106
Calypso Trial Toxicity
Carboplatin / PLD
n = 466
Grade 2
(%)
Grade 3 / 4
(%)
Carboplatin / Paclitaxel
n = 507
Grade 2
(%)
P Value
Grade 3 / 4
(%)
Non-Hematologic Toxicity
31
4
20
4
< 0.001
Arthralgias / Myalgias
4
0
18
1
< 0.001
Hand-Foot Syndrome
11
2
2
0
< 0.001
Mucositis
13
2
6
1
< 0.001
Neuropathy
4
1
24
4
< 0.001
Alopecia
7
Nausea / Vomiting
84
< 0.001
Hematologic Toxicity
Neutropenia
35
46
< 0.01
Thrombocytopenia
16
6
< 0.01
107
GOG-218 Toxicity
Adverse Events, n (%)
GI events* (grade ≥ 2)
Hypertension (grade ≥ 2)
Proteinuria (grade ≥ 3)
Arm III
Arm I
Arm II
CP
CP + BEV
(n = 601)
(n = 607)
7 (1.2)
43 (7.2)
†
4 (0.7)
17 (2.8)
100 (16.5)
4 (0.7)
CP + BEV 
BEV
(n = 608)
16 (2.6)
†
139 (22.9)
†
10 (1.6)
Pain (grade ≥ 2)
250 (41.7)
252 (41.5)
286 (47.1)
Neutropenia (grade ≥ 4)
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; *Perforation / fistula / necrosis / leak; †P < 0.05.
108
GOG-218: Prospective Analysis of
Gastrointestinal Perforation
• Overall incidence
in 1759 patients
Odds Ratio
14
12
Multivariate OR
– Placebo: 1.7%
– Concurrent
bevacizumab:
3.4%
– Concurrent +
maintenance
bevacizumab:
3.4%
16
10
8
6
4
2
0
IBD
LBR
SBR
Bev
Characteristic
IBD = inflammatory bowel disease, LBR = large bowel resection
SBR = small bowel resection, Bev = bevacizumab
109
Burger R, et al. Society of Gynecologic Oncologists 2011 Annual Meeting. Abstract 7.
Summary of Bevacizumab Toxicity
in Other Trials
• Gastrointestinal perforation
– 11% incidence in heavily pretreated recurrent
disease patients
– Management difficult due to risk of surgical
complications
• Thromboembolism (TE)
– Pooled analysis found increased risk of
arterial TE over chemotherapy alone (3.8% vs
1.7%)
– Risk factors: prior arterial TE, age > 65 years
110
Stone RL, et al. Lancet Oncol. 2010;11(5):465-475.
Summary of Bevacizumab Toxicity
in Other Trials
• Hypertension
– Dose-related incidence
• < 7.5 mg/kg: 3%-32%
• > 7.5 mg/kg: 18%-36%
– Requires medication manipulation in ~ 10%
• Proteinuria
– Grade 3/4 in 1%-4%
– Urine dipstick should be monitored
• If > 2 +, 24-hour collection obtained
• If > 2 g/24-hour, hold bevacizumab until resolved
111
Stone RL, et al. Lancet Oncol. 2010;11(5):465-475.
Case 5 Revisited: Treatment Toxicity
• A 66-year-old woman with stage IIIC serous
ovarian cancer recently underwent TAH / BSO
and omentectomy resulting in suboptimal
cytoreduction with small volume residual
• PMH:
– HTN treated with lisinopril, current BP 140/88
– DVT 20 years ago after elective cholecystectomy
– PS = 1
• Surgical wound healing well and patient is
without current complaint
112
CaseMat Home
•
•
•
•
•
•
•
•
Introduction
Conclusion
113
Recurrent Ovarian Cancer
Novel Biologics and
Developmental Therapeutics
Ovarian Cancer: Novel Targets
Tumor Cell
SURFACE MARKERS
NUCLEAR TARGETS
EGFR
ER
Her2
PDGFR
Folate
Receptor
Integrins
CA125
Erlotinib
Gefitinib
Trastuzumab
Pertuzumab
Lapatinib
Imatinib
Dasatinib
Sorafenib
XL 999
G706
Farletuzumab
EC17
EC145
Volociximab
Oregovomab
Abagovomab
PARP
Tamoxifen
Anastrozole
Exemestane
Letrozole
LHRH
Olaparib
Iniparib
Veliparib
INO 1001
Microenvironment
INTRACELLULAR
SIGNALING
ANGIOGENESIS
VEGF
PI3K/AKT
mTOR
RAS/RAF
PKC
Farnesyl
IC486068
Haloquinone
PX-316
Perifosine
BX-795
BX-912
BX-320
CCI-779
Everolimus
AP-23573
Sorafenib
Enzastaurin
Tipifarnib
Bevacizumab
Aflibercept
VEGFR
Sunitinib
Sorafenib
Cediranib
XL999
Integrins
Volociximab
Angiopoietin AMG386
IMMUNE CELLS
Cytokines Interferon
Aldesleukin
T-regs
Denileukin
diftitox
115
Adapted from Matei D, et al. Exp Opin Invest Drug. 2007;16:1227-1239.
Phase II Oral Multi-Kinase Inhibitors
in Relapsed Disease
Agent
Prior
Treatment
N
% Platinum
Resistant
Cediranib
≤ 2 prior lines
46
55
Cediranib
1 prior line
60
57
Sunitinib
≤ 2 prior lines
30
27
Sorafenib
≤ 2 prior lines
71
-
Pazopanib
≤ 2 prior lines
36
25
ORR
(CR + PR)
Grade 3 / 4 Toxicity
17%
Hypertension, fatigue,
diarrhea, CNS
hemorrhage
≈ 7%
(3 / 41 evaluable)
3%
3.4%
(2 / 59 evaluable)
18%*
(3 / 17 evaluable)
Hypertension, fatigue
Fatigue, hand-foot
syndrome
Rash, hand-foot
syndrome, metabolic,
GI, cardiovascular,
pulmonary
Diarrhea, ALT elevation
*Primary endpoint CA-125 response.
Matulonis UA, et al. J Clin Oncol. 2009;27(33):5601-5606; Hirte HW, et al. J Clin Oncol. 2008;26(suppl). Abstract 5521;
Biagi JJ, et al. Ann Oncol. 2011;22(2):335-340; Matei D, et al. J Clin Oncol. 2011;29(1):69-75; Friedlander M, et al. Gynecol
Oncol. 2010;119:32-37.
116
ICON-6
Phase III Second-Line Therapy
Patients relapsed > 6 months
post primary platinum-based
chemotherapy
RANDOMIZATION
2:3:3
N = 2000
Chemotherapy
+ Placebo
6
Placebo 18 months
(max) or until
progressive disease
Chemotherapy 6
+ Cediranib
Placebo 18 months
(max) or until
progressive disease
Chemotherapy 6
+ Cediranib
Cediranib 18 months
(max) or until
progressive disease
117
Available at: http://www.clinicaltrials.gov/ct2/show/NCT00544973?term=icon-6&rank=1. Accessed February 22, 2011.
Poly (ADP-Ribose) Polymerase
(PARP)
• Key regulator of DNA damage repair
– Involved in DNA base-excision repair
• Binds directly to DNA damage and produces
large branched chains of poly (ADP-ribose)
DNA damage
PARP
NAD+
nicotinamide
+ pADPr
118
Tutt A, et al. Lancet.2010;376(9737):235-244.
PARP Inhibitors
Suggested Mechanism of Action
Chemotherapy inflicts DNA
damage via adducts and
DNA cross-linking
PARP1
PARP
Inhibitor
PARP1
PARP1 Upregulation
Base-excision repair of
DNA damage
Inhibition of
PARP1
PARP1
Disables DNA
base-excision
repair
Replication
fork collapse
Double strand
DNA break
BRCA1
BRCA2
CELL SURVIVAL
CELL DEATH
119
O’Shaughnessy J, et al. J Clin Oncol. 2009;27(15S). Abstract 3.
Phase I Trial of the
PARP Inhibitor Olaparib
120
Fong PC, et al. N Engl J Med. 2009;361(2):123-134.
Expansion Cohort of
Phase I Olaparib Trial (200 mg BID)
Characteristic
BRCA1 mutation, n
BRCA2 mutation, n
Strong family history, n
Mean age, years (range)
41
8
1
52 (37-80)
Platinum status, n (%)
Sensitive
Resistant
Refractory
13 (26)
24 (48)
13 (26)
Number of prior therapies, n (%)
1
2
3
>4
5 (20)
11 (22)
11(22)
23 (46)
121
Clinical Activity by RECIST + GCIG
Total
Platinum
Sensitive
Platinum
Resistant
Platinum
Refractory
50
13
24
13
Responders by
RECIST
14 (28%)
4 (46%)
8 (34%)
0 (0%)
Responders by
GCIG CA-125
17 (34%)
8 (62%)
7 (30%)
2 (15%)
Responders by
either RECIST or
GCIG criteria
20 (40%)
8 (62%)
10 (42%)
2 (15%)
SD (> 16 weeks)
3 (6%)
1 (7%)
1 (4%)
1 (8%)
28 (23-33)
28 (20-37)
28 (19-38)
Not
evaluable
Number of
evaluable patients
Median duration of
response in weeks
(95% CI)
122
Adverse Events > 8 % Incidence
Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%)
Lymphopenia
0
0
6
2
Anemia
0
6
8
0
Nausea
36
6
6
0
Vomiting
14
4
2
0
Diarrhea
4
2
2
0
Dyspepsia
6
10
0
0
Anorexia
12
4
0
0
Dysgeusia
8
2
0
0
Fatigue
8
32
4
0
Dizziness
4
2
2
0
123
Correlation of Platinum-Free Interval and Best Response
Platinum-Free Interval (months)
24
Sensitive
Resistant
Refractory
18
12
6
0
CR/PR
SD > 4mos
PD
124
Phase II Study of Olaparib of Patients
With BRCA1 or BRCA2 Mutation
• Two dosages tested in sequential cohorts of patients
with recurrent, measurable disease
• Primary endpoint: response rate
400 mg BID
n = 33
ORR = 33%
100 mg BID
n = 24
ORR = 13%
• Adverse events: nausea, fatigue, anemia
125
Audeh MW, et al. Lancet. 2010;376(9737):245-251.
• BRCA1/2 germline
carriers with ovarian
cancer
• Progressive or
recurrent disease < 12
months after previous
platinum-based
chemotherapy
RANDOMIZATION
Open label
Planned N = 90
Primary objective: Compare efficacy (PFS) of 2 dose levels of olaparib
(OLA) with pegylated liposomal doxorubicin (PLD)
OLA
200 mg bid in
28-day cycles
OLA
400 mg bid in
28-day cycles
PLD 50 mg/m2 IV
every 4 weeks
PD or withdrawal
from treatment for
other reason
As above or max
lifetime cumulative
dose reached
Patients in PLD group were allowed to
cross over to
olaparib 400 mg bid on confirmed PD
126
Proportion of Patients Progression Free
Median PFS (80% CI)
1.0
OLA 200 mg
OLA 400 mg
0.9
0.8
6.5 (5.6-8.0) months
8.8 (6.3-9.2) months
PLD 50 mg/m2 7.1 (5.5-7.8) months
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
HR vs PLD (80% CI)
OLA 200 mg: 0.91 (0.60-1.39); P = 0.78
OLA 400 mg: 0.86 (0.56-1.30); P = 0.63
OLA 200 mg + 400 mg: 0.88 (0.62-1.28); P = 0.66
0
Number of patients at risk:
OLA 200 mg
32
OLA 400 mg
32
PLD
33
2
4
6
8
10
12
3
1
3
0
0
0
Time From Randomization (months)
24
28
25
21
21
18
13
17
15
8
12
8
127
RECIST
Response
OLA 400
PR
SD ≥ 4 mos
OLA 200
SD 2-4 mos
PLD
PD
0%
20%
40%
60%
80%
100%
> Grade 3 toxicities
OLA 200 (n = 32)
OLA 400 (n = 32)
PLD (n = 32)
Any (%)
34
38
69
Anemia (%)
6
13
0
Fatigue (%)
3
9
9
PPE syndrome (%)
0
0
34
Rash (%)
0
0
9
128
Selection of PARP Inhibitors in
Clinical Trials
Agent
Administration
AZD-2281 (olaparib)
Oral
ABT-888 (veliparib)
Oral
BSI-201 (iniparib)
IV
KU59436
Oral
AGO14699
IV
INO-1001
IV
MK4827
Oral
GPI 21016
Oral
129
Adapted Ratnam K, et al. Clin Cancer Res. 2007;13:1383-1388; http://www.clinicaltrials.gov.
ASCO 2010:
Developmental Therapeutics
• EC145
– Folate receptor / vinca
alkaloid conjugate
• Farletuzumab
– Folate receptor alpha
antagonist
• NKTR-102
– Pegylated irinotecan
• Nab-paclitaxel
– Nanoparticle albumin
bound paclitaxel
• Voreloxin
– DNA intercalation /
topoisomerase II inhibitor
• AMG-386
– Angiopoietin 1/2 inhibitor
130
ASCO 2011:
Anticipated Presentations
• OCEANS
– Carboplatin / gemcitabine + bevacizumab
• MIMOSA
– Abagovomab (anti-idiotype antibody against CA-125)
– After optimal response to initial surgery plus
chemotherapy
• Olaparib maintenance
• OVA-301 final survival
• CALYPSO final survival
131
CaseMat Home
•
•
•
•
•
•
•
•
Introduction
Conclusion
132
Conclusion
• Emerging clinical trials coupled with evolving
basic science discoveries have changed the
treatment of ovarian cancer
– Historic treatment paradigms in ovarian cancer
are being challenged
– The safe and appropriate addition of new agents
into the treatment paradigm is a priority
– The development and incorporation of new
therapeutic approaches are needed to improve
patient outcomes
133
CaseMat Home
•
•
•
•
•
•
•
•
Introduction
Conclusion
134

Case 1: Frontline Therapy

Transcription

Similar documents