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7/21/2011
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GYN-Oncology Update: ASCO 2011
Joanne L. Blum, MD, PhDBaylor-Sammons Cancer CenterBaylor Sammons Cancer Center
Texas OncologyDallas, TX
Study design & Results• Aim: Evaluate effect on mortality of screening for ovarian cancer using CA-
125 & transvaginal ultrasound (TVU)
Intervention arm (n=39,105)
Usual care (n=39,111)176 Ov Ca = 100 deaths (57%)
( )Annual screening (CA-125 x 6 yrs &
TVU x 4 yrs)212 Ov Ca = 118 deaths (56%)
3,285 FP’s = 166 SAE’s10 US screening centers78,216 women recruited(55-74 years)
RANDOMIZE
• Participants & health care providers received screening test results
• All followed for up to 13 years for cancer diagnoses & death
• Primary outcome: ovarian cancer mortality
• Secondary outcomes: ovarian cancer incidence, complications associated with screening exams & diagnostic procedures
Buys et al. J Clin Oncol 2011;29 (suppl; abstr 5001)
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Homologous recombination repair deficiency in ovarian cancer
• 10–15% of epithelial ovarian cancers are deficient in homologous recombination repair due to BRCA1 or BRCA2 mutations1
• Up to 50% of high-grade serous ovarian cancer patients could be deficient in homologous recombination repair because of:2
– Germ-line or somatically acquired BRCA1 or BRCA2 mutations
– Epigenetic inactivation of BRCA1– BRCA1/BRCA2-independent defects in the homologous
recombination pathway
1. Bast Jr, RC et al. Nat Rev Oncol 2009;9:415–428; 2. Press JZ et al. BMC Cancer 2008;8:17
Maintenance Olaparib: Study design
Patients
Placebo(n=129)
Olaparib400mg bid, orally
(n=136)
•Platinum-sensitive high-grade serous ovarian cancer
•≥2 previous platinum regimens
•Maintained PR or CR following last platinum regimen
Primary endpoint
PFS by RECIST
Secondary endpoints
TTP by CA-125 (GCIG criteria) or RECIST, OS, safety
Randomized 1:1
( )
Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003)
82 sites in 16 countries
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Time to progression by CA125 (GCIG) or RECIST
0.9
1.0No. of events: Total patients (%)
Median TTP (months)
Olaparib66:136 (48.5)
Placebo 106:129 (82.2)
0.6
0.8
Pro
po
rtio
n o
f p
atie
nts
pro
gre
ssio
n f
ree
0.2
0.3
0.4
0.5
0.7
Median TTP (months) 8.3 3.7
Randomized treatment
Hazard ratio 0.35 (95% CI, 0.25–0.47)P<0.00001
0
Time from randomization (months)
136 98 47 22 5 0 0
129 66 20 7 0 0 0
At risk (n)
Olaparib
Placebo
P
0
0.1
3 6 9 12 15 18
Olaparib 400 mg bidPlacebo
Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003)
Tolerability
Olaparib(n=136)
Placebo(n=129)
AEs more commonly reported on olaparib than placebo (by >10%)
Nausea 68% 35%
Fatigue 49% 38%
Vomiting 21% 14%
Anemia 17% 5%
AEs leading to treatment discontinuation 2.2% 0.8%
Dose reductions and interruptions 23% 7%Dose reductions and interruptions 23% 7%
• Majority of AEs CTCAE grade 1 or 2 • Most frequent CTCAE grade ≥3 events
• Olaparib: fatigue (9 pts), anemia (7 pts)• Placebo: abdominal pain and fatigue (4 pts each)
Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003)
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Conclusions
• The study achieved primary objective: Olaparib significantly prolonged PFS
• First study to demonstrate statistically significant benefit of maintenance treatment for platinum-sensitive relapsed serous ovarian cancer
• 50% of olaparib and 16% of placebo patients still on treatment at time of the analysis
• Olaparib well tolerated and toxicities consistent with• Olaparib well tolerated and toxicities consistent with those of previous studies
• Further studies will be performed to determine the role of olaparib in the routine treatment of ovarian cancer
Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003)
Results: platinum-sensitive disease
• Patients with platinum-sensitive disease (relapse ≥6 months following primary treatment termination)
• Analysis for first 17 patients
– ORR of 70.6% (12 confirmed responses)
– No indication of relationship between BRCA status and objective response
– Safety profiles: consistent with previous studies
• Conclusions
– Iniparib + GC demonstrated activity in patients with platinum-sensitive recurrent ovarian cancer
– No unexpected toxicities
Penson et al. J Clin Oncol 2011;29 (suppl; abstr 5004)
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Results: platinum-resistant disease
• Patients with platinum-resistant disease (relapse 2-6 months following primary treatment termination)
• Analysis for first 19 patients
– ORR of 31.6% (6 confirmed responses)
– Early analysis: median PFS 5.9 months (95% CI, 3.0-NE)
– Safety profiles consistent with previous studies
C l i• Conclusions
– Iniparib + GC demonstrated activity in patients with platinum-resistant recurrent ovarian cancer
– No unexpected toxicities
Birrer et al. J Clin Oncol 2011;29 (suppl; abstr 5005)
ASCO 2011 PARP StudiesAb. Title Autho
rN = Results Comments
2520 Ph I Olaparib + Carbo BRCA+ Ov /Br pts
Lee J 30 26 ov
83% Clin benefitC =AUC5; O=400 mg bid d 1-7 q 21d
DLT not reached
3102 Ph I MK-4827 Adv BrCA+/-Ov
Schel-man
60 MTD=300 mg d1-21 q28; 12 (20%) PR
5003 R Ph II Olaparib or placebo Plat-S ov after Plat resp
Leder-mann
265 PFS 8.4 (O @ 400 mg bid) vs 4.8 mos.
> 2 prior platMaintenance
5004 Ph II Iniparib + Carbo/Gem Plat-S
Penson R
41 ORR = 65%PFS 9.4 mos
BrCa status independent
00 Ph II I i ib Bi 48 ORR 2 % B C5005 Ph II Iniparib + Carbo/Gem Plat-R
Birrer M
48 ORR = 25% PFS = 6.4 mos.
BrCa status independent
5025 Sequence Specific efects of Olaparib/Carbo
Hays JL
Cell lines
O Then C is less effective
5028 Ph I Olaparib/Cediranib
Liu J 1813 ov
C = 30 & O = 200 bid; 56% RR
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ICON7: a phase III Gynaecologic Cancer InterGroup (GCIG) trial of adding bevacizumab
to standard chemotherapy in women with newly diagnosed epithelial ovarian, primary peritoneal
or fallopian tube cancerTim Perren, Ann Marie Swart, Jacobus Pfisterer, Jonathan Tim Perren, Ann Marie Swart, Jacobus Pfisterer, Jonathan
Ledermann, Alain Lortholary, Gunnar Kristensen, Mark Carey, Ledermann, Alain Lortholary, Gunnar Kristensen, Mark Carey, Philip Beale, Andreas Cervantes, Amit Oza Philip Beale, Andreas Cervantes, Amit Oza
on behalf of GCIG ICON7 collaborators on behalf of GCIG ICON7 collaborators (MRC/NCRI AGO(MRC/NCRI AGO--OVAR GINECO NSGO ANZGOGOVAR GINECO NSGO ANZGOG(MRC/NCRI, AGO(MRC/NCRI, AGO--OVAR, GINECO, NSGO, ANZGOG, OVAR, GINECO, NSGO, ANZGOG,
GEICO, NCICGEICO, NCIC--CTG)CTG)ESMO 2010ESMO 2010
ICON7: Study Design
Carboplatin Carboplatin AUC 6*AUC 6*
F tliF tli
Primary Primary endpoint: PFSendpoint: PFS
Paclitaxel 175 Paclitaxel 175 mg/mmg/m22
AUC 6AUC 6
Carboplatin AUC Carboplatin AUC 6*6*Paclitaxel 175Paclitaxel 175
Frontline Frontline EOC, PP or EOC, PP or FT cancerFT cancer
•• Stage IStage I--IIA (Gr IIA (Gr 3 3 or CC) or CC) •• Stage IIB/CStage IIB/C•• Stage IIIStage III•• Stage IVStage IV
n=1528 n=1528
endpoint: PFSendpoint: PFS
Secondary Secondary endpoints: OS, endpoints: OS, RR, safety, QOL, RR, safety, QOL, costcost--effectiveness,effectiveness,translationaltranslational
Stratification variables: Stratification variables: •• Stage / surgeryStage / surgery•• Time since surgeryTime since surgery•• GCIG groupGCIG group *Might vary based on GCIG group.*Might vary based on GCIG group.
††Omit cycle 1 bevacizumab if < 4 weeks from Omit cycle 1 bevacizumab if < 4 weeks from surgery.surgery.
Paclitaxel 175 Paclitaxel 175 mg/mmg/m22
12 months12 months
Bevacizumab 7.5 mg/kgBevacizumab 7.5 mg/kg††
No IRC presentNo IRC present
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ASCO 2011
Kristensen G et al J Clin Oncol 29: 2011 (suppl; abstr LBA5006)
ICON7: Preliminary Analysis ofOverall Survival*
1.00
g
ESMO 2010
CP CPB7.5+
Patients with event, n (%) 130 (17) 111 (15)
Log-rank test P = 0.098
Hazard ratio (95% CI) 0.81 (0.63-1.04)
1-year survival rate, % 93 95
Anti-VEGF after progression, n (%) 30 (4) 14 (2)
0.75
0.50
Pro
port
ion
Sur
vivi
ng
0.25
0Number at riskCP 764 741 724 701 652 486 368 252 159 83 33CPB7.5+ 764 753 737 716 678 525 404 259 162 89 40
Time (months)0 3 6 9 12 15 18 21 24 27 30
*Based on immature OS data (241 of 715 required events, 16% of all patients) as required by regulatory authorities (approved by IDMC and TSC).
Perren T, et al. Annals Oncol. 2010;21(suppl 8). Abstract LBA4.
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ASCO 2011
Kristensen G et al J Clin Oncol 29: 2011 (suppl; abstr LBA5006)
GOG-0218: Schema
Frontline: Frontline: Epithelial OV, PPEpithelial OV, PP RR
Paclitaxel (P) 175 mg/mPaclitaxel (P) 175 mg/m22
Carboplatin (C) AUC 6Carboplatin (C) AUC 6
Pl bPl b
II
ArmArm
Epithelial OV, PP Epithelial OV, PP or FT canceror FT cancer
•• Stage III optimal Stage III optimal (macroscopic)(macroscopic)
•• Stage III Stage III suboptimalsuboptimal
•• Stage IVStage IV
N = 1800 N = 1800 (planned)(planned)
Carboplatin (C) AUC 6Carboplatin (C) AUC 6
Paclitaxel (P) 175 mg/mPaclitaxel (P) 175 mg/m22
PlaceboPlaceboBEV 15 mg/kgBEV 15 mg/kg
IIII
AANNDDOOMMIIZ Z EE
1:1:11:1:1
PlaceboPlacebo
Stratification variables:Stratification variables:•• GOG performance status GOG performance status
(PS)(PS)•• Stage / debulking statusStage / debulking status
15 months15 monthsCytotoxic Cytotoxic (6 cycles)(6 cycles)
BEV 15 mg/kgBEV 15 mg/kg
Carboplatin (C) AUC 6Carboplatin (C) AUC 6
Paclitaxel (P) 175 mg/mPaclitaxel (P) 175 mg/m22IIIIII
MaintenanceMaintenance(16 cycles)(16 cycles)
Burger RA, et al. J Clin Oncol. 2010;28(18s). Abstract LBA1.
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GOG-0218: Investigator-Assessed PFS
Arm I CP
(n = 625)
Arm IICP + BEV(n = 625)
Patients with event, n (%)423
(67.7)418
(66.9)
sio
n F
ree
sio
n F
ree
1.01.0
0.90.9
0.80.8
Arm IIICP + BEV BEV
(n = 623)
360 (57.8)
Median PFS, months 10.3 11.2
Stratified analysis HR (95% CI)
0.908(0.759-1.040)
One-sided P value (log rank) 0.080*
rtio
n S
urv
ivin
g P
rog
ress
rtio
n S
urv
ivin
g P
rog
ress
0.70.7
0.60.6
0.50.5
0.40.4
0.30.3
0 20 2
14.1
0.717 (0.625-0.824)
< 0.0001*
+ BEV (Arm II)+ BEV (Arm II)CP (Arm I)CP (Arm I)
**PP value boundary = 0.0116.value boundary = 0.0116.
+ BEV → BEV maintenance (Arm III)+ BEV → BEV maintenance (Arm III)
Pro
po
rP
rop
or
Months Since RandomizationMonths Since Randomization
0.20.2
0.10.1
0000 1212 2424 3636
Burger RA, et al. J Clin Oncol. 2010;28(18s). Abstract LBA1.
GOG-0218: Overall Survival Analysis At time of final PFS analysis (January 2010)
Arm ICP
(n = 625)
Arm IICP + BEV(n = 625)
Arm IIICP + BEV
BEV(n = 623)
Patients with events, n (%) 156 (25.0) 150 (24.0) 138 (22.2)
Median OS, months 39.3 38.7 39.7
Stratified analysis 1.036 0.915
1.01.0
0 90 9 HR (95% CI) (0.827-1.297) (0.727-1.152)
One-sided P value 0.361 0.252
rop
ort
ion
Su
rviv
ing
rop
ort
ion
Su
rviv
ing
0.90.9
0.80.8
0.70.7
0.60.6
0.50.5
0.40.4
0.30.3
+ BEV (Arm II)+ BEV (Arm II)CP (Arm I)CP (Arm I)
+ BEV → BEV maintenance (Arm III)+ BEV → BEV maintenance (Arm III)
Pr
Pr
Months Since RandomizationMonths Since Randomization
0.30.3
0.20.2
0.10.1
0000 1212 2424 3636 4848
Burger RA, et al. J Clin Oncol. 2010;28(18s). Abstract LBA1.
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OCEANS: A randomized, double-blinded, placebo-, , pcontrolled, phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary
peritoneal, or fallopian tube cancer
PI = Carol Aghajanian
Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007)
CG + PL
OCEANS: Study schema
Platinum-sensitiverecurrent OCa
•Measurable disease
G 1000 mg/m2, d1 & 8
C AUC 4
CG f 6 ( t 10) lStratification variables:
•ECOG 0/1•No prior chemo for recurrent OC•No prior BV
(n=484)
PL q3w until progression
C AUC 4
BV 15 mg/kg q3w until progression
G 1000 mg/m2, d1 & 8CG + BV
CG for 6 (up to 10) cycles• Platinum-free interval
(6–12 vs >12 months)
• Cytoreductive surgery for recurrent disease (yes vs no)
BV = bevacizumab; PL = placeboaEpithelial ovarian, primary peritoneal, or fallopian tube cancer
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OCEANS: Primary analysis of PFSCG + PL(n=242)
CG + BV(n=242)
Events, n (%) 187 (77) 151 (62)
Median PFS, months (95% CI)
8.4(8 3–9 7)
12.4(11 4–12 7)
1.0fr
ee
months (95% CI) (8.3–9.7) (11.4–12.7)
Stratified analysis HR (95% CI)Log-rank p-value
0.484 (0.388–0.605)
<0.0001
0.8
0.6
0.4
0.2po
rtio
n p
rog
ress
ion
f
242 177 45 11 3 0CG + PL
MonthsNo. at risk
242 203 92 33 11 0CG + BV
0
Pro
p
0 6 12 18 24 30
Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007)
OCEANS: Objective response
100
%Difference: 21.1%
p<0.0001
Duration of response CG + PL (n=139)
CG + BV (n=190)
Median, months 7.4 10.4
HR (95% CI) 0.534(0.408–0.698)
p<0.0001a
100
80
60
40
20
78.5
57.4 PR = 61
PR = 48
0CR = 17CR = 9
aCompared for descriptive purposes only
CG + PL (n=242)
CG + BV (n=242)
Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007)
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OCEANS: Interim OS1.0
0.8
0.6
0.4
0.2
Pro
po
rtio
n a
live
CG + PL(n=242)
CG + BV(n=242)
Events, n (%) 78 (32) 63 (26)
Median OS, months (95% CI)
29.9(26.4–NE)
35.5(30.0–NE)
Stratified analysis HR (95% CI)Log-rank p-value
0.751(0.537–1.052)
0.094a
0
0Months
6 12 30 36 42
No. at risk:
18 24
242 235 195 26 8 0CG + PL 131 77242 238 200 42 8 0CG + BV 146 82
NE = not estimableap-value does not cross pre-specified boundary of 0.001
Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007)
Conclusions: OCEANS• Statistically significant & clinically relevant benefit with
addition of bevacizumab to chemotherapy in patients with recurrent, platinum sensitive EOC, PPC, and FTC– Improved PFS: HR 0.484 (p<0.0001);
median 8.4 → 12.4 months
– Improved ORR and duration of response
– OS data not yet mature
• Safety data consistent with bevacizumab profile
No GI perforations and no new safety signals– No GI perforations and no new safety signals
• First phase III trial of an anti-angiogenic agent to demonstrate clinical benefit for Platinum-Sensitive recurrent disease
Aghajanian et al. J Clin Oncol 2011;29 (suppl; abstr LBA5007)
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Activity of cabozantinib (XL184) in advanced ovarian cancer patients: Results from a phase II
randomized discontinuation trial
Ronald J. Buckanovich
Buckanovich et al. J Clin Oncol 2011;29 (suppl; abstr 5008)
Cabozantinib: background• MET (membrane receptor for hepatocyte growth factor) found in low
levels in most normal tissues
• MET upregulated in many tumors, including ovarian cancerMET upregulated in many tumors, including ovarian cancer
• MET upregulation results in more invasive and aggressive behavior of tumor cells, resulting in metastasis
• Hypoxia resulting from angiogenesis inhibition further upregulates MET
• Hypoxia also stimulates the expression of VEGF
• Cabozantinib simultaneously blocks MET and VEGFR2Cabozantinib simultaneously blocks MET and VEGFR2
http://metinhibition.com/downloads/Cabozantinib%20MOA%20Brochure.pdf
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Study details
• Patients (n=68) with epithelial OC and progressive measurable disease (mRECIST)
28 t i t t– n=28 pt-resistant
– n=17 pt-sensitive
– n=6 unknown status
• Treatment
– Cabozantinib: 100 mg qd PO for 12 weeks
– Treatment ≥ week 12: based on response:
PR ti t ti d l b l b ti ib• PR: patients continued open-label cabozantinib
• SD: randomization cabozantinib vs placebo
• PD: discontinued
• Primary endpoint:
– ORR per mRECIST in first 12 weeks, PFS in randomized period
Buckanovich et al. J Clin Oncol 2011;29 (suppl; abstr 5008)
Results
• ORR at 12 wks (n=51 evaluable)
– ≥ PR 24%, ≥ SD 58%,
– ≥ PR pt-resistant 18%
• Most common AEs ≥Grade 3:
– hand-foot syndrome (10%), diarrhea (8%), fatigue (4%)≥ PR pt-resistant 18%
– ≥ PR pt-sensitive 29%
• CA125 response (n=40 with ≥1 post-baseline result) 18%
• Median follow up 4 months
– Median duration of response
d a ea (8%), at gue ( %)
• Dose reductions and permanent discontinuations for Aes
– 43% and 10%, respectively
• Median maximum increase in hemoglobin Hbin anemic pts (Hb Median duration of response
and PFS not reached < 11 g/dL): 1.9 g/dL
• Conclusion– Cabozantinib exhibits clinical activity in patients with advanced
disease, regardless of prior platinum status
Buckanovich et al. J Clin Oncol 2011;29 (suppl; abstr 5008)
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Pegylated liposomal doxorubicin and carboplatin gy p pversus paclitaxel and carboplatin in platinum-sensitive
ovarian cancer patients: Treatment at recurrence and overall survival final
analysis from CALYPSO phase III GCIG trial
C. Marth
Marth et al. J Clin Oncol 2011;29 (suppl; abstr 5052)
Marth C, Alexandre J, Hanker L et al. Proc ASCO 2011 abstr 5052
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Conclusion
Patients with platinum-sensitive relapse treated withPatients with platinum sensitive relapse treated with C-PLD or C-P in the CALYPSO trial have a similar overall survival (OS) with a median ranging from 30.7 to 33.0 months
OS in CALYPSO may have been influenced by subsequent treatments (70% of the patients q ( preceived > 2 lines of treatment further CALYPSO) and by imbalance of cross-over
Marth C, Alexandre J, Hanker L et al. Proc ASCO 2011 abstr 5052
ASCO 2011 PI3 Kinase EndometrialAb. Title Author N = Results Comments
5013 Ph II Ridaforolimus in Recurrent/Locally Adv.
Mackay 30 eval
PR = 7.7%SD = 15% (7 mos.)Mucositis & Anorexia = 64%
40 mg/d on d 1-5 q wk PO
5012 Ph II Everolimus & Letrozole in Recurrent
Slomovitz 32 CR = 5% PR = 16%SD = 21% (CB = 42 vs 21% of E alone)
E = 10 mg poL = 2.5 mg po
5015 R Ph II Temsirolimus vs. Tem & Megace & Tamoxifen Meas Adv or Recurr; GOG0248
Fleming G 20 vs. 21
T alone to 2nd phase (30% RR)T & HT (14%) but 35% DVT
If recurr prev chemo allowed only
5009 R Ph II Oza A 64 vs CB= 35% (all SD) vs BrCa status5009 R Ph II Ridaforolimus vs. Prog or Chemo in Recurrent/ Meas St III-IV Adv.
Oza A 64 vs. 66
CB= 35% (all SD) vs. 21%PFS 3.8 vs. 1.9 mos HR = 0.53 Fav R
BrCa status independent
5016 Predictive Biomarker for mTOR Response
Meyer L 28 PTEN/PS6K/Kras mutations not helpful;Kras Wt predictive?
Used Evero study in recur 21% CB
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Gyn Onc Summary 2011
• PARP inhibitor evolving but encouraging
• Bevaciumab active and tolerable in front-line andBevaciumab active and tolerable in front-line and recurrent ovarian cancer– GI perforation if >2 lines of prior therapy or
obstruction
• 3 options in platinum sensitive recurrent ovarian cancer (+Gemcitabine, +PLD, +Paclitaxel)
• PI3K pathway activated in endometrial cancer:• PI3K pathway activated in endometrial cancer: unclear of impact on therapy yet