the future of antiangiogenic therapies in ovarian cancer: a series of community and academic grand...
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Downloadable slide decks are a great tool for self study and teaching purposes. They are non-certified resources available to enhance your knowledge. Review a downloadable slide deck by Deborah K. Armstrong, MD, covering the most clinically relevant new data reported from The Future of Antiangiogenic Therapies in Ovarian Cancer: A Series of Community and Academic Grand Rounds. Target Audience This activity has been designed to meet the unique learning needs of oncologists, surgeons, gynecologists, and other healthcare professionals involved in the treatment of patients with ovarian cancer. Format: Microsoft PowerPoint (.ppt) | File size: 9.7 MB | Date posted: 8/06/2012 Slide Deck Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of August 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details. Activity Overview Although progress continues to be made in the treatment of ovarian cancer, making clinical decisions remains a challenge due to the many treatment options available in several different settings. Selective inhibitors of the VEGF/PDGF/FGF pathways have shown activity in patients with ovarian cancer in phase II and III clinical trials either as monotherapy or in combination with other chemotherapy. Community and academic oncologists who treat patients with ovarian cancer need to stay abreast of the latest research that can affect treatment decisions and patient outcomes. As controversy still exists regarding how and when to incorporate the use of antiangiogenic agents into the treatment paradigm for ovarian cancer patients, this case-based activity developed by expert faculty will provide clinicians with the practical application of new data into community and academic practice settings.TRANSCRIPT
DISCLAIMERDISCLAIMERThis slide deck in its original and unaltered format is for educational purposes and is
current as of August 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. Thesematerials may discuss therapeutic products that have not been approved by the US
Food and Drug Administration and off-label uses of approved products. Readersshould not rely on this information as a substitute for professional medical advice,
diagnosis, or treatment. The use of any information provided is solely at your own risk,and readers should verify the prescribing information and all data before treating
patients or employing any therapeutic products described in this educational activity.
Usage RightsUsage RightsThis slide deck is provided for educational purposes and individual slides may be
used for personal, non-commercial presentations only if the content and referencesremain unchanged. No part of this slide deck may be published in print or
electronically as a promotional or certified educational activity without prior writtenpermission from IMER. Additional terms may apply. See Terms of Service on
IMERonline.com for details.
DISCLAIMERDISCLAIMERParticipants have an implied responsibility to use the newly acquired information
to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by
clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s
product information, and comparison with recommendations of other authorities.
DISCLOSURE OF UNLABELED USEDISCLOSURE OF UNLABELED USEThis educational activity may contain discussion of published and/or investigational
uses of agents that are not indicated by the FDA. Albert Einstein College of Medicine and IMER do not recommend the use of any agent outside of the labeled
indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Albert Einstein College of Medicine and IMER. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Disclosure of Conflicts of InterestDisclosure of Conflicts of InterestDeborah K. Armstrong, MDDeborah K. Armstrong, MD
Reported a financial interest/relationship or affiliation in the form of: Consultant, Eisai Inc.; Contracted Research, Eisai, Inc., MedImmune, LLC, Roche Pharmaceuticals, Inc.
Learning ObjectivesLearning ObjectivesUpon completion of this activity, Upon completion of this activity,
participants should be better able to:participants should be better able to:
Assess data on recent clinical trials incorporating antiangiogenic agents into the treatment of patients with ovarian cancer
Implement effective toxicity prophylaxis and side-effect management for patients receiving antiangiogenic therapies
Assess optimal dose and schedule when incorporating antiangiogenic agents into the treatment of patients with ovarian cancer
Implement the use of antiangiogenic agents into the treatment paradigm in newly diagnosed, maintenance, or relapse settings
Activity AgendaActivity Agenda Activity Overview (5 mins)
Incorporating Antiangiogenic Therapies Into the Treatment Armamentarium (50 mins)
– Case Study 1: Managing a newly diagnosed ovarian cancer patient
– Case Study 2: Managing a patient in the maintenance setting
– Case Study 3: Managing a patient with recurrent disease (platinum-resistant and platinum-sensitive)
Questions & Answers (5 mins)
Case Study 1: Case Study 1: Managing A Newly Diagnosed Managing A Newly Diagnosed
Ovarian Cancer PatientOvarian Cancer Patient
Case Study 1: Front-Line TherapyCase Study 1: Front-Line Therapy A 52-yr-old small business owner presents with
ascites and an adnexal pelvic mass on exam and CT scan
– Omental cake and ascites seen on CT; CA-125 = 580
Exploratory laparotomy with radical tumor debulking including TAH/BSO, omentectomy, appendectomy, lymphadenectomy
Optimally cytoreduced stage IIIC papillary serousovarian cancer
PS = 0; No significant comorbidities
CT = computed tomography; CA-125 = cancer antigen-125; TAH = total abdominal hysterectomy; BSO = bilateral salpingo-oophorectomy; PS = performance status.
Question 1Question 1
What treatment would you recommend for this patient?
1) IV carboplatin and IV paclitaxel
2) IV platinum and taxane plus bevacizumab
3) IV paclitaxel, IP cisplatin, and IP paclitaxel
4) IP cisplatin, IV paclitaxel, and IP paclitaxel with bevacizumab
Ovarian Cancer: ChemotherapyOvarian Cancer: Chemotherapy
Standard front-line chemotherapy today is paclitaxel 175 mg/m2 plus carboplatin AUC 6–7, q21days for 6 cycles
Result of several studies over last decade
– GOG 111 and OV10 – paclitaxel/cisplatin vs. cyclophosphamide/cisplatin
– GOG 158 and AGO OVAR-3 – carboplatin instead of cisplatin
AUC = area under the curve; GOG = Gynecologic Oncology Group; AGO = Arbeitsgemeinschaft Gynaekologische Onkologie.
NCCN, 2012; McGuire et al, 1996; Piccart et al, 2000; Ozols et al, 2003; du Bois et al, 2003.
GOG 172 SurvivalGOG 172 Survival
IV: 18 mosIP: 24 mosHR: 0.80, p = .05
IV: 50 mosIP: 66 mosHR: 0.75, p = .03
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 12 24 36 48 60
Time (mos on study)
Pro
po
rtio
n P
FS
(%
)
PFS
Rx GroupIVIP
5063
PF Failed Total160142
210205
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 12 24 36 48 60
Time (mos on study)
OS
Rx GroupIVIP
Alive93117
Dead11788
Total210205
PFS = progression-free survival; OS = overall survival.
Armstrong et al, 2006.
JGOG: Dose-Dense Wkly PaclitaxelJGOG: Dose-Dense Wkly Paclitaxel
JGOG = Japanese Gynecologic Oncology Group.Katsumata et al, 2009.
OSOSPFSPFS
VEGF-AVEGF-BPlGF
VEGFR-1
VEGF-AVEGF-CVEGF-DVEGF-E
VEGFR-2
NRP-1
AngiogenesisVasculogenesis
NRP-2
VEGF-CVEGF-D
VEGFR-3
Lymphangiogenesis
NRP-1
NRP-2
The VEGF/VEGF-Receptor AxisThe VEGF/VEGF-Receptor Axis
VEGF = vascular endothelial growth factor. Courtesy of Dr. Bradley Monk.
VEGF Ligand Agents in the ClinicVEGF Ligand Agents in the Clinic
Bevacizumab Aflibercept
Presta et al, 1997 Hu et al, 2005
GOG 218: SchemaGOG 218: Schema
Front-Line EOC, PP, or FT
• Stage III optimal (macroscopic)
• Stage III suboptimal• Stage IV
N = 1,800 (planned)
Front-Line EOC, PP, or FT
• Stage III optimal (macroscopic)
• Stage III suboptimal• Stage IV
N = 1,800 (planned)
Stratification variables – GOG PS – Stage/debulking status
1:1:1
15 mos
P 175 mg/m2
C AUC 6
Placebo
I
Arm
Cytotoxic
(6 cycles)
Maintenance
(16 cycles)
(CP)
C AUC 6
P 175 mg/m2
PlaceboBev 15 mg/kg
II(CP + Bev)
Bev 15 mg/kg
C AUC 6
P 175 mg/m2 III
(CP + Bev)
(Bev)
C = carboplatin; P = paclitaxel; EOC = epithelial ovarian cancer; PP = primary peritoneal; FT = fallopian tube. C = carboplatin; P = paclitaxel; EOC = epithelial ovarian cancer; PP = primary peritoneal; FT = fallopian tube. Burger et al, 2011. Burger et al, 2011.
CP (Arm I)
GOG 218: Investigator-Assessed PFSGOG 218: Investigator-Assessed PFS
+ Bev (Arm II)
+ Bev Bev maintenance (Arm III)
Pro
po
rtio
n P
FS
(%
)
Time (Mos Since Randomization)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 12 24 36
Arm I
CP (n = 625)
Patients with event (n; %)423
(67.7)
Median PFS (mos) 10.3
Stratified analysis HR (95% CI)
One-sided p value (log rank)
Arm III
CP + Bev Bev(n = 623)
360 (57.8)
14.1
0.717
(0.625–0.824)
< .0001a
Arm II
CP + Bev(n = 625)
418 (66.9)
11.2
0.908
(0.759–1.040)
.080a
a p = .0116Burger et al, 2010.
a p = .0116Burger et al, 2010.
GOG 218: OS Analysis GOG 218: OS Analysis At Time of Final PFS Analysis (January 2010)At Time of Final PFS Analysis (January 2010)
Arm I
CP
(n = 625)
Arm II
CP + Bev
(n = 625)
Arm III
CP + Bev Bev
(n = 623)
Patients with events (n; %)
156
(25.0)
150
(24.0)
138
(22.2)
Median (mos) 39.3 38.7 39.7
HRa
(95% CI)
1.036
(0.827–1.297)
0.915
(0.727–1.152)
One-sided
p value.361 .252
Pro
por
tion
Aliv
e (%
)
Time (Mos Since Randomization)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 12 24 36 48
625/625/623 442/432/437 173/162/171 46/39/40No. at risk
aStratified analysis.Burger et al, 2010.
aStratified analysis.Burger et al, 2010.
ICON7: Study DesignICON7: Study Design
Stratification variables – Stage/surgery– Time since surgery
– GCIG group
P 175 mg/m2
C AUC 6a
C AUC 6a
P 175 mg/m2
Arm A
Arm A
Arm A
Arm A
ArmArm BBArmArm BB
12 mos12 mos
Front-Line EOC, PP, or FT
• Stage I/IIA (grade 3) • Stage IIB/C• Stage III• Stage IV
N = 1,520 (planned)
Front-Line EOC, PP, or FT
• Stage I/IIA (grade 3) • Stage IIB/C• Stage III• Stage IV
N = 1,520 (planned)
Bev 7.5 mg/kg
Primary end point:
PFS
Secondary end points:
OS, RR, QOL, safety,
cost-effectiveness,
translational
No IRC present
VaMight vary based on GCIG group.GCIG = Gynecologic Cancer Intergroup; IRC = independent review committee; RR = response rate; QOL = quality of life.Perren et al, 2011.
VaMight vary based on GCIG group.GCIG = Gynecologic Cancer Intergroup; IRC = independent review committee; RR = response rate; QOL = quality of life.Perren et al, 2011.
ICON7 PFS: UpdatedICON7 PFS: Updated
17.4
19.8
Control
Research
Kristensen et al, 2011.
PFS: “High Risk” Subgroup (Ad Hoc Analysis)PFS: “High Risk” Subgroup (Ad Hoc Analysis)
No. At RiskControl 234 205 98 36 14 2Research 231 213 159 56 10 1
No. At RiskControl 234 205 98 36 14 2Research 231 213 159 56 10 1
1.00
0.75
0.50
0.25
0
1.00
0.75
0.50
0.25
0Pro
po
rtio
n A
liv
e W
ith
ou
t P
rog
res
sio
n (
%)
Pro
po
rtio
n A
liv
e W
ith
ou
t P
rog
res
sio
n (
%)
Time (mos)Time (mos)
0 3 6 9 12 15 18 21 24 27 30 0 3 6 9 12 15 18 21 24 27 30
Control(n = 234)
Research (n = 231)
Events, n (%) 173 (74) 158 (68)Median (mos) 10.5 15.9Log-rank test p < .001HR (95% CI) 0.68 (0.55–0.85)Restricted mean 13.3 16.5
10.5 15.9
ControlResearch
High Risk: Stage IIIC Suboptimal/Stage IV
Kristensen et al, 2011.
Kristensen et al, 2011.
ICON7 OS by Risk GroupsICON7 OS by Risk Groups
GOG 252: Stage II/III Disease: GOG 252: Stage II/III Disease: Small Volume ResidualSmall Volume Residual
Carboplatin AUC = 6 (IV)Paclitaxel 80 mg/m2 (Days 1, 8, 15, 3 hrs)Bevacizumab (C2+ C22) x 21 days
Cisplatin 75 mg/m2 (IP Day 2)Paclitaxel 135 mg/m2 (Day 1, 3 hrs)Paclitaxel 60 mg/m2 (Day 8, IP)Bevacizumab (C2+ C22) x 21 days
EOC Optimal stage III No prior therapy
Phase III PFS primary end point
Open: 27 Jul 2009Closed: November 2011 Accrual: 1,100
I
III
II
Carboplatin AUC = 6 (IP)Paclitaxel 80 mg/m2 (Days 1, 8, 15, 3 hrs)Bevacizumab (C2+ C22) x 21 days
US NIH, 2009a.
Nintedanib (BIBF 1120) – First Triple Nintedanib (BIBF 1120) – First Triple Angiokinase Inhibitor: Mode of Action Angiokinase Inhibitor: Mode of Action
Ligands Cell Type/Receptors
VEGFs
FGFs
PDGFs
Endothelial CellsVEGFRs, FGFRs
PericytesPDGFRs
Smooth Muscle CellsFGFRs, PDGFRs
Stimulation
By Targeting 3 Major Angiogenesis Signalling Pathways, Nintedanib Prevents Further Tumor Growth and Related Tumor Escape Mechanisms
BIB
F 1
120
FGF = fibroblast growth factor; PDGF = platelet-derived growth factor.Hilberg et al, 2008.
Multicenter, Randomized, Double-Blind, Phase III Trial to Investigate the Efficacy and Safety of Nintedanib in Combination With Standard Treatment of Carboplatin and Paclitaxel Compared to Placebo Plus Carboplatin and
Paclitaxel in Patients With Advanced Ovarian Cancer
R
C
T
C
T
C
T
C
T
C
T
C
T
C
T
C
T
C
T
C
T
C
T
C
T
= Nintedanib 2 x 200 mg po qd
= Placebo
≤ 120 wks
C = Carboplatin AUC 5–6 Day 1
T = Paclitaxel 175 mg/m2 (3 hrs) Day 1
q21days / 6 courses
Nintedanib / Placebo- No intake on days of chemotherapy- Dose: 200 mg po bid (combi + mono)- Dose adaptation in case of undue toxicity- Max. duration of 120 wks in non-progressing patients
2
1
SURGERY
N = 1,300
US NIH, 2009b.
AGO-OVAR12: Nintedanib ConsolidationAGO-OVAR12: Nintedanib Consolidation
PFS
(A)OS
Ledermann et al, 2011.
Nintedanib: Phase II PFS and OSNintedanib: Phase II PFS and OSRandomized Phase II Placebo-Controlled Trial of Maintenance Therapy Randomized Phase II Placebo-Controlled Trial of Maintenance Therapy
Using the Oral Triple Angiokinase Inhibitor BIBF 1120 After Using the Oral Triple Angiokinase Inhibitor BIBF 1120 After Chemotherapy for Relapsed Ovarian CancerChemotherapy for Relapsed Ovarian Cancer
OS
TRINOVA-3 (GOG 3001)TRINOVA-3 (GOG 3001)::TC ± AMG 386 as First-Line Therapy of TC ± AMG 386 as First-Line Therapy of
Stage III–IV Ovarian CancerStage III–IV Ovarian Cancer Concurrent Treatment Maintenance Phase
ARM A:AMG 386Paclitaxel
Carboplatin (TC)
ARM B:Placebo
PaclitaxelCarboplatin
Paclitaxel 175 mg/m2 IV q3wksCarboplatin AUC 5 or 6 IV q3wks
for Maximum of 6 cycles+
AMG 386 15 mg/kg IV qwk orAMG 386 Placebo IV qwk
AMG 386 Monotherapy
Until Progression or 18 mos
AMG 386 Placebo Monotherapy
Until Progression or 18 mos
END OF TREATMENT
Progressive disease or unacceptable
toxicity or withdrawal of
consent or death
N = 2,000
Neoadjuvant Chemo +Interval Debulking
Allowed in Both Arms After 3 Courses
US NIH, 2011.
Key TakeawaysKey Takeaways
Bevacizumab with and following chemotherapy improves PFS
Patients with large volume disease may benefit most
Bevacizumab can be given with IP therapy but impact on outcome is unknown
Bevacizumab can be given with dose-dense paclitaxel regimen based on completion of GOG 252 (and 262) without stopping for safety concerns
Case Study 2: Case Study 2: Managing A Patient In The Managing A Patient In The
Maintenance SettingMaintenance Setting
Case Study 2Case Study 2
A 62-yr-old woman comes to you to ask your opinion about maintenance therapy after treatment for ovarian cancer. She had stage IV disease based on thoracic nodal involvement and was treated with 6 cycles of paclitaxel and carboplatin with excellent tolerance. At completion of chemotherapy CA-125 had normalized, CT shows persistent enlarged thoracic nodes up to 1.5 cm but PET shows no uptake in these nodes.
She wants to know if you recommend any further treatment for her at this time.
PET = positron emission tomography.
Clinical Decision QuestionClinical Decision Question
What do you recommend for her at this time?
1) No further therapy
2) Three more cycles of paclitaxel and carboplatin
3) Paclitaxel alone q4wks x 12
4) Bevacizumab
5) Another VEGF targeted agent
Consolidation Therapy: GOG 178Consolidation Therapy: GOG 178
EOC, FT, PPStage III/IVPrior chemo 5–6 cyclesRegister 3–8 wksCCRNeuropathy ≤ grade II
Paclitaxel (3 hrs) 175 mg/m2 q28days x 12
Paclitaxel (3 hrs) 175 mg/m2 q28days x 3
RRAANNDDOOMMIIZZEEN = 450 anticipated
Accrual closed 9/6/01N = 277; 222 with FU54 progression events
End points• PFS• OS
FU = follow-up.Markman et al, 2003.
GOG 178: ConsolidationGOG 178: Consolidation
Unadjusted Log Rankp (1-sided) = .0035
Adjusted Log Rankp (1-sided) = .0023
Markman et al, 2003.
GCIG Intergroup Protocol: GINECOGCIG Intergroup Protocol: GINECO
French/German Study Group
EOC (Stage IIB–IV)All Strata
N = 1,308
Paclitaxel (3 hrs) 175 mg/m2 q21days x 6Carboplatin AUC = 5.0 q21days x 6
Paclitaxel (3 hrs) 175 mg/m2 q21days x 6Carboplatin AUC = 5.0 q21days x 6
RRAANNDDOOMMIIZZEE
Topotecan 1.25 mg/m2 q21days x 4
Pfisterer et al, 1999.
Maintenance Therapy: GOG 212 Maintenance Therapy: GOG 212
EOC, FT, PPStage III/IVPrior chemo 5–8 cyclesRegister 3–8 wksCCRNeuropathy ≤ grade II
PG-Ptx (paclitaxel poliglumex) 135 mg/m2 q28days x 12
Paclitaxel (3 hrs) 135 mg/m2 q28days x 12
RRAANNDDOOMMIIZZEE
N = 1,400 anticipatedPhase III; Superiority Design
End points• PFS• OS
Observation
US NIH, 2005.
EOC, FT, or PP Primary platinum-based therapy (IV, IP, neoadjuvant permitted) CR, PR, or SD after initial therapy Primary end point: PFS Secondary end point: OS (with interim analysis)
AGO-OVAR16: Pazopanib ConsolidationAGO-OVAR16: Pazopanib Consolidation
I Pazopanib 800 mg po qd (2 yrs)
II Placebo po qd (2 yrs)
Estimated Enrollment: 900 Study Start: May 2009 Estimated Completion: March 2013
Primary Rx:Platinum and Taxane
CR = complete response; PR = partial response; SD = stable disease. US NIH, 2009c.
Sorafenib: Study 12007 Sorafenib: Study 12007 (Phase IIb Maintenance)(Phase IIb Maintenance)
Patients with FIGO stage III/IV ovarian epithelial
cancer or PPC who have achieved clinical CR after standard platinum/taxane therapy and cytoreductive
surgery
Sorafenib 400 mg po bid,
continuous dosing
US NIH, 2008.
Placebo 400 mg po bid,
continuous dosing
RR
Estimated Enrollment: 247 Study Start: November 2008 Primary Completion: July 2011 Estimated Study Completion July 2012*
Patients stratified according to the degree of residual disease following initial diagnosis and surgical debulkment Primary objective: PFS Secondary objectives: Abnormal CA-125, OS 1:1 randomization
*This trial is ongoing, but not recruiting participants - status updated April 2012
Key TakeawaysKey Takeaways
Given the high rate of disease recurrence in ovarian cancer, there is impetus to consider consolidation or maintenance therapy
Continuing paclitaxel for 1 year after initial chemotherapy past 6 cycles improves PFS
Bevacizumab with and following chemotherapy improves PFS and OS in some situations
There is no data on using only bevacizumab for maintenance therapy, after chemotherapy
Case Study 3: Case Study 3: Managing A Patient In The Managing A Patient In The
Resistant/Refractory Setting (Platinum-Resistant/Refractory Setting (Platinum-Resistant and Platinum-Sensitive)Resistant and Platinum-Sensitive)
Case Study 3Case Study 3
A 60-yr-old woman with a PMH of HTN presents with extensive pelvic and peritoneal implants, ascites, and large volume disease at the root of the mesentery. A diagnosis of ovarian cancer was made by paracentesis showing papillary serous carcinoma. She was deemed unresectable by a gynecologic oncologist.
Received neoadjuvant paclitaxel and carboplatin x 3 without response
She then received topotecan x 3 without response
She now has persistent ascites requiring paracentesis q5–8days for palliation
CA-125 = 6,916
PS = 1
PMH = past medical history; HTN = hypertension.
CA-125 = 6,516, exam shows marked ascites The patient requires frequent paracenteses wkly PS = 1
Paclitaxel, Carboplatin, and Topotecan Paclitaxel, Carboplatin, and Topotecan Refractory, Platinum-Resistant Ovarian CancerRefractory, Platinum-Resistant Ovarian Cancer
Clinical Decision QuestionClinical Decision Question Based on data presented at ASCO 2012 what
treatment would you recommend for this patient?
1) Pegylated liposomal doxorubicin (PLD, doxil, lipodox)
2) Wkly paclitaxel
3) 1 or 2 with bevacizumab
4) Bevacizumab
5) Gemcitabine, carboplatin
6) Gemcitabine, carboplatin, bevacizumab
Recurrent Ovarian Carcinoma:Recurrent Ovarian Carcinoma: Pegylated Liposomal Doxorubicin Pegylated Liposomal Doxorubicin
Author/Year DosePlatinum-Refractory
(< 6 mos) Response
Platinum-Sensitive
(> 6 mos) Response
Muggia et al, 1997* 50 mg/m2
q3wks
9/35 26% -- --
Gordon et al, 2000 40–50 mg/m2
q4wks
15/82 18% -- --
Gordon et al, 2001 50 mg/m2
q4wks
16/130 12% 31/109 28%
Ferrandina et al, 2008*
40 mg/m2
q4wks
11/70 16% -- --
*Enrolled patients with platinum-refractory and platinum-sensitive disease.
Platinum-Resistant Ovarian Cancer Platinum-Resistant Ovarian Cancer Cytotoxic TherapyCytotoxic Therapy
STUDY* AGENT N RR (%)
126-J Docetaxel 58 22
126-N Wkly Paclitaxel 48 21
126-M Ixabepilone 50 14
126-Q Pemetrexed 48 21
126-R nab-Paclitaxel 47 23
Thresholds: 10%, 25%
*1 prior line.
Randomized Phase II,
NKTR-102*
145 mg/m2 q14days 33 21
145 mg/m2 q21days 31 23
Vergote et al, 2010.
*Median of 3 prior lines.
Bevacizumab Trials: Relapsed EOCBevacizumab Trials: Relapsed EOC
*Burger et al, 2007. **Garcia et al, 2008. ***Cannistra et al, 2007.
GOG 170-D*(N = 62)
NCI 5789**(N = 70)
Genentech Study***(N = 44)
Study Treatment
Single-agent BV 15 mg/kg q3wks
BV 10 mg/kg q2wks + low-dose oral
cyclophos.
Single-agent BV 15 mg/kg
q3wks
Prior Regimens
1 – 21/62 (34%) 2 – 41/62 (62%)
Median = 2Range 1–3
2 – 23/44 (52%)3 – 21/44 (48%)
Platinum-Resistant
42% 40% 100%
Efficacy ORR 21% 24% 16%
6-mos PFS 39% 56% 27%
GIP or Fistula 0 4 (6%) 5 (11%)
GI Perforations With BevacizumabGI Perforations With Bevacizumabin Ovarian Cancerin Ovarian Cancer
Study Gl Perforations
Burger (GOG 170D) 0/62 (0)
Garcia (ASCO, 2005) 2/29 (6.9)
Cannistra (ASCO, 2006) 5/44 (11.4)
Wright (ASCO, 2006) 4/62 (6.5)
Friberg (ASCO, 2006) 2/13 (15.4)
Monk (Gyn Oncol, 2006) 1/32 (3.1)
Wright (Cancer, 2006) 2/23 (8.7)
Bidus (Gyn Oncol, 2006) 0/3 (0)
Penson (ASCO, 2006) 0/30
Total 16/298 (5.4%)
GI = gastrointestinal.Han et al, 2007.
Note: A recent history of bowel obstruction symptoms may be associated with GI perforation
Ovarian Cancer: GOG Trials of Targeted TherapyOvarian Cancer: GOG Trials of Targeted Therapy
Study* Agent Target N RR (%) PFS at
6 Mos (%)
170-C Gefitinib EGFR 27 3.7 14.8
170-D Bevacizumab VEGFA 62 21 40.3
170-E Imatinib bcr-abl/c-kit/PDGFR 56 1.8 16.1
170-F Sorafenib VEGFR/PDGRR/Raf 59 3.4 23.7
170-G Lapatinib EGRR/HER2neu 26 0 7.7
170-H Vorinostat HDAC 27 3.7 7.4
170-I Temsirolimus¥ mTor 54 9.3 24.1
170-J Enzastaurin PKC-beta 27 7.4 11.1
170-K Mifepristone PR 22 4.5 13.6
170-M Dasatinib Scr/bcr-abl/c-kit 34 0 20.6
170-N A6 uPAR 31 0 6.5
170-P AMG-102 HGF (c-met) Suspended after first stage
170-Q EGEN-001 IL-12 First stage accrual in progress
*1–2 priors; ¥1–3 priors.
Thresholds: RR – 10%, 25%; PFS – 15%, 35%
Reference Agent Target N RR (%)
Tew et al, 2007 Aflibercept
(VEGF-TRAP) VEGF
2 mg/kg
215
3.8
4 mg/kg 7.3
Biagi et al, 2011 (NCIC-CTEP)
Sunitinib VEGF/PDGF 30 3.3
Matulonis
et al, 2009
(DFCI-CTEP)
Cediranib VEGF/c-kit 46 17
Buckanovich
et al, 2011
Cabozantinib VEGFR2/c-met 70 24
Friedlander
et al, 2010
Pazopanib VEGFR/PDGFR/c-kit
36 18
Ovarian Cancer: VEGF Targeted Ovarian Cancer: VEGF Targeted TherapyTherapy
Aflibercept for Ascites in Advanced Ovarian Cancer: Aflibercept for Ascites in Advanced Ovarian Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase II StudyA Randomized, Double-Blind, Placebo-Controlled Phase II Study
Time to Repeat ParacentesisTime to Repeat Paracentesis
Median 55 vs. 23 days
Fatal GI Perforation:
Aflibercept 3/30
Placebo 1/25
Gotlieb et al, 2011.
Kaplan-Meier curve Waterfall plot
Randomized Phase II Trial of Wkly Paclitaxel Randomized Phase II Trial of Wkly Paclitaxel +/- AMG 386 in Recurrent Ovarian Cancer+/- AMG 386 in Recurrent Ovarian Cancer
EOC, FT, EOC, FT, or PPor PP
N = 161N = 1611–3 Prior 1–3 Prior
LinesLines
Wkly PaclitaxelWkly Paclitaxel
AMG 386 10 mg/kg IV wklyAMG 386 10 mg/kg IV wkly
(n = 53)(n = 53)Wkly PaclitaxelWkly Paclitaxel
AMG 386 3 mg/kg IV wklyAMG 386 3 mg/kg IV wkly
(n = 53)(n = 53)Wkly PaclitaxelWkly Paclitaxel
PlaceboPlacebo
(n = 55)(n = 55)
R
A
N
D
O
MI
Z
E
Paclitaxel 80 mg/m2 IV wkly, 3 wks on/1 wk off
AMG 386AMG 386
10 mg/kg IV10 mg/kg IV
wklywkly
10 mg/kg 3 mg/kg Placebo
*Median PFS (mos) 7.2 5.7 4.6
*HR (Arm A+B vs. placebo) = 0.76 (80% CI, 0.59, 0.98), p = .17Trend Test, p = .037
ORR (CR + PR; %) 37 19 27
PD = progressive disease.Karlan et al, 2012.
PD
TRINOVA-1:TRINOVA-1:Randomized Phase III on AMG 386 in Combination With Randomized Phase III on AMG 386 in Combination With
Paclitaxel in Advanced Recurrent Ovarian CancerPaclitaxel in Advanced Recurrent Ovarian Cancer
US NIH, 2010.
* Blinded.† Radiographic PD, unacceptable toxicity, withdrawal of consent, or death.
SA
FE
TY
F
U
ScreeningEnrollment
Treatment Phase
LO
NG
-TE
RM
FU
FUPhase
RA
ND
OM
IZA
TIO
N
AMG 386 15 mg/kg* IV qwk +Paclitaxel 80 mg/m2 IV qwk
(3 on/1 off)
Placebo* IV qwk +Paclitaxel 80 mg/m2 IV qwk
(3 on/1 off) EN
D O
F T
RE
AT
ME
NT
†
N = 900
Pujade-Lauraine et al, 2012.
Platinum-Resistant OCa
• ≤ 2 prior anticancer regimens
• No history of bowel obstruction/abdominal fistula, or clinical/ radiological evidence of rectosigmoid involvement
Platinum-Resistant OCa
• ≤ 2 prior anticancer regimens
• No history of bowel obstruction/abdominal fistula, or clinical/ radiological evidence of rectosigmoid involvement
Treat to PD/toxicity
Treat to PD/toxicity
Treat to PD/toxicity
Treat to PD/toxicity
Investigator’s choice
(without BEV)
Investigator’s choice
(without BEV)
Optional BEV monotherapyc Optional BEV monotherapyc
BEV 15 mg/kg q3wkb
+ chemotherapyBEV 15 mg/kg q3wkb
+ chemotherapy
Chemotherapy
RR
1:1
Stratification Factors • Chemotherapy selected
• Prior antiangiogenic therapy
• Treatment-free interval (< 3 vs. 3–6 months from previous platinum to subsequent PD)
Chemotherapy Options(investigator’s choice)
• Paclitaxel 80 mg/m2 Days 1, 8, 15, & 22 q4wks
• Topotecan 4 mg/m2 Days 1, 8, & 15 q4wks (or 1.25 mg/m2, Days 1–5 q3wks)
• PLD 40 mg/m2 Day 1 q4wks
aEOC, FT, or PP.bOr 10 mg/kg q2wks.c15 mg/kg q3wks, permitted on clear evidence of progression.
AURELIA Trial DesignAURELIA Trial Design
Pujade-Lauraine et al, 2012.
CT (n = 182)
BEV + CT (n = 179)
Events, n (%) 166 (91%) 135 (75%)
Median PFS (mos) (95% CI)
3.4(2.2‒3.7)
6.7(5.7‒7.9)
HR (unadjusted)(95% CI)Log-Rank p Value (2-sided, unadjusted)
0.48 (0.38‒0.60)
< .001
1.0
0.8
0.6
0.4
0.2
0
1.0
0.8
0.6
0.4
0.2
0
Est
ima
ted
Pro
bab
ility
(%
)E
stim
ate
d P
roba
bili
ty (
%)
0 6 12 18 24 300 6 12 18 24 30
Time (mos)Time (mos)
182182 3737 8 8 11 00179179 8888 1818 11 00
CTCTBEV + CTBEV + CT
No. at risk:No. at risk: 93 93140140
20204949
1144
0011
3.4 6.7
Median duration FU: 13.9 mos (CT arm) vs. 13.0 mos (BEV + CT arm)
Progression-Free Survival Progression-Free Survival
Summary of Best ORRSummary of Best ORR
a2-sided chi-square test with Schouten correction.
p = .001a
p < .001ap < .001a
Pujade-Lauraine et al, 2012.
Pa
tient
s (%
)
Adverse Events of Special InterestAdverse Events of Special Interest
Grade ≥ 3 Adverse Events of Special Interest, n (%)
CT (n = 181)
BEV + CT(n = 179)
HTN 2 (1.1) 13 (7.3)
Grade ≥ 2 12 (6.6) 36 (20.1)Proteinuria 0 3 (1.7)
Grade ≥ 2 1 (0.6) 19 (10.6)GI perforation 0 3 (1.7) Grade ≥ 2 0 4 (2.2)Fistula/Abscess 0 2 (1.1) Grade ≥ 2 0 4 (2.2)Bleeding 2 (1.1) 2 (1.1)Thromboembolic Event Arterial Venous
8 (4.4)0
8 (4.4)
9 (5.0)4 (2.2)5 (2.8)
Wound-Healing Complication 0 0RPLS 0 1 (0.6)CHF 1 (0.6) 1 (0.6)Cardiac Disorders (excluding CHF) 0 0
RPLS = reversible posterior leukoencephalopathy syndrome; CHF = congestive heart failure.Pujade-Lauraine et al, 2012.
CG + PL
OCEANS: Study SchemaOCEANS: Study Schema
CG for 6 (up to 10) cyclesStratification Variables
• Platinum-free interval (6–12 vs. > 12 mos)
• Cytoreductive surgery for recurrent disease (yes vs. no)
Platinum-Sensitive Recurrent OCa
• Measurable disease• ECOG 0/1• No prior chemo for recurrent ovarian cancer• No prior BEV
N = 484
ECOG = Eastern Cooperative Oncology Group.aEOC, FT, or PP.
G 1,000 mg/m2, Day 1 & 8
C AUC 4
PL q3wks until progression
C AUC 4
BEV 15 mg/kg q3wks until progression
G 1,000 mg/m2, Day 1 & 8CG + BEV
OCEANS: PFS, ORR, and DOROCEANS: PFS, ORR, and DOR
Data cutoff date: September 17, 2010
GC + PL(n = 242)
GC + BV(n = 242)
PFS by INV
Median PFS (mos) 8.4 12.4
Stratified Analysis, HR (95% CI)
0.484 (0.388–0.605)
Log-Rank p Value < .0001
PFS by IRC
Median PFS (mos)8.6 12.3
Stratified analysis, HR (95% CI)
0.451 (0.351–0.580)
Log-Rank p Value < .0001
ORR and DOR by INV
ORR (%) 57 79
Median DOR (mos) 7.4 10.4
HR (95% CI) 0.53 (0.41–0.70)
INV-Assessed
GC + PL(n = 242)
GC + BEV(n = 242)
0.0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 24 30
Time (mos)
Pro
po
rtio
n P
FS
(%
)
DOR = duration of response; INV = investigator-assessed; IRC = independent review committee; ORR = objective response rate.Aghajanian et al, 2012.
Pro
po
rtio
n S
urv
ivin
g (
%)
OCEANS: OS AnalysesOCEANS: OS Analyses
aData cutoff date: September 17, 2010. Median FU 24 mos in both arms, with 141 deaths (29% of patients). bData cutoff date: August 29, 2011. Median FU 33.7 mos in PL arm and 35.4 mos in BV arm, with 235 deaths (49% of patients)..
GC + PL(n = 242)
GC + BV(n = 242)
No. Events (%) 78 (32.2) 63 (26.0)
Median OS (mos) 29.9 35.5
HR (95% CI) 0.751 (0.537–1.052)
Log-Rank p Value .0944
GC + PL (n = 242)
GC + BV(n = 242)
No. Events (%) 112 (46.3) 123 (50.8)
Median OS (mos) 35.2 33.3
HR (95% CI) 1.027 (0.792–1.331)
Log-Rank p Value .8422
0 6 12 18 24 30 36 42Time (mos)
1.0
0.8
0.6
0.4
0.2
0.0
Pro
po
rtio
n S
urv
ivin
g (
%)
GC + PL(n = 242)
GC + BEV(n = 242)
First Interim Analysisa
1.0Second Interim Analysisb
0 6 12 18 24 30 36 42 48 54
Time (mos)
0.8
0.6
0.4
0.2
0.0
Aghajanian et al, 2012.
DOR CG + PL (n = 139)
CG + BV (n = 190)
Median (mos) 7.4 10.4
HR (95% CI) 0.534(0.408–0.698)
p < .0001a
OCEANS: Objective ResponseOCEANS: Objective Response
100
80
60
40
20
0
100
80
60
40
20
0
%%
78.5
57.4 PR = 61
PR = 48
CR = 17CR = 9
Difference: 21.1% p < .0001
aCompared for descriptive purposes only.
CG + PL (n = 242)
CG + BV (n = 242)
Aghajanian et al, 2012.
Pre-Treatment Post-4 cycles
Single-Agent Bevacizumab in Single-Agent Bevacizumab in Refractory Ovarian Cancer: GOG 170DRefractory Ovarian Cancer: GOG 170D
Key TakeawaysKey Takeaways
There are multiple cytotoxic agents with modest activity in platinum-refractory and platinum-resistant ovarian cancer
Antiangiogenic agents have significant single-agent activity in recurrent ovarian cancer
Bevacizumab added to chemotherapy improves response and PFS in recurrent ovarian cancer (platinum-resistant and platinum-sensitive)
A recent history of bowel obstruction symptoms may be associated with an increased risk of perforation in patients treated with bevacizumab