angiogenesis inhibitors and novel targeted agents in ovarian cancer
DESCRIPTION
Angiogenesis Inhibitors and Novel Targeted Agents in Ovarian Cancer. Robert L. Coleman, MD Professor & Deputy Chair Vice Chair, Clinical Research Department Gynecologic Oncology & Reproductive Medicine M.D. Anderson Cancer Center. Disclosures. Research Funding: - PowerPoint PPT PresentationTRANSCRIPT
Angiogenesis Inhibitors and Novel Targeted Agents in Ovarian Cancer
Robert L. Coleman, MDProfessor & Deputy Chair
Vice Chair, Clinical ResearchDepartment Gynecologic Oncology & Reproductive Medicine
M.D. Anderson Cancer Center
Disclosures
• Research Funding:– OCRF, CPRIT, NCI (P50, N01)
– Regeneron, sanofi-aventis, Novartis, Morphotek, Merck, GSK, Esperance, Genentech/Roche
– Marcus Foundation
• Scientific Steering Committee/Advisory:– Regeneron, sanofi-aventis, GSK, Esperance, Boehinger-
Ingleheim, Genentech/Roche, Morphotek/Eisai, Merck, Nektar, Endocyte, Medimmune, AstraZeneca
Today’s Focus
• New therapeutics update– Angiogenesis targeting– FR-alpha targeting– Rare ovarian tumors
Today’s Focus
• New therapeutics update– Angiogenesis targeting– FR-alpha targeting– Rare ovarian tumors
Cancer is a Disease of Tissues
Joyce JA, et al. Nat Rev Cancer. 2009;9(4):239-252.
AURELIA: A randomized phase III trial evaluating bevacizumab plus chemotherapy for platinum-resistant recurrent ovarian cancer
Recurrent EOC• Platinum resistant• ≤ 2 prior therapies• No clinical or radiologic
evidence of bowel involvement
Non-Platinum Chemotherapy
RANDOMIZE
Non-Platinum Chemotherapy + Bevacizumab 15 mg/kg
Chemotherapy Options• Paclitaxel 80 mg/m2 d 1,8,15, 22 q28• Topotecan 4 mg/m2 d 1, 8 ,15 q28 or • Topotecan 1.25 mg/m2 d 1-5 q21• PLD 40 mg/m2 d 1 q28
Stratifiedchemotherapy
PFI (< 3 vs 3-6 mo)prior anti-angiogenesis
Treat to progression
Treat to progressionN = 361
Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.
Baseline Characteristics
CT = chemotherapy; ECOG PS = Eastern Cooperative Oncology Group performance status; PFI = platinum-free intervalaStratification factor. bFrom last platinum to subsequent PD
Characteristic, n (%)CT
(N=182)BEV + CT
(N=179)Median age, years 61 62 (range) (25‒84) (25‒80)Origin of cancer: Ovary 157 (86) 167 (93)Serous at diagnosis 152 (84) 156 (87)Histologic grade at diagnosis 1 9 (5) 10 (6) 2/3 153 (84) 147 (82)Prior anti-angiogenic therapya 14 (8) 12 (7)Two prior chemotherapy regimens 78 (43) 72 (40)PFI <3 monthsa,b 46 (25) 50 (28)ECOG PS
0 99 (54) 107 (60)1/2 80 (44) 70 (39)
Measurable disease 144 (79) 143 (80)Ascites 54 (30) 59 (33)
Baseline Characteristics
CT = chemotherapy; ECOG PS = Eastern Cooperative Oncology Group performance status; PFI = platinum-free intervalaStratification factor. bFrom last platinum to subsequent PD
Characteristic, n (%)CT
(N=182)BEV + CT
(N=179)Median age, years 61 62 (range) (25‒84) (25‒80)Origin of cancer: Ovary 157 (86) 167 (93)Serous at diagnosis 152 (84) 156 (87)Histologic grade at diagnosis 1 9 (5) 10 (6) 2/3 153 (84) 147 (82)Prior anti-angiogenic therapya 14 (8) 12 (7)Two prior chemotherapy regimens 78 (43) 72 (40)PFI <3 monthsa,b 46 (25) 50 (28)ECOG PS
0 99 (54) 107 (60)1/2 80 (44) 70 (39)
Measurable disease 144 (79) 143 (80)Ascites 54 (30) 59 (33)
Summary of Overall Response Rates
Responders (RECIST and/or CA-125) (n=350)
RECIST responders (n=287) CA-125 responders (n=297)05
101520253035404550
12.6 11.8 11.6
30.927.3
31.8
CT BEV + CT
aTwo-sided chi-square test with Schouten correction
p=0.001ap<0.001a p<0.001a
Patie
nts (
%)
AURELIA Progression-Free Survival
1.0
0.8
0.6
0.4
0.2
0.06 12
Time (months)
Est
imat
ed P
roba
bilit
y
18 3024
182 93 37 8 1 1 0 020179 140 88 18 4 1 149
0
BEV + CTCTNumber at risk
Events, n (%)Median PFS, months(95% CI)
166 (91%)3.4
(2.2-3.7)
135 (75%)
CT(n = 182)
BEV + CT(n = 179)
6.7(5.7-7.9)
HR (unadjusted)(95% CI)Log-rnak P-value(2-sided, unadjusted)
0.48(0.38-0.60)
< 0.001
3.4 6.7
Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.
AURELIA: QoL
OS: ITT population
Data cut-off: 25 January 2013. Median duration of follow-up: 27.4 months in both armsITT = intent to treata2-sided log-rank, unadjusted
Est
imat
ed p
roba
bilit
y
CTBEV + CT
No. at risk:
CT (N=182)
BEV + CT (N=179)
Events, n (%) 136 (75) 128 (72)Median OS,months (95% CI)
13.3(11.9‒16.4)
16.6(13.7‒19.0)
HR (unadjusted)(95% CI)
0.85 (0.66‒1.08)
p=0.174a
182 130 98 63 29 12 1 0179 148 106 75 39 13 1 0
0 6 12 18 24 30 36 42Time (months)
1.00
0.75
0.50
0.25
0
Subgroup
No. of events/No. of
patients
Median OS, months
HR (95% CI)aBEV + CT
betterCT
better CT BEV + CT
All patients 264/361 13.3 16.6 0.85 (0.66–1.08)
Age, years <65 ≥65
178/22886/133
12.916.7
14.718.3
0.82 (0.61–1.10)0.95 (0.62–1.46)
PFI, monthsb <33‒6
79/97181/258
11.915.7
11.118.3
1.02 (0.65–1.58)0.78 (0.58–1.05)
Measurable disease, cm
<11‒<5≥5
58/7574/125
132/161
13.020.211.3
18.317.414.3
0.75 (0.45–1.27)1.06 (0.67–1.68)0.72 (0.51–1.01)
Ascites YesNo
98/113166/248
7.917.0
11.719.3
0.67 (0.45–1.00)0.86 (0.63–1.16)
Chemotherapy PaclitaxelPLDTopotecan
77/115100/12687/120
13.214.113.3
22.413.713.8
0.65 (0.42–1.02)0.91 (0.62–1.36)1.09 (0.72–1.67)
Exploratory Subgroup Analysis Of OS
aUnstratified. bMissing N=3
0.2 0.3 0.5 1 2 3 4 5
Paclitaxel Cohort: OSO
vera
ll su
rviv
al (%
) 75
50
25
00 6 12 18 24 30 36 42
100
CTBEV + CT
No. at risk:55 40 32 22 13 3 060 52 43 34 19 4 1
Time (months)
CT (N=55)
BEV + CT (N=60)
Events, n (%) 41 (75) 36 (60)Median OS,months (95% CI)
13.2(8.2‒19.7)
22.4(16.7‒26.7)
HR (unadjusted)(95% CI)
0.65 (0.42‒1.02)
PFS, was significantly improved with bevacizumab
OS HR was 0.85 (95% CI 0.66‒1.08) (ITT population)
Median OS: 16.6 months (BEV + CT) vs 13.3 months (CT)
Interpretation of OS is complicated by bevacizumab crossover (40%) and the lack of information on post-progression therapy
Exploratory subgroup analyses suggested:
Generally consistent effects on OS
More pronounced OS treatment effect in the weekly paclitaxel subgroup
Conclusions
After blockade of the VEGF pathway, there is a compensatory upregulation of FGF and PDGF
Casanovas O, et al. Cancer Cell. 2005;8(4):299-309.
Beyond VEGF: FGF and PDGF Expression in Ovarian Cancer
Nintedanib (BIBF 1120): A Triple Angiokinase* Inhibitor
*Angiokinase refers to tyrosine receptor kinases involved in promoting angiogenesis.
Hilberg F, et al. Cancer Res. 2008;68(12):4774-4782. Stopfer P, et al. Ann Oncol. 2008;19(S8):Abstract 478P.
Endothelial cells(VEGFRs, FGFRs)
Pericytes(PDGFRs)
Smooth muscle cells (FGFRs, PDGFRs)
VEGFs
FGFs
PDGFs
StimulationLigands Cell types (proliferation, survival)
Nintedanib blocks three critical factors involved in angiogenesis
AGO-OVAR-12
Stratification variables: • FIGO stage:
II/III vs IV• residual tumor:
0 cm vs >0 cm (no macroscopic vs macroscopic
Paclitaxel 175 mg/m²
Carboplatin AUC 5/6
Carboplatin AUC 5/6
Paclitaxel 175 mg/m²
Arm
A
Arm B
Placebo po BID
BIBF 1120a 200 mg po bid
Front-line EOC, PP or FT cancer
• Stage IIB-IV• Primary
max. surgery
• N = 1366Primary endpoint: PFS
2 years
2:1
National Institutes of Health. Available at: http://clinicaltrials.gov/show/NCT01015118. Accessed: February 12, 2013.
AGOStudy Group
GCIG Intergroup Study AGO-OVAR 12 /LUME-Ovar 1
AdB 2013
Primary Endpoint: Progression-Free SurvivalRECIST 1.1 and CA-125 in conjunction with Clinical MBO Criteria
0 6 12 18 24 30 36 420
0.5
1
Time from randomization (months)
455 381 257 168 76 3 0 0
911 761 542 352 160 17 1 0
TC +Nintedanib
(n=911)
TC +Placebo(n=455)
Events, n (%) 486 (53.3) 266 (58.5)
Median, months 17.3 16.6
HR* (95% CI) 0.84 (0.72, 0.98)
p value 0.0239
All patients (N=1366) – Cut-off date: 29 April 2013
*Stratified for macroscopic residual postoperative tumour, FIGO stage and carboplatin dose
AGOStudy Group
GCIG Intergroup Study AGO-OVAR 12 /LUME-Ovar 1
AdB 2013
Exploratory Subgroup Analysis“ICON 7 defined low-risk patients subgroup” (FIGO II or FIGO III and ≤ 1cm residual postoperative tumor)
Patients at risk
Estim
ated
per
cent
age
aliv
e a
nd p
rogr
essi
on-fr
ee
Time from randomization (months)
Placebo 283 248 186 123 52 2 0
Nintedanib 556 478 380 270 124 9 0
TC +Nintedanib
(n=556)
TC +Placebo(n=283)
Events, n (%) 234(42.1) 149(52.7)
Median, months 27.1 20.8
HR (95% CI) 0.74 (0.61, 0.91)
0 6 12 18 24 30 36 420
0.5
1
Median PFS difference: + 6.3 months
Presented by Monk BJ at the European Society of Gynecologic Oncology 2013
Trebananib (AMG 386) – Peptibody That Binds and Neutralizes Ang1 and Ang2
• Trebananib is an investigational recombinant peptide-Fc fusion protein (peptibody)
• In clinical studies trebananib has shown:
• Single-agent activity in relapsed ovarian cancer in a phase 1 study1
• Prolongation of PFS in a randomized phase 2 study in combination with paclitaxel in recurrent ovarian cancer2
1. Herbst RS, et al. J Clin Oncol. 2009;27:3557‒3565.2. Karlan BY, et al. J Clin Oncol. 2012;30:362‒371.
Presented by Monk BJ at the European Society of Gynecologic Oncology 2013
TRINOVA-1: Trial Design
EOC = epithelial ovarian cancer including primary peritoneal, or fallopian tube cancer; PD = progressive disease
Stratification factors • Platinum-free interval (PFI) (≤ 6 vs. > 6 months)• Measurable disease (Yes/No)• Region (North America, Western Europe/Australia, Rest of World)
Recurrent EOC• ≤ 3 prior anticancer
regimens• Evaluable or measurable
disease• GOG Performance
Status of 0 or 1• PFI < 12 months
Treat to PD/toxicity
Treat to PD/toxicity
Weekly Paclitaxel+
Trebananib
Weekly Paclitaxel+
PlaceboR
1:1
Paclitaxel 80 mg/m2 IV on days 1, 8, 15 Q4WTrebananib 15 mg/kg IV QW
ClinicalTrials.gov Identifier: NCT01204749
TRINOVA-1: DemographicsPaclitaxel +
PlaceboN = 458
Paclitaxel + Trebananib
N = 461Histologic grade, n (%)
Well differentiatedModerately differentiatedPoorly differentiatedUnknown
31 (7)84 (18)
256 (56)87 (19)
24 (5)69 (15)
274 (59)94 (20)
Prior lines of therapy, n (%)*123
172 (38)172 (38)114 (25)
190 (41)174 (38)94 (20)
Platinum-free interval, n (%)†
6 months> 6 months 245 (53)
212 (46)235 (51)223 (48)
Measureable disease at baseline, n (%) 433 (95) 435 (94)
Region, n (%)North AmericaWestern Europe/AustraliaRest of the world
91 (20)189 (41)178 (39)
93 (20)193 (42)175 (38)
*Three patients had 4 or unknown lines of prior therapy (protocol deviation); †Four patients were “refractory” (protocol deviation)
Presented by Monk BJ at the European Society of Gynecologic Oncology 2013
TRINOVA-1: PFS Primary Analysis
Pac + Placebo (n = 458)
Pac + Trebananib (n = 461)
Events, n (%) 361 (79) 310 (67)Median PFS, months 5.4 7.2
HR = 0.66 (95% CI, 0.57–0.77)P (stratified log rank) < 0.001
Eve
nt-fr
ee P
roba
bilit
y
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Study Month0 3 6 9 12 15 18 21 22
Patients at risk:
461458
356310
176132
10568
5024
2210
142
30
10
Presented by Monk BJ at the European Society of Gynecologic Oncology 2013
TRINOVA-1: Overall Survival(Interim Analysis)
Pac + Placebo(n = 458)
Pac + Trebananib (n = 461)
Events, n (%) 163 (36) 150 (33)Median OS, months 17.3 19.0
HR = 0.86 (95% CI, 0.69–1.08)P (stratified log rank) = 0.19
Eve
nt-fr
ee P
roba
bilit
y
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Study Month0 3 6 9 12 15 18 21 24 27
Patients at risk:
461458
430434
342346
242234
163160
10899
6546
2818
63
TRINOVA-3
Available at: http://clinicaltrials.gov/ct2/show/NCT01493505. Accessed Feb 2014.
Previously untreatedepithelial ovarian, primary peritoneal, or fallopian tube cancer
• Post operative • Stage III, IV• Neoadjuvant Carboplatin AUC 5-6 IV d 1
Paclitaxel 175 mg/m2 IV d 1Trebananib (AMG 386)
weekly
Carboplatin AUC 5-6 IV d 1Paclitaxel 175 mg/m2 IV d 1
Placebo weekly
N = 1000 (rev)
Weekly Placebo
x 18 months
Maintenance
Trebananib x 18 m
onths
R(2:1)
Randomised double-blind phase III trial of cediranib (AZD 2171) in
relapsed platinum sensitive ovarian cancer: Results of the ICON6 trial.
An academic sponsored GCIG trial
Ledermann JA, Perren T, Raja FA, Embleton AC, Rustin GJS,Jayson G, Kaye SB, Swart AM, Vaughan M, Hirte H
on behalf of the ICON 6 Collaborators(NCRN, NCIC-CTG, ANZGOG, GEICO)
ICON6: Cediranib with platinum-based chemotherapy in ‘platinum-sensitive’ relapsed ovarian cancer• Cediranib targets: VEGFR-1/2/3
6 Cycles platinum-basedChemotherapy Carboplatin/paclitaxel Carboplatin/gemcitabine Single agent platinum
Maintenance phase
Study schema
Treatment continued to 18 months or until progression (>18 for patients
continuing to benefit)
Continueplacebo
Switch toplacebo
Maintenance cediranib
Chemotherapy + cediranib
Chemotherapy + placebo
Arm A(Chemo only)
Arm B (Concurrent)
Arm C (Maintenance)
Chemotherapy + cediranib
Relapse > 6 months after completion of first
line platinum-based chemotherapy
Randomise2 : 3 : 3
0.00
0.25
0.50
0.75
1.00
164 148 65 21 7 118 90 24 8 3
.
0 3 6 9 12 15 18 21 24Months
Chemo.Maint.
Chemotherapy
Maintenance
Restricted mean survival time increases by3.1 months with maintenance treatment
Chemo. Maint.PFS events, n (%) 112 (94.9) 139 (84.8)
Median, months 8.7 11.1
Log-rank test p=0.00001
HR (95% CI) 0.57 (0.45 – 0.74)
Test for non-proportionality p=0.024
Restricted means, months 9.4 12.5
Progression-free survival – arms A vs. C
0.00
0.25
0.50
0.75
1.00
164 148 65 21 7 174 152 53 20 12 118 90 24 8 3
.
0 3 6 9 12 15 18 21 24Months
Chemo. Conc. Maint.PFS events, n (%) 112 (94.9) 152 (87.4) 139 (84.8)
Median, months 8.7 10.1 11.1
Log-rank test (trend) p=0.0003
HR vs. Chemo only(95% CI)
0.67 (0.53–0.87)
0.57(0.44–0.74)
Restricted means, months 9.4 11.4 12.5
Progression-free survival – all three arms
Conc.Maint.
Chemo.
Concurrent
Chemotherapy
Maintenance
0.00
0.25
0.50
0.75
1.00
164 159 139 89 48 2222 118 106 89 46 27 1111
.
0 6 12 18 24 30Months
Chemo. Maint.OS events, n (%) 63 (53.3) 75 (45.7)
Median, months 20.3 26.3
Log-rank test p=0.042
HR (95% CI) 0.70 (0.51 – 0.99)
Test for non-proportionality p=0.0042
Restricted means, months 17.6 20.3
Restricted mean survival time increases by 2.7 months with maintenance treatment (over two years)
Overall survival
Chemo.Maint.
Chemotherapy
Maintenance
Angiogenesis as a Target: Ovarian
1. Burger RA et al. N Engl J Med. 2011;365:2473‒2483.2. Perren TJ et al . N Engl J Med. 2011;365:2484‒2496.3. du Bois A et al. J Clin Oncol. 2013;31(18suppl):LBA5503.4. du Bois A et al. LBA ESGO 2013 Liverpool, UK
5. Pujade-Lauraine E et al. J Clin Oncol. 2012;30(18suppl):LBA5002.6. Monk BJ, et all., LBA ESGO, Liverpool, UK7. Aghajanian C et al. J Clin Oncol. 2012;30:2039‒2045.8. Ledermann JA et al . Eur J Cancer. 2013;49(suppl):LBA
Study Agent Setting HR-PFS (95% CI)
HR-OS (95% CI)
GOG 2181 Bevacizumab Front-line/Maintenance 0.72 (0.63-0.82) 0.89 (0.75-1.04)
ICON72 Bevacizumab Front-line/Maintenance 0.81 (0.70-0.94) 0.99 (0.85-1.14)
AGO-OVAR123 Nintedanib Front-line/Maintenance 0.84 (0.72-0.98) Neg
AGO-OVAR164 Pazopanib Primary Maintenance 0.77 (0.64-0.91) 0.99 (0.75-1.32)
AURELIA5 Bevacizumab Recurrence, Platinum-resistant, 1-2 priors 0.48 (0.38-0.60) 0.85 (0.66-1.08)
TRINOVA-16 Trebananib Recurrence, Platinum-resistant/sensitive, 1-3 priors 0.66 (0.57-0.77) 0.86 (0.69-1.08)
OCEANS7 Bevacizumab Recurrent, Platinum-sensitive, 1 prior 0.53 (0.41-0.70) 0.96 (0.76-1.21)
ICON68 Cediranib Recurrent, Platinum-sensitive, 1 prior 0.57 (0.44-0.74) 0.70 (0.51-0.99)
Bottom Line… Anti-angiogenesis agents in ovarian cancer
– PFS appears to be enhanced by biological targeting
– The menu of available agents is expanding
– Toxicity and impact of therapy is needed to adjudicate use
Intervention is extending post treatment life expectancy
Better and selected therapy is needed for OS
Today’s Focus
• New therapeutics update– Angiogenesis targeting– FR-alpha targeting– Rare ovarian tumors
Folate Metabolism: MoA
Vergote, Marth, Coleman. Cancer Met Rev 2014
Increases DNA synthesisInhibits apoptosisIncreases anoikisIncreases cell motility
Folate Receptor Expression
Utilizing the Folate Receptor: EC145
Folate-Vinca conjugate
Relevant for imaging targeting and therapy
EC145: Novel Folate Receptor Targeted Therapeutic
Randomized Phase II, Platinum-resistant ovarian Prior therapy: no more than 2 priors Regimen:
– PLD 50 mg/m2 IBW q 28 days– PLD 50 mg/m2 IBW q 28 days + EC145 2.5 mg weeks 1 and 3
(cycle: 28 days) Toxicity similar in both arms: total AEs, SAEs, TETs
Naumann W, et al. J Clin Oncol (2013)
Arm PFS HR PPLD 11.7 wks - -PLD+EC145 24.0 wks 0.497 0.014
PROCEED: Randomized Phase III PLD +/- EC145 (Vintafolide) in Platinum-Resistant Ovarian Cancer
Platinum resistant ovarian cancer patients (failed first or second platinum therapy <6
months)
2:1
EC145 (vintafolide) + PLD
PLD + placebo
Receptor scan
50 mg/m2 (IBW) every 28 days
N = 640 patients
• Primary endpoint: PFS
• Co-primary analysis
─ EC20 (++/+): 85% power to detect HR = 0.70─ EC20 (++): 85% power to detect HR = 0.56
• Secondary endpoints─ OS (no crossover)─ ORR─ Duration of Response─ Quality of Life Assessment
EC145 = 2. 5mg TIW weeks 1, 3PLD = 50 mg/m2 (IBW) every 28 days
Farletuzumab: Pre-Clinical Data Humanized MoAb to FRa Mechanism:
– Blocks Lyn kinase phosphorylation
– Induces cytotoxicity via ADCC & CDC
Active in xenograft model Favorable toxicity profile in
primate studiesNucleus
Cell transformation& proliferation
Cell stasis &suppressed proliferation
antibody mediated cytoxicity via
ADCC and CDC
Lyn kinase
over-expressed folate receptor alpha
Farletuzumab Phase 2: DesignPatients with EOC experiencing first platinum sensitive
relapse
After first remission of 6-18 months duration
Evaluable disease by CA125
Asymptomatic relapse
Single agent Farletuzumab
Until progression
Symptomatic relapse
Combination Therapy:Original Carbo/Taxane regimen
Plus farletuzumab6 cycles
Farletuzumab maintenance Rx
For responders
Single Agent ORR
Compare lengths of first and second
remissions
Combination ORR
Armstrong, et al. Gynecol Oncol (2013) 129:452
Target Lesion Response by RECIST (Combination Therapy)
Best Response
CR = 7%
PR = 63%
SD = 23%
PD = 7%
ORR = 70%
Patient Benefit 93%
Armstrong, et al. Gynecol Oncol (2013) 129:452
44
Farletuzumab Phase 3 in platin-sensitive ovarian cancer first recurrence
EOC in first relapse> 6months or < 24 months
Randomize 1:1:1
6 CyclesCarboplatin &Taxane Plus:
Farletuzumab1.25 mg/kg
N =300
Farletuzumab2.5 mg/kg
N=300
Placebo(Saline)
N=300
Single Agent Maintenance
Key Secondary Endpoint: Overall Survival
Primary Endpoint: Progression-Free Survival
Primary endpoint: PFS (each Farletuzumab arm vs control
2 sided 0.05 level, power 95%Median PFS control group 12 months
HR: 0.70, 43% improvement to 17.1 months*
*accrual was increased from 900 to 1080 to account for non-progression based discontinuation
45
Farletuzumab Phase 3 in platin-sensitive ovarian cancer first
recurrence Strata - characteristics
Parameter
Placebo + Carboplatin/
Taxane(N= 364)
FAR 1.25 mg/kg + Carboplatin/
Taxane(N= 370)
FAR 2.5 mg/kg + Carboplatin/
Taxane(N= 366)
Total FAR
(N= 736)
Length of first remission n (%)
6 – <12 months 194 (53.3) 196 (53.0) 193 (52.7) 389 (52.9) 12 – <18 months 108 (29.7) 112 (30.3) 111 (30.3) 223 (30.3) 18 – 24 months 62 (17.0) 62 (16.8) 62 (16.9) 124 (16.8) Route of administration for first-line therapy n (%)
Intraperitoneal 26 (7.1) 28 (7.6) 26 (7.1) 54 (7.3) Intravenous 338 (92.9) 342 (92.4) 340 (92.9) 682 (92.7)
Geographic region n (%)
North America and Western Europe
183 (50.3) 186 (50.3) 185 (50.5) 371 (50.4)
Other Countries 181 (49.7) 184 (49.7) 181 (49.5) 365 (49.6) Planned taxane therapy n (%)
Paclitaxel 294 (80.8) 298 (80.5) 296 (80.9) 594 (80.7) Docetaxel 70 (19.2) 72 (19.5) 70 (19.1) 142 (19.3)
46
Farletuzumab Phase 3 in platin-sensitive ovarian cancer first recurrence Progression Free Survival (ITT)
47
Farletuzumab Phase 3 in platin-sensitive ovarian cancer first
recurrence Overall Survival (ITT) (2013 April Update)
48
Neither FAR dose met the study’s primary PFS endpoint in the ITT population
Most commonly reported adverse events across arms were those known to be associated with the study chemotherapy agents
Higher dose and exposure of FAR seems to be correlated with PFS improvement
Hypotheses: CA125 may inhibit the potential ADCC effect of FAR Hence, FAR in adequate dosing may have a potential effect in lower
CA125 populations
Farletuzumab Phase 3 in Platinum Sensitive Ovarian Cancer First Recurrence
Conclusions
Today’s Focus
• New therapeutics update– Angiogenesis targeting– FR-alpha targeting– Rare ovarian tumors
Relevant Mutations in Ovarian Cancer
High Grade Serous Low Grade Serous CCC Endometrioid Mucinous0
10
20
30
40
50
60
70
80P53 Kras BRAF PIK3CA PTEN CTNNB
GOG 239: AZD6244 (Selumetinib) Phase II
Recurrent low-grade serous carcinoma of the ovary– Central pathology review for
eligibility
AZD6244 (ARRY-142886) small molecule inhibitor of the MEK-1/2
– 68% of low-grade serous tumors have mutations in BRAF or KRAS genes
GOG 239: Results
† Three patients remain on study therapy (after receiving 20, 33, and 54 cycles).
CR: 2%
PR: 14%
SD: 65%
Prog:15%
0
10
20
30
40
50
60
1 2 3 4 5 6 7 10 12 13 15 15+14
Duration of TherapyResponse
MILO: MEKi vs Chemotherapy
GOG-281: Randomized Phase II/III
Recurrent Low-Grade Serous Carcinoma• Measurable Disease• Primary Endpoint: PFS (futility assessment)• N=250 (Global)• Translational endpoints: Pathway aberration, Seq
Trametinib(MEKi)
Physician’s ChoiceHormone or Chemo
Activated: 2-26-2014
Example: Studies with Companion Diagnostics
HRD (Rad51c,d)
FR-a: Etarfolatide (EC-20)
BRAFv600E (D, K)
K-ras mutation (G12V)
PIK3CA/Akt/PTEN
IGF-1R expression
EGFR catalytic domain mutation
UGT 1A1*28 homozygosity
Her2-neu copy number
Selected Therapy Based on Biology
Option 1
Option 2Options 3, 4
Options 5, 6
Novel Drug Development: Ovarian Many new agents being explored based on molecular
profiling Challenges:
– How can we improve OS?» Post-progression survivorship is long and increasing» Are there better measures of treatment effect?
– What is the best strategy to meet individualization of care?– How do we identify, prevent, avoid, and overcome drug-
resistance?– How can therapy be optimized while reducing off/on-target
toxicity?
Thank You!
Two great virtues:– Patience– Wisdom