gyn-oncology update: asco 2011 - imedexinc.comimedexinc.com/ei/conference-materials/a253-03/blum gyn...

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


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)


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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


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.


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)


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


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


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


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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


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)


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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


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


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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


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


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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


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

gyn-oncology update: asco 2011 - imedexinc.comimedexinc.com/ei/conference-materials/a253-03/blum gyn...

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