Best of ASCO in Gyn Oncology Adnan R Munkarah. Biologics in Recurrent Ovarian Ca Cediranib- highly selective and potent oral TK inhibitor of VEGFR1, VEGFR2,

Best of ASCO in Gyn Best of ASCO in Gyn OncologyOncology

Adnan R MunkarahAdnan R Munkarah

Biologics in Recurrent Ovarian Biologics in Recurrent Ovarian CaCa

CediranibCediranib- highly selective and potent oral - highly selective and potent oral TK inhibitor of VEGFR1, VEGFR2, VEGFR3 TK inhibitor of VEGFR1, VEGFR2, VEGFR3 and c-Kit(and c-Kit(Matulanis #5501, Hirte#5521Matulanis #5501, Hirte#5521))

SunitinibSunitinib- multitargeted RTK inhibitor - multitargeted RTK inhibitor ((Biagi #5522Biagi #5522))

PertuzumabPertuzumab- monoclonal ab prevents - monoclonal ab prevents HER2 dimerization + CBDCA (HER2 dimerization + CBDCA (Kaye #5520, Kaye #5520, Lalla #5550Lalla #5550))

SorafenibSorafenib- oral TKI targeting raf & VEGFR, - oral TKI targeting raf & VEGFR, PDGFR, Flt3, c-kit ( PDGFR, Flt3, c-kit ( Matei D, GOG #5537Matei D, GOG #5537))

Folate Receptor Folate Receptor FRFR Overexpressed in majority of EOC, absent in Overexpressed in majority of EOC, absent in

nomrla tissuesnomrla tissues MORAb-003 humanized monoclonal ab to FRAMORAb-003 humanized monoclonal ab to FRA Armstrong D #5500Armstrong D #5500

52 patients with platinum sensitive EOC in first 52 patients with platinum sensitive EOC in first relapserelapse

Asymptomatic patients treated with single agent Asymptomatic patients treated with single agent ab (SA)ab (SA)

Symptomatic patients or those with progression on Symptomatic patients or those with progression on SA receive ab with platinum & TaxaneSA receive ab with platinum & Taxane

MOAb-003 significantly increased overall response MOAb-003 significantly increased overall response and duration of responseand duration of response

Folate Receptor Folate Receptor FRFR

Bell-McGuinn #5517Bell-McGuinn #5517 Phase I trrial in platinum resistant Phase I trrial in platinum resistant

EOC patientsEOC patients Well toleratedWell tolerated + response+ response

BelinostatBelinostat Histone deacetylase inhibitorHistone deacetylase inhibitor Preclinical studiesPreclinical studies

Synergy with carboplatinum and taxolSynergy with carboplatinum and taxol Effect in platinum resistant and sensitive Effect in platinum resistant and sensitive

EOCEOC Well tolerated in combination with Well tolerated in combination with

taxol/carbo and clinical benefit in heavily taxol/carbo and clinical benefit in heavily pretreated patients (pretreated patients (Finkler #5519Finkler #5519))

Promising activity in LMP ovarian Promising activity in LMP ovarian tumors (tumors (Mackay # 5518Mackay # 5518))

Seiji Isonishi,Seiji Isonishi,1 1 Makoto Yasuda, Makoto Yasuda,1 1 Fumiaki Fumiaki Takahashi,Takahashi,22 Noriyuki Katsumata, Noriyuki Katsumata,33 Eizo Kimura, Eizo Kimura, 1 1

Daisuke Aoki,Daisuke Aoki,44 Toshiko Jobo, Toshiko Jobo,55 Fumitoshi Fumitoshi Terauchi,Terauchi,66 Hiroshi Tsuda, Hiroshi Tsuda,44 Toru Sugiyama Toru Sugiyama77

1.The jikei University1.The jikei University School of Medicine, 2. Kitasato School of Medicine, 2. Kitasato University,3. National Cancer CenterUniversity,3. National Cancer Center Hospital, 3.Hospital, 3. Kousei Kousei General Hospital, 4. Keio University School of Medicine, 5. General Hospital, 4. Keio University School of Medicine, 5. Social Insurance Sagamino Hospital, 6. Tokyo Medical Social Insurance Sagamino Hospital, 6. Tokyo Medical University, 7.University, 7. Iwate Medical University School of MedicineIwate Medical University School of Medicine

jjgog0606@[email protected]

mailto:[email protected]






Conventional administration of paclitaxel and carboplatin Conventional administration of paclitaxel and carboplatin (c-TC) every 21 days is a standard therapy for advanced (c-TC) every 21 days is a standard therapy for advanced epithelial ovarian cancer.epithelial ovarian cancer.

Several phase II clinical trials of dose-dense weekly Several phase II clinical trials of dose-dense weekly administration of paclitaxel and carboplatin (dd-TC) in administration of paclitaxel and carboplatin (dd-TC) in ovarian cancer have demonstrated promising efficacy and ovarian cancer have demonstrated promising efficacy and favorable tolerabilityfavorable tolerability ((Gynecol Oncol 2005; 96: 296, Cancer Chemother Pharmacol 2008; 61: 243Gynecol Oncol 2005; 96: 296, Cancer Chemother Pharmacol 2008; 61: 243))..

Recent randomized phase III trials for breast cancer Recent randomized phase III trials for breast cancer demonstrated weekly paclitaxel improved survivaldemonstrated weekly paclitaxel improved survival 　　　　　　　　 ((NEJM 2008;358:1663-71, JCO 2008; 26:1642-1649NEJM 2008;358:1663-71, JCO 2008; 26:1642-1649))..

Conventional administration of paclitaxel and carboplatin Conventional administration of paclitaxel and carboplatin (c-TC) every 21 days is a standard therapy for advanced (c-TC) every 21 days is a standard therapy for advanced epithelial ovarian cancer.epithelial ovarian cancer.

Several phase II clinical trials of dose-dense weekly Several phase II clinical trials of dose-dense weekly administration of paclitaxel and carboplatin (dd-TC) in administration of paclitaxel and carboplatin (dd-TC) in ovarian cancer have demonstrated promising efficacy and ovarian cancer have demonstrated promising efficacy and favorable tolerabilityfavorable tolerability ((Gynecol Oncol 2005; 96: 296, Cancer Chemother Pharmacol 2008; 61: 243Gynecol Oncol 2005; 96: 296, Cancer Chemother Pharmacol 2008; 61: 243))..

Recent randomized phase III trials for breast cancer Recent randomized phase III trials for breast cancer demonstrated weekly paclitaxel improved survivaldemonstrated weekly paclitaxel improved survival 　　　　　　　　 ((NEJM 2008;358:1663-71, JCO 2008; 26:1642-1649NEJM 2008;358:1663-71, JCO 2008; 26:1642-1649))..

Ovarian Epithelial, Primary Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube cancerPeritoneal, or Fallopian Tube cancer

FIGO Stage II-IVFIGO Stage II-IV

Ovarian Epithelial, Primary Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube cancerPeritoneal, or Fallopian Tube cancer

FIGO Stage II-IVFIGO Stage II-IV

Conventional TC (c-TC)Conventional TC (c-TC)　　 Paclitaxel 180mg/mPaclitaxel 180mg/m22, day 1, day 1　　 Carboplatin AUC 6.0, day 1Carboplatin AUC 6.0, day 1　　 every 21 days for 6-9 every 21 days for 6-9 cyclescycles

Conventional TC (c-TC)Conventional TC (c-TC)　　 Paclitaxel 180mg/mPaclitaxel 180mg/m22, day 1, day 1　　 Carboplatin AUC 6.0, day 1Carboplatin AUC 6.0, day 1　　 every 21 days for 6-9 every 21 days for 6-9 cyclescycles

Dose-dense weekly TC (dd-TC)Dose-dense weekly TC (dd-TC)　　 Paclitaxel 80mg/mPaclitaxel 80mg/m22, days 1,8,15, days 1,8,15　　 Carboplatin AUC 6.0, day 1Carboplatin AUC 6.0, day 1　　 every 21 days for 6-9 cyclesevery 21 days for 6-9 cycles

Dose-dense weekly TC (dd-TC)Dose-dense weekly TC (dd-TC)　　 Paclitaxel 80mg/mPaclitaxel 80mg/m22, days 1,8,15, days 1,8,15　　 Carboplatin AUC 6.0, day 1Carboplatin AUC 6.0, day 1　　 every 21 days for 6-9 cyclesevery 21 days for 6-9 cycles

RandomizationRandomizationStratification; Stratification;

Residual disease: Residual disease: <<1cm, > 1cm1cm, > 1cmFIGO StageFIGO Stage ：： II vs. III vs. IVII vs. III vs. IVHistologyHistology ：： clear cell/mucinous vs.serous/others clear cell/mucinous vs.serous/others

NNewew OvOvarianarian ElElaborateaborate trialtrial:: NOVEL NOVEL trialtrialNNewew OvOvarianarian ElElaborateaborate trialtrial:: NOVEL NOVEL trialtrial

I.I. Histologically or cytologically* confirmed stage II-IV ovarian epithelial, primary Histologically or cytologically* confirmed stage II-IV ovarian epithelial, primary

peritoneal, or fallopian tube cancerperitoneal, or fallopian tube cancer

II.II. No prior chemotherapy No prior chemotherapy

III.III. Age: 20 and more Age: 20 and more

IV.IV. Performance status: ECOG 0-3Performance status: ECOG 0-3

V.V. 1) Absolute neutrophil count at least 1,500/mm1) Absolute neutrophil count at least 1,500/mm33

2) Platelet count at least 100,000/mm2) Platelet count at least 100,000/mm33

3) Bilirubin less than 1.5mg/dL3) Bilirubin less than 1.5mg/dL

4) SGOT less than 100 IU/l4) SGOT less than 100 IU/l

5) Serum creatinine less than 1.5mg/dL5) Serum creatinine less than 1.5mg/dL

VI. VI. Written informed consentWritten informed consent

I.I. Histologically or cytologically* confirmed stage II-IV ovarian epithelial, primary Histologically or cytologically* confirmed stage II-IV ovarian epithelial, primary

peritoneal, or fallopian tube cancerperitoneal, or fallopian tube cancer

II.II. No prior chemotherapy No prior chemotherapy

III.III. Age: 20 and more Age: 20 and more

IV.IV. Performance status: ECOG 0-3Performance status: ECOG 0-3

V.V. 1) Absolute neutrophil count at least 1,500/mm1) Absolute neutrophil count at least 1,500/mm33

2) Platelet count at least 100,000/mm2) Platelet count at least 100,000/mm33

3) Bilirubin less than 1.5mg/dL3) Bilirubin less than 1.5mg/dL

4) SGOT less than 100 IU/l4) SGOT less than 100 IU/l

5) Serum creatinine less than 1.5mg/dL5) Serum creatinine less than 1.5mg/dL

VI. VI. Written informed consentWritten informed consent

*CA125/CEA　>25,　and　GI　cancer　should　be　ruled　out*CA125/CEA　>25,　and　GI　cancer　should　be　ruled　out

Primary endpoint:Primary endpoint:

Progression-free SurvivalProgression-free Survival

Secondary endpoints:Secondary endpoints:Overall survival (OS)Overall survival (OS)Response rateResponse rateAdverse eventsAdverse eventsQuality of life (FACT)Quality of life (FACT)

Primary endpoint:Primary endpoint:

Progression-free SurvivalProgression-free Survival

Secondary endpoints:Secondary endpoints:Overall survival (OS)Overall survival (OS)Response rateResponse rateAdverse eventsAdverse eventsQuality of life (FACT)Quality of life (FACT)

Hypothesis:Hypothesis: 5 months improvement in median 5 months improvement in median PFS (from 16 to 21 months)PFS (from 16 to 21 months)

Statistical test:Statistical test: 2 sided log-rank with α=0.05, 2 sided log-rank with α=0.05, β=0.2β=0.2

Sample size:Sample size: 380 patients initially on Apr. 2003380 patients initially on Apr. 2003

600 patients with one interim 600 patients with one interim analysisanalysis after amendment on Jan. 2005after amendment on Jan. 2005

Progression defined as:Progression defined as:

appearance of any measurable or appearance of any measurable or evaluable lesionevaluable lesion

OROR

CA125 level CA125 level >> 2 times UNL or 2 times UNL or nadir nadir for 2 consecutive for 2 consecutive measurements at measurements at least 1 week apartleast 1 week apart

Hypothesis:Hypothesis: 5 months improvement in median 5 months improvement in median PFS (from 16 to 21 months)PFS (from 16 to 21 months)

Statistical test:Statistical test: 2 sided log-rank with α=0.05, 2 sided log-rank with α=0.05, β=0.2β=0.2

Sample size:Sample size: 380 patients initially on Apr. 2003380 patients initially on Apr. 2003

600 patients with one interim 600 patients with one interim analysisanalysis after amendment on Jan. 2005after amendment on Jan. 2005

Progression defined as:Progression defined as:

appearance of any measurable or appearance of any measurable or evaluable lesionevaluable lesion

OROR

CA125 level CA125 level >> 2 times UNL or 2 times UNL or nadir nadir for 2 consecutive for 2 consecutive measurements at measurements at least 1 week apartleast 1 week apart

637 Patients enrolled and randomly assigned

320 Assigned to c-TC 317 Assigned to dd-TCdd-TC 317 Assigned to dd-TCdd-TC

319 Eligible Patients

312 Eligible Patients

1 Ineligible

5 Ineligible

6 cycles of treatmentAdditional 3 cycles should be given if clinical responses were observed.Interval or secondary debulking surgery were allowed.

319 Primary intention to treat efficacy analysis

314 Safety analysis

312 Primary intention to treat efficacy analysis

312 Safety analysis

CharacteristicCharacteristic Conventional TCConventional TC(n = 319) (n = 319)

Dose-dense TCDose-dense TC(n = 312)(n = 312)

Median age Median age (range)(range) 57 (25-84)57 (25-84) 57 (25-87)57 (25-87)

FIGO stage, %FIGO stage, %IIIIIIIIIIIVIV

171767671616

202065651515

ECOG PS, %ECOG PS, %0 or 10 or 12233

90906644

90907722

Disease, %Disease, %OvarianOvarianFallopian tubeFallopian tubePrimary Primary

peritonealperitoneal

87876688

8383551212

CharacteristicCharacteristicConventional Conventional

TCTC(n = 319) (n = 319)

Dose-dense TCDose-dense TC(n = 312)(n = 312)

Surgery, %Surgery, % Primary debulkingPrimary debulking Interval debulkingInterval debulking Secondary/Second Secondary/Second LookLook

8989991818

898911111212

Residual disease, %Residual disease, %<< 1cm 1cm> 1cm> 1cm

45455555

46465454

Histologic type, %Histologic type, %Clear or MucinousClear or MucinousSerous or othersSerous or others

16168484

17178383

MeasurableMeasurable% of patients% of patients

c-TCc-TC(n = 135) (n = 135)

dd-TCdd-TC(n = 147)(n = 147)

Objective Objective

responseresponse

CRCR

PRPR

NCNC

PDPD

NENE

5353

1616

3838

3131

77

99

5656

2020

3636

2929

33

1212

P=0.72

Evaluated by WHO criteria

Clinical Response

Adverse EventAdverse Event c-TCc-TC(n = 314) (n = 314)

dd-TCdd-TC(n = 312)(n = 312) P valueP value

no. (%)no. (%)

NeutropeniaNeutropenia 276 (80)276 (80) 286 (92)286 (92) 0.150.15

ThrombocytopeniaThrombocytopenia 120 (38)120 (38) 136 (44)136 (44) 0.190.19

AnemiaAnemia 137 (44)137 (44) 214 (69)214 (69) < 0.0001< 0.0001

Febrile neutropeniaFebrile neutropenia 29 (9)29 (9) 29 (9)29 (9) 1.001.00

Neuropathy-motorNeuropathy-motor 43 (14)43 (14) 37 (12)37 (12) 0.550.55

Neuropathy-sensoryNeuropathy-sensory 86 (27)86 (27) 71 (23)71 (23) 0.200.20

Evaluated by NCI-CTC ver.2.0

c-TC c-TC (n = 319) (n = 319)

dd-TCdd-TC(n = 312)(n = 312)

>> 6 cycles (all patients) 6 cycles (all patients)9 cycles (responding 9 cycles (responding patients)patients)

231231 (72%)(72%)5050

186186 (60%)(60%)3737

Completed protocol therapyCompleted protocol therapy

Discontinued protocol Discontinued protocol

therapytherapy

progression/deathprogression/death

toxicitytoxicityhematologichematologicneuropathyneuropathyallergyallergypatient refusal for patient refusal for

toxicitytoxicityothersothers

patient refusalpatient refusal

other reasonsother reasons

UnknownUnknown

200200 (63%)(63%)

117117 (37%)(37%)

2828

69693030557712121313

88

1111

22

147147 (47%)(47%)

165165 (53%)(53%)

2828

1131136868334413132525

66

1717

00

TreatmeTreatmentnt nn EventEvent Median PFSMedian PFS P valueP value HR HR 95%CI 95%CI

c-TCc-TC 319 319 200 200 17.2 mos.17.2 mos.

dd-TCdd-TC 312 312 160 160 28.0 mos.28.0 mos. 0.0015 0.0015 0.7140.714 0.581-0.581-

0.8790.879

TreatmeTreatmentnt nn EventEvent 2-yr survival2-yr survival P P

valuevalue HR HR 95%CI 95%CI

c-TCc-TC 319 319 95 95 77.7%77.7%

dd-TCdd-TC 312 312 7070 83.6%83.6% 0.04960.0496 0.7350.735 0.540-0.540-1.0001.000

nnPS 2-3PS 2-3 6161PS 0-1PS 0-1 570570

Age > 60Age > 60 368368Age Age << 60 60 263263

Primary peritonealPrimary peritoneal 6363Fallopian tubeFallopian tube 3232OvarianOvarian 536536

Serous/OthersSerous/Others 527527Clear Clear cell/Mucinouscell/Mucinous 104104

FIGO stage IVFIGO stage IV 9898FIGO stage IIIFIGO stage III 417417FIGO stage IIFIGO stage II 116116

Residual disease > Residual disease > 1cm1cm 342342

Residual disease Residual disease << 1cm1cm 289289

OverallOverall 631631 dd-TC　better c-TC　better

0.0 0.5 1.0 1.5 2.0

PFS was improved with dose-dense weekly PFS was improved with dose-dense weekly TC compared to conventional TC in patients TC compared to conventional TC in patients with advanced epithelial ovarian cancer.with advanced epithelial ovarian cancer.

Analysis of overall survival is ongoing.Analysis of overall survival is ongoing.

Hematologic toxicity was increased in dose-Hematologic toxicity was increased in dose-dense TC.dense TC.

Neurotoxicity was similar in both groups.Neurotoxicity was similar in both groups.

PFS was improved with dose-dense weekly PFS was improved with dose-dense weekly TC compared to conventional TC in patients TC compared to conventional TC in patients with advanced epithelial ovarian cancer.with advanced epithelial ovarian cancer.

Analysis of overall survival is ongoing.Analysis of overall survival is ongoing.

Hematologic toxicity was increased in dose-Hematologic toxicity was increased in dose-dense TC.dense TC.

Neurotoxicity was similar in both groups.Neurotoxicity was similar in both groups.

AZD2281 (KU-0059436), a PARPAZD2281 (KU-0059436), a PARP(poly ADP-ribose polymerase) (poly ADP-ribose polymerase)

inhibitorinhibitorwith single agent anticancer activity with single agent anticancer activity

in patients with BRCA deficient in patients with BRCA deficient ovarian cancer:ovarian cancer:

Results from a phase I studyResults from a phase I studyPeter C Fong1, David S Boss2, Craig P Carden1, Marja Mergui-Roelvink2,

Jacques De Greve3, Charles M Gourley4, James Carmichael5,Johann S de Bono1, Jan H Schellens2, Stan B Kaye1

1The Royal Marsden Hospital and The Institute of Cancer Research, UK, 2The Netherlands Cancer Institute, The Netherlands, 3UZ Brussel Oncologisch Centrum, Belgium,

4Edinburgh Cancer Research Centre, UK, 5KuDOS Pharmaceuticals/AstraZeneca, UK

PARPPARP Poly(ADP-ribose) polymerase-1- member Poly(ADP-ribose) polymerase-1- member

of PARP enzymesof PARP enzymes Abundant nuclear proteinAbundant nuclear protein Binds to DNA breaksBinds to DNA breaks Activated PARP cleaves NAD+ into Activated PARP cleaves NAD+ into

nictoinamide and ADP-ribose and nictoinamide and ADP-ribose and polymerizes the latter onto nuclear polymerizes the latter onto nuclear receptor proteins including histones, receptor proteins including histones, transcription factors and PARP itselftranscription factors and PARP itself

Contributes to repair of single strand Contributes to repair of single strand breaks in DNAbreaks in DNA

Poly ADP-Ribose Polymerase Poly ADP-Ribose Polymerase (PARP)(PARP)

PARP inhibitors & BRCAPARP inhibitors & BRCA

10 -9 10 -8 10 -7 10 -6 10 -5 10 -40-4

-3

-2

-1

0

conc (M)

BRCA2-/-

BRCA2+/+

BRCA2+/-

Increased sensitivity of BRCA1-/- and BRCA2-/- cells to PARP inhibition

10 -9 10 -8 10 -7 10 -6 10 -5 10 -40-4

-3

-2

-1

0

conc (M)

BRCA1-/-

BRCA1+/+

BRCA1+/-

No difference in sensitivity between heterozygous and wild-type BRCA cells

Farmer et al. Nature 2005; 434:917-21

Targeted inhibition selective and less toxic therapy

From targeted therapy to the From targeted therapy to the AZD2281 Phase I study AZD2281 Phase I study

Oral, small molecule PARP inhibitorOral, small molecule PARP inhibitor ICIC5050 for PARP1 enzyme in the low nM range for PARP1 enzyme in the low nM range

Phase I trial began at RMH then NKI; later expanded to Phase I trial began at RMH then NKI; later expanded to other centresother centres

Escalation phaseEscalation phase: All tumour types: All tumour types Primary objectives of safety and tolerabilityPrimary objectives of safety and tolerability

Expansion phaseExpansion phase: BRCA mutation carriers (HR deficient) : BRCA mutation carriers (HR deficient) especially ovarian cancerespecially ovarian cancer Further assessment of efficacyFurther assessment of efficacy

Overall recruitmentOverall recruitment

Escalation PhaseEscalation Phase (n=46) (n=46)1,21,2

Various tumour types; BRCA carrier status not mandatoryVarious tumour types; BRCA carrier status not mandatory 10 dose level cohorts:10 dose level cohorts:

10mg daily given for 2 out of 3 weeks 10mg daily given for 2 out of 3 weeks 600mg bid continuous dosing600mg bid continuous dosing

11 BRCA carrier ovarian cancer11 BRCA carrier ovarian cancer

Expansion phaseExpansion phase (n=52) at 200mg bid continuous (n=52) at 200mg bid continuous22

Confirmed BRCA mutation carriersConfirmed BRCA mutation carriers 39 ovarian cancer39 ovarian cancer

1Fong et al. Proceedings of ASCO 20062Yap et al. Proceedings of ASCO 2007

ToxicitiesToxicities(first 60 patients, all tumour types)(first 60 patients, all tumour types)

Most toxicities were Grade 1-2 (Most toxicities were Grade 1-2 (≥95%)≥95%) Most common toxicities were:Most common toxicities were:

nausea 28%, vomiting 18%, dysgeusia 13%, anorexia 12%nausea 28%, vomiting 18%, dysgeusia 13%, anorexia 12% fatigue 28%fatigue 28%

Grade 3-4 toxicities were rare:Grade 3-4 toxicities were rare: myelosuppression (myelosuppression (≤≤5%) 5%) nausea and vomiting (2-3%)nausea and vomiting (2-3%) CNS: dizziness or mood changes (2-3%)CNS: dizziness or mood changes (2-3%)

Pattern of toxicity similar in BRCA mutation carriersPattern of toxicity similar in BRCA mutation carriers

Dose limiting toxicities (DLT)Dose limiting toxicities (DLT)

Dose Dose (mg)/ (mg)/

ScheduleSchedule

Tumour Tumour typetype DLTDLT OutcomeOutcome

400 bid 400 bid continuoucontinuou

ssOvarian CaOvarian Ca

G3 low mood G3 low mood andand

G3 fatigueG3 fatigue

Resolved within 24 Resolved within 24 hours of drug hours of drug

discontinuationdiscontinuation

Recurred with re-Recurred with re-challengechallenge


ss

MesothelioMesotheliomama

G4 G4 thrombocytopethrombocytope

niania

Resolved 2 weeks after Resolved 2 weeks after drug discontinuationdrug discontinuation


ssBreast CaBreast Ca G3 somnolenceG3 somnolence

Resolved within 24 Resolved within 24 hours of drug hours of drug

discontinuationdiscontinuation

G1 on lower doseG1 on lower dose

Maximum Tolerated Dose (MTD) = 400mg bid

DemographicsDemographicsBRCA-mutated ovarian cancer BRCA-mutated ovarian cancer

subpopulationsubpopulation

PatientsPatientsDose (mg bid)Dose (mg bid)

≤ ≤ 100100 200200 400400 600600Total = 50Total = 50 44 3939 66 11

No. evaluable for No. evaluable for efficacy = 46efficacy = 46 44 3737 44 11

Includes Includes primary peritoneal cancer (2 pts), fallopian tube primary peritoneal cancer (2 pts), fallopian tube carcinoma (1 pt) and 1 ovarian cancercarcinoma (1 pt) and 1 ovarian cancer pt with compelling pt with compelling family family historyhistory for BRCA mutation for BRCA mutation

Excluded pts:Excluded pts: 1 pt died from disease-related non-neutropenic sepsis after 1 cycle 1 pt died from disease-related non-neutropenic sepsis after 1 cycle 1 pt had DLT on day 1 and again on day 8 with re-challenge of drug1 pt had DLT on day 1 and again on day 8 with re-challenge of drug 2 pts had PD within 2-3 weeks after commencement2 pts had PD within 2-3 weeks after commencement

DemographicsDemographicsBRCA-mutated ovarian cancer BRCA-mutated ovarian cancer

subpopulationsubpopulationCharacteristicsCharacteristics NumberNumber

BRCA1 / BRCA2 / Family historyBRCA1 / BRCA2 / Family history 41 / 8 / 141 / 8 / 1

Median age (range)Median age (range) 52 (37-80) yrs52 (37-80) yrs

ECOG PS 0-1ECOG PS 0-1 4747

Median duration from diagnosis to treatment Median duration from diagnosis to treatment (range)(range) 4.7 (0.5–16) yrs4.7 (0.5–16) yrs

Platinum statusPlatinum statusSensitive (PD > 6 months after platinum)Sensitive (PD > 6 months after platinum)Resistant (PD Resistant (PD ≤≤ 6 months after platinum)6 months after platinum)Refractory (PD on platinum or on Refractory (PD on platinum or on completion of platinum)completion of platinum)

101027271313

Median no. of prior systemic therapies Median no. of prior systemic therapies (range)(range) 3 (1-8)3 (1-8)

23 mm

21mm

16mm

TotalTotal Platinum Platinum sensitivesensitive

Platinum Platinum resistantresistant

Platinum Platinum refractorrefractor

yy

No. of evaluable No. of evaluable patientspatients 4646 1010 2525 1111

Responders by Responders by RECISTRECIST 13 (28%)13 (28%) 5 (50%)5 (50%) 8 (32%)8 (32%) 0 (0%)0 (0%)

Responders by GCIG Responders by GCIG CA125CA125 18 (39%)18 (39%) 8 (80%)8 (80%) 8 (32%)8 (32%) 2 (18%)2 (18%)

Responders by either Responders by either RECIST or GCIG RECIST or GCIG criteriacriteria

2121 (46%) (46%) 8 (80%)8 (80%) 11 (44%)11 (44%) 2 (18%)2 (18%)

SD (> 4 cycles)SD (> 4 cycles) 6 (13%)6 (13%) 1 (10%)1 (10%) 4 (16%)4 (16%) 1 (9%)1 (9%)

Median duration of Median duration of response in weeks response in weeks (range)(range)

2424 (10-77) (10-77) 23 (16-77)23 (16-77) 24 (10-65)24 (10-65) 26 (20-32)26 (20-32)

Response to AZD2281 byResponse to AZD2281 byplatinum-free intervalplatinum-free interval




yy





21 (46%)21 (46%) 8 8 (80%)(80%) 11 (44%)11 (44%) 2 (18%)2 (18%)



2424 (10-77) (10-77) 23 (16-77)23 (16-77) 24 (10-65)24 (10-65) 26 (20-32)26 (20-32)





yy





21 (46%)21 (46%) 8 (80%)8 (80%) 1111 (44%) (44%) 2 (18%)2 (18%)



2424 (10-77) (10-77) 23 (16-77)23 (16-77) 24 (10-65)24 (10-65) 26 (20-32)26 (20-32)





yy





21 (46%)21 (46%) 8 (80%)8 (80%) 11 (44%)11 (44%) 22 (18%) (18%)



2424 (10-77) (10-77) 23 (16-77)23 (16-77) 24 (10-65)24 (10-65) 26 (20-32)26 (20-32)


AZD2281 key messagesAZD2281 key messages Well tolerated oral therapy not associated with the Well tolerated oral therapy not associated with the

typical toxicities of chemotherapytypical toxicities of chemotherapy

Clear evidence of beneficial tumour response in Clear evidence of beneficial tumour response in BRCA BRCA mutated ovarian cancer patients mutated ovarian cancer patients

46% (21/46 pts) response rate (RECIST or GCIG CA125) 46% (21/46 pts) response rate (RECIST or GCIG CA125)

13% meaningful disease stabilisation 13% meaningful disease stabilisation

Total clinical benefit rate of 59%Total clinical benefit rate of 59%

A randomised phase II trial in BRCA ovarian cancer A randomised phase II trial in BRCA ovarian cancer pts with platinum-free interval of 0-12 months pts with platinum-free interval of 0-12 months

AZD2281 vs pegylated liposomal doxorubicinAZD2281 vs pegylated liposomal doxorubicin

Documents

Best of ASCO in Gyn Oncology Adnan R Munkarah. Biologics in Recurrent Ovarian Ca Cediranib- highly selective and potent oral TK inhibitor of VEGFR1, VEGFR2,