Dr. Paul Sabbatini: Recurrent Ovarian Cancer: Now What? (SHARE Program)

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On May 22, 2013, SHARE presented "Recurrent Ovarian Cancer: Now What?" The program featured Dr. Ginger Gardner and Dr. Paul Sabbatini of Memorial Sloan-Kettering Cancer Center discussing treatment strategies, as well as new approaches and agents, for managing an ovarian cancer recurrence. Listen to the audio here http://www.sharecancersupport.org/sabbatini.

The information in this presentation is not intended to be a substitute for professional medical advice, diagnosis or treatment.

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Dr. Paul Sabbatini: Recurrent Ovarian Cancer: Now What? (SHARE Program)

  1. 1. Ovarian Cancer Recurrence: Nowwhat?Paul Sabbatini, MDMemorial Sloan-Kettering Cancer CenterNew York, New York
  2. 2. Disease States Model for Ovarian CancerAdapted from Dizon et al. J Clin Onc 20:1238-1247 2002
  3. 3. Disease States Model for Ovarian CancerAdapted from Dizon et al. J Clin Onc 20:1238-1247 2002
  4. 4. Disease States Model for Ovarian CancerAdapted from Dizon et al. J Clin Onc 20:1238-1247 2002
  5. 5. Recurrent Disease: Timing of TreatmentHarries and Gore. Lancet Oncology 3:2002.
  6. 6. Recurrent Disease: Rising CA125Normal Imaging Study No defined role for standard chemotherapy Hormonal interventions– tamoxifen– aromatase inhibitor• Anastrozole, letrozole• other– leuprolide metformin Clinical Trial
  7. 7. Disease States Model for Ovarian CancerAdapted from Dizon et al. J Clin Onc 20:1238-1247 2002
  8. 8. Recurrent Disease Therapy withMeasurable DiseasePrimary treatmentRELAPSE< 6 months > 6 monthsPlatinum Resistant Platinum Sensitive
  9. 9. Recurrent Disease with MeasurableTumor Surgical resection? Surgical resection followed by HIPECchemotherapy?– Dr. Gardner
  10. 10. Relapsed Disease: Platinum Responses17%27%57%0%20%40%60%80%< 12 12 -24>24Months27% 33%59%0%20%40%60%80%5 -1213 -24>24MonthsGore et al. Gyn Onc 36:207-11, 1990 Markman et al. JCO 9: 389-93, 1991Phase II: RR and Platinum-free interval
  11. 11. Study Agents PFS(mos)OS(mos)HRICON 4/OVAR 2.21carboplatin-or-carboplatin +paclitaxel9 12 24 29 0.082 (0.96-0.97)p = 0.023AGO2 carboplatin-or-carboplatin +gemcitabine5.8 8.6 17.3 18.0 0.072 (0.58-0.90)p = 0.0031CALYPSO3 carboplatin +paclitaxel-or-carboplatin +liposomal dox9.4 11.3 33.730.70.082 (0.82-0.94)p = 0.005NS for OSPlatinum Sensitive Recurrence:Randomized Studies1 = Lederman et al. Lancet. 2003: 361, 2099-106, 2 = Pfisterer et al. J Clin Onc 2006; 29: 4699-707, 3 = Wagner et al. BJC 107: 588-91, 2012
  12. 12. Platinum Hypersensitivity Lifetime limit of carboplatin in manypatients (12%, median of 8 cycles)– Latter third of infusion– More difficult to treat– Potentially life threatening Desensitization schedules with cautionafter reaction– 3 hour (1%,9%,90%) with premeds– 12 step protocol– Prophylactic?Markman et al. J Clin Oncol 17:1141 ff, 1999Castells et al. J All Clin Imm 122(3): 574-80, 2008
  13. 13. Carboplatin Hypersensitivity andProphylactic Use of Extended Schedule777 patients retreated withcarboplatin (1998-08)117 (17%) had HSR > secondlineHSR in 6 (3.4%) of 174 ptswith extended schedule +standard premeds(0% G 4; 50% G III)HSR in 111 (21%) of 533 ptswith standard schedule(13% G 4, 77% G III)O’Cearbhaill et al. Gyn Onc 116: 326-31, 2010
  14. 14. Disease States Model for Ovarian CancerAdapted from Dizon et al. J Clin Onc 20:1238-1247 2002
  15. 15. Ovarian Cancer: Non-platinum responsesAGENT PlatinumSensitivePlatinumResistantPaclitaxel 20-41% 12%-33 %Docetaxel 38% 27%Etoposide 35% 25%Topotecan 33% 12%Lipo doxorubicin 28% 14%Vinorelbine 29% 21%Gemcitabine 15%Altretamine 27% 10%Pemetrexed1 21%Trabectedin2 23% 0%yellow = randomized data, 1 = Miller et al. J C Onc 16: 2009, 2 = Loruso et al. Abs 5060, ASCO 2011
  16. 16. Response Rates Versus Toxicity Carboplatin – platelets, HSR Cisplatin – neuro, HSR Paclitaxel q1wk orq3wk - neuro Doxil - hand/foot (PPE) Gemcitabine – none(fatigue, inflammatory) Etoposide, oral - leukemia Topotecan – none (fatigue) Vinorelbine – WBC, bowels Tamoxifen - none 5-FU/leucovorin - GI Irinotecan - GI Ifosfamide -neuro, bonemarrow, renal Hexamethylmelamine -neuro, GI Docetaxel - neuro, fluidretentionCumulative Toxicities
  17. 17. Topotecan vs. Liposomal Doxorubicin: Issequence important?Dupont et al. IJGC 2006, suppl 1: 68-73.
  18. 18. CA-125 Patterns in Treatment forRecurrenceSabbatini et al. Int J Gyn Ca 17: 2007
  19. 19. Ovarian CancerTargeted Therapy in GOG Trials*1-3 priors Thresholds: RR -10%, 25%; PFS – 15%, 35%STUDY AGENT Target N RESPONSERATEPFS AT 6MONTHS170 – 1-2 prior therapies170-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 0.0% 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) Closed after first stage170-Q EGEN-001 IL-12 First stage accrual in progress170-R ACE-041 ALK-1 To activate 2012
  20. 20. What Is Tumor Angiogenesis?Blood vesselTumor that can grow and spreadSmall localized tumorSignalingmoleculeAngiogenesis
  21. 21. VEGF Trap1Anti-VEGFRAnti-VEGFbevacizumab2anti-sense SiRNAYYKinase Inhibitorssunitinib3vatalanib4sorafenib5pazopanib6Targeting the VEGF Pathway1 = Regeneron, 2=Genentech, 3 = Pfizer, 4= Novartis, 5 = Bayer, 6 = Glaxo Smith Kline
  22. 22. Platinum sensitive:Randomized Phase III StudyRecurrent Ovarian Cancer> 6 months DFSgemcitabine + carboplatin+ bevacizumabgemcitabine + carboplatin+ placeboPatients: 484Endpoint: > G 1 perforation, PFS; OR, OSAghajanian et al. JCO 30:2039-45, 2012“OCEANS” STUDY
  23. 23. OCEANS: Primary Analysis of PFSGC + PL(n=242)GC + BV(n=242)Median PFS (by INV), months 8.4 12.4Stratified analysisHRLog-rank P value0.484<.0001Median PFS (by IRC), months 8.6 12.3Stratified analysisHRLog-rank P value0.451<.0001ORR (by INV), % 57 79Median DOR (by INV), months 7.4 10.4HR 0.53ORR (by IRC), % 54 75Median DOR (by IRC), months 6.0 8.3HR 0.54MonthsProportionprogressionfree•0.00.20.40.60.81.00 6 12 18 24 30Aghajanian et al. JCO 30:2039-45, 2012
  24. 24. Adverse events, n (%)GC + PL(n=233)GC + BV(n=247)Arterial thromboembolic event (all grade) 2 (0.9) 7 (2.8)Venous thromboembolic event (grade ≥3) 6 (2.6) 10 (4.0)Bleeding (central nervous system) (all grade) 1 (0.4) 2 (0.8)Bleeding (non-central nervous system) (grade ≥3) 2 (0.9) 14 (5.7)Congestive heart failure (grade ≥3) 2 (0.9) 3 (1.2)Febrile neutropenia (grade ≥3) 4 (1.7) 4 (1.6)Neutropenia (grade ≥3) 130 (55.8) 144 (58.3)Hypertension (grade ≥3) 1 (0.4) 44 (17.8)Fistula/abscess (all grade) 1 (0.4) 4 (1.6)Gastrointestinal perforation (all grade)b 0 (0) 0 (0)Proteinuria (grade ≥3) 2 (0.9) 24 (9.7)Reversible posterior leukoencephalopathy syndrome (all grade) 0 (0) 2 (0.8)Wound-healing complication (grade ≥3) 0 (0) 2 (0.8)OCEANS: Adverse Events of Special InterestaAghajanian et al. JCO 30:2039-45, 2012
  25. 25. Type of therapy, n (%)aGC + PL(n=242)GC + BV(n=242)Any subsequent anticancer therapy 216 (89.3) 207 (85.5)Subsequent BV 85 (39.4) 46 (22.2)Subsequent chemotherapyb213 (98.6) 203 (98.1)OCEANS: Subsequent Anticancer Therapymakes OS hard to interpretAghajanian et al. JCO 30:2039-45, 2012
  26. 26. Fig. 1 Prevalence of histologic types of EOC and their associated molecular genetic changes.Histologic Groups and Molecular AlterationsKurman et al. Hum Path 42: 918-31, 2011
  27. 27. Other Targets?A first pass attempt to catalogue mutually exclusive potentialdriver events in HGS-OvCaBRCA1Germline8%BRCA2Germline6%BRCA1Somatic3%BRCA2Somatic3%BRCA1Methylation11%EMSYAmplification6%PTEN Loss5%Other HRD7%CCNE1Amplification15%MMRGermline2%RB1 deletion3%PIK3CAAmplification4%KRASAmplification3%NF1 Deletion3% Other21%Data provided by Douglas Levine, MD, MSKCC on behalf of tcga.cancer.gov
  28. 28. DNA Repair Mechanism: HomologousRecombination Most conservativerepair mechanism Potentially error-freeas breaks arerepaired using thesister chromatid as atemplate Relies upon BRCA1and BRCA2 activityTurner et al. Current Opinion in Pharmacology 2005
  29. 29. Rationale Behind PARP Inhibition BRCA Negative Patients– Unable to repair DNA using homologousrecombination– Rely upon base excision repair process forsingle-strand breaks and replication forkstalls Other Ovarian Cancer Patients– Chemotherapies that produce DNA strandcrosslinks or adducts(carboplatin, topotecan) will lead to stalls inDNA replication– Inhibition of PARP will not allow singlestrand repair at these sites
  30. 30. Olaparib multicenterPhase II BRCA+/-study (ovariancancer patients)3400 mg bidBRCA+ 41%BRCA- 24%BRCA+ 76%BRCA- 62%NRPARP and Ovarian Cancer: Proof of Principle1. Fong PC et al. J Clin Oncol 2010;28:2512–2519; 2. Audeh MW et al. Lancet 2010;376:245–251;3. Gelmon KA et al. J Clin Oncol 2010;28:abst 3002*Complete response (CR) + partial response (PR) + stable disease (SD); NR, not reportedOlaparib multicenterPhase II BRCAmutation ovariancancer study2400 mg bid33%69%9.5 monthsOlaparibPhase I and BRCAmutation expansionstudies1200 mg bid28%34%7.0 monthsOlaparib doseRECISTCR/PRDisease control rate*Median duration ofresponse
  31. 31. Most frequently reported AEs*n (%)Olaparib400 mg bid(n=33)Olaparib100 mg bid(n=24)Any grade Grade 3/4 Any grade Grade 3/4Nausea 21 (64) 2 (6) 15 (63) 3 (13)Fatigue 17 (52) 1 (3) 13 (54) 0Diarrhea 12 (37) 0 7 (29) 0Vomiting 11 (33) 2 (6) 6 (25) 2 (8)Abdominal pain 9 (27) 1 (3) 4 (17) 1 (4)*≥25% reported in either cohortCTCAE, Common Terminology Criteria for Adverse EventsAudeh et al., ASCO 2009
  32. 32. Ongoing Questions… Why is the optimal dose or dose combination? Who to treat and when?– BRCA 1 and 2– Serous ovarian cancer patients– Platinum sensitive vs. platinum resistant How to predict who will respond? What are long term side effects?
  33. 33. ACTNOW/ARRA FUNDEDPhase A: Cycle repeated every 21 days for a total of 6 cycles.* Bevacizumab started in Cycle 2.Phase B: Bevacizumab will be continued as maintenance for Cycles 7-22 every 21 days.** ABT-888 will be dose escalated to determine the MTD; a feasibility phase will follow.GOG 9923Initial Therapy
  34. 34. Eligible PatientsRecurrent ovarian, fallopian tube and primary peritoneal carcinomaOne prior platinum-based treatment regimenAlternating cohorts of3 patientsRegimen IPLD 30 mg/m2 – Day 1Carboplatin AUC 5 – Day 1ABT-888 twice daily – Day 1-7One Cycle = 28 daysRegimen IIPLD 30 mg/m2 – Day 1Carboplatin AUC 5 – Day 1ABT-888 twice daily – Day 1-28One Cycle= 28 daysGOG 9927First Platinum Sensitive Recurrence
  35. 35. Bookman et al. JCO 21:283-290, 20037.3%IHC2+ 61 ( 7.3%)3+ 34 ( 4.1%)ERBB2 Trastuzumab (GOG 160)
  36. 36. ERBB1 (EGF) Targeted TherapiesIntracellularSignalTKInhibitors(e.g.erlotinib,gefitinib)Monoclonalantibodies(e.g. cetuximab)PR2PR1LigandATPADPReceptorDegradation(e.g.17AAG)•35-70% of ovariancancers EGFR positive•TGF-α and EGFas potential ligands
  37. 37. AURELIA: Platinum ResistantTrial DesignStratification factors:• Chemotherapy selected• Prior anti-angiogenic therapy• Treatment-free interval(<3 vs 3‒6 months from previousplatinum to subsequent PD)Platinum-resistant OCa• ≤2 prior anticancerregimens• No history of bowelobstruction/abdominalfistula, or clinical/radiological evidence ofrectosigmoid involvementTreat toPD/toxicityTreat toPD/toxicityInvestigator’schoice(without BEV)Optional BEVmonotherapycBEV 15 mg/kg q3wb+ chemotherapyChemotherapyR1:1Chemotherapy options (investigator’s choice):• Paclitaxel 80 mg/m2 days 1, 8, 15, & 22 q4w• Topotecan 4 mg/m2 days 1, 8, & 15 q4w(or 1.25 mg/m2, days 1–5 q3w)• PLD 40 mg/m2 day 1 q4wPujade Luraine et al. JCO 30: LBA 5002, 2012
  38. 38. Aurelia: Platinum Resistant PFSCT(n=182)BEV + CT(n=179)Events, n (%) 166 (91%) 135 (75%)Median PFS, months(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)<0.0011.00.80.60.40.20Estimatedprobability0 6 12 18 24 30Time (months)182 37 8 1 0179 88 18 1 0CTBEV + CTNo. at risk:93140204914013.4 6.7Pujade Luraine et al. JCO 30: LBA 5002, 2012
  39. 39. Additional grade ≥3 adverse events in≥2% of patients in either armPatients(%)≈≈≈≈
  40. 40. Aurelia: Platinum Resistant The primary objective was met• PFS HR 0.48 (p<0.001) BEV combination therapyvs single-agent CT• Median PFS: 6.7 vs 3.4 months– ORR 30.9% vs 12.6%, respectively (p=0.001)– Patients at high risk of GI perforation were excludedfrom the study– Overall survival data in 2013
  41. 41. RefractoryPRIMARYTREATMENTResistantSensitive0 3 6 12 18 24MonthsVery SensitiveSummary: Optimal SequencesDefinition of SensitivityRR 9%RR 10-20% RR 15-38%RR 60%Single, non-platinumNon-platinum orplatinumcombo*Platinumcombo*Platinum + taxol, lipodox, gem +/- bev
  42. 42. Disease States Model for Ovarian CancerAdapted from Dizon et al. J Clin Onc 20:1238-1247 2002Sabbatini and Spriggs. J Clin Onc 24:2006Remission = maintenance = consolidation“Secondary Prevention”
  43. 43. Other Randomized Trials: FirstRemissionIntervention N Outcome5 vs 10 CAP1 78 No benefit OS6 vs 12 CAP2 202 No benefit OSEpirubicin X 4 vs obs3 162 No benefit OSIP CDDP vs obs4 153 No benefit PFS/OSIFN-ά 3 X week vs obs5 300 No benefit PFS/OSBay 12-9566 (MMP)6 243 No benefit PFS, OS32IP vs. Obs7 202 No benefit PFS/OSCT-2103 vs obs8 ongoingPaclitaxel 3 vs 129 287 7 mos PFS, no OSOlaparib vs. obs10 265 3.6 mos PFS, no OS1 = Hakes et al. G Onc 45: 1992, 2 = Bertelsen et al. G Onc 49: 1993, 3= Scarfone et al. Proc ASCO21: 2002, 4 = Piccart et al. Int J Gyn Ca 13:2003, 5 = Hall et al. Br J Ca 91: 2004, 6 = Hirte et al. ProcASCO 20: 2001, 7 = Varia et al. JCO 21: 2003, 8 = GOG 212, 9 = Markman JCO 2003, 10 =Lederman NEJM 2012.
  44. 44. Immunosurveillance: Antibodies andOvarian Cancer SurvivalAnderson et al. Ca Epi Bio Prev 19:859-868, 2010
  45. 45. Progression Free Survival Overall SurvivalImmunosurveillance: Tumor InfiltratingLymphocytes and Ovarian Cancer OSZhang et al, NEJM 348: 203-13, 2003
  46. 46. Surface Antigen Targets: Ab Effectors Frozen embeddedtissue Standard immuno-peroxidase staining Blood group related,ganglioside, proteinantigenssTn (CC 49) 4/5sTn (CC 49) 3/5TF 5/5LeY 5/5MUC 1 (HMFG-2) 5/5MUC 3 4/5MUC 4 3/5KSA 5/5GM2 5/5Globo H 3/5Zhang et al. Int J Cancer 73: 50-56, 1997Zhang et al. Clin Ca Res 4: 2669-76, 1998
  47. 47. Antibody Inducing VaccinesAntigen Median IgM ELISA titers after vaccination (basedon previous studies)*Median IgM ELISA titersafter vaccination*Monovalent vaccines Heptavalent vaccine 7Pre Post Ref Pre PostTn-MUC1 20 1280 1 0 640Tn (DOSM) 0 640 2 0 160TF (DPSM) 0 1280 3 0 640Globo-H 20 80 4 0 40GM2 0 160 5 0 0Lewis-y 0 0 6 0 0STn(OSM)10 640 0 805 Phase I trials, n = 70 leading to heptavalent trial, n =111 = Slovin et al. J Clin Onc 21: 2003, 2 = Gilewski et al. Clin Ca Res 6: 2000, 3 = Slovin et al. Can ImmImm 54: 2005, 4 = Gilewski et al. Proc Ac Sci 98: 2001, 5 = Helling et al. Can Res 55: 1995, 6=Sabbatini et al. Int J Ca 87: 2000, 7 = Sabbatini et al. Clin Ca Res 13: 4170-7, 2007
  48. 48. Randomized Phase II TrialGOG 0255Patients: 164 patients, 82 / armEndpoint: PFS rate 35% to 50% 12 mos (HR .66)OS, QOL, Immunogenicity (limited)Currently 125/164 patients, anticipated accrual end2013Stage II-IV at DiagnosisSecond or Third Complete ClinicalRemissionMultiple antigen conjugate-KLH +OPT-821OPT-821
  49. 49. No Consolidation Therapy0 m 21 m 28m43 mGOG178OtherMcMeekin et al. Gyn Onc 95: 2004.Second LineThird LineIs observation as good or better?
  50. 50. Ipilimumab: Mechanism of ActionT cellTCRCTLA4APCMHCB7T-cellinhibitionT cellTCRCTLA4APCMHC B7T-cellactivationT cellTCRCTLA4APCMHC B7T-cellpotentiationIPILIMUMABblocksCTLA-4CD28CD28
  51. 51. Ipilimmumab Responses After Appearanceof New Lesions3 mg/kgipilimumabQ3W X 4Pre-treatmentWeek 36: Still RegressingWeek 12: ProgressionWeek 20: RegressionNew lesionsSource: 2008ASCO Abstract#3020 Wolchok.July 2006
  52. 52. Resected Metastatic Melanoma TumorNodule of the LungWolchok J D et al. Clin Cancer Res 2009;15:7412-7420
  53. 53. 1 mg/kg nivolumab + 3 mg/kg ipilimumabWolchok et al. NEJM, in press, 2013ASCO 2013Phase I Trials: PD-1 and Ipi MelanomaPatients with advanced melanoma
  54. 54.  Surgery vs. not Standard Therapy versus Clinical Trials Standard Therapy– Platinum Resistant Recurrence• Goal of therapy is freedom from symptoms of disease ortreatment. Single agent responses are similar.• AURELIA trial shows efficacy of bevacizumab later indisease course.Ovarian Cancer and Recurrence: 2013
  55. 55. Ovarian Cancer and Recurrence: 2013 Platinum Sensitive Recurrence– Combination platinum based therapy yields superioroutcomes over single agent platinum .– PLD/carboplatin is equivalent to paclitaxel andcarboplatin– Bevacizumab prolongs PFS with gemcitabine andcarboplatin, OS may be confounded– Parp studies underway
  56. 56. Clinical Trials in Ovarian Cancer Anti-vascular Agents PARP Immune– PD-1 / ipilimmumab– Autologous vaccines– Other vaccine/immunotherapy Novel mechanisms of action– “polo like kinase inhibitor”
  57. 57. Ovarian Cancer and MaintenanceTherapy: 2013• Standard cytotoxic agents are ineffective• Novel agents (some with SD as primary endpoint)are suited for evaluation in remission population.– PARPi, bevacizumab prolonged PFS– Ab vaccines are pending– Immune targets are plentiful, others are not (HGS)– Simultaneous targeting of antigens is better– Personalized Immunotherapy

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