CANCER DE L OVAIRE EN RECHUTE. Eric Pujade-Lauraine Hôpital Hôtel-Dieu Paris, France

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1 CANCER DE L OVAIRE EN RECHUTE Eric Pujade-Lauraine Hôpital Hôtel-Dieu Paris, France

2 When to treat? CA 125 definition of progression agreed by GCIG Doubling of CA 125 level from normal upper limit or from nadir and documented at 2 occasions (> 1 week)

3 What do patients think about CA-125 monitoring in the follow-up? Do you expect a longer survival period as a result of routine follow up? 100% 80% % 40% 20% % yes no don t know Guelten Oskay-Oezcelik et al survey of 1060 pts with ovarian cancer all primary relapsed

4 Early treatment based on CA125 level alone vs Delayed treatment Ovarian cancer in complete remission after first-line platinum based chemotherapy and a normal CA125 (N=1442) REGISTER Blinded CA125 measured every 3 months CA125>2 x upper limit of normal RANDOMISED N=529 (37%) Early treatment Clinician and patient informed N=265 Rustin G. et al, Proc Am Soc Oncol 2009 Delayed treatment Clinician not informed, treatment delayed until clinically indicated N=264

5 Proportion surviving Early versus Delayed Chemotherapy Overall time spent with good Global Health Score Overall survival HR=1.00 (95%CI ) p=0.98 Median (months) Early 7.1 Early Delayed Delayed 9.2 p=0.15 Rustin G. et al, Proc Am Soc Oncol Months since randomisation Even when CA125 rises, chemotherapy can be delayed until signs or symptoms of tumor recurrence 5

6 Is early relapse detection by routine follow-up including CA125 useful for surgery results? Patients : 99 pts asymptomatic recurrence diagnosed during routine follow-up vs 22 symptomatic recurrence Routine follow-up (n=99) Symptomatic pts (n=22) p Median PFS from initial diagnosis (months) Secondary cytoreduction surgery (%) Complete resection or < 5mm residual (%) Overall Survival from relapse (months) Overall survival from initial diagnosis N.S N.S Tanner EJ, Chi DS, Eisenhauer EL, Diaz-Montes TP, Santillan A, Bristow RE. Gynecol Oncol May;117(2):336-40

7 Recurrent ovarian cancer: population characteristics 4 th Ovarian Cancer Consensus Conference June 25 27, 2010 UBC Life Sciences Institute, Vancouver, BC Platinum-free Interval Interval from last date of platinum dose until progression Expected platinum sensitivity Progression while receiving last line of platinum based therapy or within 1 month of last platinum dose Refractory 1-6 months Resistant 6 12 months Partially sensitive >12 months Fully sensitive

8 A GiNECO study:therapy-free Interval What to and treat? Efficacy Disease: Prognostic factors/goals of treatment Survival (days) Response Rate (%) Therapy-free Interval and Treatment efficacy: a GINECO study Overall Survival /Pr Therapy-free interval (months) Response Rate PFS TFI in months Pujade-Lauraine E, et al. Proc Am Soc Clin Oncol. 2002;21: Abstract 829.

9 Recurrent ovarian cancer: population characteristics 4 th Ovarian Cancer Consensus Conference June 25 27, 2010 UBC Life Sciences Institute, Vancouver, BC Each trial will need to specify how they define the date of progression (Ca-125 alone, radiological, symptomatic). Document whether patient had maintenance/ consolidation therapy which agent and for how long. Document histological type, molecular markers (such as BRCA), and surgery for recurrent disease.

10 CA 125 Advanced Ovarian Cancer: A Chronic Disease with Multiple Relapses S carbopaclitaxel carbo- PLD carbopaclitaxel topotecan 4 months 16 months 10 months 10

11 What Are Your Most Important Goals in the Treatment of Patients With ROC? Gynecologist German Survey n = 327 Objective Platinum-Resistant Platinum-Sensitive Quality of life 37.6% 19% PFS 6.1% 15% Survival 6.7% 22.6%

12 Who to treat? - Patient & wishes Choice depends on Patient predicted fragility Age Performans status Depressive state Comorbidities

13 Treatment Considerations Choice depends on Toxicity from prior therapy Neurotoxicity Hematotoxicity Hypersentivity to previous drug Patient wish Avoid alopecia One day vs multiday infusion/course

14 Duration of response to initial platinum therapy Patient and physician preference Choice of Second-Line Therapy Previous agents used Patient s performance status Toxicities experienced in 1 st -line setting Armstrong. The Oncologist. 2002;7(suppl 5):20-28; Markman and Bookman. The Oncologist. 2000;5:26-35; Salzberg et al. Oncology. 2005;68:

15 Chemoresistant Relapse: Principles Single-agent regimens Drugs active in resistant disease (no platinum) Sequential use of agents with goal of palliation and disease control 15

16 Randomized Trials of Single Agent Versus Combination In Resistant Disease Regimens Paclitaxel vs epirubicin + paclitaxel Paclitaxel vs doxorubicin + paclitaxel Paclitaxel vs epirubicin + paclitaxel Topotecan vs topotecan + etoposide or gemcitabine Pegylated liposomal doxorubicin vs PLD + trabectidin Weekly paclitaxel (wp) vs wp + carboplatin or weekly topotecan Author Bolis et al, 1999 Torri et al, 2000 Buda et al, 2004 Sehouli et al, 2008 Monk et al, 2008 Gladieff et al, 2009 RR/PFS/OS Benefit No No No No No No

17 Resistant Relapse: single agent versus doublet - GINECO trial R A N D O M I Z A T I O N Weekly paclitaxel 80mg/m²/wk Weekly paclitaxel 80mg/m²/wk Carboplatin AUC 5,q28d Weekly paclitaxel 80mg/m²/wk Weekly Topotecan 3 mg/m²/wk Gladieff L et al ASCO 2009

18 Response rate (% of patients) wp (N=57) wp+cb (N=51) wp+wt (N=57) Response (complete + partial) 35,1 37,3 38,6 Stable disease 22,8 29,4 22,8 Progression 26,3 25,5 24,6 Non evaluable 15,8 7,8 14 Gladieff L et al ASCO 2009

19 Single agent versus doublet - trial- PFS results GINECO wp wp+wt wp+c p=0,681 ASCO 2009

20 Resistant Disease: Available Agents Agent No. of Patients Response Rate PLD (Caelyx) % Topotecan % Paclitaxel % Oral etoposide % Gemcitabine % Hexamethylmelamine % Oxaliplatin % Vinorelbine 71 23% PLD = Pegylated liposomal doxorubicin Gore M. ASCO Education Booklet

21 CAELYX vs Gemcitabine in ROC: Outcomes Global QoL score Overall Survival Global QoL Score PLD GEM *P value <.05 * * Baseline Ferrandina et al. J Clin Oncol. 2008;26:

22 Canfosfamide vs CAELYX or Topotecan: Overall Survival Platinum-resistant or refractory disease (1st-line platinum pre-treated patients) and had failed or progressed after 2nd-line therapy with CAELYX or topotecan Vergote et al. Eur J Cancer. 2009;45:

23 Platinum-sensitive relapse (PFI > 6 months)

24 DESKTOP-1: Surgical Endpoint of surgery at relapse survival probability Initial surgery Surgery at relapse 100% 75% No residuals No residuals 50% s 1-10 mm 25% s 1-10 mm >10 mm 0 >10 mm 0% months & AGO-OVAR OVAR

25 DESKTOP-1: predictor of complete resection- Multivariate Analysis Variables HR (95% CI) P-value PS ECOG 0 > ( ) <.001 Residual disease (after 1st surgery) 0 mm > 0 mm ( ).009 Ascites (cut-off 500 ml) < 500 ml > 500 ml ( ).003 * Initial FIGO-stage I/II vs III/IV alternatively, if residual disease after 1st surgery is unknown & AGO-OVAR OVAR 25

26 DESKTOP-2: Surgical results Frequency of complete resection by applying AGO Score Score positive Score positive Score positive all patients 1st relapse 2nd relapse AGO score could predict complete resection in at least 2 out of 3 patients

27 Carboplatin (Cb) Combo vs Carboplatin Alone Randomized Trials in Platinum Sensitive Disease Cb + epirubicin vs Cb Bolis pts PFS NS 0S NS Cb + paclitaxel vs Cb Icon4 AGO pts S S Cb + paclitaxel vs Cb Gonzales-Martin pts S S Cb + gemcitabine vs Cb Pfisterer pts S NS Cb + PLdoxorubicin vs Cb Alberts pts NS S 27

28 ICON4 Moderate or severe toxicities Neurological (grade 2) Mucositis (grade 2) Nausea and vomiting (grade 2) Alopecia (grade 2) Haematological* Infection* Renal* Plat (n = 410) 1% 6% 40% 25% 46% 14% 9% Pac-Plat (n = 392) 20% 7% 35% 86% 29% 17% 8% * toxicity not graded, but led to treatment modification or interruption 28

29 GCIG Trial Gem/Carbo vs. Carbo Hematologic Toxicity Gem/Carbo Carbo p-value Grade 3+4 (% of pts) < Anemia < Thrombocytopenia < Neutropenia < Febrile Neutropenia n.s. Infections n.s. G(M)-CSF < Parenteral Antibiotics n.s. RBC < 0.001

30 GCIG Intergroup CALYPSO Trial Design International, Intergroup, Open-label, Randomized Phase III Study Ovarian cancer in late relapse (> 6 months) after 1st- or 2nd-line platinumbased therapy (previous taxane required) Stratification Therapy-free interval (6-12 mo vs > 12 mo) Measurable disease (yes vs no) Center R N=976 Experimental arm: CD Carboplatin AUC 5 d 1 CAELYX 30 mg/m 2 IV d 1 Q 28 days x 6 courses* Control arm: CP Carboplatin AUC 5 d 1 Paclitaxel 175 mg/m 2 IV d 1 Q 21 days x 6 courses* *or progression in patients with SD or PR Pujade-Lauraine E, et al. J Clin Oncol In press.

31 CALYPSO Hematologic Toxicity Toxicity, grade(gr) Neutropenia CD (n=464) CP (n=500) Number of patients (%) P Value Grade (31) 121 (24) Grade 4 20 (4) 108 (22) <0.01 Febrile neutropenia, gr (2) 21 (4) NS Infection, gr (3) 14 (3) NS Thrombocytopenia, gr (16) 31 (6) <0.01 Bleeding, gr (0.6) 0 (0) NS Anemia, gr (8) 27 (5) NS NS=not significant. Pujade-Lauraine E, et al. J Clin Oncol.2009;27:18s. Late-breaking Abstract 5509.

32 CALYPSO Non-Hematologic Toxicities CD (n=466) CP (n=501) Grade 2 Grade3/4 Grade 2 Grade 3/4 Nausea/vomiting* 31% 4% 20% 4% Arthralgia/myalgia* 4% 0% 18% 1% Hand-foot syndrome* 11% 2% 2% 0% Mucositis* 13% 2% 6% 1% Cardiac disorders 2% 1% 3% 1% Alopecia* 7% - 84% - Neurotoxicity* 4% 1% 24% 4% Hypersensitivity* 3% 2% 10% 9% *P< Pujade-Lauraine E, et al. J Clin Oncol.2009;27:18s. Late-breaking Abstract 5509.

33 CALYPSO Progression-Free Survival (ITT) Median follow-up: 22 months Number of events: 824 (85%) CD CP Median PFS, mo HR (95% CI) 0.82 (0.72, 0.94) Log-rank p-value (superiority) P-value (non-inferiority) <0.001 Pujade-Lauraine E, et al. J Clin Oncol.2010.

34 CALYPSO Subgroup Analysis: PFS in Partially Platinum Sensitive Population CD N= 165 CP N= 183 Median PFS, mo HR (95% CI) 0.73 (0.58, 0.90) Log-rank p-value (superiority) P-value (non-inferiority) <0.001 Vasey P, et al. ECCO 15 and 34th ESMO Multidisciplinary Congress Late-breaking Abstract 18.

35 CAELYX +/- Trabectedin in ROC: OVA 301 Study of a non-platinum combination PFS Full Analysis Set Phase III trial in women with relapsed ovarian cancer following previous platinumbased standard treatment (n=672) The combination of CAELYX and trabectedin compared to CAELYX monotherapy Significantly improved PFS (by independent radiology review), with a 21% reduction in risk of progression Significantly improved response rate in patients with platinumsensitive ROC PFS in PFI > 6 Months Population Monk et al. J Clin Oncol 2010

36 Mean ALT/ULN Mean ALT Among All Patients During Treatment With Trabectedin + PLD ALT elevation leading to: Dose Reduction: 18 (5%) Dose Delay: 12 (4%) Cycle n=

37 PFS Intermediate Sensitivity (PFI 6-12 mo) Independent Radiology (n=208) PFS events= 124 HR=0.65 ( ) p= # Censored: 84 PLD 5.5 mo Trabectedin+PLD 7.4 mo Time from Randomisation (Months) PFI = Platinum Free Interval

38 Extending platinum-free internal (PFI) in partially platinum-sensitive patients Poster # ASCO 2010 Andres Poveda et al.

39 Progression-free survival in phase III trials (6-12 months) Treatment Group/Name Median PFS, mo Carboplatin-PLD CALYPSO 9.4 Carboplatin-paclitaxel CALYPSO 8.8 Carboplatin-gemcitabin AGO-GCIG 7.9 Trabectedin-PLD OVA PLD OVA Carboplatin AGO-GCIG 5.2 PLD = pegylated liposomal doxorubicin

40 Generally Accepted Guideline for Chemotherapy at Recurrence Platinum Resistant Partially Platinum-Sensitive Fully Platinum-Sensitive < 6 Months 6-12 Months > 12 Months Non-platinum single agent (PLD) Options: PLD + Carboplatin PLD + Trabectedin Carboplatin combination (PLD, Gemcitabine or Paclitaxel)

41 Faire du neuf avec de vieux pôts Nanoparticle albumin-bound (Nab)-paclitaxel (Abraxane) A phase II evaluation of nab-paclitaxel in the treatment of recurrent peritoneal cancer: a GOG study Nab weekly 23,4% N=47 TXL hebdo 20,9% N=48 TXT 22,4% N=58 Poster #5010 ASCO 2010 R. L. Coleman et

42 Faire du neuf avec de vieux pôts NKTR-102 (PEG-irinotecan) Women with platinum resistant/refractory OC 145 mg/m 2 q14d (n= 36) 145 mg/m 2 q21d (n=35) q14d q21d GCIG response rate 29% 38% Grade 3 diarrhea 25% 14% dehydratation 22% 6%

43 % of therapy Empirically derived cytoablative chemotherapy Genetically specific molecular therapy Year From Edmonson JH. Gynecol Oncol 2000; 79:

44 Anti-angiogenic agents

45 Randomized trials of bevacizumab in platinum-sensitive recurrent ovarian cancer Group Chemotherapy Bevacizumab Patients (N) GOG (213) Paclitaxel/ carboplatin OCEANS Gemcitabine / carboplatin Concurrent and maintenance (2- arm) Concurrent and maintenance (2- arm)

46 A phase II study of bevacizumab with nab-paclitaxel in patients with platinumresistant primary peritoneal carcinoma Mean CA= N= CA-125, by Cycle N=47 Median PFS of 8.1 months and OS of months compares favorably to other published reports in this population 200 N=42 N= N=32 0 N=17 N=11 N=8 N=6 N=5 N=3 N=2 N=1 N=1 N=1 N=1 BL Cycle Poster # ASCO 2010 Todd D. Tillmanns et al.

47 AURELIA: Avastin Use in REsistant ovarian epithelial cancer Patients with platinum-resistant ovarian cancer n=330, randomized 1:1 Arm 1 Chemotherapy choice of paclitaxel, topotecan or PLD If PD, unacceptable toxicity or patient request for withdrawal Arm 2 Chemotherapy + bevacizumab* If PD, unacceptable toxicity or patient request for withdrawal bevacizumab Standard of care Standard of care Survival follow up

48 A Maintenance VARGATEF (BIBF 1120) Approach to Ovarian Cancer Randomized phase II trial Relapsed ovarian cancer, responded to second/third/ fourth-line chemo, which had been started <12 months from previous chemo R A N D O M I Z E BIBF mg bd for up to 36 weeks placebo n = 43 n = 40 Completed 36 weeks PFS at 36 weeks % ( ) 0 2.9% (0-8.4) HR for PFS diff is 0.68 (95% ) Grade 3/4 adverse events: 61% vs 28% with frequent elevated transaminases on BIBF 1120 (43%) but only 2 patients discontinued Conclusion:BIBF 1120 could delay disease progression in patients with previously responding ovarian cancer Ledermann JA, et al. J Clin Oncol. 2009;27(15S): Abstract 5501.

49 CEDIRANIB in Platinum-Sensitive Relapsed Ovarian Cancer (ICON6) Platinum-sensitive relapse, >6 months interval, one prior treatment n = 2000 Primary outcome: OS (hazard ratio 0.75) R A N D O M I Z E (Paclitaxel)-carboplatin x 6 and concurrent placebo (Paclitaxel)-carboplatin x 6 and concurrent cediranib 20 mg daily, then maintenance placebo for 18 months, or until PD (Paclitaxel)-carboplatin x 6 and concurrent cediranib 20 mg daily, then maintenance cediranib for 18 months, or until PD

50 Ciblage du récepteur des folates

51 Folate-receptor targeted imaging (EC20) identifies FR+ tumors prior to FR-targeted therapy

52 Farletuzumab Humanized MoAb to FR-α Induces ADCC Phase II: design Patients with EOC experiencing first platinum-sensitive relapse After first remission of 6 18 months duration Evaluable disease by CA-125 carbo/taxane regimen plus farletuzumab (6 cycles) Farletuzumab maintenance therapy for responders Armstrong D K, et.al. EJC Supplements 2009; 7(2): Abstract O-8000 and presentation

53 Cumulative Probability Progression-Free MORAb Phase II: results 44 evaluable 39 achieved normal CA-125 (88.6%) 9 have second progression-free interval first (20.5%) Armstrong D K, et.al. 5 did not normalize CA-125 (11.4%) 3 achieved Rustin response (6.8%) PFS Time Since First Dose of Combination Therapy (Months)

54 EC145 EC145 is a conjugate of folate and the vinca alkaloid desacetylvinblastine hydrazide (DAVLBH) EC145 binds to the folate receptor FR and delivers DAVLBH into the cell via endocytosis

55 EC-FV-04 (PRECEDENT) Study Design Women with platinum-resistant OC who had received no more than 2 precious therapies Randomized PLD 50 mg/m 2 q 4 weeks PLD 50 mg/m 2 q 4 weeks + EC mg on Weeks 1 and 3 (4 week cycle)

56 EC-FV-04 (PRECEDENT) Study Design Response rate EC145/PLD (n=54) PLD (n=27) Complete Response (CR) 2 0 (0%) 0 (0.0%) Partial Response (PR) 2 9 (16.7%) 4 (14.8%) Stable Disease (SD) 2 33 (61.1%) 12 (44.4%) PFS Findings EC145 + PLD (n=60) PLD (n=31) P-value Hazard Ratio PFS 24.0 weeks 11.7 weeks

57 Inhibition de PARP poly (ADP-ribose) polymerase

58 Proposed mechanism of hypersensitivity of BRCA1- or BRCA2-deficient cells to PARP-1 inhibitors PARP-1 SSB Repair SSB BRCA1 or 2 defect PARP Inhibition Homologous Recombination Error-free Collapsed Replication Fork Slide courtesy of Thomas Helleday

59 Clinical Trial Of Olaparib Results In Ovarian Cancer Subset Patient total: 50 (46 evaluable) Median age (range): 52 (37-80) years Median no. of prior regimes: 3 (1-8) BRAC ½: 41/8 Plat. refractory/resistant/sensitive: 13/22/11 (evaluable) dose received: 100 mg bd mg bd mg bd mg bd 1 Fong DN, et al. N Engl J Med. 2009;361(2):

60 Response to Olaparib by Platinum-Free Interval Total Platinum Sensitive Platinum Resistant Platinum Refractory No. of evaluable patients Responders by RECIST 14 (30.4%) 6 (46%) 8 (26%) 0 (0%) Responders by either RECIST or GCIG criteria Median duration of response in weeks (range) 20 (43.5%) 8 (62%) 10 (45.5%) 2 (18%) 31 (10-96) 31 (16-96) 31 (30-32) 39 (27-51) Fong DN, et al. N Engl J Med. 2009,

61 Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer Recurrent ovarian cancer 1 prior regimen Cohort 1 Olaparib 400 mg po BID N=33 Confirmed BRCA mutation Sequential Cohorts Measurable Disease ECOG PS 0 2 Cohort 2 Olaparib 100 mg po BID N=24 Audeh MW, et.al. J Clin Oncol 2009; 27 (Suppl 15): Abstract 5500 Study ID: KU36-58; D0810C00008.

62 Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer RECIST response rate, n (%) Olaparib 400 mg po BID N=33 Olaparib 100 mg po BID N=24 11 (33) 3 (13) Responders by RECIST and/or GCIG criteria, n (%) 20 (61) 4 (17) Duration of response Median (days) Audeh MW, et.al. J Clin Oncol 2009; 27 (Suppl 15): Abstract 5500 Study ID: KU36-58; D0810C00008.

63 Olaparib monothérapie dans le cancer de l ovaire et du sein en rechute mutés ou non par BRCA1 BRCA 1 N=10 RR=40% Sereux haut grade non muté N=54 RR=26% CSS #3002 ASCO 2010 K. A. Gelmon et al.

64 Conclusion Treatment at relapse require a personalized approach Surgery should be considered in patient with sensitive relapse Chemotherapy : single agent in resistant/refractory disease and carboplatin combo in platinum-sensitive disease 2 drug classes are expected to significantly modify patient outcome in relapse in the next future Anti-angiogenic agents Anti-PARP (in high grade serous)