Il trattamento delle recidive Proposte di sviluppo in tema di neoplasie ovariche

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1 Il trattamento delle recidive Proposte di sviluppo in tema di neoplasie ovariche Nicoletta Colombo, MD Gynecologic Oncology Department 1

2 Ovarian Cancer: Second-line Therapies More than 80% of patients with ovarian cancer will receive chemotherapy as palliative treatment The probability of response to 2nd-line treatment is still mainly related to platinum-free interval Ongoing translational studies may identify biomarkers for response In platinum-sensitive patients the aim is to prolong survival In platinum-resistant patients the aim is to improve QoL; these patients particularly should be included in clinical trials 2

3 Effect of Platinum-free Interval on Response Rate Retreatment with Cisplatin-Based Regimen 60 N=14 59% 60 N=39 57% Response Rate, % N=20 33% N=39 27% Response Rate, % N=29 17% N=11 27% 0 < Months Markman >24 p< < Months Gore >24 Markman 1991 & Gore

4 Ovarian Cancer Activity of drugs in second-line setting DRUG OR (%) R (%) in PR Paclitaxel Paclitaxel weekly Epirubicin (60-110) 11 HD Epirubicin Doxorubicin 4 Oxaliplatin Ifosfamide HMM Topotecan (ph III) Topotecan c.i. 21d PLD (ph III) Etoposide oral Docetaxel 23.5 Vinorelbine 20 Gemcitabine Tamoxifen 18 (most in ER+) 5

5 Trabectedin (Yondelis ) A synthetic, marine-derived, anticancer agent originally isolated from marine Caribbean tunicate, Ecteinascidia turbinata 6

6 Trabectedin: A Distinct Mechanism of Action Unique in covalently binding the minor groove of DNA and bending the double helix towards the major groove (A) (A) Binding to DNA results in apoptosis after failure to repair DNA by cellular transcription coupled nucleotide excision repair (TC-NER) mechanisms (B) (B) Trabectedin inhibits the transcriptional activation of certain inducible genes (C) (C) Induces cell cycle arrest at G2/M and apoptosis through a p53 independent mechanism 7

7 Pooled Analysis of 3 Phase II Trials Study Dose-schedule No. Pts Krasner qwk 3h 0.58 mg/m² 147 (Br. J. Cancer 2007) Del Campo (Ann. Oncol. 2009) q3wk 3h 1.3 mg/m² vs. q3wk 24h 1.5 mg/m² Sessa (JCO 2005) q3wk 3h 1.3 mg/m² 41 Total: 294 patients 8

8 End Points Efficacy Time to progression (TTP) Response rate (investigator assessment-recist 1.0) Duration of response (DR) Toxicity Adverse events (AEs) > grade 3 AEs in patients with 1 or > 2 prior platinum-based lines 9

9 TTP in All Patients Yondelis (N=294 C=74) Censored Median 4.6 mo. 10

10 Time to Progression According to Different Variables Variable Median (mo) 95% CI No. of prior lines: 1 2 Disease category: refractory resistant 6-12 mo > 12 mo Regimen: weekly 3-weekly Infusion: 24-h 3-h

11 TTP by Platinum-free interval Resistant (N=107 C=17) Sensitive (N=187 C=57) Censored HR: p=< Median 6.0 mo. Median 2.1 mo. 12

12 TTP in Sensitive Population by Treatment Schedule (qwk vs q3wk) q_3wk (N=119 C=40) q_wk (N=68 C=17) Censored Median 6.7 mo. Median 5.1 mo. HR:0.615 p-value

13 Best Overall Response Pt Resistant (n=107) Pt Sensitive (n=187) CR 0 (0%) 20 (10.7%) PR 8 (7.5%) 48 (25.7%) CR+PR 8 (7.5%) 95% CI ( %) 68 (36.4%) 95% CI ( %) SD 46 (43%) 73 (39%) PD 50 (46.7%) 38 (20.3%) NE 3 (2.8%) 8 (4.3%) 14

14 Best Overall Response by Number of Prior Platinum-based Lines Platinum No. lines 1 line (N=199) 2 lines (N=95) Resistant Sensitive Resistant Sensitive (n=67) (n=132) (n=40) (n=55) CR+PR 95% CI 9% % % % SD 40% 39% 48% 40% 15

15 Toxicity: Worst Grade per Patient Prior one platinum-based line Prior >= 2 platinum-based line G1/2 G3 G4 G1/2 G3 G4 N % N % N % N % N % N % Haemoglobin Neutrophils Platelets SGPT/ALT Prior one platinum-based line Prior >= 2 platinum-based line G1/2 G3 G4 G1/2 G3 G4 N % N % N % N % N % N % Feb. Neutropenia Stomatitis Vomiting Fatigue Alopecia

16 CONCLUSIONS (I) Single agent trabectedin is active in both platinumresistant and particularly in platinum-sensitive recurrent ovarian cancer Three-weekly trabectedin (either 3-h or 24-h) has a higher activity than weekly trabectedin in the sensitive population Activity fully retained in patients with > 2 prior platinum-based lines 18

17 CONCLUSIONS (II) Overall safety profile was tolerable, manageable and non-cumulative Higher incidence of haematological toxicity and transaminase changes with q3wk schedules, without relevant clinical consequences Lack of alopecia, stomatitis, neurotoxicity, cardiotoxicity, HFS, hypersensitivity Similar toxicity profile in patients with 1 or >2 platinum-based lines Trabectedin is a promising new drug for the treatment of ovarian cancer 19

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19 ET743-OVA-301 An open-label, multicenter, randomized Phase 3 study comparing the combination of DOXIL /CAELYX and YONDELIS with DOXIL /CAELYX alone in subjects with advanced relapsed ovarian cancer Monk et al 33rd Congress of the European Society for Medical Oncology in Stockholm- Sept 2008 Abstract LBA4 21

20 Unique Mechanism of Action Trabectedin N2 Adduct PLD NER Trapping G2-M Arrest OVA-301 Regimen Topo II Active DNA Breaks Cell Death Cell Death 22

21 Goal and Hypothesis To identify a safe and effective combination, not containing a platinum or a taxane, to treat relapsed ovarian cancer Designed to test hypothesis that trabectedin in combination with PLD is more effective than PLD alone 23

22 Phase 3 Study Design: OVA-301 Strata: Platinum sensitivity and ECOG performance status Advanced relapsed epithelial ovarian cancer One prior regimen Measurable disease Platinum sensitive and resistant R A N D O M I S A T I O N Trabectedin 1.1 mg/m² 3 hour infusion + PLD 30 mg/m² q 3 weeks Dexamethasone Premedication PLD 50 mg/m 2 q 4 weeks Primary endpoint: PFS Secondary endpoints: OS, RR, Safety, PK, QoL 24

23 Demographics and Baseline Characteristics Race White Asian Black Other ECOG PS PS 0 / 1 PS 2 PLD n=335 77% 21% 1% 1% 97% 3% Trabectedin + PLD n=337 79% 20% 1% 1% 97% 3% Mean age (years) Platinum resistant 37% 35% Platinum sensitive PFI (mo) 6-12 PFI (mo) >12 Mean platinum free interval (months) 63% 43% 57% 65% 57% 43% Prior taxanes 81% 80% 25

24 Extent of Exposure Median total treatment duration (weeks) PLD n=335 Trabectedin+ PLD n= Median no. cycles (range) 5 (1-22) 6 (1-21) Patients with >6 cycles 24% 38% PLD dose intensity (mg/m 2 /week)

25 Safety Profile: Grade 3-4 AEs PLD n=330 n (%) Trabectedin + PLD n=333 n (%) Haematologic Neutropenia 74 (22) 210 (63) Leucopenia 32 (10) 111 (33) Thrombocytopenia 8 (2) 61 (18) Anaemia 20 (6) 45 (14) Febrile neutropenia 7 (2) 27 (8) Non-haematologic Alanine aminotransferase increased 3 (1) 103 (31) Aspartate aminotransferase increased 3 (1) 24 (7) Nausea/vomiting 18 (5) 51 (15) Fatigue 18 (5) 28 (8) 27

26 Safety Profile: Grade 3-4 AEs PLD n=330 n (%) Trabectedin + PLD n=333 n (%) Hand-foot syndrome 65 (20) 13 (4) Mucositis 36 (11) 9 (3) Neuropathy 0 (0) 1 (<1) Hypersensitivity 1 (<1) 1 (<1) Rhabdomyolysis 0 (0) 1 (<1) Congestive heart failure 1 (<1) 1 (<1) 28

27 Transaminase Elevations in Trabectedin & PLD arm Median time to onset of Grade 3/4 ~1 week Return to Grade 1 or less ~3 weeks from treatment Decrease in magnitude with succeeding cycles Decrease with steroid premedication Dose reductions (5%) and delays (4%) No discontinuations for transaminase elevation only 29

28 Safety Conclusions Adverse events consistent with toxicities seen with each agent given alone No new toxicities with combination Most common adverse events were neutropenia and increased transaminases Transient in most cases Not usually associated with serious sequelae Similar safety profile in older patients 30

29 PFS Final Analysis - Independent Oncology PLD Median=5.6 mo Trabectedin+PLD Median=7.4 mo PFS Events: 432 HR: 0.72 ( ) p= #censored:

30 PFS Final Analysis Platinum-Resistant Pts PFS events: 163 HR: 0.95 ( ) p= # censored: 65 PLD 3.7 mos Trabectedin+PLD 4.0 mos 32

31 PFS Final Analysis Platinum-Sensitive Pts 33

32 PFS Intermediate Sensitivity (PFI 6-12 mo.) Time from Randomisation (Months) 34

33 PFS Highly Sensitive (PFI >12 mo.) Time from Randomisation (Months) 35

34 Best Overall Response PLD n=335 Trabectedin + PLD n=337 p-value Independent Radiology (measurable disease) CR+PR 19% 28% Response duration; mo (95%CI) 7.7 ( ) 7.9 ( ) Independent Oncology CR+PR 19% 30% Response duration; mo (95%CI) ND* ND* Investigator CR+PR 27% 39% Response duration; mo (95%CI) 7.1 ( ) 9.0 ( ) *Not determined 36

35 Overall Survival % Subjects Alive PLD OS Events: 300 Median OS: PLD= 19.4 months Trab + PLD= 20.5 months HR (95% CI): 0.85 ( ) p-value: Trabectedin + PLD Time from Randomisation (Months) 37

36 OS Platinum Sensitive Time from Randomisation (Months) 38

37 OS Intermediate Sensitivity Time from Randomisation (Months) 39

38 Efficacy Conclusions OVA-301 demonstrates that trabectedin + PLD improved outcomes over PLD alone Progression free survival Overall Response rates Overall survival trend Enhanced effects in the platinum-sensitive stratum, particularly in patients with intermediate sensitivity Substantial delay in administration of subsequent platinum Statistically significant prolongation in both PFS and overall survival in patients with intermediate platinum sensitivity (interim analysis per protocol) 40

39 Regulatory Status Yondelis dossier extension for Ovarian Cancer submitted by PharmaMar to EMEA in December 2008 Based primarily on pivotal study OVA initial phase II trials of trabectedin monotherapy as support Now available with this indication: in combination with pegylated liposomal doxorubicin for the treatment of patients with relapsed, platinum-sensitive ovarian cancer. Dose: Trabectedin 1.1 mg/m 2 & PLD 30 mg/m 2 q3wk 41

40 Thank you! 42