Il trattamento delle recidive
Proposte di sviluppo in tema di
neoplasie ovariche
Nicoletta Colombo, MD
Gynecologic Oncology
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
Retreatment with Cisplatin-Based Regimen
0 10 20 30 40 50 60
Response Rate, %
<12 13-24 Months
>24
0 10 20 30 40 50 60
Markman 27%
33%
59%
17%
27%
57%
Gore N=39
Response Rate, %
N=20
N=14
N=29
N=11
N=39
<12 13-24 Months
>24 p<0.025
Effect of Platinum-free Interval on Response Rate
Ovarian Cancer
Activity of drugs in second-line setting
DRUG OR (%) R (%) in PR
Paclitaxel 19–40 6.7–20
Paclitaxel weekly 29 15
Epirubicin (60-110) 11
HD Epirubicin 20 12
Doxorubicin 4
Oxaliplatin 21–30 10–15
Ifosfamide 20 12
HMM 20–26 14
Topotecan (ph III) 28.8 6.5
Topotecan c.i. 21d 35–38
PLD (ph III) 28.4 12.3
Etoposide oral 35 27
Docetaxel 23.5
Vinorelbine 20
Gemcitabine 29 6–17
Trabectedin (Yondelis ® )
A synthetic, marine-derived, anticancer agent originally isolated from marine Caribbean tunicate, Ecteinascidia turbinata
Trabectedin: A Distinct Mechanism of Action
(A)
(B)
(C)
•
Unique in covalently binding the minor groove of DNA and bending the double helix towards the major groove (A)•
Binding to DNA results in apoptosis after failure to repair DNA by cellular transcription coupled nucleotide excision repair (TC-NER) mechanisms (B)•
Trabectedin inhibits the transcriptional activation of certain inducible genes (C)Induces cell cycle arrest at G2/M and apoptosis through a p53 independent mechanism
Pooled Analysis of 3 Phase II Trials
Study Dose-schedule No. Pts
Krasner
(Br. J. Cancer 2007)
qwk 3h 0.58 mg/m² 147
Del Campo
(Ann. Oncol. 2009)
q3wk 3h 1.3 mg/m² vs. q3wk 24h 1.5 mg/m²
53 53 Sessa
(JCO 2005)
q3wk 3h 1.3 mg/m² 41
Total: 294 patients
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
TTP in All Patients
Median 4.6 mo.
Yondelis (N=294 C=74)
Censored
Time to Progression According to Different Variables
Variable Median (mo) 95% CI
No. of prior lines: 1
≥ 2
5.3 6.2
4.1- 6.7 5.7- 7.9 Disease category: refractory
resistant 6-12 mo
> 12 mo
1.8 2.3 5.3 6.9
1.6- 4.2 1.7- 3.5 3.8- 6.1 5.6-10.8 Regimen: weekly
3-weekly
5.1 6.7
3.1- 6.4 5.6- 7.4 Infusion: 24-h
3-h
7.2 6.6
5.9-11.5 5.0- 7.4
HR: 0.436 p=<0.0001
Median 6.0 mo.
Median 2.1 mo.
Resistant (N=107 C=17) Sensitive (N=187 C=57) Censored
TTP by Platinum-free interval
TTP in Sensitive Population by Treatment Schedule (qwk vs q3wk)
HR:0.615 p-value 0.0082 Median 5.1 mo.
Median 6.7 mo.
q_3wk (N=119 C=40)
q_wk (N=68 C=17)
Censored
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 (3.3-14.2%)
68 (36.4%)
95% CI (29.5-43.7%)
SD 46 (43%) 73 (39%)
PD 50 (46.7%) 38 (20.3%)
NE 3 (2.8%) 8 (4.3%)
Best Overall Response
Platinum No. lines
1 line (N=199) ≥ 2 lines (N=95)
Resistant (n=67)
Sensitive (n=132)
Resistant (n=40)
Sensitive (n=55)
CR+PR
95% CI
9%
3.4-18.5
33%
24.7-41.3
5%
0.6-16.9
46%
32.0-59.4
SD
40% 39% 48% 40%
Best Overall Response by Number
of Prior Platinum-based Lines
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 157 79.7 5 2.5 - - 81 85.3 6 6.3 1 1.1
Neutrophils 80 40.6 17 8.6 28 14.2 43 45.3 15 15.8 17 17.9
Platelets 35 17.8 8 4.1 2 1.0 27 28.4 5 5.3 1 1.1
SGPT/ALT 102 51.8 55 27.9 13 6.6 47 49.5 38 40.0 4 4.2
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 - - 2 1.0 1 0.5 - - 1 1.1 1 1.1
Stomatitis 16 8.0 - - - - 4 4.2 - - - -
Vomiting 74 37.2 16 8.0 - - 43 45.3 9 9.5 - -
Fatigue 101 50.8 18 9.0 2 1.0 63 66.3 6 6.3 - -
Alopecia 14 7.0 1 0.5 - - 6 6.3 - - - -
Toxicity: Worst Grade per Patient
CONCLUSIONS (I)
Single agent trabectedin is active in both platinum- resistant 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
CONCLUSIONS (II)
Overall safety profile was tolerable, manageable and non-cumulative
•
Higher incidence of haematological toxicity andtransaminase 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
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
Unique Mechanism of Action
Cell Death NER
Trapping Trabectedin
N2 Adduct
G2-M Arrest
Topo II Active
Cell Death PLD
DNA Breaks
OVA-301
Regimen
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
Phase 3 Study Design: OVA-301
Strata:
Platinum sensitivity
and ECOG performance
status
R A N D O M I S A T I O N
Trabectedin 1.1 mg/m ² 3 hour infusion +
PLD 30 mg/m ² q 3 weeks
Dexamethasone Premedication
Trabectedin 1.1 mg/m ² 3 hour infusion +
PLD 30 mg/m ² q 3 weeks
Dexamethasone Premedication
PLD 50 mg/m
2q 4 weeks PLD 50 mg/m
2q 4 weeks
Advanced relapsed epithelial ovarian cancer
• One prior regimen
• Measurable disease
• Platinum sensitive and resistant
Demographics and Baseline Characteristics
PLD n=335
Trabectedin + PLD n=337
Race White Asian Black Other
77%
21%
1%
1%
79%
20%
1%
1%
ECOG PS PS 0 / 1 PS 2
97%
3%
97%
3%
Mean age (years) 58 57
Platinum resistant 37% 35%
Platinum sensitive PFI (mo) 6 - 12 PFI (mo) >12
63%
43%
57%
65%
57%
43%
Mean platinum free interval
(months) 13.3 10.6
Prior taxanes 81% 80%
Extent of Exposure
PLD n=335
Trabectedin+
PLD n=337 Median total treatment duration
(weeks) 20 19
Median no. cycles (range) 5 (1-22) 6 (1-21)
Patients with >6 cycles 24% 38%
PLD dose intensity (mg/m
2/week) 11.7 8.3
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)
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)
Safety Profile: Grade 3-4 AEs
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
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
PFS Final Analysis - Independent Oncology
PFS Events: 432 HR: 0.72 (0.60-0.88) p=0.0008
#censored:
239 Trabectedin+PLD
Median=7.4 mo PLD
Median=5.6 mo
PFS Final Analysis – Platinum-Resistant Pts
Trabectedin+PLD 4.0 mos
PLD 3.7 mos
PFS events: 163 HR: 0.95 (0.70-1.30) p=0.7540
# censored: 65
PFS Final Analysis – Platinum-Sensitive Pts
PFS – Intermediate Sensitivity (PFI 6-12 mo.)
PFS – Highly Sensitive (PFI >12 mo.)
Time from Randomisation (Months)
Best Overall Response
PLD n=335
Trabectedin + PLD
n=337 p-value Independent Radiology (measurable disease)
CR+PR 19% 28% 0.008
Response duration; mo (95%CI) 7.7 (6.5-9.0) 7.9 (7.4-9.2) Independent Oncology
CR+PR 19% 30% 0.0009
Response duration; mo (95%CI) ND* ND*
Investigator
CR+PR 27% 39% 0.0010
Response duration; mo (95%CI) 7.1 (5.8-7.6) 9.0 (7.6-10.1)
% Subjects Alive
0 3 6 9 12 15 18 21 24 27 30 33 36
Time from Randomisation (Months)
100 90 80 70
50 40 30 20 10 0
60 Trabectedin + PLD
PLD
Overall Survival
OS Events: 300
Median OS: PLD= 19.4 months
Trab + PLD= 20.5 months HR (95% CI): 0.85 (0.67-1.06)
p-value: 0.1506
Time from Randomisation (Months)
OS – Platinum Sensitive
Time from Randomisation (Months)
OS – Intermediate Sensitivity
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)
