Trabectedina + PLD nel trattamento del carcinoma ovarico Nicoletta Colombo Universita Milano Bicocca Istituto Europeo Oncologia Milano
The old definition of Recurrent Ovarian Cancer P R I M A R Y T H E R A P Y 0 3 6 12 18 24 Refractory Resistant Partially Sensitive Sensitive months Pisano C, et al. Ther Clin Risk Manag. 2009;5(5):421-426. Gadducci A, et al. Anticancer Res. 2001;21(5):3525-3533.
5th OCCC of the GCIG: Factors for Defining Recurrent Population and Selecting Therapy in Clinical Practice Treatment-free interval (TFI) TFIp (platinum) TFInp (nonplatinum), TFIb (biological agent to be specified) Histological type BRCA status (gbrca and sbrca) Type of prior therapy (anti-angiogenic agents, PARP inhibitors, chemotherapy, and others) Number of prior lines of chemotherapy Presence or absence of symptoms and type (eg, ascites, abdominal symptoms, pain, performance status) Other factors to be considered: Tumor volume and previous surgical outcome 5th Ovarian Cancer Consensus Conference (OCCC) of the Gynecologic Cancer InterGroup: Recurrent Disease. Wilson MK, et al. Ann Oncol. 2016.
Histotype Treatment-free Interval p = Platinum np = non-platin b = biological Previous agents used: PARP i, Bevacizumab Patient preference and expectation Treatment of relapse: much more than DDPfree interval Symptoms Urgent response needed? BRCA status Toxicities N prior lines
D2 What are the control arms for clinical trials in recurrent ovarian cancer In patients where platinum is not an option a control arm can include a non-platinum drug as a single agent or in combination.
Non-platinum single agent in partially platinum-sensitive (TFIp 6-12 m) is inferior to platinum combination MITO-8 R A N D O M PBC* 1:1 NPBC PD PD Probability of Overall Survival NPBC** PBC Primary Endpoint: Overall Survival *Pt-based Chemotherapy: Carboplatin + Paclitaxel or Carboplatin + Gemcitabine (in case of neurotoxicity at baseline) **Non-Pt-Based Chemotherapy: PLD or other approved single agents *Pt-based Chemotherapy: Carboplatin + Paclitaxel or Carboplatin + Gemcitabine (in case of neurotoxicity at baseline) 0.00 0.25 0.50 0.75 1.00 Number at risk PBC->NPBC NPBC->PBC Arm Median 95%CI (m) PBC- 24.5 22.4- >NPBC 33.6 NPBC- 21.8 16.3- >PBC 29.3 Adjusted* HR 1.38; 95%CI 0.99-1.94 p=0.06 * By line of treatment, residual disease and size of centre 0 6 12 18 24 30 36 42 48 54 60 66 72 Months 108 102 92 70 45 31 21 16 10 5 3 3 3 107 90 71 52 34 23 13 10 6 5 5 1 1 S. Pignata et al. ASCO 2016
OVA-301 (PFI 6-12): OS 1.0 0.9 0.8 0.7 N=214 Events/censored: 177/37 HR: 0.64 (0.47-0.86) p=0.0027 Cumulative probability 0.6 0.5 0.4 Trabectedin+PLD Median = 22.4 months 0.3 0.2 0.1 PLD Median = 16.4 months 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Time (months) Unplanned ad hoc analysis. In the subgroup with PFI between 6 and 12 months trabectedin+pld has shown a 6-months improvement in median survival relative to single-agent PLD. Monk BJ, et al. Eur J Cancer. 2012; 48:2361-68
Why a patient with platinum sensitive recurrent ovarian cancer should receive a nonplatinum therapy?
When Platinum is not an option? Persistent platinum toxicity: Allow recovery from prior neuropathy Patients unsuitable to platinum for prior hypersensitivity reactions Avoid hypersensitivity reactions No or very short response to platinum Too many lines of prior platinum Sequence effect: why trabectedin is different from other drugs?
Why trabectedin/pld if platinum is not an option? Activity of trabectedin in ovarian cancer
Trabectedin effects 1.Trabectedin interacting at DNA level DNA binding at Minor Groove Double Strand Breaks Conformation of Ternary Complexes Cell Cycle Arrest Growth Inhibition Cell Death Transcription Modulation of Specific Genes 1. D Incalci, Galmarini, Molecular Cancer Therapeutics 2010;2. Allavena et al, Cancer Research 2005; 3. Germano et al, Cancer Research 2010; 4. Germano et al, Annals of Medicine 2011
Trabectedin effects 2. Trabectedin effects on tumor microenvironment Selective cytotoxicity on tumor stroma macrophages 1,2 Inhibition of angiogenic factors and reduction of number of vessels 3,4,5 INHIBITION Tumor Growth Angiogenesis Tumor Invasion & Metastases Selective inhibition of inflammatory mediators 1,3,4,5 Epithelial Mesenchimal Transition (EMT)? 1. D Incalci, Galmarini, Molecular Cancer Therapeutics 2010; 2. Allavena et al, Cancer Research 2005; 3. Germano et al, Cancer Research 2010; 4. Germano et al, Annals of Medicine 2011; 5. Germano G, et al. Cancer Cell. 2013;23:249-262
Clinical Development of Trabectedin: Pooled Analysis of 3 Phase II Trials in OC Activity fully retained in patients with >2 prior platinumbased lines CR+PR 95% CI Platinum No. Lines 1 Line (N=199) 2 Lines (N=95) Resistant (n=67) 9% 3.4-18.5 Sensitive (n=132) 33% 24.7-41.3 Resistant (n=40) 5% 0.6-16.9 Sensitive (n=55) 46% 32.0-59.4 SD 40% 39% 48% 40% del Campo J, et al. Med Oncol. 2013;30:435. 13
Clinical Data to Support Trabectedin + PLD as Non-Platinum Option Trabectedin in the treatment of Relapsed Ovarian Cancer: Pivotal Phase III Clinical Trial OVA-301 Monk B, et al. J Clin Oncol. 2010;28:3107-14.
Trabectedin: OVA-301 Platinum Sensitive Stratum (PFI > 6 mo.) PFS OS Radiologically Measurable Disease Independent Radiology *HR and p-value for treatment comparison based on Cox regression analysis after adjustment for key prognostic factors (ECOG PS, PFI [continuous], race, baseline CA-125, age, baseline liver/lungs involvement and prior taxane). Unplanned ad hoc analysis. Monk B, et al. J Clin Oncol. 2010;28:3107-14. Monk B, et al. Eur J Cancer. 2012;48:2361-8. Poveda A, et al. Cancer Treat Rev. 2014;40:366-75.
Trabectedin: OVA-301 OS PPS Stratum (PFI = 6-12 mo.) 1.0 0.9 0.8 0.7 Events/censored: 177/37 HR: 0.64 (0.47-0.86) p=0.0027 (log-rank) Cox regression: HR*: 0.65 (0.48-0.88) p=0.0056 Cumulative probability 0.6 0.5 0.4 0.3 0.2 PLD Median=16.4 months Trabectedin+PLD Median=22.4 months 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Unplanned ad hoc analysis. Time (months) Patients at risk *HR and p-value for treatment comparison based on Cox regression analysis after adjustment for key prognostic factors (ECOG PS, PLD 91 85 78 66 58 50 37 30 24 18 17 16 13 12 11 7 5 4 3 2 0 PFI [continuous], race, baseline CA-125, age, baseline liver/lungs involvement and prior taxane) T+PLD 123 116 110 103 96 91 79 62 55 50 43 37 33 29 23 16 11 9 8 0 0 Monk B, et al. Eur J Cancer. 2012;48:2361-8; Poveda A, et al. Cancer Treat Rev. 2014;40:366-75.
Trabectedin: OVA-301 Safety Profile Hematologic Grade 3-4 AEs >5% Incidence Clinically relevant PLD n=330 (%) Trabectedin+PLD n=333 (%) Neutropenia/Febrile neutropenia 22/2 63/7 Thrombocytopenia 2 18 Anemia 6 14 Non-hematologic Alanine aminotransferase increased 1 31 Aspartate aminotransferase increased 1 7 Vomiting/Nausea 2 / 2 10/9 Fatigue 3 6 Hand-foot syndrome 20 4 Mucosal inflammation/stomatitis 6/5 2/1 Other events of interest: Alopecia (any grade 2) 44 (13) 40 (12) Monk B, et al. J Clin Oncol. 2010;28:3107-14. AEs, adverse events; PLD, pegylated liposomal doxorubicin.
Trabectedin: OVA-301 Quality of Life 100 90 80 QLQ-C30 Global Health Status Scale Mean Score Over Time - All Randomized Subjects Mean with 95% CI 70 60 50 40 30 20 10 --- PLD --- Trabectedin +PLD 0 Baseline C3 C5 C7 C9 C11 Krasner CN, et al. J Clin Oncol. 2009;27( Suppl; abstract 5526)
Trabectedin/PLD efficacy in platinum-sensitive patients without achieving complete response to previous platinum 41.4% ORR in the trabectedin + PLD arm more than double than with PLD alone: Trabectedin/PLD PLD p-value Overall response rate (ORR) 38.0% 16.5% 0.0014 Disease control rate (ORR + SD 3 months) 71.7% 56.5% 0.0414 Vergote I, et al. Int J Gynecol Cancer. IGCS International Gynecologic Cancer Society, 14th Biennial Meetingvol. 2012; 22(8 Supl3):225 (oral presentation)
Patients treated with >2 platinum lines Is the efficacy of trabectedin/pld in platinum-sensitive ovarian cancer observed at any relapse? A recent retrospective analysis in 34 heavily pretreated patients (median number of previous lines, 3; range, 2-10) showed consistent results with those observed in the second line setting: 2 Global population (N=34) ORR: 32.4% Median PFS: 6.1 months Median OS: 16.3 months Intermediate platinum sensitivity (PFI<1; N=22) ORR: 40.9% Median PFS: 6.8 months Median OS: 20.8 months 1. Sehouli J, et al. Future Oncol. (2013) 9(12 Suppl. 1), 37 39; 2. Nicoletto MO. et al. Tumori. 2015 Sep-Oct;101(5):506-10
Patients treated with >2 platinum lines Data in context: OVA-301 (2 nd line) Retrospective analysis (3 rd line and beyond) Trabectedin + PLD activity appears to be unrelated with the number of previous lines and is maintained when administered as a third or further chemotherapy line. Nicoletto MO. et al. Tumori. 2015 Sep-Oct;101(5):506-10
So far Trabectedin is an active drug in recurrent, platinum-sensitive ovarian cancer. It maintains its activity even in heavily pretreated patients It is associated with an acceptable safety profile and particularly is lacking the limiting toxocities of platinum ( neurotoxicity and hypersensitivity reactions)
A careful Strategic Planning is needed
The use of trabectedin as a strategic option in the treatment of ROC 25
Sequence Effect Hypothesis: May Trabectedin Resensitize Ovarian Cells to Next Platinum? Solid tumor NER-proficient cell sensitive to trabectedin, reduced sensitivity to platinum NER-deficient cell sensitive to platinum, reduced sensitivity to trabectedin 26 Trabectedin Tumor at relapse Increased sensitivity to Pt
Preclinical Evidence: In Vitro Ovarian carcinoma cells Parental cells Trabectedin-resistant cells A. Trabectedin cytotoxic effect Trabectedin-resistant cell lines were 6- fold more resistant to trabectedin as compared to parental cells B. Cisplatin cytotoxic effect Trabectedin-resistant cell lines were 11-fold more sensitive to cisplatin than the parental cell lines Adapted from D Incalci M, et al. Mol Cancer Ther. 2013;12:C93
Preclinical Evidence: In Vivo Tumor Xenograft Parental Cell Line Trabectedin-Resistant Cell Line Vehicle (saline): q7d 3 i.v. Cisplatin 5 mg/kg: q7d 3 i.v. Xenografts from the trabectedin-resistant ovarian cancer cell line were more sensitive to cisplatin T/C 18% (where T and C are respectively the mean tumor weight of cisplatin-treated and control groups) compared with the parental cell line, T/C 64.2% These results provide the rationale for sequential use of trabectedin and platinum compounds in ovarian cancer Adapted from Colmegna B, et al. Drug Discov Today Technol. 2014;11:73-79.
Trabectedin Selectively Suppresses Inflammatory Cytokines 30 20 10 0 CCL2 * * ** Ctrl 1.2 2.5 5 500 250 0 IL-6 * ** Ctrl 2.5 5 400 200 0 VEGF * * Ctrl 2.5 5 400 300 200 100 0 Ang2 * * Ctrl 2.5 5 40 20 0 TNF Ctrl 2.5 5 Trabectedin selectively reduces some inflammatory cytokines in monocytes and macrophages at infra-cytotoxic levels Allavena P, et al. Cancer Res. 2005 and 2010
Clinical evidences from OVA 301
OVA-301 (PFI 6-12 months): Survival from subsequent platinum given as 1 st option after OVA-301 Kaye SB et al. Annals of Oncology 2011; 22 (1): 49-58
OVA-301 (PFI 6-12 months): Time to next platinum and survival from subsequent platinum therapy After trabectedin/pld: Subsequent platinum was delayed a median of 4 months (HR=0.61; p=0.0203) OS from administration of platinum-based therapy as first subsequent line was significantly extended by a median of 8.7 months (HR=0.54; p=0.0169). Time to next platinum: Randomization OVA-301 PLD 7.5 months Trabectedin + PLD 11.5 months First Plat. 4 months First Plat. Median OS from next platinum: Platinum Immediately after OVA-301 PLD 9.9 months Trabectedin + PLD 18.6 months Death 8.7 months Death Kaye SB et al. Annals of Oncology 2011; 22 (1): 49-58
Trabectedin: OVA-301 PPS Stratum (PFI = 6-12 mo.) Overall survival in partially platinum sensitive patients with platinum as subsequent treatment 1.0 0.9 0.8 N=94 HR: 0.58 (0.37-0.90) p=0.0153 0.7 Cumulative probability 0.6 0.5 0.4 Trabectedin+PLD Median=27.7 months 0.3 0.2 PLD Median=18.7 months 0.1 Patients at risk PLD 45 44 44 39 36 32 23 18 16 12 12 11 8 7 6 3 2 1 1 0 0 T+PLD 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Time (months) Unplanned ad hoc analysis. 49 49 48 47 45 43 39 34 29 25 22 19 17 14 11 8 5 3 3 0 0 Poveda A, et al. Cancer Treat Rev. 2014;40:366-75.
Sequence Effect Hypothesis Much more than just prolonging PFI!!! HYPOTHESIS Sequence Effect by which Trab+PLD enhances the response to a subsequent platinum in addition to its initial direct effect Increased PFS Increased PFI Later lines Trab + PLD Platinum PLD Platinum Increased Overall Survival Poveda A, et al. Cancer Treat Rev. 2014;40:366-75. 35
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Potential of Trabectedin in BRCA-mutated Patients: Exploratory Analysis of OVA-301 BRCA1-mutated patients treated with T + PLD showed longer PFS and OS compared with PLD Monk BJ et al. Ann Oncol. 2015;26:914-920.
BT CR 2 (12%) Progression Free survival PR 8 (47%) RR 10 (59%) BT+C * CR 8 (47%) Progression Free survival PR 4 (23%) RR 12 (70%) Median F-UP mos 11.5 Median PFS mos 9.4 Cycles Mean duration with Carboplatin of 34 ( 9.3-99) treatment 1 (wks) 2 (11.8) Median 2 N. cycles 112 (4- (11.8) 32) 3 1 (5.9) 5 1 (5.9) 6 11 (64.7) Median F-UP mos 16.4 Median PFS mos 23.1 Mean duration of treatment (wks) 53 (20-116) Median n. cycles 13 (6-40) *11 pts completed the 6 cycles 65 had Carboplatin reduced to AUC3 AUC3 and trabectedin to 0.6 mg/m2 Efficacy
Conclusions Trabectedin + PLD offers patients a safe and effective, nonplatinum, non-taxane combination for the treatment of relapsed platinum-sensitive ovarian cancer patients, especially for patients relapsing between 6 and 12 months and for those not candidates to receive platinum-based therapy Due to its peculiar mechanism of action, extending the PFI with trabectedin may allow platinum-sensitivity to be restored while allowing time for recovery from platinum-related toxicities. The sequence effect by which trabectedin + PLD may enhance the activity of subsequent platinum and improve survival, is under investigation in a prospective phase III trial ( Inovatyon)
Platinum for platinum-sensitive recurrence