Focus su algoritmi terapeutici

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2 Focus su algoritmi terapeutici Dott.ssa Federica Tomao Dipartimento di Scienze Ginecologico-Ostetriche e Scienze Urologiche Università di Roma Sapienza

3 Algoritmi terapeutici??? Ci consentono di standardizzare il Trattamento con l ausilio anche degli enti regolatori (registrazione dei farmaci.) Si può perdere di vista l individualità del caso Riduzione delle chance terapeutiche

4 Advanced Ovarian Cancer? a chronic disease with multiple relapses. Giornelli GH et al. Springer Plus 2016

5 Ovarian Cancer Targeted Therapy Landscape Overview

6 In questo scenario le strategie terapeutiche di mantenimento rappresentano la base per garantire il più lungo periodo libero dai sintomi legati alla malattia e dalle tossicità legate ai trattamenti. Aghajanian C et al. JCO 2012; Coleman RL et al. Gynecol Oncol 2015; Ledermann J et al. Lanc Oncol 2014; Ledermann J et al. Lancet. 2016; Marth C et al. EJC. 2017; Monk BJ et al. Lancet Oncol. 2014; Pujade-Lauraine E et al. J JCO 2014; Mirza MR et al. NEJM 2016; Coleman RL et al. Lancet 2017

7 L algoritmo terapeutico alla diagnosi? Valutazione clinica, radiologica e anestesiologica: La diffusione di malattia e le condizioni della paziente rendono permissiva una chirurgia citoriduttiva ottimale? SI LPS, LPTM esplorativa NO NACT x 3 cicli Fattibilità di un debulking ottimale? Chirurgia citoriduttiva di intervallo* SI PDS Chemioterapia di I linea *se RC 0 RP o SD NO Ulteriori 3 cicli di CT

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9 Algoritmo di trattamento del carcinoma ovarico alla diagnosi Valutazione clinica, radiologica e anestesiologica: La diffusione di malattia e le condizioni della paziente rendono permissiva una chirurgia citoriduttiva ottimale? SI LPS, LPTM esplorativa Fattibilità di un debulking ottimale? NO CBDCA + PTX +/- BEV x 3 cicli Chirurgia citoriduttiva di intervallo* SI PDS NO CBDCA + PTX +/- BEV x 3 cicli^ (+ BEV in mantenimento) CBDCA + PTX +/- BEV x 6 cicli^ (+ BEV in mantenimento) ^in assenza di controindicazioni specifiche la terapia con BEV è raccomandata *se RC 0 RP o SD

10 ASPETTANDO I RISULTATI DELLO STUDIO SOLO-1

11 I II La Recidiva III-IV Riosposta ai derivati del Platino Time to recurrence Nuova risposta al Platino Platinum-sensibile (PS) >12 months 30-60% Parzialmente platino-sensibile (PPS) 6-12 months 25-30% Platino-resistente (PR) < 6 months < 10% Malattia refrattaria (PD) 0-1 months N/A

12 Definizione di PFI The historical classification of recurrent ovarian cancer according to PFI has recently been criticized for various reasons Platinum sensitivity definition has been defined arbitrarily, based on observational studies, and a probabilistic partition with the likelihood of response being a continuous variable. It can be heavily influenced by the timing of follow-up visits, and the use of CA125 as a trigger leading to further imaging examinations, modalities which have significantly changed over the time. Furthermore, improvements in surgical cytoreduction technique and the introduction of biological agents as maintenance therapy could have modified the natural course of disease. Finally, the platinum sensitivity definition only applies to chemotherapy, since no similar relationship has been demonstrated for other agents currently used in the clinical practice. Tomao F et al., Cancer 2017

13 Trials in recurrent ovarian cancer should incorporate -Treatment-free interval (TFI) TFIp (platinum) TFInp (non-platinum), TFIb (biological agent to be specified) -Histological type -BRCA status (gbrca, and others including somatic BRCA and HRDato be considered as data emerge) -Type of prior therapy (anti-angiogenic agents, PARP inhibitors, chemotherapy and others) -Number of prior lines of chemotherapy (trials should not be limited to second or third line) -Presence or absence of symptoms and type (e.g. ascites, abdominal symptoms, pain, performance status) -Other factors to be considered: tumour volume and previous surgical outcome 2. Separate trials are needed for populations with unmet needs: Medically compromised and/or elderly patients Multiple lines of prior chemotherapy Wilson MK et al., Ann Oncol 2017

14 Pianificando il trattamento della recidiva. Histotype Feasibility of Surgery Previous agents used: Bevacizumab Patient preference and expectation Treatment of relapse: much more than PFI!!! Previous agents used: PARP i BRCA status Toxicities N prior lines Symptoms Urgent response needed?

15 Days Malattia platino sensibile Percentage 0-3 Prog 0-3 Non-PD 3-12 Mos Mos 18+ Mos PFS, days OS, days Response, % Pujade-Lauraine E, et al. ASCO 2002

16 Il ruolo della chirurgia secondaria -lo studio Desktop III- and what about BRCAmut patients? With the highest benefit in patients with RT=0 courtesy of Vergote I ESMO 2017-

17 Schemi a base di platino testati nella malattia platino sensibile Authors Pts (N ) Regimen Results PFS (months) OS (months) Bolis Carboplatin 300mg/m 2 q28 16 vs 20 NS NA vs Parmar (PPS) -Carboplatin 300mg/m 2 +Epidoxorubicin 120mg/m 2 q28 - Carboplatin (AUC-5) or Cisplatin 75mg/m 2 q21 vs 9 vs 12 p= vs 29 p=.02 Gonzalez- Martin (PPS) - Carboplatin (AUC-5) or Cisplatin 50mg/m 2 + Paclitaxel 175mg/m 2 (ICON4) or 185mg/m 2 (AGO-OVAR-2)q21 - Carboplatin (AUC-5)q21 vs 8.4 vs 12.3 p = vs NA p=.0021 Pfisterer (PPS) Alberts (PPS) - Carboplatin (AUC-5) + Paclitaxel 175mg/m 2 q21 -Carboplatin (AUC-5)q21 vs - Carboplatin (AUC-4) + Gemcitabine 1000mg/m 2 d1,d8q21 - Carboplatin (AUC-5)q28 vs - Carboplatin (AUC-5) + PLD 30mg/m 2 q vs 8.6 p=.0031 NS 8 vs 12 p= vs 26 p =.02 Tomao F et al., Cancer 2017

18 Platinum-Based Strategies in Recurrent, Platinum-Sensitive Disease Authors Pts (N ) Regimen Results Pujade- Lauraine Carboplatin (AUC-5) + Paclitaxel 175mg/m 2 q21 vs - Carboplatin (AUC-5) + PLD 30mg/m 2 q28 Aghajanian Carboplatin (AUC-4) + Gemcitabine 1000mg/m 2 d1,d8 + placebo q21 for 6-10 cycles Placebo until progression vs - Carboplatin (AUC-4) + Gemcitabine 1000mg/m 2 d1,d8 + Bevacizumab 15mg/kg q21 for 6-10 cycles Bevacizumab until progression PFS (months) PS 9.4 vs 11.3 (p=.005) PPS (334 pts) 8.8 vs 9.4 (p=.004) PS 8.4 vs 12.4 (p=.0001) PPS 7.4 vs 12.5 (p=na) OS (months) NS NS NS^ NS Tomao F et al., Cancer 2017

19 Carboplatin + Paclitaxel vs Carboplatin + PLD (the CALYPSO trial) -976 pts- Experimental arm: PLD (30 mg/m2) p1q28 and carboplatin (AUC5) p1q28 Interval since last chemotherapy, months Carboplatin + PLD (466 pts) Median Carboplatin + PTX (507 pts) > vs 11.3 (p=.005) in PS 8.4 vs 12.4 (p=.0001) in PPS Multivariate analysis according to baseline characteristics Therap y free interval No HR 95% CI P to 0.65 <.001 > Pujade-Lauraine E et al., JCO 2010

20 Carboplatin + Gemcitabine with or without Bevacizumab (the OCEANS study) -976 pts- Time to recurrence since last platinum based therapy Beva (242) Beva (242) 6-12 (months) >12 (months)

21 The PARP-Inhibitors ERA N of publication on Parp-Inhibitors N of publication (PUBMED)

22 Progression-free survival (%) Proportion of patients progression-free Olaparib: dallo Studio 19 al SOLO 2 82% risk reduction of progression Olaparib BRCAm Placebo BRCAm Time from randomization (months) PFS by investigator and central assessments in BRCA mut population HR= % CI: , p< HR= % CI: , p< Olaparib Placebo Months since randomization 30.2 HR= % CI (0.11, 0.31); P< months vs 4.3 months Ledermann J et al, Lancet Oncol, 2012 Ledermann J et al, Lancet Oncol, 2014

23 Niraparib Phase III study (2:1) Objective: efficacy of maintenance treatment with Niraparib after platinum-based therapy 553 Pts affected by platinum-sensitive disease PFS: 21.0 vs 5.5 months PFS: 12.9 vs 3.8 months PFS: 9.3 vs 3.9 months P<0.001 P<0.001 P<0.001 Mirza MR et al., New Eng J Med, 2016

24 Study HR NOVA 0.27 Study Oza 0.21 Solo BRCA mut PFS OS P< Study HR Study P=0.03 Oza 1.28 Solo PFS Study HR NOVA 0.45 wt P= Study Oza 0.77 Study HR OS P=0.38 Study

25 Study 19 Hematologic adverse events (Study 19 vs SOLO 2) All grades Grade 3 Olaparib (n=136) Placebo (n=128) Olaparib (n=136) Placebo (n=128) Anaemia 29 (21%) 7 (5%) 7 (5%)* 1 (<1%) Neutropenia 7 (5%) 5 (4%) 5 (4%) 1 (<1%) SOLO 2 Adverse events (any grade) in 10% of patient overall and grade 3 events in 3% of patients in either treatment group. * 1 patient with a grade 4 adverse event. 3 patients with a grade 4 adverse event. Olaparib (n=195) All grades Placebo (n=99) Olaparib (n=195) Grade 3 Placebo (n=99) Anemia* 85 (43.6) 8 (8.1) 38 (19.5) 2 (2.0) Neutropenia* 38 (19.5) 6 (6.1) 10 (5.1) 4 (4.0) Thrombocyto penia* 27 (13.8) 3 (3.0) 2 (1.0) 1 (1.0) MDS/AML: 4 cases in olaparib group (2.1%), including one case of CMML; 4 cases in placebo group (4.0%) Whereas in NOVA study Grade III-IV advers events: Trombocytopenia (in 33.8%), Anemia (in 25.3%), Neutropenia (in 19.6%)

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27 L algoritmo terapeutico del carcinoma ovarico recidivante? Malattia platino-sensibile con intervallo libero 12 mesi dopo BEV in I linea Mutazione patogenetica di BRCA1-2 SI Chemioterapia con CBDCA associato a: PTX PLD Gemcitabina NO Chemioterapia con CBDCA associato a: PTX PLD Gemcitabina RC, RP o SD RC, RP o SD SI NO SI NO Olaparib Chemioterapia di III linea Niraparib Chemioterapia di III linea

28 L algoritmo terapeutico del carcinoma ovarico recidivante? Malattia platino-sensibile con intervallo libero 12 mesi (pz BEVA naïve) A) Mutazione patogenetica di BRCA1-2 SI Chemioterapia con CBDCA associato a: PTX PLD Gemcitabina NO Chemioterapia con CBDCA associato a: Gem + BEV (con BEV in mantenimento) PTX PLD Gemcitabina RC, RP o SD RC, RP o SD SI NO SI NO Olaparib Chemioterapia di III linea Niraparib Chemioterapia di III linea B) CBDCA+ Gem + BEV (con BEV in mantenimento) soprattutto se ascite o high tumor load

29 Days Malattia parzialmente platino sensibile No platinum based when PFI < 6 m Tra 6-12: Platino o no? Percentage Prog 0-3 Non-PD 3-12 Mos Mos 18+ Mos PFS, days OS, days Response, % Pujade-Lauraine E, et al. ASCO 2002

30 PLD-Trabectedina PLD= 16.4 months Yondelis+PLD = 22.4 months Furthermore: Longer time to new treatment (Kaye S et al., 2011) longer OS in patients treated successively with platinum based strategy (Colombo N et al., 2011) Monk et al EJC, 2012

31 INOVATYON Relapsed ovarian cancer with platinum-free interval (PFI) of 6-12 months Randomization (strata: ECOG, Measurable disease, PFI) PLD 30 mg/m2 1 hour i.v. + Carboplatin AUC 5 q4weeks Up to 6 cycles or progression PLD 30 mg/m2 1 hour i.v. + Trabectedin 1.1 mg/m2 q3weeks Up to 6 cycles or progression 3rd line chemotherapy: at investigator discretion and the accrual is completed. 3rd line chemotherapy: platinum rechallenge

32 L algoritmo terapeutico del carcinoma ovarico recidivante? A) Malattia platino-sensibile con intervallo libero tra 6 e 12 mesi Mutazione patogenetica di BRCA1-2 SI Chemioterapia con CBDCA associato a: PTX PLD Gemcitabina NO Chemioterapia con CBDCA associato a: PTX PLD Gemcitabina RC, RP o SD RC, RP o SD SI NO SI NO Olaparib Chemioterapia di III linea Niraparib Chemioterapia di III linea B) PLD + Trabectedina C) CBDCA+ Gem + BEV (con BEV in mantenimento) soprattutto se ascite o high tumor load

33 Days Malattia Platino Refrattaria/Resistente Percentage 0-3 Prog 0-3 Non-PD 3-12 Mos Mos 18+ Mos PFS, days OS, days Response, % Pujade-Lauraine E, et al. ASCO 2002 QOL

34 Studi di fase III sull uso di combinazioni vs singoli agenti nella malattia refrattaria/resistente Author N pts Drugs RR (%) PFS (median) Buda PTX vs PTX+EPI Bolis PTX vs PTX+EPI Sehouli TPT vs TPT+ VP 16 vs TPT +GEM Vergote PLD vs CAN+PLD Monk PLD vs PLD + ET743 Lortholary PTX w vs CBDA + PTX w vs TPT w m 6.0 m NR NR 7.0 m 7.8 m 5.3 m 3.7 m 5.6 m 4.0 m 3.7 m 3.7 m 4.8 m 5.4 m OS (median) 14.0 m 12.0 m (2-year OS) 17.2 m 17.8 m 15.2 m NR NR 12.4 m 14.2 m 19.9 m 15.2 m 18.6 m Note Increased toxicity in the combination arm Increased toxicity in the combination arm Increased toxicity in the combination arm Increased toxicity in the combination arm Increased toxicity in the combination arm Increased toxicity in the combination arm

35 Aurelia Pujade-Lauraine E, et al. JCO, 2014

36 Paclitaxel cohort Poveda AM et al., JCO 2015

37 Bevacizumab nella malattia Platino-resistente

38 L algoritmo terapeutico del carcinoma ovarico recidivante? Malattia platino-refrattaria (progressione durante la I linea) Monochemioterapia con: PTX settimanale PLD Gemcitabina Topotecan Incoraggiata l inclusione e lo sviluppo di trials clinici Best supportive care

39 L algoritmo terapeutico del carcinoma ovarico recidivante? Malattia platino-resistente Intervallo libero <6 mesi) Monochemioterapia con: PTX settimanale PLD Gemcitabina Topotecan Incoraggiata l inclusione e lo sviluppo di trials clinici

40 v The BAROCCO Study Italian multicenter randomized phase II study of weekly paclitaxel vs. Cediranib-Olaparib with continuous schedule vs. Cediranib-Olaparib with intermittent schedule in patients with platinum resistant high grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. SPONSOR: Mario Negri Gynaecology Oncology Group (MaNGO) PI: Prof.ssa Nicoletta Colombo, Istituto Europeo di Oncologia SUPPORT: AstraZeneca

41 Algoritmi terapeutici??? In uno scenario in cui le opzioni terapeutiche si sono ampliate notevolmente, applicare un algoritmo terapeutico è di grande ausilio per garantire alle nostre pazienti la miglior strategia terapeutica SENZA DIMENTICARE L IMPORTANZA DI FARE RETE PER INCENTIVARE L ARRUOLAMENTO DELLE STESSE NEI PROTOCOLLI DI RICERCA

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