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Open Issue in Oncology: new drugs for GI, Ovarian and lung cancer Roma 21/05/2016 Domenica Lorusso Gynecologic Oncologic Unit National Cancer Institute-Milan The angiogenesis in ovarian cancer: bevacizumab and beyond Minimal improvement in ovarian cancer mortality rates – no new front-line therapy for >20 years Alkylating agents (melphalan or cyclophosphamide) Platinum-based therapy Platinum/taxane therapy Mortality per 100,000 women 20 Front line 15 10 PLD and trabectedin Platinum-based therapy 5 Paclitaxel, gemcitabine, doxorubicin, topotecan 0 1975 1985 1995 Year Recurrent 2005 Jemal et al. CA Cancer J Clin 2009 The challenge of going beyond carboplatin/paclitaxel: key trials worldwide Trial 1995 GOG-0162 AGO-GINECO 324 1,282 Regimens compared Outcome Cis + either 24 h or 96 h pac Efficacy similar Carbo/pac vs carbo/pac/epirubicin No benefit of a third agent MITO-1 273 Carbo/pac x6 topo x4 or surveillance No PFS benefit with topo maintenance GOG-0172 429 IV cis/IV pac vs IP cis/IP pac IP has better efficacy/worse toxicity and QoL GCIG 887 Carbo/pac vs carbo/pac/epirubicin No benefit of a third agent Carbo/pac topo x4 or surveillance No benefit of topo maintenance 277 Cis/pac pac x3 vs x12 cycles in patients in CR PFS improved with pac x12 cycles/no OS difference in a selected patient population 4,312 Carbo/pac vs carbo/pac/gem (2 regimens) vs carbo/pac/topo vs carbo/pac/PLD No benefit of a third agent 819 Carbo/pac x8 vs cis/topo x4 carbo/pac x4 Efficacy similar; tolerability better with carbo/pac 1,742 Carbo/pac vs carbo/pac/gem No benefit of a third agent AGO-GINECO GOG-0178 GOG-0182 OV16 2010 n AGO-OVAR9 1,308 Carbo = carboplatin; cis = cisplatin; CR = complete response; cyclo = cyclophosphamide; gem = gemcitabine; IP = intraperitoneal; IV = intravenous; pac = paclitaxel; PLD = pegylated liposomal doxorubicin; topo = topotecan Ovarian cancer is not a single disease 70 % 5% 2% Romero I et al. Endocrinology 2012; 153: 1593-1602 15% 5% Ovarian Cancer - not one disease<br />Outcome depends on histiotype © Colombo, IEO 2015 Progress in the Management of Ovarian Cancer: Evolution Over 40 Years Five-year 15% survival Key advances in chemotherapy 30% 40% ?50%? First use of oral PARPi First use of cisplatin 1970 First use of carboplatin 1980 First use of Paclitaxel First reports of bevacizumab 1990 2000 Positive evidence for weekly paclitaxel in first line 2010 Four positive trials with antiangiogenic agents in front line Can we choose which anti-angiogenic drug ? 1st line Concomitant + Maintenance GOG 218 1st line Maintenance ICON7 OVAR 16 Not approved Bevacizumab Pazopanib Not approved OVAR12 Nintedanib Two positive trials with bevacizumab in front line Overall Survival Deaths 1-Year Survival Arm I CP (n = 625) Arm II CP + Bev (n = 625) Arm III CP + Bev Bev (n = 623) 156 (25.0%) 150 (24.0%) 138 (22.2%) 90.6% 90.4% 91.3% Events were observed in ~ 24% of patients at the time of database lock. Burger RA et al. Proc ASCO 2010;Abstract LBA1. OS estimate OS benefit is suggested with chemotherapy + Avastin and continued single-agent Avastin in stage IV disease CPP CPB CPB15 93 (61) 99 (60) 81 (49) 1.0 Deaths, n (%) 32.8 32.9 40.6 0.8 Median survival (months) 0.98 (0.74–1.31) 0.72 (0.53–0.97) HR (95% CI) 0.6 0.4 CPP (n=153) CPB15 (n=165) CPB15+ (n=165) 0.2 0.0 0 CPP CPB CPB15 153 165 165 12 144 149 154 Randall, et al. SGO 2013: Abstract 80 Randall, et al. SGO 2013: Abstract 80 129 142 144 24 113 117 130 95 104 117 36 Time (months) 72 73 83 42 44 57 28 30 37 48 15 15 21 60 5 10 10 3 3 3 72 0 1 0 0 0 0 Chemotherapy + Avastin with continued single-agent Avastin improves progression-free interval – The proportion of patients progression-free 6 and 12 months after last dose of carboplatin is increased with Avastin-based therapy (70.6 vs 52.7) at 6 months and (41.7 vs 25.9) at 12 GOG analysis months 65.6 70.6 52.7 41.7 32.1 25.9 14.0 8.4 9.2 Randall, et al. SGO 2013: Abstract 287 Randall, et al. SGO 2013: Abstract 287 © Colombo, IEO 2015 A GiNECO study:Therapy-free Recurrent Ovarian Cancer: Population Interval and Efficacy Characteristics Survival Response P Rate6 (%) R (days) 3 0 12 100 1000 I M A Refractory 80 800 R Y LA SENSIBILITA’ AL PLATINO E’ T H E R A P Y Overall Survival UNA VARIABILE CONTINUA!!! Resistant 60 600 400 40Partially Sensitive 217 200 366 PFS Fully Sensitive 166 90 0-3/Pr Response Rate 32 20 9 0 24 months 18 0-3 3-6 6-9 9-12 12-18 ≥18 Therapy-free interval (months) © Colombo, IEO 2015 Pisano et al. Ther Clin Risk Manag. 2009;5:421-426; Gadducci et al. Anticancer Res. 2001;21:3525-3533. STUDIO AURELIA ASCO 2012 Sopravvivenza globale: popolazione generale Sopravvivenza globale: w paclitaxel 100 75 Overall survival (%) Overall survival (%) Events, n (%) 75 50 25 0 0 12 Time (months) 18 24 Median OS, months (95% CI) HR (unadjusted) (95% CI) 50 CT (N=55) BEV + CT (N=60) 41 (75) 36 (60) 13.2 (8.2‒19.7) 22.4 (16.7‒26.7) 0.65 (0.42‒1.02) 25 0 0 6 12 18 24 30 36 ESMO 2013 TRINOVA-1 Weekly paclitaxel Recurrent partially platinum sensitive or resistant OC, PP, FTC, (PFI <12 months, >6months after the beginning of the firstline platinum-based chemotherapy) Radiographically evaluable disease, documented PD Prev Chemo <3 Toxicity <G3 n=900 Placebo IV qw to progression Weekly paclitaxel AMG-386 IV 15 mg/kg qw to progression Primary endpoint: PFS Secondary endpoints: OS, ORR, DOR, CA125 response rate, safety and tolerbality of AMG386, PK of AMG386 ClinicalTrials.gov. Identifier NCT01204749 Progression-free Survival (Primary Analysis) Events, n (%) Median PFS, months Pac + Placebo (n = 458) Pac + Trebananib (n = 461) 361 (79) 310 (67) 5.4 7.2 HR = 0.66 (95% CI, 0.57–0.77) P (stratified log rank) < 0.001 Presented by Monk BJ at European Cancer Congress European Journal of Cancer 49; suppl 3, Sept 2013 LBA 41 MITO-11: A randomized multicenter phase II trial testing the addition of pazopanib to weekly paclitaxel in platinum-resistant or -refractory advanced ovarian cancer (AOC). Presented By Sandro Pignata at 2014 ASCO Annual Meeting Progression-free survival Presented By Sandro Pignata at 2014 ASCO Annual Meeting Overall survival Presented By Sandro Pignata at 2014 ASCO Annual Meeting Can we choose which anti-angiogenic drug ? 2st line resistant Concomitant + Maintenance Aurelia Not approved Trinova 1 Bevacizumab Trebananib MITO 11 Not approved Pazopanib STUDI RANDOMIZZATI DI FASE III SULLE COMBINAZIONI A BASE DI PLATINO NELLA RECIDIVA PLATINO SENSIBILE DI CARCINOMA DELL’OVAIO Autore Trattamento PFS HR OS HR Tossicita’ Parmar 2003 CBDA vs CBDA+TAX 0.76 0.82 Neurotossicita Alopecia Reazioni allergiche Pfisterer 2006 CBDA vs CBDA+GEM 0.72 0.96 Mielotossicita Reazioni allergiche Pujade 2010 CBDA+TAX vs CBDA+PLD 0.82 0.99 Piastrinopenia PPE Proportion surviving progression-free GOG-0213: primary analysis of PFS 0.8 Carboplatin + Paclitaxel (n=337) Carboplatin + Paclitaxel + Avastin (n=337) Events, n (Total) 304 296 Median (months) 10.4 13.8 HR, adj. (95% CI) 0.614 (0.522–0.722) p-value 0.6 0.4 p<0.0001* 39% reduction in risk of PD or death 0.2 0.0 0 • 12 Coleman, et al. SGO 2015 (Abstract 3) 24 36 48 60 GOG-0213: primary analysis of OS Carboplatin + Paclitaxel (n=337) Carboplatin + Paclitaxel + Avastin (n=337) Events, n 214 201 Median (months) 37.3 42.2 1.0 Proportion surviving 0.8 HR, adj. (95% CI) 2 tailed p-value 0.6 0.4 0.829 (0.683–1.005) p=0.056 17% reduction in risk of death 5-month difference in median overall survival, favouring Avastin arm 0.2 0.0 0 • 12 Coleman, et al. SGO 2015 (Abstract 3) 24 36 Time (months on study) 48 60 Randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: Results of the ICON6 trial. Ledermann JA, Perren T, Raja FA, Embleton AC, Rustin GJS, Jayson G, Kaye SB, Swart AM, Vaughan M, Hirte H on behalf of the ICON 6 Collaborators (NCRN, NCIC-CTG, ANZGOG, GEICO) An academic sponsored GCIG trial Progression-free survival – arms A vs. C 1.00 Maintenance PFS events, n (%) Chemo. Maint. 112 (94.9) 139 (84.8) 8.7 11.1 Median, months Chemotherapy 0.75 Log-rank test p=0.00001 HR (95% CI) 0.57 (0.45 – 0.74) Test for non-proportionality p=0.024 Restricted means, months 0.50 9.4 12.5 Restricted mean survival time increases by 3.1 months with maintenance treatment 0.25 0.00 0 3 6 9 12 Months 15 18 21 24 . Chemo 118 Maint.. 164 90 148 24 65 8 21 3 7 Overall survival Maintenance 1.00 Restricted mean survival time increases by 2.7 months with maintenance treatment (over two years) Chemotherapy 0.75 Chemo. Maint. OS events, n (%) 63 (53.3) 75 (45.7) Median, months 20.3 26.3 0.50 0.25 Log-rank test p=0.042 HR (95% CI) 0.70 (0.51 – 0.99) Test for non-proportionality p=0.0042 0.00 Restricted means, months 0 6 17.6 20.3 12 18 24 30 46 89 27 48 11 22 Months . Chemo. 118 Maint 164 . 106 159 89 139 Can we choose which anti-angiogenic drug ? 2st line sensitive Concomitant + Maintenance Ocean /GOG213 Not yet6approved Icon Bevacizumab Cediranib Ruolo essenziale del VEGF nell’ovaio: fisiologia e patologia Moghaddam, et al. Cancer Metastasis Rev 2012 Single Agent Activity of Bevacizumab Tumor Type Dose ORR (PR+CR) Ovarian Cancer 15mg/kg q3wk 16-21% Renal Cell 10mg/kg q2wk 10% Met Breast Cancer 3-20mg/kg q2wk 7% NHL 10mg/kg q2wk 5% CRC 10mg/kg q2wk 3% HRPC 10mg/kg q2wk 0% GOG Phase II Response Rates What is Post Progression Survival (PPS)? Post Progression Survival: Time from disease progression till death OS = PFS + PPS Start Progression Death OS PFS 33 PPS PPS influences chance to translate PFS into OS benefit • • OS = PFS + SPP ( Survival Post Progression) As SPP increases, comparable OS benefit needs very large sample If PPS = 2 months PFS and OS benefit = 3mo Patients needed to demonstrate significant OS = 350 Control Arm Active Arm PFS 3 mo PPS 2 mo PFS 6 mo Total OS = 5 mo PPS 2 mo Total OS = 8 mo If PPS = 24 months PFS and OS benefit = 3mo Patients needed to demonstrate significant OS = 2440 Control Arm Active Arm 34 PFS 3 mo PFS 6 mo PPS 24 mo Total OS = 27 mo PPS 24 mo Total OS = 30 mo Can we choose which patients to treat with bevacizumab? Bevacizumab more active in high risk patients? Trial Chemotherapy Bevacizumab PFS HR GOG-02181 (n=1873) Paclitaxel Carboplatin Concurrent and maintenance 15 mg/kg q3w (3-arm placebo) 0.72 ICON72 (n=1528) Paclitaxel Carboplatin Concurrently only 7.5 mg/kg q3w (2 arm) 0.81 Platinum resistant Aurelia3 (n=361) Caelyx Topotecan Paclitaxel Concurrent 10 mg/kg q2w (2 arm) 0.48 Platinum sensitive OCEANS4 (n=484) Gemcitabine Carboplatin Concurrent 15 mg/kg q3w (2 arm) 0.48 First line Second line 1. Burger et al. N Engl J Med 2011 2. Perren et al. N Engl J Med 2011 3. Pujade-Laurain et al. J Clin Oncol 2012 4. Aghajanian et al. J Clin Oncol 2012 Can we choose which patients? Subgroup efficacy Amit Oza, ECC 2013 Pujade-Lauraine, ESGO 2013 Interpretation of results Type of analyses Which data should we consider when making treatment decisions? Primary analyses ITT population Pre-specified Primary objective is shown Subgroup analyses Pre-specified (stratified) Subgroup analyses Exploratory Post-hoc Primary endpoint is met Primary endpoint is met Assessment whether consistent treatment effects have been observed across pre-specified subgroups Assessment whether consistent treatment effects have been observed across post-hoc subgroups Hypothesis generating ICON7: OS per risk groups Subgroup analyses were not preplanned in the protocol Data from low-risk patients are immature (37% events) Elaborato da Oza, et al. ECC 2013 (abstract LBA6) Oza et al is available at: http://eccamsterdam2013.eccoorg.eu/Amsterdam2013/Webcasts%20Photos/ WebcastDetail.aspx?webcasturl=http://www.ecco-org.eu/webcasts/ecco17/SP0993/SP0993.flv , Last access 28/03/2014 ICON 7 PFS: Stage IIIB-IV PFS: Stage IIIB-IV, No residual Antonio Gonzales-Martin, ASCO 2015, Abstract 5548 How reliable is the definition of risk based on residual tumor after primary surgery? Correlation between surgical evaluation and postsurgery CT scan Chi, et al. 52% Sala et al. 59% Lorusso et al 20% Int J Gynecol Cancer 2010 Int J Gynecol Cancer 2011 Oncology 2014 © Colombo, IEO 2015 • Avastin, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of advanced (FIGO stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer • Avastin is administered in addition to carboplatin and paclitaxel for up to 6 cycles of treatment followed by continued use of Avastin as single agent until disease progression or for a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier • The recommended dose of Avastin is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion In the era of personalised medicine… Is there any group of patients obtaining the most benefit from bevacizumab according to a molecular profile? Women with Ovarian Cancer Molecular Classification of HGS Ovarian Cancer TCGA Tothill, et al Cancer Genome Atlas Research 474, 2011 The Cancer Genome The Atlas Research Network, Nature.Network. 2011 JunNature 29;474(7353):609-15 Presented by: Boris Winterhoff ICON7: retrospective molecular TCGA subgroup analyses by the AGO group 1.0 Mesenchymal Bevacizumab Control 0.8 0.6 0.4 0.2 0 11.8 0 12 21.9 24 Time (months) 36 48 Proportion alive without progression Proportion alive without progression Proliferative 1.0 Bevacizumab Control 0.8 0.6 0.4 0.2 0 12.4 0 1.0 Bevacizumab Control 0.8 0.6 0.4 0.2 0 17.0 0 12 20.8 24 Time (months) 24 Time (months) 36 48 Differentiated 36 48 Proportion alive without progression Proportion alive without progression Immunoreactive 12 20.6 1.0 Bevacizumab Control 0.8 0.6 0.4 0.2 0 17.9 0 21.6 12 24 Time (months) 36 Proliferative and mesenchymal subtypes appeared to benefit most from the addition of bevacizumab Winterhoff, et al. ASCO 2014 100 80 “Immune subgroup” 41% (n=116) CP CP + bev 60 40 20 00 18.5 10 35.8 20 30 40 Time (months) 50 PFS probability (%) PFS probability (%) ICON7: histological subgroup analyses using retrospective 63-gene immune signature 100 80 60 40 20 00 60 12.3 10 Test for interaction, p=0.015 100 80 60 40 Univariate HR 2.00 (1.11–3.61), p=0.022 20 Multivariate HR 2.37 (1.27–4.41), p=0.007 00 10 20 30 40 50 Time (months) OS probability (%) “Immune subgroup” 41% (n=116) OS probability (%) “Pro-angiogenic subgroup” 59% (n=168) 60 17.4 20 30 40 Time (months) 50 60 “Pro-angiogenic subgroup” 59% (n=168) 100 80 60 40 20 00 Univariate HR 1.19 (0.80–1.78), p=0.386 Multivariate HR 1.10 (0.73–1.66), p=0.637 10 20 30 40 Time (months) Test for non-proportionality negative in both molecular subgroups 50 60 Gourley, et al. ASCO 2014 BEVACIZUMAB AND BRCA MUTATED PATIENTS George J et al Clinical Cancer Res 2013 © Colombo, IEO 2015 GOG 218: Mutation in BRCA e response to Bev Norquist AACR 2015 © Colombo, IEO 2015 PFS: Five candidate BMs (median cut-off) Presented By Michael Birrer at 2015 ASCO Annual Meeting PFS by CD31 (median cut-off) Presented By Michael Birrer at 2015 ASCO Annual Meeting For how long should maintenance bevacizumab be continued ? © Colombo, IEO 2015 53 PFS in ROSiA and ICON7 (ITT populations) Caveats • Differing tumour assessment schedules • Prior neoadjuvant chemotherapy permitted in ROSiA Estimated probability of PFS 1.00 0.75 0.50 ROSiA BEV 15 (or 7.5) mg/kg + CP ICON7 BEV 7.5 mg/kg + CP1,2 0.25 19.3 25.5 0 0 3 6 9 12 15 18 21 24 27 Time (months) 30 33 36 39 42 45 1Avastin CP = carboplatin + paclitaxel 2Roche SmPC; data on file 2012 (ICON7 CSR addendum). 54 PFS in ROSiA and ICON7 according to ‘MRC’ risk status High (N=468) ICON7 ICON7 nonhigh high risk riska (N=516) (N=248)21 Non-high risk (N=553) 324 (69) 266 204 (50) (82) 234 (42) 18.3 (16.8–20.6) 25.9 16.0 (23.6–NE) 32.0 (30.9–40.2) riska PFS 1.00 Events, n (%) Estimated probability of PFS Median PFS, months (95% CI) 0.75 0.50 Caveats • Differing tumour assessment schedules • Prior neoadjuvant chemotherapy permitted in ROSiA 0.25 16.0 0 0 3 6 9 12 15 18.3 25.9 18 21 24 27 Time (months) NE = not estimable aFIGO stage III and >1 cm residual disease or any FIGO stage IV or no debulking surgery. 30 32.0 33 36 39 1Gonzalez-Martin 2Unpublished 42 45 A, et al. ASCO 2015 data, courtesy of MRC AGO-OVAR 17 Design Bevacizumab 15 mg/kg q21 days Paclitaxel 175 mg/m² Carboplatin AUC5 q21 days 1:1 15 Months = 22 Courses R N = 900 Bevacizumab 15 mg/kg q21 days Paclitaxel 175 mg/m² Carboplatin AUC5 q21 days Strata Residual tumor (yes vs no) FIGO Stage (IIB-III vs IV) Group 30 Months = 44 Courses National Institutes of Health. Available at: http://clinicaltrials.gov/show/NCT01462890. Accessed: 6 February 2013. Any other choice for the future ? High grade serous ovarian cancer: Potential benefit of PARP inhibition in 50% Not ‘BRCA-ness’ is frequent HRD in ovarian cancer Cancer Genome Atlas Research Network. Nature. 2011;474(7353):609-615. HRD SOLO-1 Trial BRCAm Population Only First-line maintenance 344 patients Olaparib PFS/PFS2/OS + QoL Randomization 2:1 Response to platinum-based chemotherapy Placebo Cediranib and olaparib have synergistic activity in vitro Presented By Joyce Liu at 2014 ASCO Annual Meeting Primary Outcome: Cediranib/olaparib significantly increased PFS compared to olaparib alone Presented By Joyce Liu at 2014 ASCO Annual Meeting Paola 1: Study Design Bevacizumab is not provided © Colombo, IEO 2015 Recurrent platinum sensistive trial Randomised Trial of Cediranib and Olaparib Maintenance in Patients with Relapsed Platinum Sensitive Ovarian Cancer Shibani Nicum and Jonathan Ledermann For the NCRI Clinical Studies Group MITO-16/MaNGO OV-2: Avastin plus chemotherapy at progression after front-line Avastin plus chemotherapy in platinum sensitive Carboplatin PLD or gemcitabine or paclitaxel 1:1 Carboplatin PLD or gemcitabine or paclitaxel Avastin15mg/kg q3w until PD • Primary endpoint: PFS • Secondary endpoint: OS • 60 Italian centres involved and involvement of others European groups (ENGOT – Italy, Germany, France, Greece, Switzerland) (sponsor: INT Napoli) Principal investigators: Sandro Pignata, Nicoletta Colombo x 6 – 8 cycles Stage IIIB–IV EOC, FT or PPC progressing or recurring at least 6 months after front-line chemotherapy plus Avastin (n≈400) TREATMENT ALGORYTMS IN RECURRENT OVARIAN CANCER Treatment according to histotype is the future! Antiangiogenic agents and parp inhibitors are changing the natual history of ovarian cancer disease. The best treatment algorytm is the one which allows patients to receive all the available and effective treatment options. The future is very dynamic!!!!