ESMO SUMMIT AFRICA. Latest evidence and current standard of care in advanced ovarian cancer. C.Sessa. Cape Town February 2018

Transcription

1 ESMO SUMMIT AFRICA Latest evidence and current standard of care in advanced ovarian cancer C.Sessa IOSI, Bellinzona, CH Cape Town February 2018

2 CONFLICT OF INTEREST DISCLOSURE None

3 Ovarian carcinoma clinical course

4 Surgery First-line therapy Primary cytoreductive surgery Standard chemotherapy Interval debulking Anti-VEGF therapy Recurrent disease Chemo-sensitive Chemo-resistant PARP inhibitors Immunotherapy

5 The impact of residual tumor on outcome: What is optimal debulking? Data from a metaanalysis of three randomised phase III trials with 3,126 pts.

6 EORTC/NCIC Study: NACT + Interval-OP vs. Primary OP

7 ASCO/SGO guideline on neoadjuvant demotherapy (NACT) for newly diagnosed advanced OC Key guideline recommendations Rec 1 Rec 2.1 All women with suspected stage IIIc/IV invasive epithelial OC should be evaluated by gyneoncol to determinate whether primary cytoreductive surgery (PCS) is feasible (strong) Women with high perioperative risk profile or low likelihood of cytoreduction to <1cm (ideally no visible disease) should receive NACT (moderate) Rec 3.2 For women with a high likelihood of achieving cytoreduction to <1cm (ideally no visible disease) with acceptable morbidity PCS is recommended over NACT (moderate) August 2016

8 ASCO/SGO guideline on neoadjuvant demotherapy (NACT) for weekly diagnosed advanced OC (cont.) Rec 4 Before NACT all patients should have histologic confirmation of invasive OC (FT or PC) (moderate) Rec 5 For NACT a platinum/taxane doublet is recommended (moderate) Rec 6 ICS should be performed after 4 cycles of NACT for women in response or with SD (weak) Rec 7 Patients with PD on NACT have a poor prognosis (strong) August 2016

9 Primary cytoreductive surgery TAH BSO Omentectomy Appendectomy Removal of all macroscopic tumor/metastases Lymphadenectomy LION TRIAL

10 LION TRIAL Lymphadenectomy in ovarian cancer neoplasms. A prospective randomized AGO study group Gynecologic cancer GCIG trial. P. Harter et al. Question What is the role of pelvic / paraortic lymphadenectomy in patients with advanced OC with macroscopic complete resection and clinically negative lymph nodes? ASCO 2017

11 LION TRIAL Qualification of centres before participation Suspected or proven diagnosis of advanced epithelial ovarian/tubal/peritoneal cancer FIGO IIB-IV Clinically/radiologically negative pelvic and para-aortic lymph nodes Macroscopic complete resection seems possible No prior chemotherapy No prior lymphadenectomy ECOG 0/1 1 endpoint OS 2nd endpoints: PFS, QoL, number resected lymph nodes

12 LION TRIAL

13 LION Characteristics of surgery Bilateral salpingooophorectomy LNE (%) No LNE (%) 319 (98.8) 320 (98.8) Histerectomy 321 (99.4) 322 (99.4) Peritonectomy 291 (90) 291 (89.8) GI tract resection 169 (52.3) 167 (51.5) Splenectomy 62 (19.2) 56 (17.3) Complete resection 321 (99.4) 322 (99.4)

14 LION Characteristics of surgery Resected LN total (median) LNE (%) No LNE (%) Difference P-Value 57 (45-73) Para aortic LN 22 (16-33) Pelvic LN 35 (26-43) Lymph node metastases Duration (median) (min) Blood loss (median) (ml) 180 (55.7) 340 ( ) 280 ( ) + 1 hour < ( ) 500 ( ) ml < Transfusions 205 (63.7) 181 (56) + 8 % 0.005

15 LION Post-surgical outcome Infections requiring antibiotics LNE (%) No LNE (%) P-Value 83 (25.8) 60 (18.6) 0.03 Thrombosis 7 (2.2) 5 (1.6) Asymptomatic lymph cysts Symptomatic lymph cysts Rate of re-laparotomy for complications 60 day postoperative mortality 14 (4.4) 10 ( 3.1) 1 (0.3) 0 < (12.4) 21 (6.5) (3.1) 3 (0.9) 0.049

16 LION Study results LNE No LNE HR (95% CI) Overall survival (mo) ( ) Progression free survival (mos) ( )

17 LION Conclusions Omitting systematic lymphadenectomy in this setting seams reasonable - No difference on oncologic outcome - Improved peri-operative outcomes - Expect cost effective benefits Does this apply to NAC patients?

18 First-line therapy in adv OC Standard CT is a combination of paclitaxel 175mg/m 2 and carboplatin AUC 6-5 both given IV every 3 weeks for 6 cycles ESMO Guidelines I,A 5 th OCCC of GCIG recommended ICON 8 I,A The addition of BEV is recommended for OC with poor prognostic features (stage IV, suboptimal debulking) ESMO Guidelines I,B 5 th OCCC of GCIG not recommended ICON 7 I,A

19 ICON 7: final OS, High-risk (n=502)

20 DESKTOP III Randomized controlled phase III study evaluating the impact of secondary cytoreductive surgery in recurrent ovarian cancer: interim analysis of AGO DESKTOP III / ENGOT ov 20 A. du Bois et al. Question What is the role of cytoreductive surgery before medical treatment in recurrent ovarian cancer? ASCO 2017

21 DESKTOP III Design

22 AGO DESKTOP I (AGO) RETROSPECTIVE ANALYSIS N = 267 Predictors for optimal secondary cytoreduction Pre-op variable OR P-value No ascites (> 500 ml) 5.08 ( ) <0.001 PS (ECOG 0 vs > 0) 2.65 ( ) < RD initial Debulking 2.46 ( ) < Localisation Recurrence RFS NS NS

23 AGO DESKTOP III Patients characteristics No surgery (%) Surgery (%) No of patients Age (median, yrs) Initial FIGO stage IIIB-IV 149 (73.4) 152 (74.9) Prior platinum + taxane 182 (89.7) 191 (93.6) Median Pt free-interval 18.7 mos 21.1 mos

24 AGO DESKTOP III Surgery arm Duration of surgery (min; median) 220 ( ) Bowel resection (%) 33.2 Blood loss (ml; median) 250 (50-500) RBC transfusion (%) 20.3 Antibiotic treatment (mainly urinary inf.) (%) 19 Relaparotomy rate (%) 3.2 Macroscopic complete resection rate (%) 72.5

25 AGO DESKTOP III Outcome Median PFS (mos) Surgery No Surgery HR (95% CI) P Value 0.66 ( ) < Surgery Complete Incomplete No Surgery HR (95% CI) P Value Median PFS (mos) ( ) 0.98 ( ) <

26 AGO DESKTOP III Conclusions Cytoreductive surgery in OC patients with 1 st relapse after a Treatment Free Interval platinum > 6 mos and a positive AGO score resulted in a meaningful increase of PFS Secondary cytoreductive surgery could be a valuable option in patients with a positive AGO score

27 Recurrent disease Factors to be considered when selecting the treatment 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 HRD as data emerge) Type of prior therapy (anti-angiogenic agents, PARP inhibitors, CT and others) Number of prior lines of CT Presence or absence of symptoms and type ( e.g. ascites, abdominal symptoms, pain, performance status) 5th OCCC of GCIC

28 What are the endpoints for clinical trials in recurrent OC? PFS acceptable only if supported by additional endpoints If the expected median OS is >12mos PFS supported by PRO and TSST are preferred If the expected median OS is <12mos PFS is acceptable only if supported by PRO 5th OCCC of GCIC

29 Clinical Trials in platinum-sensitive relapse Single agent platinum or combination therapy? Platinum v Platinum + paclitaxel [ ICON4] Survival benefit in favour of combination therapy Carboplatin v Carboplatin + gemcitabine [OVAR2.5] Significant improvement in PFS, but not survival Carboplatin+ paclitaxel v Carboplatin + PLDH CALYPSO Non inferiority design- PFS results only; possible advantage for Carboplatin/PLD ICON 4 Lancet 361:2099 (2003); Pfisterer et al JCO 24:4699 (2006); Pujade-Lauraine et al JCO 28:3323(2010)

30 Regimens of proven value in recurrent disease platinum sensitive Patients Platinum-sensitive Time to recurrence >12 mos Regimens Platinum-doublet Level of evidence I,A > 6 mos Platinum-doublet (Carbo-GEM, Carbo-PLD) Platinum-doublet + Beva (OCEANS) I,B I,A Platinum-partially sensitive > 6 mos *To be verified INOVATYON study Platinum-doublet followed by licensed PARPi 6-12 mos Carboplatin-doublet Non platinum-doublet I,A I,B I,B* ESMO Guidelines

31 Antiangiogenic therapy Bevacizumab in Recurrent Ovarian Cancer: Platinum-Sensitive Relapse Coleman RA et al. Lancet Oncol. 2017

32 AURELIA trial design

33 Antiangiogenic therapy Bevacizumab in Recurrent Ovarian Cancer: Platinum-Resistant Relapse

34 Antiangiogenic therapy Facts & Clinical Considerations But do we have any biomarkers to select the right population? If not: what are the selection criteria? So far, only Bevacizumab is approved in ovarian cancer Bevacizumab is only allowed once in the course of disease The benefit of adding bevacizumab is given in primary, early and late relapse What are the risks of bevacizumab Pulmonary embolism Hypertension Bowel perforation and fistula Every ovarian cancer patient should receive bevacizumab during the course of disease M. Mirza 2017

35 Recurrent disease Separate trials are needed for population with unmet needs Medically compromised and/or elderly patients Multiple lines of prior CT Asymptomatic rise in CA125 5th OCCC of GCIC

36 BRCA testing recommendations NCCN, ACOG and ASCO recommend offering genetic counseling and genetic testing to patients either affected or with a personal history of OC, irrespective of family history at the time of diagnosis SIGN (Scotland UK) recommends offering genetic counseling and genetic testing to all women with non mucinous or borderline OC, FT or PC, irrespective of family history at the time of diagnosis

37 e Update ESMO CPGL ovarian cancer 1. Personalised medicine Patients with recurrent HGSOC and a germline or tumor BRCA mutation should be offered maintenance olaparib after a response to platinum based chemotherapy. 2. Testing for a BRCA mutation Patients with HG tumours should be tested for a germline mutation. Consideration should be given to testing tumors for a somatic BRCA mutation.

38 Maintenance with PARP inhibitors Results from randomized trials Olaparib Study 19 phase 2 ENGOT-OV21/SOLO 2 phase 3 Niraparib ENGOT-OV16/NOVA phase 3 Rucaparib Ariel 3 phase 3

39 SOLO2/ENGOT-Ov21

40 Maintenance with niraparib in platinum-sensitive recurrent OvCa ENGOT- OV16/NOVA TRIAL

41 ARIEL3: a Phase 3 randomised double blind study Patient eligibility Stratification *CR (defined by RECIST v1.1) or PR (defined by RECIST v1.1 and/or a GCIG CA-125 response [CA-125 within normal range]) maintained until entry to ARIEL3 ( 8 weeks of last dose of chemotherapy). ATM, ATR, ATRX, BARD1, BLM, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, RPA1. HRR, homologous recombination repair; NGS, next-generation sequencing. Ledermann, ESMO 2017

42 ARIEL3: Primary Endpoint and Step-Down Analysis Primary endpoint: Investigator-assessed PFS (per RECIST) BRCA mutation and LOH in tumour samples were measured using Foundation Medicine s T5 NGS assay *Investigator-assessed PFS at a two-sided 0.05 significance level Ledermann, ESMO 2017

43 Maintenance with PARP inhibitors Conclusions PARPi significantly improved PFS in patients with platinum sensitive recurrent OC. Efficacy is higher in BRCA mut population Level 1 evidence Niraparib Olaparib Rucaparib g BRCA mut HR 0.27 HR 0.30 HR 0.23 Non-g BRCA mut HR Non-g BRCA mut HRD-positive HR Non-g BRCA mut HRD-negative HR 0.58 A better HRD test is needed to identify responders. Until then, beyond BRCA, platinum sensitivity remains the best biomarker for response to PARP inhibitors M. Mirza 2017

44 PARP inhibitors Approved indications in OC 2014 EMA Olaparib cps: maintenance BRCA mut, HGS platinum sensitive 2016 FDA Rucaparib treatment BRCA mut, 2 prior lines 2017 FDA Niraparib maintenance (regardless BRCA HRD) 2017 EMA Niraparib maintenance (regardless BRCA HRD) HGS platinum sensitive 2017 FDA Olaparib tablets: maintenance HGS platinum sensitive

45 When to treat with PARP inhibitors Efficacy greatest in BRCA mut HGSOC (similar efficacy somatic and germline, benefit in BRCA testing) Maintenance in platinum sensitive recurrent Await for results as maintenance in first line Await for results as treatment (ARIEL 4) Combination studies ongoing Olaparib ± Cediranib Olaparib + Cediranib or CT (Gy 004) in BRCA mut platinum sensitive OC Olaparib + Cediranib or CT (Gy 005) in BRCA mut platinum resistant OC Bev ± Olaparib as maintenance in first line (PAOLA)

46 Surgery First-line therapy Primary cytoreductive surgery Standard chemotherapy Interval debulking Anti-VEGF therapy Recurrent disease Chemo-sensitive Chemo-resistant PARP inhibitors Immunotherapy