Post ASCO 2017 Gynækologisk kræft. Læge, PhD Zarah Zimling Onkologisk afdeling, Rigshospitalet.

Transcription

1 Post ASCO 2017 Gynækologisk kræft Læge, PhD Zarah Zimling Onkologisk afdeling, Rigshospitalet.

2 Endometrie cancer Final results of the international randomized PORTEC-3 trial of adjuvant chemotherapy and radiationtherapy (RT) versus RT alone for women with high-risk endometrial cancer. Abstract 5502

3 PORTEC-3 trial design High risk Endometrial Cancer (HREC) n: 660 R Pelvic RT 48.6 Gy + 2x Cisplatin 50mg/m2 5 weeks 2 wks 12 weeks RT alone 4x Carboplatin AUC5 Paclitaxel 175mg/m2 Endometrial carcinoma stage I grade 3, with deep invasion or LVSI+ stage II - III stage I-III serous or clear cell cancers (>25%) WHO PS 0-2 No residual macroscopic tumor after surgery 5 weeks PORTEC-3 results 6/2/2017

4 Tumour & treatment characteristics Tumour characteristics RT alone CTRT Treatment characteristics RT alone CTRT Histology Type of surgery (%) Endometrioid grade 1-2 Endometrioid grade 3 Serous/ clear cell/ other 39.7% 32.1% 28.2% 38.5% 32.4% 29.1% TAH or TLH / BSO TH/BSO plus LND 41.8% 58.2% 42.4% 57.6% LVSI Yes No Stage (%) I II III 58.2% 41.8% 29.4% 27.3% 43.3% 59.7% 40.3% 29.7% 24.2% 46.1% RT completion(%) EBRT BT boost (cervical invasion) CT completion (%) 2 cisplatin 4 carboplatin-paclitaxel 98.5% 47.8% % 45.8% 93% 80%-72% PORTEC-3 results 6/2/2017

5 Survival (OS) Subgroup analysis FIGO stage III 5-year FFS 69% for CTRT vs 58% for RT [HR 0.66, 95% CI , p=0.032] HR 0.79 [ ], p= year OS 79% vs 70% [HR 0.69, , p=0.114] 5 yr OS: 82% (CTRT) versus 77% (RT) PORTEC-3 results 6/2/2017

6 Konklusion PORTEC-3 5-yr survival G1 G2 G3 Ia Ib Ic IIa IIb % patients with G1-2 disease Studiet inkluderer en stor andel pt med favorabel prognose (grad 1-2 (38 %), st. I + II (55%)) Ingen systematisk lymfeknude staging, hvilket også kan skævvride resultaterne Ved post-hoc subgruppe analyse er der FFS gevinst og en trend mod overlevelses gevinst (OS) ved stadium III sygdom. I DK anbefales i forvejen kun adjuverende behandling i form af kemo-radioterapi ved stadium III sygdom. Resultaterne fra PORTEC 3 kommer ikke til at ændre på dette. Creasman et al., IJGO, 2007 Nødvendigt at færdiggøre ENGOT-EN2-DGCG studiet

7 Cervix cancer An open-label, multicohort, phase I/II study of nivolumab in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic (R/M) cervical, vaginal and vulvar cancers. Abstract 5504

8 CheckMate 358 Study Design: Metastatic Monotherapy Cohort CheckMate 358 (NCT ) is an ongoing, open-label, phase 1/2, multicohort study Eligibility Treatment Assessments Follow-up Eligible tumor types EBV+ gastric carcinoma HPV+ SCCHN Cervical, vaginal, and vulvar cancers Merkel cell carcinoma Nasopharyngeal carcinoma Key eligibility criteria 2 prior treatments for R/M disease 1 target lesion a ECOG PS: 0 1 PD-L1 unselected 24 patienter Nivolumab 240 mg Q2W until progression or unacceptable toxicity Imaging Q8W for the first year of treatment Imaging Q12W thereafter Minimum follow-up: 12 weeks Survival follow-up Primary endpoints: ORR a Secondary endpoints: DOR, PFS, OS a Per investigator-assessed RECIST v1.1 criteria DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group; EBV = Epstein-Barr virus; OS = overall survival; QXW = every X weeks; RECIST = Response Evaluation Criteria In Solid Tumors; SCCHN = squamous cell carcinoma of the head and neck

9 Best reduction from baseline in target lesions (%) Best Reduction in Target Lesions CheckMate 358: Nivolumab Monotherapy in R/M Cervical, Vaginal, and Vulvar Cancers Cervical (n = 19) Vaginal/Vulvar (n = 5) ORR, n (%) 5 (26.3) 0 Disease control rate, n (%) 13 (68.4) 4 (80.0) Cervical cancer * PR PR PR * 100 Vaginal/vulvar cancer *PR not achieved as 1 patient had a new lesion and 1 patient did not have confirmed response 1 patient is not shown due to unavailable postbaseline tumor assessment prior to subsequent anti-cancer therapy CR = complete response; PR = partial response PR CR

10 Konklusion CheckMate 358 Nivolumab har aktivitet i recidiverende/metastatisk cervix/vulva cancer, med responsrate på 26% Mulig effektiv behandling til en patientgruppe med få behandlingsmuligheder 10

11 Ovariecancer LION: Lymphadenectomy in ovarian neoplasms A prospective randomized AGO study group led gynecological cancer intergroup trial Abstract 5000 Randomized controlled phase III study evaluating the impact of secondary cytoreductive surgery in recurrent ovarian cancer: The interim analysis of AGO DESKTOP III /ENGOT ov20 Abstract 5501

12 Randomization (n=640) Design: LION Pre-operative In/exclusion Criteria (18 75 yrs, PS 0/1, No prior chemo, no prior ln.diss) Registration at least one day prior to surgery Strata: Center Age PS ECOG Registered patients (n=1895) Randomized (n=650) 1:1 randomization Intra-operative randomisation if: Epithelial ovarian cancer FIGO IIB-IV Macroscopic complete resection No contra-indication to LNE Absence of bulky nodes Excluded (n=1245) Other histology/stage (n=650) No complete resection achieved (n=473) Presence of bulky lymph nodes (n=360) Withdrawn informed consent (n=28) Multiple reasons possible Systematic pelvic and para-aortic lymphadenectomy No lymphadenectomy Presented by: Philipp Harter AGO & KEM Essen, Germany

13 LION: Patient characteristics LNE (%), n= 323 No LNE (%), n=324 P-value Age (median, range) [years] 60 (21-83) 60 (23-78) 0.66 Performance status ECOG 0 ECOG (84.2) 51 (15.8) 280 (86.4) 44 (13.6) 0.43 Histologic diagnosis before registration 106 (32.8) 106 (32.7) 0.98 CA 125 pre-op (median, IQR) [U/ml] 416 ( ) 347 ( ) 0.42 Final histological diagnosis Ovarian / Fallopian Tube / Peritoneal Ca Others 304 (94.1) 19 (5.9) 303 (93.5) 21 (6.5) 0.75 Final FIGO stage* I-IIA IIB-IIIA III-IV missing 15 (4.6) 41 (12.7) 261 (80.8)** 6 (1.9) 17 (5.2) 52 (16.0) 244 (75.3)*** 11 (3.4) 0.32 Histology: G2/3 serous others 234 (72.4) 89 (27.6) Microscopic LN metastasis 180 (55,7) 227 (70.1) 97 (29.9) 0.54 * According to FIGO 2009 classification; including **7 and ***6 pts with T1-2a, N1 Presented by: Philipp Harter AGO & KEM Essen, Germany

14 LION: Secondary endpoint PFS Product-Limit Survival Estimates With Number of Subjects at Risk Censored 0.8 Survival Probability Arm N E Median PFS HR (95%CI) LNE ( ) No LNE pfs_month Arm LNE No LNE LNE No LNE Presented by: Philipp Harter AGO & KEM Essen, Germany

15 LION: Primary endpoint OS Product-Limit Survival Estimates With Number of Subjects at Risk Censored 0.8 Survival Probability Arm N E Median OS HR (95%CI) LNE months ( ) No LNE months 1 Total OS_month Arm LNE No LNE Stratified Log-Rank Test (Strata Age >60J vs <=60J und ECOG 0 vs >0): p=0.65 LNE No LNE Presented by: Philipp Harter AGO & KEM Essen, Germany

16 Konklusion LION Hverken PFS eller OS fordel ved systematisk lymfeknude fjernelse, trods forekomst af mikro-metastaser hos > 50 % af patienterne. Ekstensiv fjernelse af lymfeknuder er forbundet med ikke uvæsentlig toksicitet. Systematisk lymfeknudefjernelse hos pt. uden kliniske lymfeknude metastaser kan IKKE anbefales. Presented by: Philipp Harter AGO & KEM Essen, Germany

17 Randomized controlled phase III study evaluating the impact of secondary cytoreductive surgery in recurrent ovarian cancer DESKTOP III AGO Score: good Performance Status (ECOG 0) complete resection during 1 st line therapy ascites less than 500 ml. 1 pts. with platinum-free-interval of 6+ months (PSROC) Primary endpoint OS; final analysis after 244 OS events in all 408 planned pts. Important secondary endpoints: PFS, resection rate, treatment burden Courtesy A du Bois; ASCO 2017

18 DESKTOP III: Design Pts. with: 1 st relapse PSROC AGO Score +ve Complete resectionrate 72,5% 80 centres in 12 countries Recruitment 9/2010-3/ of 409 pts evaluated ( 2 screening failures) 3rd line Courtesy A du Bois; ASCO 2017

19 DESKTOP III: Progression-Free Survival Surgery No surgery Median PFS 19.6 mos 14.0 mos Δ median PFS 5.6 mos HR (95% CI) 0.66 ( ) P-value < Courtesy A du Bois; ASCO 2017

20 AGO DESKTOP III: Outcome 3 (PFS by surgical outcome) (AGO OVAR OP.4; ENGOT-ov20; NCT ) Median PFS [mos] Δ PFS [mos] HR (95% CI) P-value Wald-test No surgery Surgery but with residual tumor ( ) Surgery with complete resection ( ) < Presented by: Andreas du Bois AGO & KEM Essen, Germany

21 Konklusion DESKTOP III 2 linie kirurgi til første platinfølsomme recidiv gav en PFS gevinst på ca 6 mdr. Gevinsten i PFS sås kun hos patienter som blev radikalt opereret, her var median PFS 21 mdr. vs 14 mdr i standard armen. AGO-scoren kan prædikerer for makro-radikal operation (komplet resektionsrate var 72,5%) Der er tale om interim-analyse og der foreligger endnu ikke OS data. Resultaterne er dog lovende og kunne meget vel ændre behandlingsstrategien for første platin-følsomme recidiv Presented by: Andreas du Bois AGO & KEM Essen, Germany

22 Evolution of PARP INHIBITORS In the Treatment of Ovarian Cancer Mansoor Raza Mirza NSGO: Nordic Society of Gynaecological Oncology & Rigshospitalet: Copenhagen University Hospital, Denmark

23 Status of phase III PARP inhibitors trials Reported Awaited Niraparib ENGOT-OV16 / NOVA PRIMA Olaparib ENGOT-OV30 / SOLO2 SOLO1 PAOLA1 Rucaparib - ARIEL3 Veliparib - GOG3005 Talazoparib - Ovarian Cancer Strategy Unclear

24 Status of FDA & EMA approvals Maintenance Therapy Niraparib FDA All patients regardless of histology, BRCA & HRD status EMA awaited Olaparib awaited BRCAmut only Post Multiple-Lines of Therapy FDA EMA Rucaparib BRCAmut only - Olaparib BRCAmut only -

25 Results from Randomized Trials in Ovarian Cancer Olaparib ENGOT-OV21 / SOLO2 phase 3 randomized Niraparib ENGOT-OV16 / NOVA phase 3 randomized

26

27 Ledermann et al.; abstract 5518

28 Ledermann et al.; abstract 5518

29 abstract 5507

30 abstract 5507

31 abstract 5507

32 Results from Randomized Trials in Ovarian Cancer Olaparib ENGOT-OV21 / SOLO2 phase 3 randomized Niraparib ENGOT-OV16 / NOVA phase 3 randomized

33 ENGOT-OV16 / NOVA Study Design Platinum-Sensitive Recurrent High Grade Serous Ovarian Cancer Treatment with 4-6 Cycles of Platinum-based Therapy Response to Platinum Treatment gbrcamut n 203 n 553 Non-gBRCAmut n 350 Niraparib 300 mg once daily 2:1 Randomization 2:1 Randomization Placebo Treat until Progression of Disease Niraparib 300 mg once Placebo daily Treat until Progression of Disease Mirza MR et al. N Engl J Med 2016;375:

34 ENGOT-OV16 / NOVA Study End-Points Recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer following a complete or partial response to platinum-based therapy Evaluate gbrca mutation status* gbrcamut non-gbrcamut HRDpos HRDneg HRD-ND Primary Efficacy Groups sbrcamut BRCAwt Exploratory Efficacy Subgroups Mirza MR et al. N Engl J Med 2016;375: Two main cohorts (gbrca and non-gbrca) were independently powered (did not share α). If HRDpos was positive, then both the HRDpos and the overall non-gbrca cohort shared the α

35 ENGOT-OV16 / NOVA Primary End-Points: Progression-free Survival gbrcamut Non-gBRCA Non-gBRCA HRD pos Treatme nt Niraparib (N=138) Placebo (N=65) PFS Median (95% CI) (Months) 21.0 (12.9, NR) 5.5 (3.8, 7.2) Hazard Ratio (95% CI) p-value 0.27 (0.173, 0.410) p< % of Patients without Progression or Death 12 mo 18 mo 62% 50% 16% 16% Treatmen t Niraparib (N=234) Placebo (N=116) Mirza MR et al. N Engl J Med 2016;375: PFS Median (95% CI) (Months) 9.3 (7.2, 11.2) 3.9 (3.7, 5.5) Hazard Ratio (95% CI) p-value 0.45 (0.338, 0.607) p< % of Patients without Progression or Death 12 mo 18 mo 41% 30% 14% 12% Treatme nt Niraparib (N=106) Placebo (N=56) PFS Median (95% CI) (Months) 12.9 (8.1, 15.9) 3.8 (3.5, 5.7) Hazard Ratio (95% CI) p-value 0.38 (0.243, 0.586) p< NR=not reached % of Patients without Progression or Death 12 mo 51% 18 mo 37 % 13% 9%

36 Niraparib: PFS for Patients with a PR to the Last Platinum-based Chemotherapy PR to Last Treatment gbrcamut Non-gBRCAmut Overall PR to Last Treatment Overall PFS HR Mirza et al. ASCO 2017; abstract 5517

37 Niraparib: Long Term Benefit Matulonis et al. ASCO 2017; abstract 5534

38 Niraparib Had No Impact on the Efficacy of Next-Line Therapy 1 (PFS2 PFS1) in the Pooled gbrcamut and Non-gBRCAmut Cohorts Platinum Niraparib or placebo Chemo Chemo PFS1 PFS2 PFS1 PFS2 Note: The numbers at the bottom of the display represent number at risk for niraparib (top row) and placebo (bottom row) CI=confidence interval. 1 Mirza et al. N Engl J Med. 2017;376:801-2 Matulonis et al. ASCO 2017; abstract 5534

39 Ovarian Cancer Targeted Therapy Landscape Overview PARPi PDL1/L1i VEGFi PARPi + VEGFi PARPi + PD1/L1i VEGFi + PD1/L1i First-line Treatment Veliparib + chemo VELIA Avelumab + chemo JAVELIN 100 Bev + chemo GOG-218 Bev + chemo ICON7 Atezolizumab + Bev + chemo; IMagyn50 First-line Maintenance Olaparib, SOLO-1 Niraparib PRIMA gbrca Olaparib + Bev PAOLA-1 Rucaparib + Bev, MITO25 tbrca, HRD+ Recurrent, PS Treatment Olaparib, SOLO-3 Rucaparib; ARIEL4 Niraparib QUADRA gbrca tbrca Bev + chemo; OCEANS Bev + chemo; GOG- 213 Olaparib + Cediranib, GY-004 Niraparib + Bev AVANOVA Ola.+ Durva. MEDIOLA Ruca. + Atezo. (Part 2) gbrca Atezolizumab + Bev + chemo; ATLANTE Rucaparib; ARIEL3 Recurrent, PS Maintenance Olaparib, SOLO-2 gbrca Niraparib, NOVA Olaparib; OReO Recurrent, PROC Treatment Avelumab + chemo; JAVELIN 200 Bev + chemo; AURELIA Ola. + Cediranib, CONCERTO Olaparib + Cediranib, GY-005 Niraparib + Pembro TOPACIO Atezolizumab + Bev + chemo *Includes PARPs (niraparib, olaparib, rucaparib, veliparib) and PD1/L1s (atezolizumab, avelumab). Key: Olaparib Atezolizumab Veliparib Bevacizumab Rucaparib Avelumab Niraparib

40 Conclusions PARP significantly improved PFS in patients with platinum-sensitive recurrent ovarian cancer. Efficacy is highest in BRCAmut population Level 1 evidence Niraparib Olaparib Rucaparib gbrcamut: HR 0.27 HR 0.30 ESMO 17 Non-gBRCAmut: HR ESMO 17 Non-gBRCAmut HRD-positive: HR ESMO 17 Non-gBRCAmut HRD-negative (exploratory): HR ESMO 17 Who are the long-term responders? A better HRD test is needed to separate responders from non-responders; Until then, beyond BRCA, platinum-sensitivity remains the best biomarker for response to PARP inhibitors