Gynecologic Oncology Unit IRCCS Istituto Tumori Milano G. Maltese. Milan - Italy

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1 Gynecologic Oncology Unit IRCCS Istituto Tumori Milano G. Maltese Milan - Italy

2 Mutations typically associated with ovarian carcinoma subtypes High-grade serous ovarian cancer TP53: encodes a protein that regulates the cell cycle BRCA1 and BRCA2: encode proteins that are involved in genome protection Other subtypes Low-grade serous BRAF; KRAS TP53, tumour protein 53 Romero I et al. Endocrinology 2012;153: Mucinous carcinoma KRAS Endometrioid carcinoma PTEN (low grade); TP53; BRCA1/2 Clear cell carcinoma PTEN; PIK3CA; ARID1A Colombo, IEO 2015

3 Alterazioni molecolari e opzioni terapeutiche Sierosi HG Sierosi LG Clear Cell Endometrioide Mucinoso p53 p16 prb pathway BRCA-HRD BRAF K-ras ER-PgR HNF-1β IL6/JAK2/STAT PI3K/MSI ARID1A PTEN; β-catenin, K-ras, MSI ARID1A K-ras HER2 PARP-I Antiangiogenetici Selumetinib Trametinib MEK162 OT Dasatinib Temsirolimus Nintedanib OT Temsirolimus Trastuzumab Pertuzumab Lapatinib Cetuximab Colombo, IEO 2015

4 HIGH GRADE SEROUS TUMORS E PARP-INIBITORI

5 Colombo, IEO 2015

6 39 Author 00 Month Year Set area descriptor Sub level 1 Colombo, IEO 2015

7 Presented by: Colombo, IEO 2015

8 Presented by: Colombo, IEO 2015

9 Colombo, IEO 2015

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11 Impact of Germline BRCA1/2 Mutations

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13 Efficacy of platinum based therapy in BMOC Response rate Comment Author First line 87%-96% (n= 105) 71% (p=0.002) in sporadic OC No difference between BRCA1 and BRCA2 Venken et al 1 Tan et al 2 Recurrent 2nd- 3 line % (n=67) Mostly platinum sensitive Only one cohort of 10 pts had primary platinum resistant disease with 8 reponders (80%) Platinum based therapy more active in BRCA mutated than in sporadic patients Alsop et al 3 Tan et al 2 1. Venken et al Ann Onc Tan et al Jco Alsop et al JCO2012

14 BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study Lesnock et al. British Journal of Cancer (2013) 108,

15 Efficacy of Pegylated liposomal doxorubicin (PLD)- based treatment in BMOC Response rate (RECIST or Ca125) Median PFS (months) Comment Author 68% (n= 40) 15.8 mo PLD plus platinum in 22 Mostly platinum sensistive (31) RR for PD/platinum in NH of 49%; mpfs of 8 mo (p=0.009) Safra et al 1 56% (n= 23) 6.3 mo Single agent PLD RR for PD/platinum in NH of 19%; mpfs of 4 mo (p=0.004) Non correlation with platinum sensitivity Adams et al 2 39% (n=33) 7.1 mo Single agent PLD Patients had 0-12 months of PFI Part of randomized trial vs olaparib wich had a RR of 59% and mpfs of 8.8 mo Kaye et al 3 1. Safra et al Mol Canc Ther Adams et al Gyn Onc Kaye et al J Clin Oncol 2012

16 Overall population MITO-15 results According to BRCA mutational status Lorusso D et al. ESMO 2014 Abstract 886PD.

17 Study 19: trial design, endpoints and BRCA testing N=265 Platinum-sensitive recurrent high-grade serous ovarian cancer 2 prior regimens of platinum-based chemotherapy Complete or partial response to most recent platinum-based regimen n=136 Double-blind randomization 1:1 n=129 Olaparib maintenance monotherapy (400 mg bid, capsules) Treatment until progression Placebo (bid, capsules) Primary endpoint: Progression-free survival (PFS) by RECIST 1.0 Secondary endpoints included: Overall survival (OS), safety and tolerability Exploratory endpoints: Time to first subsequent therapy or death (TFST), time to second subsequent therapy or death (TSST) BRCA testing: Previous local germline BRCA testing (case report forms) Retrospective germline BRCA testing or tumour BRCA testing BRCAm: n=136 BRCAwt:* n=118 *BRCAwt patients did not have a detected BRCAm or had a BRCAm of unknown significance. bid, twice daily; BRCAwt, BRCA1/2 wild type; RECIST, Response Evaluation Criteria in Solid Tumours Colombo, IEO 2015

18 Probability of PFS Primary endpoint At DCO 30 June 2010, the study met its primary endpoint of a statistically significant PFS benefit in the overall study population PFS HR=0.35 (95% CI: ) p<0.001 Events: patients (%) Olaparib 60:136 (44.1) Placebo 93:129 (72.1) Median (months) Randomised treatment Placebo Olaparib 400 mg bid monotherapy ,6 m Time from randomisation (months) Overall survival (OS) analysis in December 2011 (38% maturity) did not indicate progression-free survival (PFS) benefit translating into OS benefit in the overall population (HR=0.94; 95% CI: , p=0.75 Ledermann J et al. N Engl J Med 2012;366: Colombo, IEO 2015

19 Proportion of patients progression-free PFS by BRCA mutation status BRCAm (n=136) Olaparib Placebo 1.0 Events: total patients (%) 26:74 (35.1) 46:62 (74.2) Median PFS (months) HR= % CI: ; p< Olaparib BRCAm Placebo BRCAm + 6,9 m 0 Number at risk: Olaparib BRCAm Placebo BRCAm Time from randomization (months) % reduction in risk of disease progression or death with olaparib Ledermann JA et al. J Clin Oncol 2013;31(15S); abstr 5505 Colombo, IEO 2015

20 Study 19 OS analyses 28 Aug Oct Nov Sep 2015 FSI DCO DCO DCO OS data maturity: 38% Alpha (two-sided) = 0.1% HR= % CI: , p= OS data maturity: 58% Alpha (two-sided) = 3% HR= % CI: , p= OS data maturity: 77% Alpha (two-sided) = 0.95% Additional follow-up since previous analysis = 3 years CI, confidence interval; DCO, data cut-off; FSI, first subject; OS, overall survival 1. Ledermann J et al. New Engl J Med 2012;366: ; 2. Ledermann J et al. Lancet Oncol 2014;15: Colombo, IEO 2015

21 Olaparib vs Placebo in Relapsed Serous Ovarian Cancer: OS Restricted means analysis performed because of insufficient evidence to dismiss the proportional hazards assumption for OS [1,2] OS Difference in mean survival strengthens olaparib OS advantage BRCAm patients demonstrated greatest OS advantage Overall study population (N = 265) Olaparib (n = 136) Placebo (n = 129) BRCAm subgroup (n = 136) Olaparib (n = 74) Placebo (n = 62) Restricted mean OS, mos Difference in restricted mean OS, mos (95% CI) 5.2 (-0.8 to 11.2) 7.4 (-1.1 to 16.0) No inconsistency between OS data for somatic BRCAm subgroup and OS data for BRCAm, germline BRCAm, or overall population, however, conclusions limited by sample size (n = 20) 1. Grambsch P, et al. Biometrika. 1994;81: Anderson PK, et al. Lifetime Data Anal. 2004;10: Ledermann JA, et al. ASCO Abstract Slide credit: clinicaloptions.com

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23 Secondary efficacy endpoints Time to first subsequent therapy, or death (TFST) HR= % CI: p< PFS Median not reached HR= % CI: p= Time to second subsequent therapy, or death (TSST) Not reached Median not reached 18.2 HR= % CI: p< Overall survival Data immature Olaparib Placebo Median (months) Colombo, IEO 2015

24 Health-related quality of life: TOI of the FACT-O TOI over first 12 months Olaparib (n=185) Placebo (n=94) Change from baseline, adjusted mean Estimated difference in adjusted means = 0.03 (95% CI: , p=0.98) TOI, trial outcome index; FACT-O, functional assessment of cancer therapy for ovarian cancer Colombo, IEO 2015

25 *Primary endpoint for HRQoL was trial outcome index (TOI) of the FACT-O (Functional Assessment of Cancer Therapy Ovarian) SOLO2/ENGOT-Ov21: study design Patients BRCA1/2 mutation Platinum-sensitive relapsed ovarian cancer At least 2 prior lines of platinum therapy CR or PR to most recent platinum therapy Randomized 2:1 Olaparib 300 mg bid n=196 Placebo n=99 Primary endpoint Investigator-assessed PFS Sensitivity analysis: PFS by blinded independent central review (BICR) Key secondary endpoints: Time to first subsequent therapy or death (TFST), time to second progression (PFS2), time to second subsequent therapy or death (TSST), overall survival (OS) Safety, health-related quality of life (HRQoL*)

26 Progression-free survival (%) PFS sensitivity analysis using BICR Olaparib (n=196) Placebo (n=99) Events (%) 81 (41.3) 70 (70.7) Median PFS, months No. at risk Olaparib Placebo Months since randomization Olaparib Placebo HR ,7 m

27 ENGOT-OV16/ NOVA Trial Platinum-Sensitive Recurrent High Grade Serous Ovarian Cancer N=553 gbrcamut N=203 Non-gBRCAmut N=350 2:1 Randomization 2:1 Randomization Niraparib N=138 Placebo N=65 Niraparib N=234 Placebo N= Ongoing Treatment* 4 Ongoing Treatment* 46 Ongoing Treatment* 12 Ongoing Treatment* *Median duration of follow-up at time of data cutoff was 16.9 months

28 Progression-free Survival: gbrcamut Treatmen t Niraparib (N=138) Placebo (N=65) PFS Median 21.0 (12.9, NR) 5.5 (3.8, 7.2) Hazard Ratio 0.27 (0.173, 0.410) p< % of Patients without PD or Death 12 mo 18 mo 62% 50% 16% 16% + 15,5 m PFS was analyzed using a 2-sided log-rank test using randomization stratification factors, and summarized using the Kaplan-Meier methodology. Hazard ratios with 2-sided 95% confidence intervals were estimated using a stratified Cox proportional hazards model, with the stratification factors used in randomization. NR=not reached

29 Exploratory Analysis: PFS in Subgroups of Non-gBRCAmut Cohort HRD-positive HRD-negative sbrcamut BRCAwt Treatme nt Niraparib (N=35) Placebo (N=12) PFS Median 20.9 (9.7, NR) 11.0 (2.0, NR) Hazard Ratio 0.27 (0.081, 0.903) p= % of Patients without PD or Death 12 mo 18 mo 62% 52% 19% 19% Treatme nt Niraparib (N=71) Placebo (N=44) PFS Median 9.3 (5.8, 15.4) 3.7 (3.3, 5.6) Hazard Ratio 0.38 (0.231, 0.628) p= % of Patients without PD or Death 12 mo 18 mo 45% 27% 11% 6% Treatme nt Niraparib (N=92) Placebo (N=42) PFS Median ( 6.9 (5.6, 9.6) 3.8 (3.7, 5.6) Hazard Ratio 0.58 (0.361, 0.922) p= % of Patients rwithout PD or Death 12 mo 18 mo 27% 19% 7% 7% + 9,9 m + 5,6 m + 3,1 m NR=Not reached

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31 BRCA m HRD m

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33 Ruolo essenziale del VEGF nell ovaio: fisiologia e patologia Moghaddam, et al. Cancer Metastasis Rev 2012

34 GOG Phase II studies: Response Rates 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%

35 Four positive trials with antiangiogenic agents in front line

36 Two positive trials with bevacizumab in front line 1,873 pz Median PFS 18 vs 12 (+ 6) No OS 1,528 pz Median PFS 20 vs 17 (+3) Median PFS correct 19 vs 13 (+6) OS + 5 m

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38 Overall survival (%) Overall survival (%) STUDIO AURELIA Sopravvivenza globale: popolazione generale ASCO 2012 Sopravvivenza globale: w paclitaxel 100 CT (N=55) BEV + CT (N=60) Events, n (%) 41 (75) 36 (60) Median OS, months (95% CI) 13.2 ( ) 22.4 ( ) HR (unadjusted) (95% CI) 0.65 ( ) Time (months) ESMO 2013

39 x 6 8 cycles MITO-16/MaNGO OV-2: Avastin plus chemotherapy at progression after front-line Avastin plus chemotherapy in platinum sensitive Carboplatin Stage IIIB IV EOC, FT or PPC progressing or recurring at least 6 months after front-line chemotherapy plus Avastin (n 400) 1:1 PLD or gemcitabine or paclitaxel Carboplatin PLD or gemcitabine or paclitaxel Avastin15mg/kg q3w 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) until PD Principal investigators: Sandro Pignata, Nicoletta Colombo

40 Bevacizumab in ovarian cancer: four pivotal trials: Dose? Duration? First line Trial Chemotherapy Bevacizumab PFS HR GOG (n=1873) Paclitaxel Carboplatin Concurrent and maintenance 15 mg/kg q3w (3-arm placebo) 0.72 ICON7 2 (n=1528) Paclitaxel Carboplatin Concurrently only 7.5 mg/kg q3w (2 arm) 0.81 Second line Platinum resistant Aurelia 3 (n=361) Caelyx Topotecan Paclitaxel Concurrent 10 mg/kg q2w (2 arm) 0.48 Platinum sensitive OCEANS 4 (n=484) Gemcitabine Carboplatin Concurrent 15 mg/kg q3w (2 arm) Burger et al. N Engl J Med Perren et al. N Engl J Med Pujade-Laurain et al. J Clin Oncol Aghajanian et al. J Clin Oncol 2012

41 Molecular Classification of HGS Ovarian Cancer TCGA Tothill, et al The Cancer Genome The Atlas Cancer Research Genome Network, Atlas Nature. Research 2011 Network. Jun 29;474(7353): Nature 474, 2011 Presented by: Boris Winterhoff

42 OS for TCGA subtypes in Separate Mayo Cohort (n=173) Proangiogenic Signatures { Hypothesis: Subtypes with proangiogenic signatures might derive more benefit from treatment with bevacizumab. Konecny GE, J Clin Oncol 31, 2013 Presented (suppl; by: Boris abstr Winterhoff 5510)

43 A Randomized Phase 2 Trial Comparing Efficacy of the Combination of the PARP-inhibitor Olaparib and the Anti-angiogenic Cediranib Against Olaparib Alone in Recurrent Platinum-sensitive Ovarian Cancer Presented By Joyce Liu at 2014 ASCO Annual Meeting Colombo, IEO 2015

44 Cediranib and olaparib have synergistic activity in vitro Colombo, IEO 2015

45 Study Design Presented By Joyce Liu at 2014 ASCO Annual Meeting Colombo, IEO 2015

46 Primary Outcome: Cediranib/olaparib significantly increased PFS compared to olaparib alone Vantaggio in PFS di 8 mesi Presented By Joyce Liu at 2014 ASCO Annual Meeting Colombo, IEO 2015

47 Cediranib/olaparib significantly increased PFS in patients without a BRCA mutation Presented By Joyce Liu at 2014 ASCO Annual Meeting Colombo, IEO 2015

48 Secondary Outcome: Cediranib/olaparib significantly increased overall response rate (ORR) compared to olaparib alone Presented By Joyce Liu at 2014 ASCO Annual Meeting Colombo, IEO 2015

49 Response to platinum-based chemotherapy in Platinum-sensitive relapsed ovarian cancer Presented By Jonathan Ledermann at 2014 ASCO Annual Meeting Colombo, IEO 2015

50 Paola 1: Study Design Bevacizumab is not provided Colombo, IEO 2015

51 MITO 25 Study design FIGO stage IIIB-IV high grade serous or endometrioid ovarian cancer, primary peritoneal and / or fallopiantube cancer, HRD positive N= 216 R A N D O M I Z A T I O N 1:1: 1 ARM A: Carboplatin AUC 5+Paclitaxel 175 mg/mq q 21 for 6 cycles + Bevacizumab 15 mg/kg q 21 for 22 cycles ARM B: Carboplatin AUC 5+ Paclitaxel 175 mg/mq q 21 + Bevacizumab 15 mg/kg for 22 cycles + Rucaparib 600 mg bid q 28 until progression or unacceptable toxicity ARM C: Carboplatin AUC 5+ Paclitaxel 175 mg/mq q 21 + Rucaparib 600 bid q 28 mg until progression or unacceptable toxicity Stratification Factor: Residual tumor at primary surgery; Stage of disease; HRD status (BRCA mutated vs BRCA like) MITO 25

52 BRCA1/2-mutated HGSOCs may be more sensitive to PD-1/PD-L1 inhibitors compared to HR-proficient HGSOCs BRCA1/2-mutated tumors exhibited: significantly increased CD3+ and CD8+ TILs elevated expression of PD-1 and PD-L1 in tumorassociated immune cells compared to HR-proficient tumors. BRCA1/2-mutation status and number of TILs were independently associated with outcome very poor prognosis group (HR proficient with low number of TILs) and one with very good prognosis (BRCA1/2-mutated tumors with high number of TILs) These findings support trials of immune-checkpoint inhibitors targeting the PD1/PDL1 pathway in BRCA1/2-mutated OC An elevated number of CD3+ and CD8+ in BRCA1/2-mutated OC may provide an additional explanation for the improved clinical outcomes associated with these mutations Evaluation in the future of additional immune checkpoint (e.g.ctla4, IDO, LAG3) vs HR-intact tumors Strickland KC, et al. Oncotarget StricklandK et al. JCO Colombo, ASCO Annual IEO Meeting

53 Pembrolizumab (Keytruda): Trials in OC Phase II Trial MITO 28 First line treatment of Advanced OC FIGO stage III-IV Carboplatin + Paclitaxel +Pembrolizumab Phase II Trial First line treatment of Advanced OC FIGO stage III-IV Carboplatin + w Paclitaxel + Pembrolizumab 6 cycles (or 3 IDS other 3 cy) followed by Pembrolizumab maintenance for 20 cycles Phase II Trial KEYNOTE 100 Relapsed OC -0-2 prior lines -3-5 prior lines Pembrolizumab for up to 24 months Phase II MITO 29 Relapsed Platinum resistant OC Standard chemotherapy + Pembrolizumab Standard chemotherapy Colombo, IEO 2015

54 Targeting PD1 Nivolumab in Ovarian cancer a phase II trial Nivolumab ASCO 2014 preliminary results of efficacy in Platinum-resistant OC, but the potential of durable anti-tumor response was unknown. Single center, open-label phase II trial, in two cohorts of advanced or relapsed platinum-resistant OC patients Hamanishi J ASCO Annual Meeting Colombo, IEO 2015

55 [TITLE] Pujade Lauraine E. et al, 2016 ASCO meeting Colombo, IEO 2015

56 Atezolizumab (Tecentriq): Trials in OC Phase II Trial from MITO GROUP First line treatment of Advanced OC FIGO stage III-IV A B Carboplatin + Paclitaxel + Bevacizumab + Atezolizumab Carboplatin+ Paclitaxel+ Bevacizumab Phase II Trial Recurrent Platinum Resistant OC A B Bevacizumab Atezolizumab + Placebo C Atezolizumab + ASA D Atezolizumab + Bevacizumab + Placebo E Atezolizumab + Bevacizumab + ASA Phase III Trial ATLANTE Recurrent Platinum Sensitive OC A B Platinum based chemotherapy + Bevacizumab + Placebo Platinum based chemotherapy+ Bevacizumab+ Atezolizumab Colombo, IEO 2015

57 1 st line treatment options in advanced ovarian cancer at present Carboplatin-Paclitaxel (IIIA) Carboplatin-Paclitaxel + Bevacizumab (IIIB-IIIC-IV) Intraperitoneal Chemotherapy (?) Weekly Carboplatin-Paclitaxel (??) PFS = months OS = months PFS = + 6 months PFS = months OS = + 15 months PFS = months PFS, progression-free survival; OS, overall survival Karam A et al. Ann Oncol 2017 Colombo, IEO 2015

58 2 st line treatment options in advanced ovarian cancer at present Platinum-free-interval Platinum resistant/refractory Platinum interm-sensitive Platinum fully sensitive Previous Treatment Beva vs No beva BRCA Status BRCA WT vs BRCA mut Colombo, IEO 2015

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60 Platinum sensitive recurrent ovarian cancer: BRCA WT 1L PREVIOUS BEV NON PREVIOUS BEV 2L Platinum- based combinations Carboplatin- Gemcitabine- Bevacizumab Platinum-based combinations Trabectedin-PLD is a valid option for patients not willing to receive or unable to receive platinum based chemotherapy

61 Platinum sensitive recurrent ovarian cancer: BRCA MUT 1L PREVIOUS BEV NON PREVIOUS BEV 2L Platinum based combinations Carboplatin-Gemcitabine- Bevacizumab (particoularly in patients with high tumor load and ascites) Platinum based combinations followed by Olaparib (if patient in partial or complete response) 3L Olaparib maintenance (if partial or complete response) Platinum based combinations followed by Olaprib at subsequent platinum sensitive recurrence Trabectedin-PLD combination at subsequent platinum sensitive recurrence or in patients unable to receive platinum Trabectedin-PLD combination at subsequent platinum sensitive recurrence or in patients unable to receive platinum

62 TREATMENT ALGORYTMS IN 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. Immunotherapy the raising star for the future!!!!