Principal changes in clinical trials involving patients with Ovarian Cancer

Transcription

1 Verona,

2 Principal changes in clinical trials involving patients with Ovarian Cancer

3 Principal changes in clinical trials involving patients with Ovarian Cancer Agenda 1. Patients: Biomarker driven trials Histotype driven trials 2. Intervention: Cytotoxic - based trials Antiangiogenic - based trials PARPi - based trials Combination - based trials (ickpi, PARPi..) 3. Comparison/Complexity 4. Outcomes

4 From one-size-fits-all trials to tailored trials. 1. Patients: Biomarker driven trials (BRCA 1-2 status) Histotype driven trials

5 Ovarian cancer is not a single disease. Vaughan et al Nat Rev Cancer (2011)

6 About 70% of patient with OC have a HGSOC. HRD~50% Konstantinopoulos PA et al. Cancer Discov. 2015;5:

7 BRCA 1-2 status is a prognostic biomarker in patients with HGSOC. Bolton KL et al. JAMA. 2012;307(4):

8 SOLO-1: a trial designed for BRCA 1-2 carriers. Moore K et al. N Engl J Med 379;26(2018).

9 BRCA 1-2 is a predictive biomarker for PARPi therapy. SOLO-1 PFS Moore K et al. N Engl J Med 379;26(2018)

10 NiCC trial recruit patients with Clear Cell cancers of the ovary AND endometrium. clinicaltrials.gov/ct2/show/nct

11 High incidence of KRAS mutation in LGSOC. clinicaltrials.gov/ct2/show/nct

12 LGSOC seems to respond to anti-hormonal therapy. clinicaltrials.gov/ct2/show/nct

13 New experimental treatments: PARPi, ickpi, anti-angiogenetic drugs. 1. Gyo 2. Intervention: Chemo- based trials Antiangiogenic - based trials PARPi - based trials Combination - based trials (ickpi, PARPi..)

14 Chemotherapy: standard of care for 20 years. GOG-111 (2000) GOG-158 (2003)

15 Chemo- based trials: a past story of failures in 1 line setting. MITO-2 (2011) GOG 182-ICON5 (2003) AGO-OVAR (2006) Bookman, M.A., et al. (2009) Bolis, G., et al. (2010) MITO-7 trial (2014) ICON-8 trial (2017) GOG-262 (2016)

16 Chemo- based trials: a closed area of interest? Of course NO. clinicaltrials.gov/ct2/show/nct

17 Antiangiogenic based trials and new standard of treatment. Bevacizumab Nintedanib, Pazopanib

18 Antiangiogenic based trials: ICON 7 trial. Perren TJ et al. N Eng J Med. 2011;365:

19 Antiagiogenic drugs + PARPi: rational. Norman C. et al. Clin Cancer Res (2010)

20 Antiagiogenic drugs + PARPi: ongoing trial.

21 PARPi-based trials: present and future of RCTs.

22 PARPi: active disease setting.

23 Single agent therapy with immune checkpoint inhibitors in OC. Nivolumab 1 Pembrolizumab (KEYNOTE-28) 2 Pembrolizumab (KEYNOTE-100) 3 Avelumab 4 Atezolizumab 5 Ipilimumab 6 Anti-PD1 Anti-PD1 Anti-PD1 Anti-PD-L1 Anti-PD-L1 Anti-CTLA4 Patients N. Prior Therapy 4 (55%) 3 (65%) A: 1-3 B: 4-6 % PDL % [IHC] 100% [IHC] 62% CPS <1/>1(>10) ORR 15% 11.5% 8%(17.3% CPS>10) 3 (58%) >6 (58%) >1 77% 83% / 9.7% 25% 10% 1. Hamanishi J et al. J Clin Oncol. 2015;33(34): ; 2. Varga A et al. ASCO Abstract 5510; 3. Matulonis U et al. ASCO 2018; 4. Disis ML et al. ASCO Abstract 5533; 5. Infante J et al. ESMO Abstract 871P; 6. Hodi et al

24 PARPi combination therapy: anti-pd1/pdl1 + PARPi. Konstantinopoulos et al. ESMO 2017 Madrid; Poster: 1143 PD

25 Combination of PARPi and Checkpoint-inhibitors in Xenograft. LS. Jiao et al., Clin. Cancer Res. 2017; 23:

26 Trials testing combination treatments with PARPi + ickpi in OC.

27 New standard treatments in clinical practice means new control arms in trials. 1. Patients: 2. Intervention: 3. Comparison

28 New standard treatments in clinical practice means new control arms in trials. Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: recurrent disease (2016).

29 The change s price: complexity 1. tyuu 2. Intervention: 3. Complexity: Procedural Clinical (Immuno AEs)

30 Complexity: a possible menagement Teamwork

31 Outcomes and measure of outcomes (endpoints). 1. Patients: 2. : 3. Comparison 4. Outcomes

32 SOLO - 1: the best PFS ever seen. SOLO-1 PFS

33 Crossover and post-progression treatments could dissolve PFS benefit. U. Matulonis et al. Cancer (2015 )

34 Intermediate endpoints (PFS2 and TSST) can provide supportive evidence for a PFS benefit. U. Matulonis et al. Cancer (2015 )

35 Principal changes in clinical trials involving patients with Ovarian Cancer? Conclusions. Patients selection: Biomarker - driven trials Histotype - tailored trials New treatments: PARPi New outcomes

36 OS remains the most appropriate endpoint in setting with short PPS. Dr. Michele Bartoletti