Verona, 18.01.2019
Principal changes in clinical trials involving patients with Ovarian Cancer
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
From “one-size-fits-all” trials to tailored trials.
1. Patients:
• Biomarker – driven trials (BRCA 1-2 status)
• Histotype – driven trials
Ovarian cancer is not a single disease.
Vaughan et al Nat Rev Cancer (2011)
About 70% of patient with OC have a HGSOC.
Konstantinopoulos PA et al. Cancer Discov. 2015;5:1137-54
HRD~50%
BRCA 1-2 status is a prognostic biomarker in patients with HGSOC.
Bolton KL et al. JAMA. 2012;307(4):382–389.
SOLO-1: a trial designed for BRCA 1-2 carriers.
Moore K et al. N Engl J Med 379;26(2018).
Moore K et al. N Engl J Med 379;26(2018)
SOLO-1 PFS
BRCA 1-2 is a predictive biomarker for PARPi therapy.
NiCC trial recruit patients with Clear Cell cancers of the ovary AND endometrium.
clinicaltrials.gov/ct2/show/NCT03317951
High incidence of KRAS mutation in LGSOC.
clinicaltrials.gov/ct2/show/NCT02101788
LGSOC seems to respond to anti-hormonal therapy.
clinicaltrials.gov/ct2/show/NCT03531645
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..)
GOG-111 (2000) GOG-158 (2003)
Chemotherapy: standard of care for 20 years.
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)
clinicaltrials.gov/ct2/show/NCT01379989
Chemo- based trials: a closed area of interest? Of course NO.
Antiangiogenic – based trials and new standard of treatment .
Bevacizumab
Nintedanib, Pazopanib
Antiangiogenic – based trials: ICON 7 trial.
Perren TJ et al. N Eng J Med. 2011;365:2484-2496
Antiagiogenic drugs + PARPi: rational.
Norman C. et al. Clin Cancer Res (2010)
Antiagiogenic drugs + PARPi: ongoing trial.
PARPi-based trials: present and future of RCTs.
PARPi: active disease setting.
Single agent therapy with immune checkpoint inhibitors in OC.
1. Hamanishi J et al. J Clin Oncol. 2015;33(34):4015-4022; 2. Varga A et al. ASCO 2015. Abstract 5510; 3. Matulonis U et al. ASCO 2018; 4. Disis ML et al. ASCO 2016.
Abstract 5533; 5. Infante J et al. ESMO 2016. Abstract 871P; 6. Hodi et al. 2008.
Nivolumab1 Pembrolizumab (KEYNOTE-28)2
Pembrolizumab (KEYNOTE-100)3
Avelumab4 Atezolizumab5 Ipilimumab6
Anti-PD1 Anti-PD1 Anti-PD1 Anti-PD-L1 Anti-PD-L1 Anti-CTLA4
Patients 20 26 376 124 12 9
N. Prior Therapy
≥4 (55%) ≥3 (65%) A: 1-3 B: 4-6
≥3 (58%) >6 (58%) >1
% PDL-1 + 80% [IHC] 100% [IHC] 62%
CPS
<1/>1(>10)
77% 83% /
ORR 15% 11.5% 8%
(17.3%CPS>10)
9.7% 25% 10%
PARPi combination therapy: anti-PD1/PDL1 + PARPi.
Konstantinopoulos et al. ESMO 2017 Madrid; Poster: 1143 PD
Combination of PARPi and Checkpoint-inhibitors in Xenograft.
LS. Jiao et al., Clin. Cancer Res. 2017; 23:3711-3720
Trials testing combination treatments with PARPi + iCKPI in OC.
New standard treatments in clinical practice means new control arms in trials.
1. Patients:
2. Intervention:
3. Comparison
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).
The change’s price: complexity
1. tyuu
2. Intervention:
3. Complexity:
• Procedural
• Clinical (Immuno AEs)
Complexity: a possible menagement
Teamwork
Outcomes and measure of outcomes (endpoints).
1. Patients:
2. :
3. Comparison
4. Outcomes
SOLO-1 PFS
SOLO - 1: the best PFS ever seen.
Crossover and post-progression treatments could dissolve PFS benefit.
U. Matulonis et al. Cancer (2015 )
Intermediate endpoints (PFS2 and TSST) can provide supportive evidence for a PFS benefit.
U. Matulonis et al. Cancer (2015 )
Principal changes in clinical trials involving patients with Ovarian Cancer?
Conclusions.
• Patients selection:
• Biomarker - driven trials
• Histotype - tailored trials
• New treatments:
• PARPi
• New outcomes
OS remains the most appropriate endpoint in setting with short PPS.
Dr. Michele Bartoletti michele.bartoletti@cro.it