I trials clinici: cosa sta cambiando?

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%

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 [email protected]