Learning from sensitivity and resistance in ovarian cancer trials - - PowerPoint PPT Presentation
The whole of science is nothing more than a refinement of everyday thinking Albert Einstein Learning from sensitivity and resistance in ovarian cancer trials June 2, 2017 Stephanie Lheureux, MD PhD Clinician Investigator Drug
June 2, 2017
Stephanie Lheureux, MD PhD
Clinician Investigator – Drug Development Program Staff Medical Oncologist, Gyne Medical Oncology Department of Medicine Princess Margaret Cancer Centre Assistant Professor, Faculty of Medicine, University of Toronto
“The whole of science is nothing more than a refinement of everyday thinking”
Albert Einstein
Lheureux S, Oza AM 2017
– Patients with a BRCA1/2 mutation receive greater treatment benefit – Non-mutation carriers may also benefit from olaparib treatment
Time from randomization (months)
1.0
Proportion of patients progression-free
3 6 9 12 15
Olaparib BRCAm Olaparib BRCAwt
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 BRCAm (n=136) BRCAwt (n=118) Olaparib Placebo Olaparib Placebo Median PFS, months 11.2 4.3 7.4 5.5 HR=0.18 P<0.00001 HR=0.53 P=0.007 BRCAm (n=136) BRCAwt (n=118) Olaparib Placebo Olaparib Placebo Median PFS, months 11.2 4.3 7.4 5.5 HR=0.18 P<0.00001 HR=0.53 P=0.007
Placebo BRCAm Placebo BRCAwt
Ledermann J et al,. Lancet 2014
Pujade Lauraine E et al., SGO 2017
Pujade Lauraine E et al., SGO 2017
Levine, D. The Cancer Genome Atlas 2011
NO HR DEFICIENCY HR DEFICIENCY
RECIST ORR: 36% RECIST ORR: 16% RECIST ORR: 75%
Swisher EM et al., Lancet Oncology 2017
BRCAwt
Treatme nt PFS Median (95% CI) (Month s) Hazard Ratio (95% CI) p-value % of Patients without Progression
12 mo 18 mo Nirapari b (N=71) 9.3 (5.8, 15.4) 0.38 (0.231, 0.628) p=0.000 1 45 % 27 % Placebo (N=44) 3.7 (3.3, 5.6) 11 % 6% Treatme nt PFS Median (95% CI) (Month s) Hazard Ratio (95% CI) p-value % of Patients without Progression
12 mo 18 mo Nirapari b (N=35) 20.9 (9.7, NR) 0.27 (0.081, 0.903) p=0.024 8 62 % 52 % Placebo (N=12) 11.0 (2.0, NR) 19 % 19 %
sBRCAmut
NR=Not reached
Treatme nt PFS Median (95% CI) (Month s) Hazard Ratio (95% CI) p-value % of Patients without Progressio n or Death 12 mo 18 mo Nirapari b (N=92) 6.9 (5.6, 9.6) 0.58 (0.361, 0.922) p=0.022 6 27 % 19 % Placebo (N=42) 3.8 (3.7, 5.6) 7% 7%
HRD-positive
HRD-negative
Mirza MR et al. NEJM 2016
Lheureux S et al, CCR 2017
OLALA Study
Lheureux S et al, CCR 2017
Giornelli GH, Springerplus 2016 McGranahan N, Cell. 2017
Given the evolutionary capabilities of tumors, monitoring disease evolution to guide therapeutic interventions and to understand evolutionary trajectories of individual tumors has become a vital research area.
McGranahan N, Cell. 2017
McGranahan N, Cell. 2017
NEJM 2017 April
Jamal-Hanjani M et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1616288
Instability appears to be the predominant driver of parallel evolution and can lead to both mutational and copy-number diversity among subclones.
free survival Patients who have early-stage tumors with high levels of copy-number heterogeneity may represent a high-risk group who may benefit from close monitoring and early therapeutic intervention during follow-up.
inform strategies to limit tumor adaptation in the clinical setting.
Gelmon et al. Lancet Oncol 2011
OLALA Study
20 40 60 80 Position (Mb) 0.5 1.0 1.5 2.0 Depth Ratio
BRCA1 Expression Log2(TPM+1) 0.5 1.0 1.5 2.0 2.5 BRCA1 Cancer Cell Fraction 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
Primary Progression
8 1 1 BRCA1 LOH p53 R248W HRD Signature 11 12 15 18 19 1A 20 3 4 6 7 16
Legend:
Signature CNVs+SNVs 25% 10% 5%
Primary Progression
Unknown Surgery Recurrence Platinum-based chemotherapy Gemcitabine chemotherapy Olaparib
HGSOC Initial diagnosis
2005 2006 2008 2013 2015 CA125 level over time
Death
January 2009 Radiation 30 Gy in 10 fractions June 2009 At the start of
June 2010 Response on
December 2012 Isolated spleen progression July 2015 At progression
20 40 60 80 100 500 3500 6500 9500 12500 15500
UI/mL
Biopsy
1997
X) ry n
CCNE1 Expression Log2(TPM+1) 0.5 1.0 1.5 2.0
Lheureux S et al, JCO 2017
PATIENT 1
Primary Progression
Cancer Cell Fraction 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 12 19 1 7 BRCA2 LOH
5 5 5
BRCA2 Expression Log2(TPM+1) 0.5 1.0 1.5 2.0 2.5 3.0
)
PARP1 Expression Log2(TPM+1) 1 2 3 4 5 15 1A 10
Legend:
Signature CNVs+SNVs 25% 10% 5% Unknown
2002 2008 2015
HGSOC Initial diagnosis August 2008 At the start of olaparib January 2009 Response on olaparib April 2015 At progression on olaparib
CA125 level over time
200 400 50 100
UI/mL
Surgery Recurrence Platinum-based chemotherapy Olaparib Biopsy
Lheureux S et al, JCO 2017
PATIENT 2
Primary
Cancer Cell Fraction 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
A
BRCA1 W353*
HRD Signature
12 1B 1A 3 4 7
Legend:
Signature CNVs+SNVs 25% 10% 5% Unknown BRCA1 LOH
2009 2016
HGSOC Initial diagnosis
June 2009 At the start of
August 2016 complete response on
CA125 level over time
20 40 60 80 100
UI/mL
Surgery Recurrence Platinum-based chemotherapy Olaparib
Copy-Number Allele-A: Allele-B: 0.5 1.0 1.5 2.0 Chromosome Position (Mb) 20 40 60 80 BRCA1 W353*
1 2 3 4 chr1 chr2 chr3 chr4 chr5 chr6 chr7 chr8 chr9 chr10 chr11 chr12 chr13 chr14 chr15chr16chr17 chr18 chr19 chr20 chr21 chr22 chrX
Allele-A: Allele-B:
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X
Chromosome
Primary Copy-Number 1 2 3 4
Chromosome 17 H&E Initial diagnosis
Lheureux S et al, JCO 2017
PATIENT 3
Trial design: Determining whether a cancer driver event occurs early or late can indicate whether it is involved in tumor initiation or maintenance, and its clonality may inform potential therapeutic strategies Trial correlatives: Integration in clinical trial – Time biopsies Biomarkers in practice: Well defined, Reproducible, Robust, Sensitive, Clinically meaningful, cost effective assay, time impact Technique: Biomarkers test Type of tissue
Discovery Preclinical validation Clinical trials Clinical practice