new directions in treatment of ovarian cancer · 2017. 3. 20. · ovarian cancer amit m. oza...
TRANSCRIPT
![Page 1: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/1.jpg)
New Directions in Treatment of Ovarian Cancer
Amit M. Oza
Princess Margaret Hospital University of Toronto
![Page 2: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/2.jpg)
Newly diagnosed: scenario
Ist line
• Surgery
• chemotherapy
Cure
![Page 3: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/3.jpg)
If can’t cure – can we turn into chronic disease?
Ist line 2nd line 3rd line
![Page 4: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/4.jpg)
BRCA Histology Genomic Signature
Patient group
Drug toxic but beneficial
Drug NOT toxic and NOT beneficial
Same diagnosis, same prescription
Drug NOT toxic and beneficial
Drug toxic but NOT beneficial
![Page 5: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/5.jpg)
Ovarian Cancer • Approach - understand
the biology – Its not one disease
– Origins - fallopian, GI, endometriosis
– “Seed, soil and nourishment”
• Improve precision of diagnosis and treatment
![Page 6: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/6.jpg)
• Define populations and treat according to profile
• Determine activity which is clinically meaningful – Appropriate control for
reference
• Characterize responders and resistant patients
Targeted
Therapy
Synthetic
Lethality Genomic Signature
VEGF, Tie 2, IGF1R Parp inhibition and Wee 1 Profiling
![Page 7: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/7.jpg)
Personalized therapy or precision therapy
Current targeting activities
• Pathology based trials – Define population - but
control may also fare better
• Activation pathways
• Homologous Recombination deficiency
• P53 mutations
• Receptor targeting
• Immunotherapy
Challenges
• Genomic instability and chaos
• Heterogeneity: temporal and spatial
• Resistance and sensitivity
• Macro-environment
![Page 8: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/8.jpg)
Targeted therapies in ovarian cancer.
Banerjee S , and Kaye S B Clin Cancer Res 2013;19:961-
968
©2013 by American Association for Cancer Research
![Page 9: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/9.jpg)
Histologic subtypes of epithelial ovarian carcinoma and associated mutations/molecular
aberrations. *, CHK2, BARD1, BRIP1, PALB2, RAD50, RAD51C, ATM, ATR, EMSY, Fanconi
anemia genes.
Banerjee S , and Kaye S B Clin Cancer Res 2013;19:961-
968
©2013 by American Association for Cancer Research
![Page 10: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/10.jpg)
Clinical Trials
• The rigorous testing to safely assess toxicity and activity of new treatments
• To compare new therapies with established to show if improve outcomes – Do women live longer
– Do they have a longer period of time without disease
– Do they feel better and have better quality of life
– How safe is it – risk vs benefit?
![Page 11: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/11.jpg)
Conducting a clinical trial
• Protocol • Has to be approved by Health Canada, Hospital • Has to have independent approval from an ethics
board • Risks and benefits explained clearly to patients • Has to be conducted to Good Clinical Practice
standards – Protocol has to be followed exactly – Side effects and activity measured accurately and
promptly
![Page 12: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/12.jpg)
How does a new drug get approved for use in Canada? Clinical Trials
Regulatory Approval – Health Canada
Provincial Approval and Funding
How long?
Strength of the evidence?
Restrictions on use?
![Page 13: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/13.jpg)
Surgery
Chemotherapy Biology - novel
therapies
•Improve our understanding of biology. •Design the right studies. •Individualize therapy. •Measure improvement in outcomes that make sense
![Page 14: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/14.jpg)
Why we do trials at PMH
• To improve treatment and outcome: Cure and Control
• Offer new therapies to patients
• To learn how best to introduce new treatment
• Carefully assess risks and benefits – Close monitoring in early stages
– Make sure risks are minimized
– Learn how to manage side effects
– Communicate with peers internationally
![Page 15: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/15.jpg)
Whats new, whats hot – but don’t forget the tried and tested…
• Anti-angiogenics – first line, second line
• Parp and DNA repair inhibitors
• Improving drug delivery – precision bombing
• Disrupting cancer cell’s internal machinery for messaging and growth
• Immune approaches
• Using viruses against the cancer
• Combinations of the above
![Page 16: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/16.jpg)
So what approaches can we take?
• Modulate the micro-environment
• Leverage potential for synthetic lethality
• Target driver mutations.
• Exploit unique expression on cells
• Immunologic approaches
• Remember the macro-environment.
![Page 17: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/17.jpg)
Treatment modalities
Surgery
Chemotherapy
Chemotherapy
Surgery
Chemotherapy
![Page 18: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/18.jpg)
Chemotherapy after surgery
• Any disease visible?
• Is there a role for intraperitoneal chemotherapy?
• What type of iv chemotherapy?
• Every 3 weeks or weekly?
• New drugs?
![Page 19: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/19.jpg)
Improving personalization and precision in ovarian cancer
• Understanding genetic susceptibility: BRCA
• Use available treatments more effectively
• Use new treatments
![Page 20: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/20.jpg)
New agents in maintenance
Anti-angiogenics
• Bevacizumab – Concurrent with
chemotherapy and continue beyond chemotherapy in first line
– Delays recurrence
– Improves survival in women at high risk
– 5-9months on average
• Pazopanib – Start after chemotherapy
– Delays recurrence
Parp inhibitors
• Delay recurrence if given post chemotherapy
• Effect greatest in women with BRCA mutations
• Oral, generally well tolerated
• Several trials for women with and without BRCA mutations
– First line
– Second/subsequent line platinum sensitive
![Page 21: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/21.jpg)
Rationale •Ovarian cancer secretes protein to control blood vessel growth •This protein makes vessels leaky – ascites •Can be targeted in many ways
![Page 22: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/22.jpg)
3 initial studies in 150 women
5 studies in 5000 women
Anti-angiogenic treatment
![Page 23: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/23.jpg)
Anti-angiogenics Bevacizumab
• PFS
• OS in high risk
ICON7
• PFS
GOG 218
• PFS
• Not OS
Oceans
• PFS
• Crossover Design
Aurelia
•4 RP3 studies – positive
•Outcome related to disease burden
•Duration of therapy?
•When to initiate bevacizumab?
•Bev – combinations
•Approval in Europe
•First line
•Second line sensitive
![Page 24: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/24.jpg)
Anti-Angiogenics
GOG 218 PFS
ICON7 •PFS
•?OS in high risk
Oceans •PFS
•Not OS
Aurelia •PFS
•Cross over
AGO-Ovar 16 Pazopanib
Trinova 1 AMG386
Bevacizumab 4 RP3 studies – positive
Duration of therapy?
When to initiate bevacizumab?
Bev – combinations
Pazopanib AGO-Ovar 16
Trebananib – AMG386 Trinova 1 – ECCO 2013
? BIBF 1120
![Page 25: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/25.jpg)
Bevacizumab (Avastin) Fi
rst
Lin
e Delays recurrence
Improves survival in women at highest risk
Seco
nd
Lin
e With chemotherapy
Delays recurrence of disease
In r
esi
stan
t re
curr
ence
With chemotherapy
Delays recurrence
May improve survival in some settings
![Page 26: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/26.jpg)
Parp Inhibitors: Olaparib, Niraparib, Veliparib, Rucaparib
• Oral pills/capsules
• Well tolerated, manageable side effects
• Active in women with BRCA mutations
• Active in women with high grade serous cancers (PMH)
• How should drug best be incorporated in therapy
– With chemo?
– On its own following chemotherapy?
– Which groups of women?
![Page 27: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/27.jpg)
23 mm
Strong family history
Ovarian BRCA1-/-
![Page 28: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/28.jpg)
So what approaches can we take? Exploiting unique expression on cells.
Target driver mutations.
Modulate the micro-environment
Leverage potential for synthetic lethality
Exploit unique expression on cells
Immunologic approaches
Remember the macro-environment.
FR FR
An
ti-F
R a
nti
bo
dy
con
juga
ted
wit
h c
he
mo
FR
tagged
po
rph
ysom
es
load
ed
with
che
mo
the
rapy
![Page 29: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/29.jpg)
Folate Receptor Expression
![Page 30: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/30.jpg)
30
Folate receptor targeting: Endocyte Trial
Platinum resistant ovarian cancer patients (failed first or second platinum therapy < 6 months)
2:1
EC145 + Doxil®
Doxil® only
Receptor Scan
2.5mg TIW wks 1, 3
50 mg/m2 (IBW) every 28 days
n= 640 patients
![Page 31: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/31.jpg)
High-dose IL-2 Tumor excision
Expand Cells
Dudley et al Science (2002) 298; 850 J Clin Oncol (2005) 22;2346 J Clin Oncol (2008) 26;5233 Gattinoni L, et al 2006) Nat. Rev. Immunol. 6:383.
Transfer into treated patients (1010 – 1011 cells)
Culture T cells
Test T cell specificity
30-70 % objective response
22% complete responders
Adoptive T cell Therapy
Pam Ohashi
![Page 32: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/32.jpg)
Initiation and Progression of HGS Bowtell: 2010
HGS
• Genomic instability – Associated with improved
outcome
• Aneuploidy: common in OC
• High expression of PLK4 – Centrosome/centriole
duplication and segregation
• PLK4 inhibitor: CFI400945
![Page 33: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/33.jpg)
Circulating DNA Murtaza, Rosenfeld, Brenton et al.
Science Translational Med Nature
![Page 34: New Directions in Treatment of Ovarian Cancer · 2017. 3. 20. · Ovarian Cancer Amit M. Oza Princess Margaret Hospital University of Toronto . Newly diagnosed: ... •Anti-angiogenics](https://reader035.vdocuments.mx/reader035/viewer/2022063015/5fd373df312130083854b29a/html5/thumbnails/34.jpg)
PMH Foundation NCI OICR