Expert Roundtable, Michael Seiden, MD, PhD

The US Oncology Network is supported by McKesson Specialty Health. © 2016 McKesson Specialty Health. All rights reserved.
New Avenues in Ovarian Cancer
A Roundtable Discussion
Michael Seiden M.D. Ph.D.

Translational Research in Ovarian Cancer

Biology of Ovarian Cancer - 3 treatment categories
Epithelial cancers (majority)
Stromal or sex cord tumors (about 5%)
Germ cell tumors (about 5% and the female
equivalent to testicular cancer)

Ovarian Cancers
Serous Several distinct
subtypes
Perhaps some
subtypes (Her-2
positive and negative)
Perhaps some subtypes
(some like serous, some
like clear cells)
Likely at least 2 subtypesClear Cell
Endometriod
Mucinous

Challenges in Science
Intra-tumor genetic variability
Limited knowledge of best treatment for each
subtype of epithelial ovarian cancer
Complexity of the genetics - Most
known about serous tumors
Genetic evolution

Gene Mutations in Serous Cancer

Does your Tumor have Microsatellite Instability?
Things to Consider
Seen in patients with Lynch Syndrome
Seen in a subset of patients with clear cell tumors
Consider trial with PD1 or PDL-1 inhibitor (nivolomab (Opdivo),
pembrolizumab (Keytruda), or atezolizumab, (Tencentriq)

Circulating DNA and Tumor Cells

Clinical Research

Clinical Trials 101
Phase I Phase II Phase III Phase IV
Post Approval
Trials

Phase I
• Typically in patients with extensive prior therapy and usually
platinum resistant tumors
• Earliest trials, example single agent-difungomuctane
• Later Phase I involve novel drug mixed with standard agent-
example-difungomuctane with carboplatin
Dose
Level 1
3 Patients
Dose
Level 2
3 Patients
Dose
Level 3
3 Patients
Dose
Level 4
3 Patients
Toxicity

Phase I
Pros • Risk are often
uncertain
• Drug effectiveness
often uncertain
• Might get good drug
but at too low of a dose
• Might get a good drug
but at a toxic dose level
• Might get a drug that
proves completely
ineffective
• Careful monitoring
• Earliest access to a
new drug
• Increasing success in
Phase I trials especially
if molecular screening
is required
PROS
CONS

Phase II
• Typically looks to define the activity and toxicity of a new agent in a
well defined patient population
• Sometimes randomizes patients between 2 new agents or
alternatively one agent delivered over two different schedules in a
pick the winner design
• Typically sets either a response rate or time to progression as
defining an agent as “interesting and worthy for further study”
• Active agents typically progress next to Phase III
13

PROS
CONS
Phase II
•Typically some
evidence of activity
and toxicity
•No placebo
•Still limited evidence
of activity in specific
clinical situations
14

Phase III
• Usually designed to challenge the standard of care or gain
approval of new drug
Taxol, Carboplatin and
New Drug
Taxol and Carboplatin
Woman with first recurrence of Ovarian Cancer
>6 months from completion of platinum
Outcomes
• Response rates & time till tumor progresses

Phase III
PROS
CONS
• Randomized
• In at least 50% of
phase III studies,
experimental arm is
no better than
standard therapy
• More time and effort
than standard therapy
• Typically getting
either the standard of
care or that same
therapy and a new
agent with
considerable data
supporting its further
evaluation
• Potential access to a
new drug

Parp Inhibitors
• Olaparib
• Approved for women with BRCA-1/2 mutations
and 3 or more prior lines of chemotherapy
• Niraparib
• Rucaparib
• Velaparib
• Talazoparib
• E7449

AKT Pathway

AKT Inhibitors
• Pilaralisib
• MK-2206
• TAK-228
• AZD5363
• GSK2110183

Inhibitors to Interesting Enzymes
• Acalabrutinib
• Sorafenib
• Cabozantinib
• Masitinib mesylate
• Cediranib
• MK-1775/ AZD1775
• ENMD-2076
• NMI900
• Selumetinib
• Ganetespib

Evaluating Breast Cancer Drugs

Breast Cancer Drugs
• Ibrance
• Margetuximab
• Neratinib
• Ribociclib
• Abemaciclib
• Acolbifene
• Seribantumab

Blocking Blood Vessels

Inhibiting Blood Vessels
• Ramucirumab
• Trebananib
• Fosbretabulin
• Cediranib
• BNC105
• VB-111

Monoclonal Antibodies

Antibodies to Interesting Molecules
•Sacituzumab Govitecan-
Anti EGP
•Bavituximab-
Phosphatidylserine
•Glembatumumab vedotin
•Demcizumab
•Olaratumab
•PankoMab-GEX
•IMAB027
•hu3S193
•TRC105
•Monalizumab
•Mirvetuximab soravtansine

Immune Therapy

Immuno-oncology
Tumors have mechanisms to silence the immune system

Immuno-oncology
Improved survival in the most common type of lung cancer

PD-1 and PD-1 Inhibitors
• Atezolizumab
• Pembrolizumab
• Nivolumab
• Avelumab
• Durvalumab

Clinical Responses to Pembrolizumab
Treatment and Mismatch Repair
Le DT et al. N Engl J Med 2015;372:2509-2520

Clinical Responses to Pembrolizumab Treatment
Le DT et al. N Engl J Med 2015;372:2509-2520

Vaccines

Vaccines
•Vigil
•Cvac
•DPX-Survivac
•GEN-1
•Ovapuldencel-T
•Globo-H-GM2-sTn-TF-
Tn
•TVI-Ovary-1
•P53-SLP
•DPX-0907
•CRS-207
•Enadenotucirev
•GALE-301
•Globo822
•TroVax
•Monalizumab

Immune Enhancers
• Yervoy
• Tremelimumab
• Epacadostat
• Motolimod
• Gen-1
• Ovax
• Ampligen

CAR-T Cells

Stem Cell Poisons?
Stem Cell Theory
Early Drugs
•Odomzo
• BBI503

Virotherapy

Avatar Models

Clinical Trial Challenges

FACT
FICTION
Clinical Trials: Fact and Fiction
•Only 4% of patient
enter clinical trials
•Recent study
suggests only 35% of
patients would
consider trials
•Only 40% have a
positive attitude
towards clinical trials
•Most trials contain
placebos or sugar pills
•Most trials are only for
patients who have no
other options

Patient Concerns in the MSKCC Survey
•Worries over feeling
like “guinea pigs”
Worry over side effects / safety
Uncertainty about insurance
and out-of-pocket costs
Inconvenience of trial
locations
•Concerns about
getting a placebo
Skeptical of a treatment
that is not yet proven to
work

Considerable extra time to
explain and enroll a patient
RESTRICTIONS
WAITING LIST
TIME
Other Barriers to Clinical Trial
Serious medical illnesses
may preclude patients
“Waiting list” or pretrial testing
could delay treatment

Closing Comments
• Many drugs and scientific developments in active development
• Still much basic science on cancer is needed
• Pharma is an important partner to engage
• Speed of progress is partially dependent on patients participating in
clinical trials
• Thank you for your advocacy

Expert Roundtable, Michael Seiden, MD, PhD

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