expert roundtable, michael seiden, md, phd
TRANSCRIPT
The US Oncology Network is supported by McKesson Specialty Health. © 2016 McKesson Specialty Health. All rights reserved.
New Avenues in Ovarian CancerA Roundtable Discussion
Michael Seiden M.D. Ph.D.
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Translational Research in Ovarian Cancer
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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)
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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
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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
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Gene Mutations in Serous Cancer
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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)
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Circulating DNA and Tumor Cells
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Clinical Research
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Clinical Trials 101
Phase I Phase II Phase III Phase IV
Post Approval Trials
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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
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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
PRO
S
CO
NS
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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
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PRO
S
CO
NS
Phase II
•Typically some evidence of activity and toxicity•No placebo
•Still limited evidence of activity in specific clinical situations
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Phase III
• Usually designed to challenge the standard of care or gain approval of new drug
Taxol, Carboplatin and New DrugTaxol and Carboplatin
Woman with first recurrence of Ovarian Cancer>6 months from completion of platinum
Outcomes• Response rates & time till tumor progresses
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Phase III PR
OS
CO
NS • 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
The US Oncology Network is supported by McKesson Specialty Health. © 2016 McKesson Specialty Health. All rights reserved.
The US Oncology Network is supported by McKesson Specialty Health. © 2016 McKesson Specialty Health. All rights reserved.
Parp Inhibitors
• Olaparib• Approved for women with BRCA-1/2 mutations
and 3 or more prior lines of chemotherapy• Niraparib• Rucaparib• Velaparib• Talazoparib• E7449
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AKT Pathway
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AKT Inhibitors
• Pilaralisib• MK-2206• TAK-228• AZD5363• GSK2110183
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Inhibitors to Interesting Enzymes
• Acalabrutinib• Sorafenib• Cabozantinib • Masitinib mesylate• Cediranib• MK-1775/ AZD1775• ENMD-2076• NMI900• Selumetinib• Ganetespib
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Evaluating Breast Cancer Drugs
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Breast Cancer Drugs
• Ibrance• Margetuximab• Neratinib• Ribociclib• Abemaciclib• Acolbifene• Seribantumab
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Blocking Blood Vessels
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Inhibiting Blood Vessels
• Ramucirumab• Trebananib• Fosbretabulin• Cediranib• BNC105• VB-111
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Monoclonal Antibodies
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Antibodies to Interesting Molecules
•Sacituzumab Govitecan-Anti EGP•Bavituximab-Phosphatidylserine•Glembatumumab vedotin•Demcizumab•Olaratumab•PankoMab-GEX
•IMAB027•hu3S193•TRC105•Monalizumab•Mirvetuximab soravtansine
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Immune Therapy
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Immuno-oncology
Tumors have mechanisms to silence the immune system
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Immuno-oncology
Improved survival in the most common type of lung cancer
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PD-1 and PD-1 Inhibitors
• Atezolizumab• Pembrolizumab• Nivolumab• Avelumab• Durvalumab
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Clinical Responses to Pembrolizumab Treatment and Mismatch Repair
Le DT et al. N Engl J Med 2015;372:2509-2520
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Clinical Responses to Pembrolizumab Treatment
Le DT et al. N Engl J Med 2015;372:2509-2520
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Vaccines
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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
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Immune Enhancers
• Yervoy• Tremelimumab• Epacadostat• Motolimod• Gen-1• Ovax• Ampligen
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CAR-T Cells
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Stem Cell Poisons?
Stem Cell Theory
Early Drugs • Odomzo• BBI503
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Virotherapy
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Avatar Models
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Clinical Trial Challenges
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FAC
T
FIC
TIO
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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
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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
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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
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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