Expert Roundtable, Michael Seiden, MD, PhD

New Avenues in Ovarian CancerA 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

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

Phase II

•Typically some evidence of activity and toxicity•No placebo

•Still limited evidence of activity in specific clinical situations

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

Phase III PR

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

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

•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

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

Considerable extra time to explain and enroll a patient

RESTRICTIONS

WAITING LIST

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

Health & Medicine

Transcript of Expert Roundtable, Michael Seiden, MD, PhD

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