1. Clinical and Research Updates in Gynecologic Oncology
Michelle Boisen, MD
Assistant professor of Gynecologic oncology
Magee-Womens Hospital of UPMC

2. Gynecologic Cancer in the United States
American Cancer Society, 2017

3. Gynecologic Cancer in the United States
New Cases
Cancer Deaths
Ovary
22,440
14,080
Uterus
61,380
10,920
Cervix
12,820
4,210
Vulva
6,020
1,150
Vagina
4,810
1,240
American Cancer Society, 2017

4. Gynecologic Cancer in the United States
American Cancer Society, 2017

5. Ovarian Cancer
Surgery and chemotherapy are the cornerstones of treatment
Brief timeline of treatment advancements
1980s: Platinum therapy becomes standard backbone of treatment
1990s: Taxane therapy improves survival when combined with platinum
2000s: IP chemotherapy demonstrates a survival advantage over traditional IV therapy
2010s: Neoadjuvant chemotherapy and dose dense chemotherapy become part of standard of care
2010s: Avastin becomes the first targeted therapy approved to treat ovarian cancer

6. Ovarian Cancer: Innovations in Treatment
PARP Inhibitors
Mechanism of action
BRCA positive patients
Banafif et al., 2015

7. Ovarian Cancer: Innovations in Treatment
FDA Approves 3 PARP inhibitors for treatment in women with ovarian cancer
Olaparib, 2015
Studied as both a maintenance therapy and as a treatment for recurrence
Has shown effect in patients with both BRCA mutations (germline and somatic) and BRCA wild-type
Approval in patients with BRCA germline mutations with recurrent cancer after 3 lines of prior therapy
Rucaparib, 2016
Approval for patients with BRCA mutation (germline or somatic) and recurrent cancer after 2 lines of prior therapy
Also shows promise for patients with defects in other homologous recombination pathways

8. Ovarian Cancer: Innovations in Treatment
FDA Approves 3 PARP inhibitors for treatment in women with ovarian cancer
Niraparib
Approval as a maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer after platinum-based treatment
Ongoing questions:
What is the “best” patient population in which to use a PARP inhibitor?
How do we identify patients without BRCA mutations most likely to benefit from PARP inhibitors?

9. Ovarian Cancer: Innovations in Treatment
What about molecular targets?
TCGA, 2011

10. Ovarian Cancer: Innovations in Treatment
Immunotherapy in ovarian cancer
Immune-based approaches to the treatment of ovarian cancer include:
Monoclonal antibodies
Vaccines
Immune cellular therapy
Immune checkpoint blockade
Limited studies have shown some efficacy, 20-40% response rates
How do we define response with these drugs?
More studies are needed to define the patients most likely to respond and how to harness the potential of these drugs in ovarian cancer

11. Development History and FDA Approval Process for Keytruda
Cancer Immunotherapy
Development History and FDA Approval Process for Keytruda
                                                           
Mar 15, 2017
FDA Approves Merck’s Keytruda (pembrolizumab) for Classical Hodgkin Lymphoma (cHL)
Oct 24, 2016
FDA Approves Merck’s Keytruda (pembrolizumab) for First-Line Treatment of Certain Patients with Metastatic Non-Small Cell Lung Cancer
Aug  5, 2016
FDA Approves Merck’s Keytruda (pembrolizumab) for Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
Dec 18, 2015
FDA Approves Expanded Indication for Keytruda (pembrolizumab) for the Treatment of Patients with Advanced Melanoma
Oct  2, 2015
FDA Approves Keytruda (pembrolizumab) for Advanced Non-Small Cell Lung Cancer
Sep  4, 2014
FDA Approves Keytruda (pembrolizumab) for Advanced Melanoma
Sep  2, 2014
Merck to Present New Data in Five Tumor Types from Studies Evaluating Pembrolizumab
Jun 30, 2014
Merck’s Investigational Anti-PD-1 Antibody, Pembrolizumab, Under Regulatory Review in Europe for Advanced Melanoma

12. PD-1 and PD-L1
To keep T-cell action of killing “foreign” cells in check, there is a natural stop signal
Tumor cells use over-expression of PD-L1 to “turn off” T-cell and evade natural immune response
By blocking PD-1 or its ligand, the tumor cell can no longer evade the action of the T-cell, because it remains “on

13. Endometrial Cancer: Innovations in Treatment
Trials ongoing to establish the optimal treatment for high-intermediate risk, high risk, and advanced endometrial cancers:
GOG249: What is the optimal treatment for early stage, high-intermediate and high-risk endometrial cancers?
GOG261: What is the optimal chemotherapy regimen for patients with uterine carcinosarcoma?
PORTEC3: What is the role of chemotherapy in high-risk, early stage endometrial cancer?
GOG258: How should chemotherapy and radiation therapy be given to women with advanced stage endometrial cancers after surgery?
GOG238: What is the best therapy for pelvic recurrence of endometrial cancer?
The role of sentinel lymph node evaluation in endometrial cancer?

14. Endometrial Cancer: Innovations in Treatment
Molecular characterization of endometrial cancers
The Cancer Genome Atlas
POLE subtype
Copy-number low
MSI (hyper-mutated)
Copy-number high (p53)
Frequent mutations in:
PI3K/PTEN/mTOR
RTK/RAS/beta-catenin
TCGA, 2013
Stelloo et al., 2015

15. Endometrial Cancer: Innovations in Treatment
Other targets:
Angiogenesis (VEGF)
Her2/neu
Hormonal targets
Immunotherapy
NEJM, 2015
Pembrolizumab, PD1 inhibitor
40% response rate in MSI tumors
2 patients with endometrial cancer, 1 with complete an 1 with partial response
Growing evidence of high response rates to immune checkpoint inhibition in POLE mutated tumors
Bartlett et al., 2015

16. Cervical Cancer: Innovations in Treatment
GOG240
First trial to demonstrate an overall survival benefit with bevacizumab in a gynecologic cancer
4 month survival advantage in the patients who rec’d bevacizumab
Tewari et al., 2014

17. Rare Gynecologic Tumors
Vulvar cancer
Sentinel lymph node mapping
First gynecologic malignancy where sentinel node mapping has become standard of care
Minimizes surgical recovery and morbidity for the patient
GROINSS VII
Is a full lymph node dissection necessary in patients with positive sentinel nodes?
May allow us to avoid the increased risks with full lymph node dissection with radiation

18. Rare Gynecologic Tumors
Vulvar cancer: targeted therapies
Many vulvar tumors express EGFR, a transmembrane protein receptor that can drive tumor growth
Horowitz et al., 2012
Erlotinib, EGFR inhibitor
27.5% partial response rate and 40.0% stable disease rate
Small sample size, but an option for patients with metastatic disease
Case reports of response to cetuximab (EGFR antagonist)

19. Targeted Therapies, the Future of Cancer Treatment?
Courtesy of Dr. Matt Powell

20. Summary
With a better understanding of disease biology, we have a better sense of how targeted therapies might work
Challenging to move a single targeted therapy to advanced phase clinical trials
Many are static and not cytotoxic
Many tumors have multiple mutations
Need to determine how to harness the potential of these drugs, potentially in combination with other targeted agents or cytotoxic drugs

21. Questions?