Download Clinical and Research Updates in Gynecologic Oncology

Clinical and Research Updates
in Gynecologic Oncology
MICHELLE BOISEN, MD
ASSISTANT PROFESSOR OF GYNECOLOGIC
ONCOLOGY
MAGEE-WOMENS HOSPITAL OF UPMC
Gynecologic Cancer in the United States
American Cancer Society, 2017
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
Gynecologic Cancer in the United States
American Cancer Society, 2017
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
Ovarian Cancer: Innovations in Treatment
 PARP Inhibitors
 Mechanism of action
BRCA positive
patients
Banafif et al., 2015
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

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 platinumsensitive 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?
Ovarian Cancer: Innovations in Treatment
 What about molecular targets?
TCGA, 2011
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
Cancer Immunotherapy
Development History and FDA Approval Process for
Keytruda
Mar 15, 2017
FDA Approves Merck’s Keytruda (pembrolizumab) for Classical
Hodgkin Lymphoma (cHL)
FDA Approves Merck’s Keytruda (pembrolizumab) for FirstOct 24, 2016 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
FDA Approves Expanded Indication for Keytruda
Dec 18, 2015 (pembrolizumab) for the Treatment of Patients with Advanced
Melanoma
Oct 2, 2015
FDA Approves Keytruda (pembrolizumab) for Advanced NonSmall 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
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 overexpression 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
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, highintermediate 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?
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
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
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
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

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)

Targeted Therapies, the Future of Cancer
Treatment?
Courtesy of Dr. Matt Powell
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
Questions?