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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?