Advances in the Management of Ovarian Cancer: Highlights from the 2014 ASCO Annual Meeting

This activity is supported by independent educational grants from AstraZeneca Pharmaceuticals LP and Genentech.

EditorsAngeles Alvarez Secord, MDProfessor Department of Obstetrics and Gynecology Division of Gynecologic OncologyDuke Cancer InstituteDuke University Health SystemDurham, North Carolina

Don S. Dizon, MD, FACPMedical Gynecologic Oncology and Oncology Sexual HealthMassachusetts General Hospital Cancer CenterAssociate Professor (Pending)Harvard Medical SchoolAssociate Professor of Obstetrics & Gynecology Associate Professor of MedicineThe Warren Alpert Medical School of Brown UniversityBoston, Massachusetts

Advances in the Management of Ovarian Cancer: Highlights from the 2014 ASCO Annual Meeting

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TABLE OF CONTENTS (CLICK THE SECTION YOU WISH TO VIEW)

INTRODUCTION ......................................................................................................................................... 1

INCORPORATING PARP INHIBITORS INTO TREATMENT ......................................................................... 1

PARP Inhibition and Anti-Angiogenesis in Recurrent Platinum-Sensitive Ovarian Cancer ................ 1

Biomarker Correlates of Response to Cediranib and Olaparib .........................................................................4

Olaparib in Combination With Weekly Carboplatin and Paclitaxel in Relapsed Ovarian Cancer ...... 4

Predicting Response to PARP Inhibitors ............................................................................................... 5

CLARIFYING THE ROLE OF ANTI-ANGIOGENESIS IN OVARIAN CANCER ................................................ 6

Response to Bevacizumab in Molecularly Defined Subgroups ........................................................... 6

Molecular Subtypes in the United Kingdom Cohort of ICON7 .........................................................................6

Molecular Subtypes in the German Cohort (AGO-OVAR11) of ICON7 ...........................................................7

Genomic Alterations During Pazopanib Treatment .......................................................................... 10

Pazopanib With Weekly Paclitaxel in Platinum-Resistant or Refractory Disease ............................. 10

THERAPY FOR RARE OVARIAN CANCER SUBTYPES .............................................................................. 11

Genotype Matched Treatment in Advanced Type I Epithelial Ovarian Cancer ................................ 11

Paclitaxel/Carboplatin vs Cisplatin/Irinotecan in Newly Diagnosed Clear Cell Carcinoma ............. 13

Molecular Profiling in Clear Cell and Late-Stage Ovarian Cancer ..................................................... 15

IMMUNOTHERAPY .................................................................................................................................. 15

Anti-PD-1 Antibody in Platinum-Resistant Ovarian Cancer .............................................................. 15

Mucin-1 Autologous Dendritic Cell Therapy in Ovarian Cancer Patients ......................................... 17

CONCLUSION ............................................................................................................................................ 19

POST-TEST AND EVALUATION ................................................................................................................. 20

REFERENCES ............................................................................................................................................. 20


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MEDIA: NEWSLETTEREstimated time to complete activity: 1.0 hourRelease date: Wednesday, July 30, 2014 | Expiration date: Wednesday, July 29, 2015

INTRODUCTIONThe 2014 American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago, Illinois, provided a comprehensive review of key experimental and clinical data. Included in this newsletter are highlights from the conference covering major plenary sessions, key symposia, and targeted oral and poster presentations on the advances in the management of ovarian cancer.

EDITORSAngeles Alvarez Secord, MD Professor Department of Obstetrics and Gynecology Division of Gynecologic OncologyDuke Cancer InstituteDuke University Health SystemDurham, North Carolina

TARGET AUDIENCE The target audience for this activity is medical oncologists, gynecologic oncologists, hematologist/oncologists, surgeons, radiation oncologists, pathologists, oncology pharmacists, and other allied healthcare professionals caring for patients with ovarian cancer.

EDUCATIONAL OBJECTIVESAt the conclusion of this activity, participants should be able to:

• Discuss updated efficacy and toxicity data for clinically available treatment options for patients with ovarian cancer• Incorporate clinical data describing new therapeutic agents or strategies into clinical practice to improve response and survival rates for patients with

ovarian cancer• Correlate toxicity and tolerability data for therapeutic agents used to treat ovarian cancer with their impact on patient quality of life • Describe the proposed mechanisms of action of new and emerging therapeutic agents in development for the management of patients with ovarian

cancer• Explain the implications of genetic analysis and biomarkers on treatment selection and response as they currently relate to patients with ovarian cancer

DESIGNATION OF CREDITPHYSICIAN CONTINUING EDUCATION Accreditation Statement

Educational Concepts Group, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation Statement Educational Concepts Group, LLC designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

METHOD OF PARTICIPATIONThere are no fees for participating and receiving CME credit for this activity. During the period Wednesday, July 30, 2014 through Wednesday, July 29, 2015, participants must 1) read the educational objectives and faculty disclosures; 2) study the educational activity; 3) complete the post-test and evaluation.

Don S. Dizon, MD, FACPMedical Gynecologic Oncology and Oncology Sexual HealthMassachusetts General Hospital Cancer CenterAssociate Professor (Pending)Harvard Medical SchoolAssociate Professor of Obstetrics & Gynecology Associate Professor of MedicineThe Warren Alpert Medical School of Brown UniversityBoston, Massachusetts

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CME CREDITPhysicians who complete the post-test with a score of 80% or better may view and print their credit letter or statement of credit via the website, www.ecgcme.com.

POLICY ON DISCLOSUREIt is the policy of ECG that the faculty, authors, planners, and other persons who may influence content of this CME activity disclose all relevant financial relationships with commercial interests in order to allow ECG to identify and resolve any potential conflicts of interest.

The Following Faculty Members Have Declared Relevant Financial Relationships

Angeles Alvarez Secord, MD Grants/Research Support and Salary Relationships Consultant Fees

Astellas Pharma US, Inc., Astex Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Eisai Inc., Genentech, Incyte Corporation, Precision Therapeutics, Inc., sanofi-aventis, TESARO, Inc.

Boehringer Ingelheim Pharmaceuticals Inc., Genentech, GlaxoSmithKline, Precision Therapeutics, Inc.

Don S. Dizon, MD, FACP Salary Relationships UpToDate, Inc. STAFF DISCLOSUREPlanners and managers at ECG have no relevant financial relationships to disclose.

ACKNOWLEDGEMENTThe editors wish to thank Steven F. Candela, PhD and Sara R. Fagerlie, PhD, CCMEP for assistance in writing this document.

DISCLOSURE OF OFF-LABEL USEThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. ECG does not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity do not necessarily represent the views of ECG. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Please refer to the official prescribing information for each product or consult the Physicians’ Desk Reference for discussion of approved indications, contraindications, and warnings.

ACKNOWLEDGEMENT OF COMMERCIAL SUPPORTThis activity is supported by independent educational grants from AstraZeneca Pharmaceuticals LP and Genentech.

CME INQUIRIESFor further information, please contact:Educational Concepts Group, LLC 1300 Parkwood Circle SE, Suite 325Atlanta, Georgia 30339Phone: 1.866.933.1681 | Fax: 1.866.933.1692www.ecgcme.com

None of the contents may be reproduced in any form without prior written permission from the publisher. This activity may be accessed at www.ecgcme.com.

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INTRODUCTIONImproving outcomes for patients with ovarian cancer remains an urgent public health need. Estimates suggest that in 2014, more than 14,000 deaths in the United States will be attributed to this disease. Ovarian cancer is the 5th leading cause of cancer-related death among women and the leading cause of gynecological-cancer fatality.1 Over the past 10 to 15 years, neither the sequential addition of non-cross resistant agents to standard chemotherapy with carboplatin and paclitaxel nor the use of triplet combination chemotherapies have led to improved outcomes in ovarian cancer. This has shifted development away from such approaches and towards the incorporation of molecularly targeted and biological therapies with standard chemotherapy.2

At the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, a number of studies focused on personalized treatment for patients with ovarian cancer. Important themes included the development of PARP inhibitors, potential predictors of response to anti-angiogenic agents, and the role of immunotherapeutic agents as treatment for the disease. Therapy for rare ovarian cancers was also given particular attention. A unifying theme to this year’s ovarian-related work mirrored that of the Annual Meeting itself, as a greater emphasis was placed on the emerging use of molecular analyses and genotypic information to guide treatment with all therapies. While many of this year’s ASCO results were preliminary and require further validation, they suggest the future treatment landscape for ovarian cancer will include an increased set of therapeutic options and improved personalized treatment selection.

INCORPORATING PARP INHIBITORS INTO TREATMENT Poly (ADP-ribose) polymerase (PARP) enzymes, are a family of proteins involved in a number of critical cellular processes, including repairing DNA damage.3 PARPs, are primarily involved in correcting single-strand breaks (SSBs) in DNA via the base excision repair pathway.4 Blocking DNA repair via PARP inhibition has been regarded as a promising anti-cancer approach, and multiple strategies for preventing PARP-mediated DNA repair are being pursued in clinical trials.

BRCA mutation-associated ovarian cancers are an attractive target for PARP inhibitors because they are deficient in another DNA repair mechanism, homologous recombination. As a result, BRCA mutated cells rely on PARP to repair DNA damage, and the application of PARP inhibitors may result in synthetic lethality.5 Other high-grade tumors of the ovary, including serous and grade 3 endometrioid cancer, appear to have defects in DNA repair that mirror those of BRCA mutation-associated ovarian cancer. As such, PARP inhibitors are also being explored in these tumors, to take advantage of their phenotypic BRCAness.4

PARP Inhibition and Anti-Angiogenesis in Recurrent Platinum-Sensitive Ovarian CancerData from a study evaluating the oral combination of the PARP inhibitor, olaparib, and the anti-angiogenic tyrosine kinase inhibitor, cediranib, were among the more exciting results presented at the 2014 ASCO Annual Meeting.6 In vitro preclinical data previously demonstrated that the activity of cediranib with olaparib was synergistic against ovarian cell lines compared to either agent alone, which may be due, in part, to decreases in angiogenesis following PARP inhibition.7 Additionally, the sensitivity to PARP inhibition may be increased in hypoxic cells.8 Finally, both cediranib and olaparib have shown activity in ovarian cancer.9-11

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A previously reported phase I dose escalation study of the combination yielded an overall response rate (ORR) of 44% (8 of 18 patients) in patients with recurrent ovarian cancer, with 3 patients experiencing stable disease that lasted 6 months or longer.12 At the 2014 ASCO Annual Meeting, Dr Joyce Liu presented results from a randomized phase II trial comparing the efficacy of this combination versus olaparib alone in women with recurrent platinum-sensitive ovarian cancer.6

This study enrolled women with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer, with platinum sensitivity defined as the absence of recurrence within 6 months of the last course of platinum. All eligible patients had high-grade serous or endometrioid histology; however, patients with other histologic subtypes were allowed as long as the patient had a documented deleterious germline BRCA mutation. Patients previously treated with a PARP inhibitor (any setting) or anti-angiogenic therapy were excluded. There was no limit on prior platinum-based therapies received prior to study entry and up to 1 non-platinum-based line of therapy in the recurrent setting allowed. In addition, patients were required to have measurable disease by RECIST version 1.1.

All patients were randomized on a one-to-one basis to the combination of daily cediranib and olaparib or daily olaparib alone and treated until disease progression (Figure 1). Patients were stratified by BRCA status and prior anti-angiogenic therapy. Computed tomography (CT) or magnetic resonance imaging (MRI) was performed every 8 weeks. The primary objective of the study was progression-free survival (PFS).

Patient characteristics were relatively well balanced across treatment arms, although there was a trend towards more prior

therapeutic lines and higher baseline CA125 scores in the olaparib arm (Table 1). After a median patient follow-up of 16.6 months (range 0.4 months to 28.5 months), the combination of cediranib with olaparib significantly increased PFS compared to olaparib alone (median PFS, 17.7 months vs 9.0 months; HR = 0.42 [95% CI 0.23-0.76]; P = 0.005) (Figure 2). Secondary efficacy analyses demonstrated that the combination

Olaparib (n = 46)

Cediranib/Olaparib (n = 44) P

Age, median (range) 58.1 (32.7-81.9) 57.8 (41.9-85.6) 0.33

ECOG Performance Status 0 1

34 (73.9%)12 (26.1%)

31 (70.5%)13 (29.5%)

0.82

BRCA mutation status Carrier Non-carrier Unknown

24 (52.2%)11 (23.9%)11(23.9%)

23 (52.3%)12 (27.3%)9 (20.5%)

0.92

Prior anti-angiogenic therapy No Yes

40 (87.0%)6 (13.0%)

38 (86.4%)6 (13.6%)

1.00

Prior platinum-free interval 6-12 months > 12 months

26 (56.5%)20 (43.5%)

23 (52.3%)21 (47.7%)

0.83

Number of prior lines 1 2 3+

17 (37.0%)18 (39.1%)11 (23.9%)

26 (59.1%)10 (22.7%)8 (18.2%)

0.11

Baseline CA125 (range) 115.3 (10.9-11,512.0) 68.0 (4.0-1,351.0) 0.08

Table 1. Patient characteristics in the phase II trial comparing cediranib with olaparib to olaparib alone.

Platinum-sensitive recurrent

ovarian cancer

Ran

dom

ized

1:1

Followed until disease progression

by RECIST 1.1 criteria

Olaparib400 mg BID

Cediranib 30 mg daily

+ Olaparib

200 mg BID

Figure 1. Design of the phase II trial comparing cediranib and olaparib to olaparib alone.

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of cediranib and olaparib led to a 79.6% ORR compared with a 47.8% in the olaparib alone arm. Overall survival (OS) data was not yet mature and was not presented.

Post-hoc analyses examined the activity of the combination in patients with and without BRCA mutations. In BRCA mutation carriers, PFS differences were more modest and not statistically significant: median PFS was 19.4 months in mutation carriers who received the combination therapy, versus 16.5 months in those who received olaparib alone (HR = 0.55 [95% CI 0.24-1.27]; P = 0.16). In those without a BRCA mutation, however, the combination of cediranib and olaparib significantly increased PFS, with a median PFS of 16.5 in the combination arm compared with 5.7 months in the single agent olaparib arm (HR = 0.32 [95% CI 0.14-0.74], P = 0.008).

Treatment-related adverse events of grade 2 or higher in either arm are summarized in Table 2. Combination therapy significantly increased the incidence of non-hematologic events such as hypertension, diarrhea,

Figure 2. Progression-free survival (primary endpoint) in the phase II trial comparing cediranib and olaparib to olaparib alone.

1.0

0.8

0.6

0.4

0.2

0.0

20 2510 1550 30

3 024 1137441 013 62646

21

+ Censored

Olaparib Ced/Olap28 19

9.0 moPFS eventsMedian PFS 17.7 mo

Prop

ortio

n Pr

ogre

ssio

n-Fr

ee

Months

P = 0.005HR 0.42 (95% CI: 0.23-0.76)

Treatment Assignment 1: Olaparib 2: Olaparib Cediranib

Olaparib

Cediranib/Olaparib

Table 2. Treatment-related adverse events in the phase II trial comparing cediranib + olaparib with olaparib alone.

Adverse Event

Olaparib Alone (n = 46) Cediranib/Olaparib (n = 44)

Maximum Grade Maximum Grade

2 3 4 2 3 4

Non-Hematologic

Hypertension -- -- -- 15 (34) 17 (39) 1 (2)

Diarrhea -- -- -- 20 (46) 10 (23) --

Fatigue 7 (15) 5 (11) -- 12 (27) 12 (27) --

Nausea 12 (26) -- -- 7 (16) 2 (5) --

Headache -- -- -- 4 (9) 2(5) --

Hypothyroidism 1 (2) -- -- 6 (14) -- --

Hematologic

Anemia 2 (4) -- -- 1 (2) -- --

Neutrophil count decreased 4 (9) -- -- 2 (5) -- --

WBC decreased 3 (7) -- -- 2 (5) -- --

Platelet Decreased -- -- -- 1(2) -- --

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and fatigue (non-hematologic adverse events did not significantly differ in frequency). The toxicities were predominantly secondary to cediranib. Toxicities were managed with anti-diarrheal medicines, dose-reduction, and/or withholding treatment. Dose reductions occurred in 77% of patients (34 of 44) in the combination arm compared with 24% (11 of 46) in the olaparib alone arm. Four patients, all on the combination arm, withdrew from the study due to toxicity. All other reasons for study withdrawal occurred in balanced proportions between the arms.

In conclusion, the combination of cediranib and olaparib was more active than olaparib alone in women with recurrent platinum-sensitive ovarian cancer, significantly improving both PFS and ORR (with OS results pending). The duration of median PFS at 17.7 months with the combination was quite impressive. Anti-tumor activity was observed in both patients with and without BRCA mutation. Dr Liu noted that the toxicity profile was acceptable and generally manageable. In aggregate, these data support additional clinical evaluation of the cediranib and olaparib combination in ovarian cancer. Given the promising efficacy results, 2 concepts are currently being developed in the NRG Oncology (Gynecologic Oncology) Cooperative Group to evaluate the combination in women with either platinum-sensitive or platinum-resistant ovarian cancer.

Biomarker Correlates of Response to Cediranib and OlaparibIn a companion poster presentation, Dr Jung-min Lee presented results of a biomarker analysis of the same phase II trial. The study examined the levels of inhibition in tumor vascularity and VEGF pathways following treatment in both arms and assessing the relationship of changes in these biomarkers to response rate and PFS.13 Blood samples were collected at baseline and day 3 from a self-selected subset of 13 eligible patients. These blood samples were used to measure circulating endothelial cells (CEC), circulating endothelial progenitor cells (CPC), and cytokine concentrations. On day 3, compared with patients receiving olaparib alone, patients receiving both cediranib and olaparib had a greater decrease in IL-8 (P = 0.016) and a median 3.5-fold increase in CEC (P = 0.013). The increase in number of CEC on day 3 correlated with a PFS greater than 6 months in 6 patients receiving the combination therapy (R2 = 0.91 [95% CI 0.47-099]; P = 0.001). Dynamic-contrast enhanced magnetic resonance images of the tumors in the full subset of patients were also assessed, but no statistically significant changes nor correlations were found in the small subset.

Olaparib in Combination With Weekly Carboplatin and Paclitaxel in Relapsed Ovarian CancerDr Saul Rivkin presented the results of a phase Ib/II study of olaparib plus weekly carboplatin and paclitaxel designed to establish the maximum tolerated dose (MTD) and evaluate dose-limiting toxicities (DLTs) and response to therapy with this combination in patients with advanced relapsed ovarian cancer.14

Patients with measurable disease, adequate organ function, and ECOG performance status of ≤ 2 who had failed first-line platinum-containing chemotherapy were eligible for the study. Subjects received metronomic therapy with paclitaxel 60 mg/m2 and carboplatin AUC2 weekly, 3 weeks out of 4, with increasing doses of olaparib (starting at 50 mg bid) orally for the first 3 consecutive days every week of each cycle. Subjects received combination therapy until DLT was reached, or until disease progression. In this trial, the MTD was found to be olaparib 150 mg bid.

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Of the 14 patients (median age of 58; median previous therapies of 4) enrolled in the phase Ib part of the study, there were no deaths due to study regimen or any grade 4 toxicities. The most common grade 3 toxicities were neutropenia, lymphopenia, anemia, fatigue, and MDS (1 patient each). Complete remission was seen in 4 subjects, 3 of whom were BRCA positive. Partial remissions occurred in 3 subjects, 2 of whom were BRCA positive and 1 of whom was variant. Stable disease occurred in 3 subjects, 2 of whom were BRCA positive. Two subjects had progressive disease (1 was BRCA positive) while 2 subjects were not evaluable. Thus, this trial suggested that olaparib can be safely administered with a weekly regimen of carboplatin and paclitaxel in heavily pretreated ovarian cancer patients.

Predicting Response to PARP InhibitorsAdditional 2014 ASCO Annual Meeting presentations further examined the issue of who responds to PARP inhibitors. Multiple lines of preclinical and clinical data suggest the efficacy of PARP inhibitors is not limited to only those with BRCA mutations, suggesting that other HR repair association genes in addition to BRCA1/2 may contribute to PARP inhibitory response. Further, not all patients with BRCA mutations respond to a PARP inhibitor.

Dr Stephanie Lheureux and her colleagues illustrated the response of women with ovarian cancer without BRCA mutations using a retrospective meta-analysis made up of patients with recurrent ovarian cancer from monotherapy and maintenance trials in the olaparib clinical program.15 In these analyses, 197 out of 372 (53%) patients were treated with olaparib for less than 6 months, and 169 out of these 197 patients had BRCA mutations. Specific outcome data from ovarian cancer patients treated with maintenance olaparib or olaparib in combination with chemotherapy followed by maintenance are summarized in Table 3. Although many long-term responders to olaparib had BRCA mutations, there were also several long-term responders with no known mutation, as well as, those with BRCA mutations who did not respond to olaparib. The clinical and molecular characterization of both sets of these patients is necessary to improve understanding of response and resistance to PARP inhibitors.

Dr Brian Dougherty and colleagues provided preliminary insight into non BRCA1/2 genes that may be associated with long-term response to olparib.16 This group reported on the exploratory characterization of genetic change in tumors from patients in an olaparib maintenance trial by examining the frequency and co-occurrence of mutations in BRCA1/2 and other genes impacting the HR repair pathway, as well as examining the presence of these mutations in patients with a long-term response. The proportion of patients with non-BRCA1/2 HRR gene mutations was relatively small in this study. However, among 33

Table 3. Impact of olaparib treatment based upon mutational status (meta-analysis across olaparib trials).

Treatment DurationOlaparib Maintenance Study

400 mg bid capsule monotherapyOlaparib + Carboplatin/Paclitaxel→Olaparib Maintenance

Patients All BRCAm BRCA wt/vus BRCA missing AllBRCAm OC subgroup

BRCA wt/vus subgroup

BRCA missing OC subgroup

n 136 74 57 5 81 20 34 27

< 6 months 49 (36%) 21 (28.4%) 25 (43.9%) 3 (60%) 19 (23.5%) 0 11 (32.4%)8

(29.6%)

> 24 months 32 (23.5% 21 (28.4%) 11 (19.3%) - 17 (21%) 11 (55%)3

(8.8%)3

(11.1%)

wt, wild-type; vus, variant of unknown significance.

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gene-sequenced long-term responders (treated with olaparib > 2 years), some candidate genes were identified that may play a potential role in prolonged treatment benefit and extended survival on either platinum or PARP inhibitors, including BRIP1, RAD51B, FANCL, PTEN, and MSH2. Further research will be needed to determine if these biomarkers can be used to direct PARP inhibition therapy.

CLARIFYING THE ROLE OF ANTI-ANGIOGENESIS IN OVARIAN CANCERSeveral anti-angiogenic agents have demonstrated improved PFS and in some cases improved OS in women with advanced as well as recurrent ovarian cancer.2,17 There is intense interest in biomarker development to identify predictive or prognostic markers of response to anti-angiogenic drugs in order to optimize patient selection and treatment benefit.14

Response to Bevacizumab in Molecularly Defined Subgroups Molecular Subtypes in the United Kingdom Cohort of ICON7The ICON7 study previously demonstrated that the addition of bevacizumab (continued for 12 months) to carboplatin and paclitaxel as first-line treatment of ovarian cancer significantly improved PFS, but not OS, compared to carboplatin and paclitaxel alone. For patients at high risk for disease progression (suboptimal stage III and stage IV disease at baseline), the addition of bevacizumab yielded a greater PFS improvement compared to the overall population and significantly improved OS (7.8-month increase in median OS in the bevacizumab-containing arm).18 At the 2014 ASCO Annual Meeting, Dr Gourley and colleagues further examined response in ICON7 by upon molecular subtype. The study focused on high-grade serous ovarian cancer (HGSOC) in Scotland and the UK to identify molecular subtypes that may eventually facilitate personalization of care.19

An initial discovery phase included mRNA extraction from 265 macrodissected formalin fixed paraffin embedded HGSOCs from Scottish patients who had been treated (outside of the ICON7 trial) with primary debulking surgery followed by platinum-based chemotherapy. Transcriptional analysis was performed using microarray chips containing 100,000 biologically relevant transcripts. In order to use gene expression to classify similar tumors together, unsupervised hierarchical clustering was performed on these data.

Three major subgroups were identified: an angiogenesis subgroup defined by high expression of genes involved in vascular development and angiogenesis (25% of the sample), an immune gene subgroup defined by high expression of immune response genes but low expression of angiogenesis genes (31%), and an angioimmune subgroup with high expression of both types of genes (44%). The immune response subgroup had significantly improved PFS and OS compared with the other 2 subgroups (Figure 3). A unique 63-gene signature was identified to differentiate the “immune response” tumors from tumors in the other 2 subgroups. This signature was independently validated in 152 HGSOCs from the Tothill dataset,20 which demonstrated that following treatment with paclitaxel and carboplatin, patients with tumors defined by an immune response genetic signature had better PFS and OS compared with patients with tumors from the other 2 molecular subgroups.

The researchers then applied these results to a cohort from the ICON7 trial, hypothesizing that in the immune molecular subtype, characterized by the absence of angiogenic biology, anti-angiogenic treatment would be less beneficial.

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In total, 284 samples of HGSOC from ICON7 patients who had consented to translational research were available for analyses; samples came from all participating ICON7 countries except Germany. The genetic signature remained prognostic in the ICON7 control arm, with patients in the immune subgroup of that arm having significantly longer PFS and OS compared to patients in the other molecular subgroups.

There were differences between the subgroups with regard to PFS impact among patients in the bevacizumab-containing arm (Figure 4A). Patients in the immune subgroup (41% of the sample) had inferior PFS when treated with bevacizumab, whereas patients in the pro-angiogenic subgroup (59% of the sample) trended toward superior PFS with bevacizumab treatment. A significance test for interaction (P = 0.015) indicated there was a significantly different response in the 2 molecularly defined subgroups. Moreover, in the immune subgroup, the addition of bevacizumab was associated with worse OS (HR = 2.00 [1.11-3.61]). There was no OS difference in the pro-angiogenic subgroup (Figure 4B).

These data suggest that the immune subtype may be harmed by the incorporation of bevacizumab into treatment. In contrast, women with a pro-angiogenic subtype may benefit from bevacizumab. These data need to be prospectively confirmed in a well-designed clinical trial, but these promising results suggest we eventually may be better able to predict the most appropriate patients for bevacizumab treatment.

Molecular Subtypes in the German Cohort (AGO-OVAR11) of ICON7In conceptually similar analyses, Dr Winterhoff and colleagues examined the German Cohort of ICON7 (AGO-OVAR11) to identify molecular subtypes or features of patients that might benefit from bevacizumab treatment.21 Subtyping by Winterhoff et al was based upon the previously-reported molecular subtyping of high-grade serous ovarian cancer as published by The Cancer Genome Atlas (TCGA), which identified 4 molecular subtypes: differentiated, immunoreactive, mesenchymal, and proliferative.22 This analysis was replicated in a Mayo Clinic study of 173 patients with high grade serous cancer, demonstrating that ovarian cancer of the proliferative and mesenchymal subtypes have the worst OS. These data suggest

Figure 3. (A) Progression-free and (B) overall survival in Scottish patients with high grade serous ovarian cancer.

100

60

20

0

40

80

80 10040 60200 120 160 180140 200

Surv

ival

Pro

babi

lity

(%)

Time (Months)

Angiogenesis subgroupAngioimmune subgroupImmune subgroup

Immune vs AngioimmuneImmune vs Angio

0.600.64

0.44 - 0.820.45 - 0.92

0.0020.02

HR 95% CI P valueImmune vs AngioimmuneImmune vs Angio

0.580.55

0.41 - 0.820.37 - 0.80

0.0010.001

HR 95% CI P value

100

60

20

0

40

80

80 10040 60200 120 160 180140 200 220 240

Surv

ival

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babi

lity

(%)

Time (Months)

Angiogenesis subgroupAngioimmune subgroupImmune subgroup

A. B.

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that these 2 subtypes represent a molecular high-risk group.23 Furthermore, both the proliferative and mesenchymal subtypes have genetic upregulation of pro-angiogenic signatures, and, thus may derive more benefit from anti-angiogenic therapy. The study utilized whole genome arrays and AGO-OVAR 11 samples to determine if response to bevacizumab differed by molecular suptype.21 The analysis consisted of 359 patients with available paraffin samples who were successfully genetically analyzed and whose diagnosis of ovarian, fallopian tube, or primary peritoneal cancer was confirmed by central pathology review. The TCGA subtyping was successfully reproduced in this cohort of 359 patients. Baseline characteristics of the 359 patients in this cohort are summarized in Table 4. Of note, both the proliferative and mesenchymal molecular subtypes had higher rates of stage 3 and stage 4 disease at baseline, and the rates of optimal debulking were lower in these 2 molecularly defined subtypes. Thus, based on the clinical characteristics previously identified by the ICON7 investigators,18 more patients in the mesenchymal and proliferative subgroups were at a high risk of progression than in the other 2 molecular subgroups; even still, almost 60% of the patients in the proliferative and mesenchymal subtype groups had molecular signatures indicating high risk for progression but were not identified as high risk per clinical characteristics.

Figure 4. (A) Progression-free and (B) overall survival by molecular subtype in the United Kingdom Cohort of the ICON7 trial.

Carboplatin, PaclitaxelCarboplatin, Paclitaxel, Bevacizumab

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Immune Subgroup Non-Immune (pro-angiogenic) Subgroup

Immune Subgroup Non-Immune (pro-angiogenic) Subgroup

A.

B.

Test for Interaction, P = 0.015

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The addition of bevacizumab to standard therapy extended PFS more for ovarian cancer patients with molecular subtypes labeled as “proliferative” or “mesenchymal” compared to those with subtypes labeled as “immunoreactive” or “differentiated,” (Table 5). Similar differences were seen between subtypes in terms of OS (Table 5). Additional analyses were conducted limiting the sample to only serous, high-grade histologies, as the original TCGA subtyping was described for these histologies alone. Again, results in the full subsample were consistent with previous observations, and the strongest signal of benefit was seen in the proliferative high-grade serous subgroup.

In summary, the studies presented by Drs Winterhoff and Gourley demonstrate that molecular subtypes may potentially be used to direct bevacizumab therapy in ovarian cancer. These studies suggest that an “immune” subtype of ovarian cancer

Table 4. Baseline characteristics of the molecularly defined subtypes of the AGO-OVAR11 German cohort from ICON7.

Molecular Subtype Differentiated Immunoreactive Mesenchymal Proliferative

n 73 122 68 96

Stage

I + II 18 (24.6%) 16 (13.1%) 4 (5.9%) 11 (11.5%)

III 44 (60.3%) 91 (74.6%) 50 (73.5%) 66 (68.8%)

IV 11 (15.1%) 15 (12.3%) 14 (20.6%) 19 (19.8%)

Debulking Status

Optimal 59 (80.8%) 99 (81.1%) 48 (70.6%) 68 (70.8%)

Sub-Optimal 13 (17.8%) 22 (18.0%) 20 (29.4%) 28 (29.2%)

Missing 1 (1.4%) 1 (0.8%) 0 (0.0%) 0 (0.0%)

High Risk of Progression (sub-stage III + stage IV)

No 55 (75.3%) 90 (73.8%) 39 (57.4) 56 (58.3%)

Yes 18 (24.7%) 32 (26.2%) 29 (42.6%) 40 (41.7%)

Table 5. Outcomes by subtype in AGO-OVAR11 cohort of ICON7.

Group NMedian ΔPFS With

Bevacizumab HR* for Overall Survival

(95% CI)

Overall Sample 3596.5 mo

P = 0.0040.68 (0.45-1.03)

P = 0.067

Clinical High Risk for Progression 1196.7 mo

P = 0.0060.52 (0.29-0.94)

P = 0.031

Molecular Subtype

Proliferative 9610.1 mo

P = 0.0150.52 (0.25-1.08)

P = 0.074

Mesenchymal 688.2 mo

P = 0.4050.56 (0.23-1.34)

P = 0.187

Differentiated 733.7 mo

P = 0.6101.41 (0.53-3.71)

P = 0.486

Immunoreactive 1223.8 mo

P = 0.0800.76 (0.33-1.76)

P = 0.518

High Grade Serous Only

All HGS 2128.8 mo

P = 0.0010.42 (0.24-0.72)

P = 0.001

Proliferative HGS 6312.8 mo

P = 0.0320.51 (0.2-1.26)

P = 0.136

Mesenchymal HGS 437.2

P = 0.0960.27 (0.08-0.96)

P = 0.30

*< 1.0 favors bevacizumab arm. HGS, high grade serous; PFS, progression-free survival; mo, months; HR, hazard ratio.

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may be harmed by the addition of bevacizumab to standard chemotherapy, while subtypes defined by vascular growth may benefit. Molecular work such as this may ultimately provide ovarian cancer patients with a more precise, patient-driven treatment. Further validation in a phase III biomarker driven trial will determine if molecular classifications can guide personalized treatment with bevacizumab in women with ovarian cancer.

Genomic Alterations During Pazopanib TreatmentAnalysis of subgroups that may or may not benefit from pazopanib anti-angiogenic treatment were also reported. Pazopanib is an oral multi-kinase inhibitor of VEFGR-1, -2, -3, PDGFR-α and -β and c-Kit that has anti-angiogenic properties. Single-agent pazopanib has been shown to be active in recurrent ovarian cancer24 and as maintenance after first-line chemotherapy in advanced ovarian cancer.25 At the 2014 ASCO Annual Meeting, Dr Heitz presented genomic analyses from a sub-sample of patients in AGO-OVAR16/VEG110655,26 a randomized, phase III study that originally demonstrated improved PFS with the use of pazopanib maintenance therapy compared with placebo therapy in women with advanced ovarian cancer who had not progressed after first-line chemotherapy.27

Paired tumor samples from primary surgery and post-progression (same patient) were examined by next generation sequencing to identify genes associated with progression of ovarian cancer or potential biomarkers for and mechanisms of response to pazopanib. In this preliminary analysis, 8 paired samples from patients in the pazopanib arm and 7 in the placebo arm were studied with a comprehensive cancer gene panel (CCP) and 10 paired samples in both arms were analyzed with a BRCA1/2 gene panel.

Fewer genetic alterations of potential damaging variants were observed in the pazopanib arm from the surgical period to post-progression, compared with the placebo arm. In the samples from the placebo arm, the BRCA panel revealed 7 BRCA2 gene changes associated with a loss of function and 3 BRCA1 gene changes associated with a loss of function. Only 1 change was noted from samples from the pazopanib arm, a gain of function in BRCA1 in 1 patient. Twelve potential driver genes were also identified, based upon those genetic aberrations at specific alleles that remained consistent from pre-treatment tumor samples to post-progression tumor samples. Most commonly, these included MLL3, TP53, and FN1. Although preliminary, these types of studies begin to address items needed to move ovarian cancer treatment to a more personalized stage.

Pazopanib With Weekly Paclitaxel in Platinum-Resistant or Refractory DiseaseFinally, results from the MITO11 study comparing pazopanib with paclitaxel to paclitaxel alone in recurrent advanced ovarian cancer were presented by Dr Pignata.28 Seventy-four (74) patients with advanced ovarian cancer who were younger than 75 years, with disease progressing during or within 6 months from the last platinum-based chemotherapy, and an ECOG performance status of 0 or 1, were randomized to either weekly paclitaxel (80 mg/m2 on days 1, 8, and 15 every 28 days) or weekly paclitaxel plus pazopanib 800 mg/day; both treatments could be continued to progression. Median patient age was 57 years, and 76% (n = 56) of patients had platinum-resistant ovarian cancer while 23% (n = 17) had platinum-refractory disease (1 platinum-sensitive patient was enrolled in error). Most of the patients had received 1 (43%) or 2 (49%) previous lines of chemotherapy.

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The addition of pazopanib to paclitaxel led to significant improvement in median PFS (6.3 months vs 3.5 months; HR = 0.42; P = 0.0002) as well as numerically superior but non-statistically significant improvement in OS (secondary endpoint; 19.1 months vs 13.7 months; HR = 0.60; P = 0.056) (Table 6). In addition, 52 patients were eligible for response analysis as per RECIST criteria. The response rate was significantly higher in the pazopanib/paclitaxel arm compared to those who received paclitaxel alone (50% versus 21%, P = 0.03).

Adverse events were more common and more serious with the addition of pazopanib and included higher rates of neutropenia (P = 0.0007), hypertension (P < 0.0001), diarrhea (P = 0.0002), mucositis (P = 0.0007), AST/ALT elevations (P = 0.019), sensory neuropathy (P = 0.025), and other neurologic events (P = 0.023). However, no treatment-related deaths were noted.

These data further confirm the role of anti-angiogenesis agents in ovarian cancer. While the efficacy results were promising, the toxicity profile is quite concerning. As a result, the future of pazopanib development in ovarian cancer remains uncertain, although the results of the MITO-11 study may build the rationale for further evaluation in a larger phase III trial. Currently pazopanib has FDA approval for renal cell carcinoma as well as advanced soft tissue sarcomas (after chemotherapy).

THERAPY FOR RARE OVARIAN CANCER SUBTYPESStandard treatment for ovarian cancers has been largely defined by clinical trials that include a high proportion of patients with tumors of serous histology, who tend to be sensitive to platinum-based chemotherapy. Ovarian tumors with less common histologic subtypes, including Type 1 epithelial ovarian cancers such as low-grade serous, low-grade endometrioid, clear cell carcinoma (CCC), and other histologies tend to be more chemotherapy resistant, leading to poorer outcomes and more dire prognoses.29 Clear cell carcinoma of the ovary, in particular, yields very low response rates to platinum-based therapy.29 The current standard of care for CCC, paclitaxel plus carboplatin, results in generally unsatisfactory outcomes. Alternative regimens for Type 1 epithelial ovarian cancer, in general, and CCC tumors specifically are under active investigation, including novel chemotherapy combinations and the use of molecularly targeted agents.

Genotype Matched Treatment in Advanced Type I Epithelial Ovarian Cancer Genomic alterations that activate the MAPK signaling pathway frequently occur in Type 1 epithelial ovarian cancers, and these alterations may sensitize such cancers to downstream MEK inhibition. In addition, a recent phase II study demonstrated promising anti-tumor activity of MEK inhibitors in low-grade serous EOC.30 Thus, genotyping and next generation sequencing may be useful in identifying actionable mutations in these cancers, and aid in clinical decision making. At the 2014 ASCO Annual Meeting, Dr Anna Spreafico and colleagues retrospectively reviewed outcomes of patients receiving genotype matched treatment at Princess Margaret Cancer Centre.31

Table 6. Survival in the MITO11 phase I study of pazopanib in platinum-resistant or - refractory ovarian cancer.

Paclitaxel(n = 36)

Paclitaxel + Pazopanib(n = 37)

Hazard Ratio (95% CI)P (one-tailed)

Median PFS (months)

3.5 6.30.42 (0.25-0.69)

0.0002

Median OS (months)

13.7 19.10.60 (0.32-1.13)

0.056

PFS, progression-free survival; OS, overall survival; CI, confidence interval.



Among 252 patients with advanced epithelial cancer, 55 (or 22%) had Type 1 EOC. These 55 patients all had an ECOG performance status of 0 or 1, and a median age of 54 years (range 24-74). Low-grade serous was the most common histology (75%), followed by clear cell (16%) and mucinous (9%). The majority of patients (64%) were diagnosed with stage III disease, with the remaining patients having stage I/II (27%) or stage IV (9%) disease. Nearly all patients (96%) received surgery at study entry, with the majority also receiving some sort of systemic therapy including chemotherapy (89% of patients). Molecular profiling was done at a median of 30 months (range 1.2 to 261 months) from diagnosis, reflecting the fact that the majority of patients were diagnosed with early or locally advanced disease. Thirty-five patients (64%) who had an identifiable mutation were compared with 20 patients (or 36%) who did not have a mutation identified during the routine molecular analysis.

In the 35 patients with 1 or more mutation identified (originally with a customized cancer panel; later genotypes were assessed with next generation sequencing using a commercially available kit), the most common mutations included KRAS (found in 57.5% of tumor samples), NRAS (15%), and PIK3CA (12.5%) (Figure 5). Fifteen (43%) patients with mutations were matched to relevant clinical trials based on these genetic analyses, while 20 patients with an identifiable mutation (57%) were not matched to a trial; 6 of these 20 “unmatched” patients (32%) experienced no progression and were still receiving standard of care treatment at the time of data analysis, 2 (10%) declined participation in a matched clinical trial, 4 (21%) were ineligible for matched clinical trials because of poor ECOG performance status, and 7 (37%) were lost to follow up or passed away.

The median age of those matched to therapy (53 years) compared to those unmatched to therapy (57 years) was similar, although those unmatched to therapy had gone a median of 13 weeks between diagnosis and molecular profiling, compared with a shorter period of 9.4 weeks among those matched to therapy, reflective of the fact that the majority of patients unmatched to treatment continued to receive standard of care therapy. KRAS and NRAS were the most common mutations in the subtype of ovarian cancer defined by low-grade serous histology, while PIK3CA was common in patients with CCC.

Responses in the patients matched to treatment in clinical trials were encouraging: 14 of 15 patients matched to therapy responded to treatment, with 13 experiencing tumor shrinkage that ranged from 3 to 62% (Figure 6). RECIST-defined partial responses were seen in 47% of patients, and stable disease in 47% of patients, with disease progression occurring in a single patient with CCC and a PIK3CA mutation matched to a single-agent mTOR inhibitor trial. In addition, 11 of the 15 patients matched to therapy also received a line of therapy immediately prior to the matched clinical trial. Median duration of therapy on the matched therapy was 17 weeks (range 4.3-67) compared with only 9 weeks (range 4-53 weeks) on the immediately prior line of therapy (Figure 7). Two patients with a shorter duration of treatment on the matched therapy compared to the prior line of therapy each discontinued the matched treatment due to adverse events (1 deemed drug-related and the other deemed not drug related).

Figure 5. Most common mutations identified in retrospective review of patients with type I epithelial ovarian cancer treated at the Princess Margaret Cancer Centre.

KRASNRASPIK3CAPTENBRAFAKT1TPS3CTNNB1

57.5%15%12.5%5%2.5%2.5%2.5%2.5%

N = 35

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Although these results come from a retrospective analysis, the results are quite promising. These data should be used to evaluate the feasibility of a genotype-matched clinical trial in ovarian cancer, such as the National Cancer institute’s umbrella trial called the Molecular Analysis for Therapy Choice (NCI-MATCH).

Paclitaxel/Carboplatin vs Cisplatin/Irinotecan in Newly Diagnosed Clear Cell CarcinomaOn behalf of the Japanese Gynecologic Oncology Group (JGOG), Dr Aikou Okamoto presented results from a randomized phase III trial comparing paclitaxel/carboplatin to cisplatin/irinotecan as first-line chemotherapy in patients with CCC of the ovary.32 Clear cell carcinoma is more common in Japan (> 20% incidence) compared to western countries (incidence ~ 5%), and the incidence in Japan appears to be increasing.

Retrospective studies33,34 and a randomized phase II trial35 had suggested that irinotecan was a promising candidate for the treatment of CCC. As a result, JGOG 3017/CGIG was designed as a phase III study randomizing 666 patients with stage I through stage IV ovarian CCC to paclitaxel (175 mg/m2 on day 1) and carboplatin (AUC 6 on day 1, every 3 weeks for 6 cycles) or irinotecan (CPT-11, 60 mg/m2 days 1, 8, and 15) and cisplatin (60 mg/m2, day 1, every 4 weeks for 6 cycles). The primary endpoint of the study was PFS and secondary endpoints included OS, response rate, and adverse events. Eligible patients with stage I to IV CCC enrolled within 6 weeks after surgery who had dominant clear cell histology (> 50%) confirmed by an international central pathology review after registration. The study enrolled 666 patients internationally.

Figure 6. Best tumor shrinkage of target lesions in patients matched to clinical trials based upon mutation status.

20

-20

-60

-80

-40

40

60

0

% C

hang

e Su

m o

f Tar

get L

esio

ns RECIST v 1.1

N = 15Clear cellLow-grade serousMucinous

RR: 47% PR47% SD6% PD

MEK + PI3K K K K K K K K K K K K K K

MEK + IGF-1R K, N

mTOR P

K, KRAS mutation; N, NRAS mutation; P, PIK3CA mutation; RR, response rate; SD stable disease; PD, progressive disease.

Inhibitor:

Figure 7. Duration of genotype-matched treatment vs prior unmatched treatment in patients with type 1 epithelial ovarian cancer.

Low-grade serousClear cell

*Ongoing = 1

Reasons off studyPD = 6Drug-related AEs = 2Drug-unrelated AEs = 2

Immediate Prior Line of TherapyImmediate Prior Line of Therapy Genotype-Matched Therapy (best response)

SDSD

PDSDSDSD

PRPR

SDPR*

PR

Median Duration9 Weeks (range 4-53)

Median Duration17 Weeks (range 4.3-67)

Weeks8162432404856647280 8 16 24 32 40 48 56 64 72 80



In total, 66.4% of patients enrolled in this trial had stage I cancer (Table 7). After 44.3 months median follow-up, compared with paclitaxel and carboplatin, irinotecan and cisplatin was not associated with a significant difference in either 2-year PFS or 2-year OS (Figure 8A and 8B). Subgroup analyses did not identify any group of patients for which the efficacy differed.

Grade 3/4 leukopenia, neutropenia, thrombocytopenia, peripheral sensory neuropathy, and joint pain occurred more frequently in the carboplatin/paclitaxel arm (P < 0.05), while grade 3/4 anorexia, diarrhea, nausea, vomiting, and febrile neutropenia occurred more frequently in the irinotecan-containing arm (P < 0.05).

Thus, in this first CCC-specific international clinical trial, a survival benefit was not observed following the use of CPT-P. Paclitaxel with carboplatin remains a standard of care for CCC. Genuine improvement in the outcomes of CCC may be dependent upon ongoing development of new agents such as mTOR inhibitors, angiokinase inhibitors, or other agents. In addition, an ongoing observational study is attempting to determine if chemotherapy is even necessary in stage I CCC, where prognoses are good.

Figure 8. (A) Progression-free and (B) overall survival in the phase III trial of paclitaxel/carboplatin (TC) vs cisplatin/irinotecan (CPT-P) in clear cell carcinoma.

1.0

0.8

0.6

0.4

0.2

0.0

48 6024 36120 72

99 40223 153255314 396 41232 153267305 3

Pro

babi

lity

Months

HR (95% CI) = 1.171 (0.867, 1.581)Two-sided log rank P value = 0.303

1: CPT-P2: TC

Events/Patients2-year PFS

CPT-P92/31473.0%

TC79/30577.6%

1: CPT-P2: TC

A. 1.0

0.8

0.6

0.4

0.2

0.0

48 6024 36120 72

106 45261 171292314 4107 44261 173293305 4

Pro

babi

lity

Months

HR (95% CI) = 1.133 (0.796, 1.613)Two-sided log rank P value = 0.486

1: CPT-P2: TC

Events/Patients2-year OS

CPT-P66/31485.5%

TC58/30587.4%

1: CPT-P2: TC

B.

PaclitaxelCarboplatin

IrinotecanCisplatin

N 305 314

Age, year (Median [range]) 53 (30-81) 53 (30-75)

Race, n Japanese 281 298

Non-Japanese 24 16

Performance Status (ECOG), n 0 268 291

1 37 23

Stage, n Ia-Ib 49 47

Ic 157 158

II-IV 99 109

Size of residual, n Complete 267 277

Optimal (≤ 1 cm) 19 17

Suboptimal (> 1 cm) 19 20

Table 7. Demographic and baseline characteristics in the phase III trial of paclitaxel/carboplatin versus cisplatin/irinotecan in clear cell carcinoma.

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Molecular Profiling in Clear Cell and Late-Stage Ovarian CancerDr Michael Friedlander and his colleagues36 evaluated over 435 patients with CCC ovarian cancer who were referred to Caris Life Sciences from 2009 to 2014. Specific testing on samples from these tumors was based on physician request and included a combination of sequencing (Sanger, NGS, or pyrosequencing), protein expression (IHC), gene amplification (CISH or FISH), or RNA fragment analysis. Such molecular profiling may identify patient subsets who could benefit from targeted therapies when standard treatment has failed and also provide insight into the genomic heterogeneity of clear cell ovarian cancers that share a similar phenotype.

Patients in these analyses were further grouped into pure CCC (n = 363) and mixed CCC (n = 72). Analyses highlighted the heterogeneity of CCC and the potential role for improving patient selection for clinical trials. In particular:

• Overexpression of TOP2A (61%), TS (52%), TLE3 (48%), loss of TUBB3 (49%), and MGMT (56%) were the most common finding among the CCC samples

• cMET was overexpressed in 19% of pure CCC tested and in 6% of mixed CCCs• Pure CCCs had lower expression of androgen, estrogen, and progesterone receptors (7%, 9%, and

15%) than mixed CCCs (21%, 39%, and 31%) and epithelial ovarian cancers (24%, 45%, and 30%)• In 69 CCCs analyzed by NGS, PIK3CA was the most common mutation (52%) followed by TP53 (16%)

and KRAS (11%)• Mutations in FBXW7 (10%), APC (7%), and ATM (6%) were observed at a higher rate than in all EOCs

In light of these results, the authors suggest drugs that target the mTOR pathway or cMET may have therapeutic potential in selected subsets of patients with clear cell ovarian cancers, while mutations in FBXW7, APC, and ATM may also help direct patients to trials of targeted therapies.

IMMUNOTHERAPY Surgery, radiotherapy, and chemotherapy have long served as the primary treatment modalities for cancer, with biological and targeted therapies entering the landscape relatively recently.37 Despite at least 50 years of interest in engaging the immune system to destroy cancer, the role of immunotherapy against cancer has been relatively limited until the last few years.37 Growing insight into the basic cellular and molecular mechanisms that govern interactions between cancer cells and the immune system has led to the identification of multiple strategies to enhance and improve the immune system’s response to cancer.38 This, in turn, has led to the rapid development of pharmaceutical agents and sophisticated techniques to augment the immune system’s ability to eradicate cancer, including antibodies, cytokines, vaccines, and cellular therapies that can prime or boost the immune system, modulate T-cell response, reduce immunosuppression in the tumor microenvironment, or enhance adaptive immunity.37-39 Exemplified by the success of the immune checkpoint inhibitor ipilimumab, the first agent to deliver a survival advantage in advanced melanoma in a phase III trial, this next generation of immunotherapy appears poised to deliver success against many other tumor types,37-39 including ovarian cancer.

Anti-PD-1 Antibody in Platinum-Resistant Ovarian CancerDr Junzo Hamanishi reported the results of the first clinical application of nivolumab, an anti-PD-1 monoclonal antibody, in ovarian cancer patients.40 The programmed death-1 (PD-1) pathway is part of an immune system pathway that includes the PD-1 receptor, which is engaged by PD-1 ligands



(PD-L1 and PD-L2). PD-1 is a co-inhibitory receptor expressed on activated T-cells that downregulates the activity of T-cells, thus serving as an immune checkpoint. Many types of cancers express PD-L1 and inactivate cancer-specific T-cells, thus escaping from host immunity. A number of PD-1 and PD-L1 antagonists are being developed to treat cancer (Table 8). Nivolumab is a PD-1 inhibitor that blocks the engagement of PD-1 by PD-1 ligands, inhibiting this critical immune checkpoint and potentially potentiating and prolonging the immune response against tumor cells. Approximately 70% of ovarian cancer cells express PD-L1, and the expression of PD-L1 is a poor prognostic factor in this cancer,41

suggesting blockade of the PD-1/PD-L1 pathway may be a useful mechanism of disease control in this cancer.

In the investigator-initiated phase II trial reported by Dr Hamanishi, 20 patients with platinum resistant recurrent or refractory ovarian cancer received nivolumab at either 1 mg/kg every 2 weeks (n = 10), or 3 mg/kg every 2 weeks (n = 10). All patients had epithelial ovarian, tubal, or peritoneal cancer that was platinum resistant, as defined by a platinum-free interval less than 6 months. All patients had also received more than 2 regimens of chemotherapy, including a taxane, and all patients had an ECOG performance status of 0 or 1. Patients with autoimmune disease were excluded. Nivolumumab was given intravenously every 2 weeks for up to one year, with anti-tumor response assessed every 8 weeks (Figure 9).

The median age of the 18 study patients whose data were presented at the 2014 ASCO Annual Meeting was 62 years (range, 49-79). Most patients (n = 13) had stage III ovarian cancer and serous (n = 14) histology. More than half the patients in the study (n = 11) had received at least 4 prior chemotherapy regimens, reflecting a heavily pretreated population.

Most adverse events, including those related to immune activation such as hypothyroidism, were mild. There was no evidence of dose-response relationships in the side effects. Two potentially

treatment-related serious adverse events were reported during the study, including grade 3 disorientation, fever, and gait disorder in 1 patient receiving 1 mg/kg nivolumab and grade 3 fever and deep vein thrombosis in 1 patient receiving 3 mg/kg of study drug.

The response rate in all 18 patients was 17%, reflecting 2 complete responses and 1 partial response; the overall disease control rate was 44% (8/18), reflecting 8 additional instances of stable disease in the study sample. Both the response rate (25%; 2/8 patients) and disease control rate (63%; 5/8 patients) were higher in

Table 8. PD-1 and PD-L1 antagonists in clinical development for the treatment of cancer.

Target Agent

PD-1 Nivolumab (BMS-936558)

Pembrolizumab (lambrolizumab, MK-3475)

Pidilizumab (CT-011)

AMP-224

PD-L1 BMS-936559

Medi4736

MPDL3280A

Figure 9. Study schedule of nivolumab in ovarian cancer patients with platinum-resistant or refractory ovarian cancer.

PD or progression

Nivolumab

Scan Scan Scan

0 2w 4w 6w 8w

1 course 2-6 courses

Every 8 wks

CR, PR, SD48w

Off study

Follow up every

8 wks

•Response rate assessed by RECIST v1.1•Adverse events evaluated by CTCAE v4.0

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Figure 10. Study design of CAN-003, CVac vaccine vs observational standard of care.

Previously cytoreduced

stage III-IV EOC; first or second

remission within 12

weeks of CR Ran

dom

ized

1:1

Control arm Observational standard of care

56 patients(ITT

Population)

Maintenance CVac10 doses (60 x 109 cells/dose)

over 56 weeks (n = 29)Safety run-in

(n = 7)

the 3 mg/kg cohort than in the 1 mg/kg cohort (10% [1/10] and 30% [3/10] response rates and disease control rates, respectively). Examination of response in individual patients suggests that durable response is possible following nivolumab treatment in ovarian cancer.

Thus, in this very preliminary study, nivolumab demonstrated encouraging clinical efficacy for platinum-resistant advanced or relapsed ovarian cancer patients. The drug was well tolerated in this heavily pretreated population, and led to disease control in over 40% of patients. The preliminary response data (17% ORR) was also quite encouraging. Further data from this study is eagerly anticipated.

Mucin-1 Autologous Dendritic Cell Therapy in Ovarian Cancer PatientsOn behalf of the CAN-003 Study Team, Dr Heidi Gray presented the results of a randomized, open-label, phase II study of autologous dendritic cell vaccine therapy against mucin-1 in ovarian cancer patients.42 Mucin 1 (MUC1) is a glycoprotein that represents a potential immunotherapeutic target: its expression is typically 40-fold greater in malignant cells compared with normal tissue, and MUC1 is overexpressed in more than 80% of patients with ovarian cancer.43 In malignant cells, the carbohydrate structure of MUC1 is thought to be altered, exposing regions of the protein not typically exposed, and thus potentially positioning MUC1 as a good target for immunotherapeutics.

CVac is an autologous cellular therapy (derived from a patient’s own blood, and thus a “personalized vaccine”) made by culturing autologous dendritic cells with a MUC1 fusion protein. This vaccine is intended to elicit a killer T-cell response that is specific to MUC1 over-expressing ovarian cancer cells. Two prior studies of the CVac platform (CAN-001 and CAN-002) demonstrated low toxicity and proof of concept, leading to the development of CAN-003. The purpose of CAN-003 was to see if the use of CVac (compared with standard observational care) in patients in first or second remission of ovarian cancer could prevent recurrence and improve outcomes. Primary objectives were to assess safety and PFS; secondary objectives included OS and immunologic response to the vaccine.

The CAN-003 trial was the first trial of CVac where manufacturing of the dendritic cells was relocated from Australia to the United States, and thus, the trial included a non-randomized run-in period, with the first 7 patients receiving CVac in order to perform quality control on the vaccine produced (Figure 10); these patients in the safety lead-in were not included in the statistical analyses. For the remaining 56 patients enrolled in the trial, who comprise the intent-to-treat (ITT) population, CVac or observation began within 10 weeks of enrollment. Patients on the CVac arm received an injection of vaccine once every 4 weeks for 7 doses, and then once every 8 weeks for 3 doses, for a total of 10 doses of vaccine. Patients were followed every 12 weeks, with CA-125 and imaging for PFS.



Demographics and baseline disease characteristics of the ITT sample are summarized in Table 9; two-thirds of patients were in their first clinical remission (CR1), while the remaining third were in their second clinical remission (CR2). The majority of patients enrolled had stage III cancer of serous histology. Patient characteristics did not differ between treatment arms. CVac was very well tolerated with little toxicity. Most adverse events were grade 1 or 2, which commonly included pain and skin changes at the injection site, dizziness, fatigue, and lethargy. There were no grade 4 or 5 adverse events related to study drug. Nine (9) serious adverse events were reported in total, including 1 death with the majority of these related to prior therapy (such as obstruction due to surgery) or disease progression. One patient in the observation arm died as a result of a subdural hematoma and subsequent respiratory failure.

Table 9. Demographics of patients enrolled in CAN-003, CVac vaccine vs observational standard of care.

CharacteristicCVac

(n = 29)Observational Standard of Care

(n = 27)

Remission Status

Achieved after first-line therapy (CR1) 19 (66%) 17 (63%)

Achieved after second-line therapy (CR2) 10 (34%) 10 (37%)

Disease stage

III 24 (83%) 20 (74%)

IV 5 (17%) 7 (26%)

Histology subtype

Serous 25 (86%) 23 (85%)

Endometrioid 1 (3%) 2 (7%)

Mucinous 1 (3%) 1 (4%)

Other (mixed, not specified) 2 (7%) 1 (4%)

Cytoreduction/debulking surgery

Optimal 27 (93%) 23 (85%)

Suboptimal 2 (7%) 4 (15%)

Age (years)

Median (range) 58 (34-75) 49 (43-70)

Despite wide inter-patient variability, the vast majority of patients were able to elicit a brisk immune response to the MUC1 antigen, as evidenced by increases from baseline in MUC1 specific CD4 and CD8 T-cell responses. Progression-free survival in the entire 56-patient cohort did not significantly differ between the 2 arms (median PFS in CVac arm, 2.89 months vs observational arm, 8.64 months; HR = 0.72 [95% CI 0.38-1.38]; P = 0.33). When results were examined separately based on remission status, PFS was not improved with CVac in patients in CR1 (Figure 11A), but CVac did lead to a significant improvement in PFS for patients in CR2 (Figure 11B). In this latter set of patients, median PFS for standard of care observation was 4.9 months. Median PFS for CVac in CR2 patients was not reached but is greater than 12.9 months. Overall survival data was not yet mature; however, in patients in CR1 (first remission), median OS had not been reached in either arm, and the hazard ratio for OS was non-significant (HR, 0.63 [95% CI 0.14-2.82]; P = 0.54). In contrast, CVac in patients in CR2 (second remission) was associated with a trend for significantly improved OS, with median OS not yet reached in the experimental arm and a median OS of 26.25 months in the control arm (HR = 0.17 [95% CI 0.02-1.44]; P = 0.07).

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Figure 11. Progression-free survival following mucin-1 autologous dendritic cell therapy in ovarian cancer patients by (A) first and (B) second remission.

1.00

0.75

0.50

0.25

0.0024 3012 186

3/8 0/03/11 0/84/17

2/6 0/35/14 2/94/19

OSC

CVac

0

Prog

ress

ion

Prob

abilit

y

Months

(Events at Risk)

OSC: median PFS 18.20 monCVac: median PFS 12.89 mon

Hazard ratio 1.18 (95% CI 0.51, 2.71)P = 0.69 by log rank test (2-sided) 1.00

0.75

0.50

0.25

0.0024 3012 186

1/1 0/02/4 1/26/10

0/2 0/02/6 0/42/10

OSC

CVac

0Months

(Events at Risk)

OSC: median PFS 4.94 monthsCVac: median PFS not reached(> 12.91 months)

Hazard ratio 0.32 (95% CI 0.10, 1.03)P = 0.04 by log rank test (2-sided)

A. B.

OSC, observational standard of care.

In conclusion CVac was well tolerated with limited toxicity in patients with ovarian cancer. The vaccine was associated with clear evidence of immunogenicity in the form of positive mucin 1-specific T-cell responses generated by treated patients. There was a signal of improved PFS following CVac treatment for patients in a second remission, as well as a very preliminary signal of OS benefit for these same patients. These results were encouraging enough that a phase III randomized, placebo controlled trial of CVac as maintenance therapy for ovarian cancer after both first- and second-lines of therapy has been initiated.

The future of immunotherapy in ovarian cancer remains to be determined, but these promising preliminary results suggest it could play an important role in treatment ovarian cancer someday. Ongoing development of an immunotherapeutic agent will not only need to provide further evidence of safety and efficacy, but in order to maximize utility, the identification of response predictors will be crucial.

CONCLUSIONData from the 2014 ASCO Annual Meeting continue to refine treatment for patients with ovarian cancer. In particular, several early-stage clinical trials provide compelling data related to new therapeutic pathways and mechanisms that are being pursued. State-of-the-art information communicated at the 2014 ASCO Annual Meeting suggests increasing treatment options in the years to come and an emerging ability to personalize therapy for patients with ovarian cancer. Clinicians should remain cognizant of opportunities to direct patients to ongoing clinical trials that will continue to investigate these agents and help to define the future practice of personalized medicine for ovarian cancer.



For additional cancer education, please go to www.ecgcme.com. The 2015 ASCO Annual Meeting will be held May 29, 2015 to June 2, 2015 in Chicago, Illinois. Additional information may be found at http://www.asco.org.

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Table of Contents

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Advances in the Management of Ovarian Cancer: Highlights from the 2014 ASCO Annual Meeting