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 PrECOG  0102:  A Randomized, Double-Blind Phase II Trial of Fulvestrant plus Everolimus  PrECOG  0102:  A Randomized, Double-Blind Phase II Trial of Fulvestrant plus Everolimus

PrECOG 0102: A Randomized, Double-Blind Phase II Trial of Fulvestrant plus Everolimus - PowerPoint Presentation

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PrECOG 0102: A Randomized, Double-Blind Phase II Trial of Fulvestrant plus Everolimus - PPT Presentation

PostMenopausal Women with HormoneReceptor Positive HER2Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy Noah S Kornblum MD 1 Judith Manola MS 2 Paula ID: 775324

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Slide1

PrECOG

0102: A Randomized, Double-Blind Phase II Trial of Fulvestrant plus Everolimus or Placebo in

Post-Menopausal Women with Hormone-Receptor Positive, HER2-Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy

Noah S Kornblum, MD1, Judith Manola, MS2, Paula Klein, MD3, Bhuvaneswari Ramaswamy, MD4,Adam Brufsky, MD PhD5, Phillip J Stella, MD6, Brian Burnette, MD7, Melinda Telli, MD8, Della F Makower, MD1,Joseph Leach, MD9, Cristina I Truica, MD10, Antonio C Wolff, MD11, Gamini S Soori, MD12, Barbara Haley, MD13, Arun Nagarajan, MD14, Timothy R Wassenaar, MD15, Lori Goldstein, MD16, Kathy D Miller, MD17,and Joseph A Sparano, MD1Institutions: 1Montefiore-Einstein Center for Cancer Care, Bronx, New York, United States, 10461; 2Dana-Farber Cancer Institute, Boston, MA, United States, 02284-9168; 3Mount Sinai Beth Israel Comprehensive Cancer Center, New York, New York, United States, 10011; 4Ohio State University Comprehensive Cancer Center, Columbus, OH, United States, 43212; 5University of Pittsburgh, Pittsburgh, PA, United States, 15213; 6Saint Joseph Mercy (Michigan Cancer Consortium), Ann Arbor, MI, United States, 48106; 7Saint Vincent Hospital, Green Bay, WI, United States, 54301; 8Stanford University Medical Center, Stanford, CA, United States, 95304; 9Metro-Minnesota Community Oncology Research Consortium, Saint Louis Park, MN, United States, 55416; 10Penn State Hershey Cancer Institute, Hershey, PA, United States, 17033; 11Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States, 21287; 12Missouri Valley Cancer Consortium, Omaha, NE, United States, 68106; 13UT Southwestern Medical Center, Dallas, TX, United States, 75390; 14CAMC Health System, Charleston, WV, United States, 25304; 15Pro Health Care, Waukesha, WI, United States, 53188, 16Fox Chase Cancer Center, Philidelphia, PA, United States, 19111 and 17Indiana University School of Medicine, Indianapolis, IN, United States, 46202-5689.

This presentation is the intellectual property of the author. Contact nkornblu@montefiore.org for permission to reprint and/or distribute.

Slide2

Background: Resistance to Aromatase Inhibitor (AI) Therapy is Inevitable

Strategies to address resistance are emergingTargeting PI3K-AKT-mTOR pathway 1 Addition of the mTOR inhibitor Everolimus to the steroidal AI exemestane improved median PFS (3.2 vs. 7.8 mo., p<0.0001) in the phase III BOLERO-2 trialUse of a selective estrogen receptor down regulator (SERD)More complete blockade of ER signaling than other anti-estrogensHypothesis: The combination of everoliumus/fulvestrant would be more effective than fulvestrant alone in AI resistant disease

This presentation is the intellectual property of the author. Contact nkornblu@montefiore.org for permission to reprint and/or distribute.

1Ma, C, et al. Nature Reviews Cancer 15, 261–275 (2015) ; 2 Baselga, J. et al, New Engl. J. Med. 366, 520–529 (2012) ; 3Yardley, D. et al, Adv Ther (2013) 30:870–884; 4 Piccart, M, et al. Ann Oncol 25, 12, 2357-2362 (2014) ; 5Bachelot, T. et al. J Clin Oncol. 30, 2718–2724 (2012); 6 Chia, S., et al. J Clin Oncol 26:1664-70 (2009).; 7Di Leo, A et al. J Clin Oncol. 28, 4594-4600 (2010)

San Antonio Breast Cancer Symposium, December 6-10, 2016

Slide3

Methods: Key Eligibility Criteria

Post-menopausal womenHR-positive, HER2-negative (ASCO-CAP)Inoperable locally advanced or metastatic breast cancer AI resistant disease:Relapse while receiving adjuvant AI therapyProgression after one or more AIs for metastatic disease ECOG PS 0-1Normal organ function< 1 prior chemotherapy regimen for metastasisMeasurable and/or non-measurable disease (RECIST 1.1) 2 doses of fulvestrant permitted within 28d prior to randomization

This presentation is the intellectual property of the author. Contact nkornblu@montefiore.org for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium, December 6-10, 2016

Slide4

Methods: Study Schema

This presentation is the intellectual property of the author. Contact nkornblu@montefiore.org for permission to reprint and/or distribute.

Induction Phase

: Treat until evidence of progressive disease or unacceptable toxicity for a maximum of 12 cycles (48 weeks)Continuation Phase: If no disease progression or unacceptable toxicity after 12 cycles, unblind and continue fulvestrant +/- everolimus

San Antonio Breast Cancer Symposium, December 6-10, 2016

Induction Phase

Continuation Phase

Treatment Plan:

Tumor measurements every 12 weeks (+/- 1 week) by local treating physician

Supportive Care:

Corticosteroid mouthwash prophylaxis was not used

Slide5

Methods: Statistical Design

Primary endpoint: progression-free survival (by investigator assessment)130 total patients (120 eligible assuming 10% ineligible)90% power1-sided Type I error 10% 70% improvement in median PFS - 5.4 mo. (CONFIRM)1 to 9.2 mo.Stratified log-rank testITT analysisFull information = 98 events (death or progression)

This presentation is the intellectual property of the author. Contact nkornblu@montefiore.org for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium, December 6-10, 2016

1

Di Leo, A et al.

J

Clin

Oncol

. 28, 4594-4600 (2010)

Slide6

Progression Free Survival(by investigator assessment – primary study endpoint)

This presentation is the intellectual property of the author. Contact nkornblu@montefiore.org for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium, December 6-10, 2016

Slide7

Conclusions

Addition of everolimus to fulvestrant improved PFSmedian PFS 5.1 vs. 10.4 months HR 0.60, p=0.02Associated with more toxicity, includingGrade 3 adverse events: 48% (F/E) vs. 14% (F/P)Most common grade 3 A.E.s occurring in > 5% included stomatitis (9%), pneumonitis (6%), fatigue (5%), & hyperglycemia (6%) Saftey profile consistent with everolimus in BOLERO-21Prophylactic corticosteroid mouthwash was not used, which has been shown to reduce risk of grade 1-2 stomatitis from about 65% to 20%2Provides additional evidence that adding everolimus to anti-estrogen therapy in AI resistant disease improves clinical outcomes

This presentation is the intellectual property of the author. Contact nkornblu@montefiore.org for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium, December 6-10, 2016

1

Baselga

, J. et al,

New Engl. J. Med. 366, 520–529 (2012)

2

Rugo

, H, et al.

J Clin Oncol 34, 2016 (

suppl

;

abstr

525)