Welcome to. American College of Surgeons. Clinical Research Program (ACS-CRP) Breast Surgical Trial Webinar

Transcription

1 American College of Surgeons Clinical Research Program Kelly K. Hunt, M.D. Program Director Welcome to American College of Surgeons Clinical Research Program (ACS-CRP) Breast Surgical Trial Webinar Moderator: Judy C Boughey MD, FACS

2 Alliance/ACS Clinical Research Program Improve cancer care outcomes through high-quality health services research that leverages the multidisciplinary collaboration and research infrastructure of the Alliance and its partners to generate new knowledge and facilitate the implementation and dissemination of research findings throughout the oncology community Improve oncological surgical practice through dissemination of best practices and clinical trial findings Increase interaction and integration between the Alliance, the ACS, and the Commission on Cancer

3 An Integrated Model Alliance for Clinical Trials in Oncology ACS CRP American College of Surgeons Cancer Care Delivery Research: Knowledge Generation Standards Committee: Implementation Education Committee: Dissemination Dissemination & Implementation Committee: Engagement

4 Trials AFT-25: Comparison of Operative to Monitoring and choice of Endocrine Therapy (COMET) Trial for Low Risk DCIS: A Phase III Prospective Randomized Trial AA011106: Alternate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant Treatment (ALTERNATE) in postmenopausal womenlternate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant Treatment (ALTERNATE) in postmenopausal women

5 Comparison of Operative to Monitoring and/or Endocrine Therapy for Low Risk DCIS: COMET Trial E. Shelley Hwang MD MPH Ann Partridge MD MPH Alastair Thompson MD FRCSEd Elizabeth Frank EdM Deborah Collyar

6 DCIS is Part of a Pathologic Continuum Rate? Fate? Burstein HJ, et al. N Engl J Med.

7 DCIS incidence paralleled the number of mammogram machines Thousands DCIS is an unintended consequence of increased screening ο ο ο ο ο ο DCIS ο ο ο ο ο 1 in 1300 screening MMG diagnose DCIS MMG Machines

8 DCIS Incidence continues to rise ( ) DCIS INVASIVE Screening mammogram s introduced WHI data published

9 Some patients are diagnosed with cancer that does not progress

10 Surgical Treatment Patterns for DCIS and LCIS Ward E, Cancer J Clin 2015

11 What happens if you don t treat DCIS? SEER year DSS: Surgery: 98.8% No surgery: 98.6% Sagara et al, JAMA Surgery

12 Active Surveillance Trials for DCIS UK (LORIS) and EORTC (LORD) trials have been initiated Newly diagnosed clinically low risk DCIS Primary outcome: ipsilateral invasive cancer-free survival Randomization: usual care (surgery and/or RT) vs. active surveillance Regular surveillance with imaging Intervene if evidence of progression to invasive cancer

13 COMET Trial for low risk DCIS Project 1: Compare cancer outcomes and clinical outcomes between patients who are treated with GCC versus AS for core biopsy-proven DCIS. Primary outcome: 2-year diagnosis of invasive cancer Additional secondary endpoints: 2-year receipt of mastectomy, radiation, chemotherapy 2-year overall mortality and breast cancer specific mortality Project 2: Compare patient reported outcomes (PRO) between GCC and AS groups. PRO measures will include both psychosocial outcomes (QOL, emotional/psychological outcomes, body image and sexual function) as well as decision quality (knowledge of DCIS, decision-making and decision regret, and risk perception).

14 COMET Study Endpoints

15 Study Flow Diagram

16 Study Flow Diagram Patients randomized to AS strongly encouraged to consider endocrine therapy of choice Eligiblity criteria: Age 40 Grade I/II DCIS without invasive cancer ER(+) and/or PR(+), HER2(-) if tested No mass on PE or imaging Endpoints: 2, 5, and 7-year invasive cancer dx 2, 5, and 7-year OS, DSS PRO endpoints (QOL, fear of cancer recurrence, body image)

17 COMET Active Surveillance Protocol

18 COMET Trial for low risk DCIS Eligibility Criteria Age >40 at diagnosis; agree to randomization Pathologic confirmation of grade I/II DCIS without invasion by 2 local pathologists (microinvasion not allowed) ER 10%; HER2-negative (0, 1+, or 2+ if testing performed) No evidence of other breast disease on physical examination and breast imaging within 6 months of registration Available for follow up examinations Ability to read, understand and evaluate study materials Speaks Spanish or English, or availability of an

19 COMET Trial for low risk DCIS Analysis Plan Hypothesis: 2-year rate of invasive cancer diagnosis is not inferior in the AS group compared to the GCC group Sample size considerations: 2-group test of non-inferiority of proportions, with the 2-year invasive cancer rate in the GCC group assumed to be 0.10 with a non-inferiority margin of Sample size of n=446 per group will have 80% power to detect the specified non-inferiority margin.

20 Patient Card and Patient Brochure

21 COMET Website: DCISoptions.org

22 COMET Trial for low-risk DCIS Study Update July 2016: NOA Enrollment over 4 years June 2017: First site open 44 Alliance sites are currently active 55 Alliance sites are working towards activation 13 Alliance sites have recruited a patient 8 Alliance sites have recruited one patient 5 Alliance sites have recruited more than one patient 33 patients have been randomized

23 Collaboration for Correlative Endpoints n~900 (UK) n~1,200 (EORTC) n~900 (US) Low grade DCIS ~3,000 women R Standard treatment (~1,500 women): Surgery +/- radiotherapy Active surveillance (~1,500 women) No treatment Annual mammography For 10 years Annual mammography For 10 years 2

24 COMET Trial for low risk DCIS COMET Project Manager: Thomas Lynch AFT Project Manager: Vance Erese AFT Clinical Research Associate: Stephanie Moine COMET PI: Shelley Hwang MD MPH COMET PI PROs: Ann Partridge MD MPH COMET Correlative Sciences PI: Alastair Thompson MBBS

25 PCORI Proposal: COMET Trial for low risk DCIS Thank you!

26 COMET Trial for low risk DCIS Questions?

27 ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment (ALTERNATE) in postmenopausal women: A Phase III Study (A011106) Cynthia X. Ma, M.D., Ph.D. (Medical Oncology) Marilyn Leitch, M.D., F.A.C.S. (Surgical Oncology) Gary W. Unzeitig, MD, FACS (Community Oncology) Souzan Sanati, M.D. (Pathology) Vera Suman, Ph.D. (Statistician) Matthew J. Ellis, M.B., BChir., Ph.D. & Lisa Carey, M.D. (Correlative Science)

28 Tumor Ki67 at 2-4 week Biopsy on Neoadjuvant Endocrine therapy Identified Non-responders Recurrence Free Survival (%) POL ER+ Stage 2/ (months) 4-week Biopsy Ellis, SABCS 2009 Letrozole S U R G E R Y Z1031B ER+ Stage 2/3 2-4 week Biopsy Letrozole Ellis, JCO 2017 Anastrozole Exemestane S U R G E R Y

29 Preoperative Endocrine Prognostic Index (PEPI) Modified PEPI excludes ER PEPI score was developed using results of PO24 trial to assess the risk of relapse based on pathologic tumor size, lymph node status, Ki67 level, and ER status of surgery specimen post neoadjuvant endocrine therapy. Ellis MJ, et al, J Natl Cancer Inst 100:1380-8, 2008

30 Modified PEPI (Data from P024 and POL trial) median F/U 62.5 mons Disease Free Survival PEPI 0 Modified PEPI 0 PEPI non-0 Modified PEPI non Months Modified PEPI 0 pt1/2 pn0 Ki67 2.7% P024 ER+ Stage 2/3 Letrozole Tamoxifen S U R G E R Y POL ER+ Stage 2/3 4-week Biopsy Letrozole S U R G E R Y

31 Z1031 Trial Recurrence Free Survival (PEPI 0 versus non-0) Median follow up 5.5 years All Patients (n=460) No chemotherapy (n=280) PEPI 0 rate: 119/460 (25.6%) Adjuvant chemotherapy was administered in 18/119 (15.1%) PEPI 0 patients Ellis, et al JCO 2017

32 Eligibility Post-menopausal Clinical Stage II or III ER+ (Allred 6-8) HER2- ALTERNATE Schema (A011106) BEFORE SURGERY AFTER SURGERY R E G I S T R A T I O N B I O P S Y R A N D O M I Z E Arm I Arm II Arm III 6 cycles (each cycle is 4 weeks) 4w 12 w B I O P S Y Ki67 <10% Ki67>10% Neoadjuvant Chemotherapy Group Chemotherapy of physician choice or weekly paclitaxel x 12 Cycle 1 day 2 optional biopsy (if receiving paclitaxel) Arm I Arm II Arm III S U R G E R Y Modified PEPI 0 Chemo NOT recommended Modified PEPI > 0 Chemo recommended Arm I A x 4.5 yrs Arm II F x 1.5 yrs then A x 3 yrs Arm III (A+F) x 1.5 yrs then Ax3 yrs Endocrine therapy of Physician s Choice Arm I: Anastrozole (A) Arm II: Fulvestrant (F) Arm III: Anastrozole + Fulvestrant F O L L O W F O L L O W SURGERY Red: required tissue collection Blue: optional tissue collection AFTER SURGERY Therapy of Physician Choice Primary Endpoints: 1 st Phase: Modified PEPI 0 rate 2 nd Phase: RFS in Modified PEPI 0 FOLLOW

33 Primary Objectives Neoadjuvant Comparison Phase (First Phase): To determine whether the mpepi 0 rate with neoadjuvant fulvestrant (F) or fulvestrant plus anastrozole (F + A) is at least 10% over that achieved by anastrozole (A). Modified PEPI 0 Validation Phase (Second Phase): To assess if the 5-year RFS in patients with mpepi 0 in A arm is > 90%. To assess the point and interval estimate of the 5-year RFS in patients treated with F or F + A.

34 Secondary Objectives To examine differences in surgical outcome, clinical and radiological response rates, and safety profile between each fulvestrant arm with the anastrozole arm. To examine pcr rate of neoadjuvant paclitaxel in patients with 4-week or 12-week Ki67>10% To examine pcr rate of standard neoadjuvant chemotherapy in patients with 4-week or 12-week Ki67>10% To summarize the frequency of severe adverse events encountered with neoadjuvant paclitaxel To assess time to breast cancer recurrence for patients with endocrine resistant tumors, each group separated or combined 1) Ki67 >10% at week 4 2) Ki67 >10% at week 12 3) modified PEPI score of non-zero

35 Correlatives Science Objectives To compare the degree of Ki67 suppression at week 4 and surgery between each of the fulvestrant arms and the anastrozole arm. To examine the impact of post-neoadjuvant ER level on RFS in each arm. To examine pathologic tumor stage (T1 vs T2) on RFS in modified PEPI 0 group. To examine whether the rate of endocrine resistance or RFS differs with respect to the degree of week 4 Ki67 suppression. To examine whether the rate of week 4 Ki67 >10% or endocrine resistance or RFS differs with respect to pre-treatment gene expression and mutation profiles. To examine whether gene expression profiles at week 4 can further refine the patient population who have modified PEPI score non-0 or shorter RFS. To assess the pcr/rcb-1 rate post neoadjuvant chemotherapy or paclitaxel in endocrine resistant population (Ki67>10% at week 4 or 12). To evaluate Cycle 1, day 2 tumor biopsy following the initiation of paclitaxel to develop early molecular markers of response. To evaluate tumor tissue, serum, and plasma specimens for biomarker discovery that aim to understand signaling pathways associated with endocrine therapy and taxane therapy sensitivity and resistance.

36 Key Inclusion Criteria (Update 5) Postmenopausal women Clinical T2-T4c (palpable), any N, M0 invasive breast cancer Palpable The largest diameter > 2cm by physical exam or radiology assessment Bi-dimensional measurement by tape, ruler or caliper must be provided. Multi focal invasive breast cancers separated by < 5 cm of radiologically normal breast tissue are eligible (Research biopsy, Ki67 and response are to be performed on the dominant mass) ER positive (Allred Score 6-8) HER2 negative (0 or 1+ by IHC or FISH ratio < 2 if IHC 2+) ECOG performance status 0-2 Required research biopsies at baseline and week 4 and tissue collection at surgery. Key Exclusion Criteria Contralateral DCIS/Invasive breast cancer Surgical axillary staging prior to study entry Excisional biopsy of the breast

37 First Phase Study Design Primary endpoint: To determine whether the mpepi 0 rate with neoadjuvant fulvestrant (F) or fulvestrant plus anastrozole (F + A) is at least 10% over that achieved by anastrozole (A). Sample size: N=425 each arm (total n=1,275) one sided alpha=0.025 chi-square test 84% power to detect at least 10% difference in ESDR rate (assuming the ESDR in A arm is 30%) Enrollment continues to anastrozole arm after completing the First Phase enrollment pending results of the First phase analysis (total N 1,455) This increases the sample size in A arm to 605 patients

38 Second Phase Study Design Primary Endpoint: To assess if the 5-year RFS in patients with mpepi 0 in neoadjuvant anastrozole (A) arm is > 90%. To assess the point and interval estimate of the 5-year RFS in patients treated with F or F + A. Sample Size: 150 (25%) to 210 (35%) mpepi 0 pts are expected in the A arm from the First Phase enrollment one-sided alpha=0.025 nonparametric Brookmeyer-Crowley type one sample survival test and a power between (80.0% to 88.4%). to reject that the 5 year RFS rate is at most 90% in patients treated with anastrozole who have endocrine sensitive disease when the true 5 year RFS rate in this patient population is at least 95%.

39 Total enrollment as of Jan 8, 2018: 1013 Number of participating sites: 141 A Monthly Enrollment *Suspended Aug 30 th - Sep 14 th due to flvestrant shortage Aug Sep Oct Nov Dec 2015-Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec 2016-Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec 2017-Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec TOP ACCRUING SITES M D Anderson Cancer Center 73 Saint Elizabeth Medical Center South 59 Doctor's Hospital of Laredo 53 Mayo Clinic 36 Cedars-Sinai Medical Center 34 Legacy Good Samaritan Hospital and Medical Center 25 Presbyterian Kaseman Hospital 25 University of New Mexico Cancer Center 24 University of Texas Southwestern/Simmons Cancer Center - Dallas 24 Baylor College of Medicine 23 Mount Sinai Medical Center (NY021) 23 University of North Carolina at Chapel Hill/ UNC Lineberger Comprehensive Cancer Center 23 University of Oklahoma Health Sciences Center 23 N