Grand Rounds Program Steering Committee

New Agents and Emerging Strategies in the Management of Early and Advanced Breast Cancer

Grand Rounds Program Steering Committee
Kimberly L Blackwell, MD Professor of Medicine Director, Breast Cancer Program Duke Cancer Institute Durham, North Carolina William J Gradishar, MD Betsy Bramsen Professor of Breast Oncology and Professor of Medicine Deputy Director, Clinical Network Robert H Lurie Comprehensive Cancer Center of Northwestern University Director, Maggie Daley Center for Women’s Cancer Care; Interim Chief, Division of Hematology/Oncology Northwestern University Feinberg School of Medicine Chicago, Illinois Harold J Burstein, MD, PhD Associate Professor of Medicine Harvard Medical School Breast Oncology Center Dana-Farber Cancer Institute Boston, Massachusetts

Sara A Hurvitz, MD Associate Professor of Medicine Director, Breast Oncology Program Division of Hematology/Oncology University of California, Los Angeles; Medical Director, Jonsson Comprehensive Cancer Center Clinical Research Unit Los Angeles, California Co-Director, Santa Monica-UCLA Outpatient Oncology Practices Santa Monica, California Joyce O’Shaughnessy, MD Chair Breast Cancer Research Program Baylor Charles A Sammons Cancer Center Celebrating Women Chair in Breast Cancer Research Texas Oncology US Oncology Dallas, Texas Mark D Pegram, MD Susy Yuan-Huey Hung Professor of Medicine; Director of the Breast Oncology Program; Associate Dean Clinical Research Quality Associate Director for Clinical Research Stanford Cancer Institute Stanford University School of Medicine Stanford, California Ruth M O’Regan, MD Professor of Medicine Chief, Division of Hematology/Oncology University of Wisconsin Carbone Cancer Center Madison, Wisconsin

Joseph A Sparano, MD Professor of Medicine and Women’s Health Albert Einstein College of Medicine Associate Chairman Department of Oncology Montefiore Medical Center Bronx, New York Project Chair Neil Love, MD Research To Practice Miami, Florida

Beyond the Guidelines …
ADJUVANT PERTUZUMAB TREATMENT GRADE ≥2 DIARRHEA Never <10% Only in patients who did not receive pertuzumab preop 33% I attempt to obtain pertuzumab for patients with higher-risk disease 15%-20% with chemotherapy, <10% after chemotherapy No 10% No 5% … Focusing on actual practical clinical decisions that investigators make in breast cancer.

Which of the following best represents your clinical background?
Medical oncologist/hematologic oncologist Radiation oncologist Radiologist Surgical oncologist or surgeon Other MD Nurse practitioner or physician assistant Nurse Researcher Other healthcare professional 10

Medical oncologist/hematologic oncologist
Radiation oncologist Radiologist Surgical oncologist or surgeon Other MD Nurse practitioner or physician assistant Nurse Researcher Other healthcare professional

Module 1: Novel Treatment Strategies in HER2-Positive Early Breast Cancer APHINITY: Adjuvant pertuzumab ExteNET: Extended Adjuvant Treatment Ongoing Studies: KATHERINE, KAITLIN, ATEMPT Module 2: Recently Approved CDK4/6 Inhibitors Palbociclib: PALOMA-1 (palbociclib/letrozole as first-line therapy) Ribociclib: MONALEESA-2 (ribociclib/letrozole as first-line therapy) Abemaciclib: MONARCH 3 (abemaciclib/AI as first-line therapy) Module 3: PARP Inhibitors in Metastatic Breast Cancer OlympiAD: Olaparib versus chemotherapy for HER2-negative, gBRCA-mutant mBC Clinical implications of OlympiAD; BRCA germline and somatic mutation testing Ongoing Phase III clinical trials Module 4: Checkpoint Inhibitors in Breast Cancer Early data with anti-PD-1/PD-L1 checkpoint inhibitors Ongoing clinical trials

What adjuvant systemic therapy would you generally recommend for a 65-year-old postmenopausal woman who at surgery is found to have a 2.5-cm ER-negative, HER2-positive infiltrating ductal carcinoma (IDC) with 0/3 positive sentinel nodes? Docetaxel/carboplatin/trastuzumab (TCH) Docetaxel/trastuzumab/pertuzumab (THP) Docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) An anthracycline-containing regimen followed by trastuzumab An anthracycline-containing regimen followed by trastuzumab/pertuzumab Paclitaxel/trastuzumab Other None 10

What adjuvant systemic therapy would you generally recommend for a 65-year-old postmenopausal woman who at surgery is found to have an ER-negative, HER2-positive infiltrating ductal carcinoma (IDC) with the following tumor size and sentinel nodal status? 2.5 CM; 0/3 SN POSITIVE 2.5 CM; 1/3 SN POSITIVE 2.5 CM; 3/3 SN POSITIVE 1.0 CM; 0/3 SN POSITIVE TCHP TCHP TCHP Paclitaxel/ trastuzumab/ pertuzumab TCH TCHP TCHP Paclitaxel/ trastuzumab TCHP TCHP TCHP Paclitaxel/ trastuzumab TCHP TCHP TCHP TCH TCH TCHP TCHP Paclitaxel/ trastuzumab TCHP TCHP TCHP TCH Paclitaxel/ trastuzumab TCH TCHP x 6 → H up to 1 y Paclitaxel/ trastuzumab Paclitaxel/ trastuzumab TCHP ACT/HP Paclitaxel/ trastuzumab

APHINITY Phase III Trial Schema
U R G E Y Chemotherapy* + trastuzumab + pertuzumab Follow-up 10 years Central confirmation of HER2 status (N = 4,805) R Chemotherapy* + trastuzumab + placebo Randomization and treatment within 8 weeks of surgery Anti-HER2 therapy for a total of 1 year (52 weeks) (concurrent with start of taxane) Radiation therapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy * A number of standard anthracycline-taxane sequences or a nonanthracycline (TCH) regimen were allowed von Minckwitz G et al. N Engl J Med 2017;377(2): von Minckwitz G et al. Proc ASCO 2017;Abstract LBA500.

Invasive Disease-free Survival Rate (%)
Three-Year Invasive Disease-Free Survival: Intention-to-Treat and Hormone Receptor Subgroups Patient subgroup Pertuzumab Placebo p-value HR-negative (N = 1,722) 92.8% 91.2% 0.08 HR-positive (N = 3,082) 94.8% 94.4% 0.28 Invasive Disease-free Survival Rate (%) Pertuzumab, 171 events (n = 2,400) Placebo, 210 events (n = 2,404) Stratified hazard ratio, 0.81 P = 0.045 Months von Minckwitz G et al. N Engl J Med 2017;377(2):

Three-Year Invasive Disease-Free Survival By Nodal Status
Node-Positive Node-Negative Invasive Disease-free Survival Rate (%) Pertuzumab, 139 events (n = 1,503) Placebo, 181 events (n = 1,502) Pertuzumab, 32 events (n = 897) Placebo, 29 events (n = 902) Months Months Unstratified hazard ratio, 1.13 P = 0.64 Unstratified hazard ratio, 0.77 P = 0.02 von Minckwitz G et al. N Engl J Med 2017;377(2):

Press Release – December 20, FDA Approval of Pertuzumab for Adjuvant Treatment of HER2-Positive Breast Cancer “The Food and Drug Administration granted regular approval to pertuzumab for use in combination with trastuzumab and chemotherapy as adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence. Approval was based on data from APHINITY (NCT ), a multicenter, randomized, double-blind, placebo-controlled trial in 4,804 patients with HER2- positive early breast cancer who had their primary tumor excised prior to randomization.”

A 65-year-old postmenopausal woman who at surgery was found to have a 2.5-cm ER-positive, HER2-positive IDC with 3/3 positive sentinel nodes completes the adjuvant regimen of your choice. Would you recommend neratinib as post-adjuvant therapy? Yes No, but I would discuss it as an option No 10

RISK BEFORE/ AFTER ADJ TX RISK BEFORE/ AFTER ADJ TX
A 65-year-old postmenopausal woman at surgery was found to have a 2.5-cm IDC with 3/3 positive sentinel nodes. What would you estimate this patient’s risk of relapse to be before/after completion of the adjuvant therapy of your choice? Would you recommend neratinib as post-adjuvant therapy? ER-/HER2+ ER+/HER2+ RISK BEFORE/ AFTER ADJ TX NERATINIB RISK BEFORE/ AFTER ADJ TX NERATINIB 40%/12%-15% Yes 40%/8% Yes 45%/15% No 45%/8% Yes 40%/10% No, but would discuss 40%/10% No, but would discuss 45%/20% No, but would discuss 40%/20% Yes 45%/10% No 45%/10% No, but would discuss 60%/20% No, but would discuss 60%/20% Yes 30%/10% No, but would discuss 30%/10% No, but would discuss 80%/10% No 80%/10% Yes

Press Release – July 17, 2017 FDA Approval of Neratinib for the Extended Adjuvant Treatment of Early-Stage HER2-Positive Breast Cancer “The US Food and Drug Administration today approved neratinib for the extended adjuvant treatment of early-stage, HER2-positive breast cancer. For patients with this type of cancer, neratinib is the first extended adjuvant therapy, a form of therapy that is taken after an initial treatment to further lower the risk of the cancer coming back. Neratinib is indicated for adult patients who have been previously treated with a regimen that includes the drug trastuzumab… The safety and efficacy of neratinib were studied in a randomized trial of 2,840 patients with early-stage, HER2-positive breast cancer who completed treatment with trastuzumab within the previous two years.”

ExteNET Phase III Schema
Accrual: 2,840 Eligibility HER2-positive breast cancer Prior adjuvant trastuzumab and chemotherapy Lymph node-positive disease* or invasive disease after neoadjuvant therapy ER/PR-positive or negative Neratinib x 1 year 240 mg/day R (1:1) Placebo x 1 year * Eligibility restricted to node-positive disease after 671 patients with node-negative breast cancer were enrolled Primary endpoint: Invasive disease-free survival Martin M et al. Proc ESMO 2017;Abstract 149O.

ExteNET: 5-Year Invasive Disease-Free Survival
Months after randomization Martin M et al. Proc ESMO 2017;Abstract 149O.

ExteNET: 5-Year Invasive Disease-Free Survival by Hormone Receptor Status
Martin M et al. Proc ESMO 2017;Abstract 149O.

ExteNET: Select Treatment-Emergent Adverse Events
Neratinib (n = 1,408) Placebo (n = 1,408) Grade 1-2 Grade 3-4 Diarrhea 55% 40% 34% 2% Nausea 41% 21% <1% Fatigue 25% 20% Vomiting 23% 3% 8% Abdominal pain 22% 10% Rash 15% 7% 0% Decreased appetite 12% No evidence of long-term toxicity with neratinib versus placebo or late-term consequences of neratinib-associated diarrhea Chan A et al. Lancet Oncol 2016;17:367-77; Martin M et al. Proc ESMO 2017;Abstract 149O.

CONTROL: Loperamide Prophylaxis for Neratinib-Associated Diarrhea
Patients with HER2-positive early breast cancer treated with neratinib Loperamide prophylaxis either alone or with budesonide (oral corticosteroid) Diarrhea CONTROL ExteNET Loperamide (n = 135) Loperamide + budesonide (n = 40) Loperamide prn (n = 1,408) Any grade 75.6% 65.0% 95.4% Grade 3/4 28.1% 15.0% 39.9% Loperamide prophylaxis reduced the incidence, severity and duration of diarrhea compared to no prophylaxis on the ExteNET trial Adding budesonide may further diminish the duration and number of episodes of diarrhea Barcenas C et al. SABCS 2016;Abstract P ; Chan A et al. Lancet Oncol 2016;17(3):

Select Ongoing Trials of HER2-Targeted Therapy in the Adjuvant Setting
Phase Setting Randomization KATHERINE III T1-4, N0-3 at presentation ≥6 cycles preoperative therapy Residual tumor in breast or axilla postoperatively T-DM1 Trastuzumab KAITLIN pN ≥1, any tumor size except T0, any hormonal receptor status pN0 with pathologic tumor size >2.0 cm and hormone receptor-negative Anthracycline → trastuzumab, pertuzumab and taxane Anthracycline → T-DM1 and pertuzumab ATEMPT II Stage I at presentation All tumor removed by modified radical mastectomy or lumpectomy with clear margins Paclitaxel/trastuzumab Accessed September 2017.

Targeting CDK4/6 in ER-Positive Breast Cancer
Finn RS et al. Breast Cancer Res 2016;18:17.

FDA-Approved CDK4/6 Inhibitors
Drug Key studies Indication in ER+, HER2- mBC Dosing Palbociclib (accelerated approval February 2015; regular approval ) PALOMA-1 (Finn Lancet Oncol 2015; Finn ASCO 2017) With letrozole, no prior endocrine-based therapy With an AI, postmenopausal women, as initial endocrine-based therapy With fulvestrant, disease progression after ET 125 mg once daily with food for 21 out of 28 days PALOMA-2 (Finn NEJM 2016) PALOMA-3 (Cristofanilli Lancet Oncol 2016) Ribociclib ( ) MONALEESA-2 (Hortobagyi NEJM 2016) With an AI, postmenopausal women, as initial endocrine-based therapy 600 mg orally (3 x 200-mg tablets) taken once daily with or without food for 21 out of 28 days Abemaciclib ( ) MONARCH 1 (Dickler Clin Cancer Res 2017) As monotherapy, previous ET and chemotherapy With fulvestrant, disease progression after ET 200 mg BID continuous until disease progression as monotherapy; 150 mg BID in combination with fulvestrant MONARCH 2 (Sledge JCO 2017) mBC = metastatic breast cancer; AI = aromatase inhibitor; ET = endocrine therapy

A 65-year-old asymptomatic postmenopausal woman presents with 4
A 65-year-old asymptomatic postmenopausal woman presents with 4.0-cm ER-positive, HER2-negative breast cancer and biopsy-proven bone metastases. Germline BRCA1/2 mutation testing is negative. Which systemic treatment would you most likely recommend (in addition to bone-targeted therapy)? Fulvestrant An aromatase inhibitor (AI) Anastrozole + fulvestrant Exemestane + everolimus Palbociclib + fulvestrant Palbociclib + letrozole Ribociclib + letrozole Abemaciclib + fulvestrant Chemotherapy 10

A 65-year-old postmenopausal woman completes 5 years of adjuvant anastrozole for an ER-positive, HER2-negative IDC but develops asymptomatic biopsy-proven bone metastases 2 years later. Germline BRCA1/2 mutation testing is negative. Which systemic therapy would you recommend (in addition to bone-targeted therapy)? Fulvestrant An aromatase inhibitor (AI) Anastrozole + fulvestrant Exemestane + everolimus Palbociclib + fulvestrant Palbociclib + letrozole Ribociclib + letrozole Abemaciclib + fulvestrant Chemotherapy 10

A 65-year-old asymptomatic postmenopausal woman with 4
A 65-year-old asymptomatic postmenopausal woman with 4.0-cm ER-positive, HER2-negative breast cancer and biopsy-proven bone metastases. Germline BRCA1/2 mutation testing is negative. Which systemic treatment would you most likely recommend (in addition to bone-targeted therapy) in the following scenarios? DE NOVO MBC MBC 2 Y ON ADJ ANASTROZOLE MBC 2 Y AFTER COMPLETING ADJ ANASTROZOLE Palbo or ribo + letrozole Palbociclib + fulvestrant Palbociclib or ribociclib + letrozole Palbociclib + letrozole Palbociclib + fulvestrant Palbociclib + letrozole Palbociclib + letrozole Palbociclib + fulvestrant Palbociclib + fulvestrant Ribociclib + letrozole Abemaciclib + fulvestrant Abemaciclib + fulvestrant Palbociclib + letrozole Palbociclib + fulvestrant Palbociclib + letrozole Ribociclib + letrozole Abemaciclib + fulvestrant Palbociclib + fulvestrant Palbociclib + letrozole Palbociclib + fulvestrant Palbociclib + letrozole Palbociclib + letrozole Palbociclib + fulvestrant Palbociclib + letrozole Palbo = palbociclib; ribo = ribociclib

The 65-year-old patient in the previous clinical scenario with asymptomatic biopsy-proven bone metastases 2 years after completing adjuvant anastrozole receives palbociclib combined with letrozole and responds but 1 year later experiences asymptomatic disease progression. What would be your likely next systemic treatment? Fulvestrant Fulvestrant Exemestane + everolimus Fulvestrant Fulvestrant Fulvestrant + everolimus Fulvestrant, possibly with everolimus Continue palbociclib, switch ET ET = endocrine therapy

PALOMA-1: Progression-Free Survival (PFS) with Palbociclib/Letrozole in the First-Line Setting
Palbo/letrozole (n = 84) Letrozole (n = 81) mPFS1 20.2 mo 10.2 mo HR = 0.488, p = mOS2 37.5 mo 34.5 mo HR = 0.897, p = 0.281 1 Finn RS et al. Lancet Oncol 2015;16:25-35. 2 Finn RS et al. Proc ASCO 2017;Abstract 1001.

PALOMA-1: Select Adverse Events
Palbociclib + letrozole (n = 83) Letrozole (n = 77) All grades Grade 3-4 Neutropenia 75% 59% 5% 1% Leukopenia 43% 18% 4% 0% Anemia 35% 7% Fatigue 41% 23% Nausea 30% 2% 14% Diarrhea 22% 12% Thrombocytopenia 20% Finn RS et al. Proc ASCO 2017;Abstract 1001.

Press Release – March 13, 2017 FDA Approval of Ribociclib in Combination with an Aromatase Inhibitor as Initial Treatment for Postmenopausal Women with HR+, HER2- mBC “The US Food and Drug Administration approved ribociclib, a cyclin-dependent kinase 4/6 inhibitor, in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. Approval was based on a randomized, double-blind, placebo- controlled, international clinical trial (MONALEESA-2), in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer who received no prior therapy for advanced disease.”

MONALEESA-2: PFS with First-Line Ribociclib/Letrozole
Median = 25.3 mo Median = 16.0 mo Median follow-up: 26 mo Median overall survival (data are immature): Ribociclib arm: not reached; placebo arm: 33 mo Hortobagyi GN et al. Proc ASCO 2017;Abstract 1038.

MONALEESA-2: Select Adverse Events
Ribociclib + letrozole (n = 334) Placebo + letrozole (n = 330) All grades Grade 3-4 Neutropenia 74% 60% 5% <1% Nausea 52% 2% 29% Infections 50% 4% 42% Diarrhea 35% 1% 22% Leukopenia 33% 20% Increased alanine aminotransferase 16% 9% Increased aspartate aminotransferase 15% 6% Hortobagyi GN et al. N Engl J Med 2016;375:

MONALEESA-7: PFS with First-Line Ribociclib with Tamoxifen or NSAI in Premenopausal Women with HR-Positive, HER2-Negative Advanced BC Ribociclib + tamoxifen/NSAI (n = 335) Median = 23.8 mo Placebo + tamoxifen/NSAI (n = 337) Median = 13.0 mo HR = 0.553 p-value = Median overall survival data are immature Tripathy D et al. Proc SABCS 2017;Abstract GS2-05.

Press Release – September 28, 2017 FDA Approval of Abemaciclib in Combination with Fulvestrant or as Single-Agent Therapy for HR+, HER2- mBC “The US Food and Drug Administration approved abemaciclib to treat adult patients who have HR-positive, HER2-negative advanced or metastatic breast cancer that has progressed after taking endocrine therapy. Abemaciclib is approved to be given in combination with fulvestrant, after the cancer had grown on endocrine therapy. It is also approved to be given on its own, if patients were previously treated with endocrine therapy and chemotherapy after the cancer had spread.” Support for the combination indication comes from the Phase III MONARCH 2 trial. The single-agent approval is based on the single-arm Phase II MONARCH 1 trial.

MONARCH 1: Single-Agent Activity of Abemaciclib in Refractory HR-Positive, HER2-Negative mBC
N = 132 patients with HR-positive, HER2-negative breast cancer and a median of 3 prior systemic therapies in the metastatic setting Abemaciclib 200 mg administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity At 12 months, confirmed objective response rate: 19.7% Clinical benefit rate: 42.4% Median progression-free survival: 6.0 months Median overall survival: 17.7 months Most common treatment-emergent adverse events (AEs) of any grade: Diarrhea Fatigue Nausea Dickler MN et al. Clin Cancer Res 2017;23(17):

MONARCH 2: PFS with Abemaciclib/Fulvestrant After Disease Progression on Prior ET
Sledge Jr GW et al. J Clin Oncol 2017;35(25):

MONARCH 2: Select Treatment-Emergent Adverse Events
Abemaciclib + fulvestrant (n = 441) Placebo + fulvestrant (n = 223) All grades Grade 3-4 Diarrhea 86% 13% 25% <1% Neutropenia 46% 27% 4% 2% Nausea 45% 3% 23% Abdominal pain 35% 16% Blood creatinine increase 12% 0% Most frequent serious adverse events possibly related to study drug 1.4% Thromboembolic events (no deaths) 2.0% 0.4% Sledge Jr GW et al. J Clin Oncol 2017;35(25):

Progression-free survival (%)
MONARCH 3: PFS with Abemaciclib and a Non-Steroidal Aromatase Inhibitor as First-Line Therapy Abemaciclib + NSAI: Not reached Placebo + NSAI: 14.7 months HR: 0.543 p = (n = 328) Progression-free survival (%) (n = 165) Time (months) Objective response rate: Abemaciclib + NSAI 48.2%; NSAI 34.5% (p = 0.002) Goetz M et al. J Clin Oncol 2017;[Epub ahead of print].

In general, what are your impressions of palbociclib, ribociclib and abemaciclib with regard to …
CLINICAL ACTIVITY TOXICITY CNS ACTIVITY Equal Abema: GI issues; palbo, ribo: bone marrow toxicity Unclear Equal Palbo and ribo equal and better tolerated Unclear Similar Similar Maybe abema more effective, data limited Abema most active Palbo and ribo more tolerable Ribo, abema cross BBB, palbo does not Equal Palbo most tolerable Unclear Palbo and ribo best in Lum A; abema better in Lum B Palbo and ribo better tolerated Only abema has proven activity Similar Palbo most tolerable, followed by ribo and then abema Unclear Palbo and ribo similar; abema need more data Abema less tolerable due to diarrhea Abema highest penetration, ribo has some Abema = abemaciclib; palbo = palbociclib; ribo = ribociclib; BBB = blood-brain barrier; Lum A = Luminal A; Lum B = Luminal B

Module 1: Novel Treatment Strategies in HER2-Positive Early Breast Cancer APHINITY: Adjuvant pertuzumab ExteNET: Extended Adjuvant Treatment Ongoing Studies: KATHERINE, KAITLIN, ATEMPT Module 2: Recently Approved CDK4/6 Inhibitors Palbociclib: PALOMA-1 (palbociclib/letrozole as first-line therapy) Ribociclib: MONALEESA-2 (ribociclib/letrozole as first-line therapy) Abemaciclib: MONARCH 3 (abemaciclib/AI as first-line therapy) Module 3: PARP Module 3: PARP Inhibitors in Metastatic Breast Cancer OlympiAD: Olaparib versus chemotherapy for HER2-negative, gBRCA-mutant mBC Clinical implications of OlympiAD; BRCA germline and somatic mutation testing Ongoing Phase III clinical trials Module 4: Checkpoint Inhibitors in Breast Cancer Early data with anti-PD-1/PD-L1 checkpoint inhibitors Ongoing clinical trials

In general, for a 65-year-old woman who presents with metastatic ER-negative, HER2-negative breast cancer and does not have a significant family history of breast or a related cancer, do you order some type of BRCA germline mutation testing? Yes No 10

In general, for a 65-year-old woman who presents with metastatic breast cancer and who does not have a significant family history of breast or a related cancer, do you order BRCA germline mutation testing or other mutation testing if the tumor is … ER-/HER2- ER+/HER2+ ER-/HER2+ ER+/HER2- gBRCA mutation assay No No No No, except BRCA for olaparib use No, except BRCA for olaparib use No, except BRCA for olaparib use No, except BRCA for olaparib use No No No No gBRCA mutation assay No No No Risk panel (incl BRCA) No No No No, but would discuss No No No No No No No No No No No

Current Guidelines for BRCA Testing in Breast Cancer
A breast cancer diagnosis meeting any of the following criteria: A known mutation in a cancer-susceptibility gene within the family Early-age-onset breast cancer Triple-negative (ER-, PR-, HER2-) breast cancer diagnosed at age ≤60 Two breast cancer primaries in a single individual Breast cancer at any age and ≥1 close blood relative with breast cancer at 50 or younger ≥1 close blood relative with invasive ovarian cancer at any age ≥2 close blood relatives with breast cancer and/or pancreatic cancer at any age Pancreatic cancer at any age From a population at increased risk Male breast cancer Ashkenazi Jewish descent with breast, ovarian or pancreatic cancer at any age NCCN Guidelines Breast and/or Ovarian Cancer Genetic Assessment v2.2017 00A_ONS-Breast-17-NL-Intro-Slides_v34fr

Cost and reimbursement issues aside, when if at all would you introduce olaparib into the treatment course of a 65-year-old woman with metastatic triple-negative breast cancer (TNBC) and a BRCA germline mutation who has disease progression 9 months after completing an adjuvant anthracycline/taxane regimen? First line After 1 line of chemotherapy After 2 lines of chemotherapy After 3 lines of chemotherapy Other I would not recommend olaparib 10

Cost and reimbursement issues aside, when if at all would you introduce olaparib into the treatment course of a 65-year-old woman with metastatic TNBC and a BRCA germline mutation who has disease progression 9 months after completing an adjuvant anthracycline/taxane regimen? First line First line or after 1 line of chemotherapy First or second line After 1 line of chemotherapy First line or after 1 line of chemotherapy First line First line or after 1 line of chemotherapy After 1 or 2 lines of chemotherapy

Cost and reimbursement issues aside, when if at all would you introduce olaparib into the treatment course of a 65-year-old woman with metastatic ER-positive, HER2-negative breast cancer and a BRCA germline mutation who has disease progression 9 months after completing adjuvant anastrozole? First line After first-line endocrine therapy (ET) + CDK4/6 inhibitor Second line after chemotherapy After ET + CDK4/6 inhibitor and everolimus/exemestane After exhausting all ET-based regimens and before chemotherapy After exhausting all ET-based regimens and after chemotherapy Other I would not recommend olaparib 10

Cost and reimbursement issues aside, when if at all would you introduce olaparib into the treatment course of a 65-year-old woman with metastatic ER-positive, HER2-negative breast cancer and a BRCA germline mutation who has disease progression 9 months after completing adjuvant anastrozole? After first-line ET + CDK4/6 inhibitor After exhaust all ET-based regimens and after chemotherapy After exhaust all ET-based regimens After exhaust all ET-based regimens and before chemotherapy After exhaust all ET-based regimens and before chemotherapy After exhaust all ET-based regimens and before chemotherapy First line or second line after chemotherapy After exhaust all ET-based regimens and after chemotherapy

Robson M et al. N Engl J Med 2017;377(6):523-33.

OlympiAD: Phase III Trial Design
HER2-negative mBC ER+ and/or PR+ or TNBC Deleterious or suspected deleterious gBRCA mutation Prior anthracycline and taxane ≤2 prior chemotherapy lines in metastatic setting HR+ disease progresses on ≥1 ET, or not suitable for ET If prior platinum use: No evidence of progression during treatment in the advanced setting ≥12 mo since (neo)adjuvant treatment Olaparib 300 mg tablets BID R Physician’s choice Capecitabine Eribulin Vinorelbine Primary endpoint: PFS by blinded independent central review (BICR) Robson M et al. N Engl J Med 2017;377(6): Robson M et al. Proc ASCO 2017;Abstract LBA4 (Plenary).

OlympiAD: Primary Endpoint PFS by BICR
Olaparib (n = 205) Standard therapy (n = 97) Hazard ratio p-value mPFS 7.0 mo 4.2 mo 0.58 <0.001 mOS 19.3 mo 19.6 mo 0.90 0.57 Median overall survival: no significant difference between arms (HR 0.9, p = 0.57) Objective response rate: olaparib (n = 167): 59.9%, standard therapy (n = 66): 28.8% Robson M et al. N Engl J Med 2017;377(6): Delaloge S et al. Proc ESMO 2017;Abstract 243PD.

OlympiAD: Grade ≥3 Adverse Events
Adverse event (AE) Olaparib (n = 205) Standard therapy (n = 91) Any grade Grade ≥3 Anemia* 40% 16% 26% 4% Neutropenia† 27% 9% 50% Nausea 58% 0% 35% 1% Vomiting 30% 15% Dose reduction due to AE 25% NA 31% Treatment interruption or delay due to AE 28% Treatment discontinuation due to AE 5% 8% * Anemia, decreased hemoglobin level, decreased hematocrit, decreased red-cell count and erythropenia † Febrile neutropenia, granulocytopenia, decreased granulocyte count, neutropenia, neutropenic sepsis, decreased neutrophil count and neutropenic infection Robson M et al. N Engl J Med 2017;377(6): Robson M et al. Proc ASCO 2017;Abstract LBA4 (Plenary).

Press Release – January 12, 2018 FDA Approval of Olaparib for the Treatment of Germline BRCA-Mutated mBC "The Food and Drug Administration granted regular approval to olaparib tablets for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2- negative metastatic breast cancer who have been treated with chemotherapy either in the neoadjuvant, adjuvant, or metastatic setting. ... Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment. Patients must be selected for therapy based on an FDA-approved companion diagnostic for olaparib."

EMBRACA: Phase III Trial Design
Eligibility Locally advanced or metastatic HER2-negative breast cancer Germline BRCA1 or BRCA2 mutation No more than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease Prior treatment with a taxane and/or anthracycline unless medically contraindicated Talazoparib 1 mg PO qd N = 431 R Physician’s choice (PCT) Capecitabine Eribulin Gemcitabine Vinorelbine 2:1 Primary endpoint: PFS by blinded independent central review (BICR) Litton JK et al. Procs SABCS 2017;Abstract GS6-07.

EMBRACA Primary Endpoint: PFS by Blinded Central Review
Talazoparib (n = 287) Overall PCT (n = 144) Median PFS 8.6 mo 5.6 mo HR (p-value) 0.54 (< ) Litton JK et al. Proc SABCS 2017;Abstract GS6-07.

TOPACIO Phase I/II Study
Eligibility (n = 14) Unresectable or metastatic TNBC treated with ≤4 prior regimens for advanced/metastatic disease Platinum-resistant ovarian cancer with ≤5 prior regimens and a CR or PR >6 months in response to first-line platinum- based therapy Niraparib + pembrolizumab Recommended Phase II dose was established as niraparib 200 mg PO daily + pembrolizumab 200 mg IV on day 1 of each 21-day cycle 1/5 patients with metastatic TNBC (BRCA wild type) had stable disease for 10 cycles Konstantinopoulos PA et al. Proc ESMO 2017;Abstract 1143PD.

Select Ongoing Phase III Studies of PARP Inhibitors in Breast Cancer
Study (Setting) No. of patients Population Randomization OlympiA (Adjuvant) 1,500 gBRCAm, high-risk, HER2- after (neo)adj chemo Olaparib Placebo PARTNER (Neoadjuvant) 527 TNBC or gBRCAm Olaparib + paclitaxel/carbo Paclitaxel/carbo BROCADE (LABC or metastatic) 500 HER2-, gBRCAm Veliparib + paclitaxel/carbo Placebo + paclitaxel/carbo TNBC (Advanced) 306 TNBC Niraparib + anti-PD-1 Ab Standard of care Carbo = carboplatin; LABC = locally advanced breast cancer; Ab = antibody Accessed October 2017.

Are there any situations currently in which you would recommend treatment with an anti-PD-1/PD-L1 antibody to patients with breast cancer outside of a clinical trial setting? Yes No 10

Are there any situations currently in which you would recommend treatment with an anti-PD-1/PD-L1 antibody to patients with breast cancer outside of a clinical trial setting? USE PD-1/PD-L1 AB IN BC # PTS PD-1/PD-L1 AB CLINICAL RESPONSE TO PD-1/PD-L1 AB Yes, TNBC 10 Not really Yes, refractory TNBC 10 Yes No 12 Yes No ~5 Possibly Yes, chemo- resistant mTNBC 3 Yes Yes, 1st-line mTNBC 10 Yes No 2 Yes, but severe complications Yes, compassionate use 2 No

KEYNOTE-086: Phase II Study of Pembrolizumab Monotherapy for Previously Treated TNBC: Cohort A
Accrual: 170 Eligibility Centrally confirmed TNBC ≥1 prior systemic treatment for mTNBC with documented PD LDH <2.5 x ULN Tumor biopsy sample for PD-L1 evaluation No radiographic evidence of CNS metastases Pembrolizumab 200 mg IV q3wk x 2 years or until PD, intolerable toxicity, patient withdrawal or investigator decision PD = progressive disease Primary endpoint: overall response rate (ORR) and safety Secondary endpoints: duration of response, disease control rate, PFS, OS Adams S et al. Proc ASCO 2017;Abstract 1008; Accessed October 7, 2017.

KEYNOTE-086: Response Rates
Cohort A (N = 170): Previously Treated, Regardless of PD-L1 Expression Cohort B (N = 52): Previously Untreated, PD-L1 Positive Adams S et al. Proc ASCO 2017;Abstract 1008.

KEYNOTE-086 Cohort A: Time to Response (TTR), Duration of Response (DOR) and Stable Disease (SD)
Median TTR: 3.0 mo (range ) No subsequent progression 0/1 with CR 5/7 with PR 12/35 with SD Median DOR: 6.3 mo (range 1.2+ to 10.3+) Adams S et al. Proc ASCO 2017;Abstract 1008.

KEYNOTE-086 Cohort A: Overall Survival by PD-L1 Status and by Best Overall Response
Events/patients Median Total 90/170 8.9 mo PD-L1-positive 58/105 8.3 mo PD-L1-negative 32/64 10.0 mo Events/ patients, n Median (95% Cl) CR or PR 0/8 Not reached (NR-NR) SD 6/35 Not reached (12.7-NR) PD 66/103 7.1 mo ( ) Adams S et al. Proc ASCO 2017;Abstract 1008.

Atezolizumab for Metastatic TNBC
All patients Atezo as first line Atezo after ≥2 lines of therapy ORR (n = 112, 19, 93) 10% 26% 7% Median duration of response 21 mo Not evaluable OS rate (n = 113, 19, 94) 1-year 3-year 41% 22% 63% Not evaluable 37% 18% Durable clinical benefit observed in responders Schmid P et al. Proc AACR 2017;Abstract 2986.

Atezolizumab with Nab Paclitaxel for Metastatic TNBC
Response First line (n = 13) Second line (n = 9) Third line + (n = 10) Confirmed objective response 46% 22% 40% Complete response 8% Partial response 38% Stable disease 67% 30% PFS not mature and median duration of response not reached Treatment-related Grade 3-4 adverse events: neutropenia/decreased neutrophil (47%), thrombocytopenia, anemia and diarrhea (6% each) Adams S et al. Proc ASCO 2016;Abstract 1009.

Key Ongoing Phase III Studies of Anti-PD-1/PD-L1 Checkpoint Inhibitors in Breast Cancer
Study Randomization Setting IMpassion131 Atezolizumab/paclitaxel Placebo/paclitaxel Previously untreated, locally advanced or metastatic TNBC IMpassion130 Atezolizumab/nab paclitaxel Placebo/nab paclitaxel Previously untreated mTNBC IMpassion031 Atezolizumab/chemotherapy Placebo/chemotherapy Neoadjuvant TNBC NeoTRIPaPDL1 Atezolizumab/nab paclitaxel/carboplatin Nab paclitaxel/carboplatin Locally advanced TNBC A-Brave Avelumab Placebo High-risk TNBC after adjuvant chemo KEYNOTE-119 Pembrolizumab Chemotherapy mTNBC KEYNOTE-355 Pembrolizumab/chemotherapy First-line HER2-positive NCI Paclitaxel/trastuzumab/pertuzumab (THP) Pembrolizumab/THP KEYNOTE-522 Neoadjuvant Accessed October 3, 2017.

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