TAILORx: Established and Potential Implications for Clinical Practice

TAILORx: Established and Potential Implications for Clinical Practice Joseph A. Sparano, MD Study Chair, TAILORx Vice-Chair, ECOG-ACRIN Cancer Research Group Hello Healthcare Summit Berlin, Germany March 10, 2017 1

Background Impact of Screening & Adjuvant Chemotherapy on Breast Cancer Mortality Most common cancer worldwide in women, leading cause of cancer death 1 Mortality rates declining due to screening and expanded use of adjuvant chemotherapy 2,3,4 Better prognosis if mammographically detected More accurate lymph node staging by sentinel node biopsy More effective cytotoxic & endocrine therapy, and addition of anti-her2 therapy Proportional risk reductions from adjuvant chemotherapy are little affected by age, nodal status, grade, ER expression, or use of endocrine therapy 5,6 U.S. N.I.H consensus panel in 2001 concluded adjuvant..chemotherapy should be recommended to the majority of women with localized breast cancer regardless of lymph node, menopausal, or receptor status. 7 Approximately 60% of women with ER+, node negative breast cancer were receiving adjuvant chemotherapy in the U.S. in 2000 8 ER+, node negative breast cancer accounts for 50% of all breast cancers (1) Torre et al. CA Cancer J Clin 2015;65:87 108 (2) Narod et t al. J Cancer Policy 2015: 5: 8-17 (3) Berry et al. N Engl J Med 2005; 353:1784-179 (4) EBCTCG. Lancet 2005;365 (9472): 1687-717 (5) Shen et al. JNCI 2005; 97: 1195) (6) EBCTCG. Lancet 379 (9814):432-44 (7) Abrams JS. Breast Cancer 2001;8:298-304 (8) Harlan et al. J Clin Oncol 2006:872-877. 2

Molecular Markers: A Potential Solution? Reduce cancer mortality and treatment associated morbidity More accurately identify high risk subjects likely to benefit from: More aggressive non-specific therapy (ie, chemotherapy) Specific targeted therapies (ie, anti-her2 therapy) Clinical trials evaluating experimental therapies Potential impact: Reduce overtreatment in low risk subjects Reduce undertreatment in high risk subjects Improve efficiency and reduce size and costs of adjuvant trials

Non-Surgical Treatment Options Treatment Selection Percent Eligible Treatment Effect Acute Toxicity Estimated Cost Chemotherapy Recurrence Risk > 5-10% Most 25-35% High $26,500 Endocrine therapy ER/PR+ 70% 50% Low $15,000 Trastuzumab Her2+ 15% 50% Low $40,000 Radiation Lumpectomy 40-60% 90% Low $9,000 (Higher for PBI)

Molecular Markers: Potential Influence on Treatment Decisions Treatment Clinical Genomic Impact Sparing Yes No Unnecessary Chemotherapy Selection No Yes Curability Direction Equipoise Yes or No More appropriate treatment choices Confirmation Yes Yes Confirm clinical decision No No

What is the scientific rationale for selecting Oncotype DX for TAILORx? (Trial Assigning IndividuaLized Options for TReatment)

Oncotype DX 21 Gene Recurrence Score (RS) Assay 16 Cancer and 5 Reference Genes From 3 Studies PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 INVASION Stromelysin 3 Cathepsin L2 HER2 GRB7 HER2 ESTROGEN ER PR Bcl2 SCUBE2 GSTM1 CD68 BAG1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC RS = + 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68-0.08 x GSTM1-0.07 x BAG1 Category RS (0 100) Low risk RS < 18 Int risk RS 18 30 High risk RS > 30

Summary of Validation Study Results When TAILORx was Developed Prognostic (B14 tamoxifen) RS - distant recurrence at breast cancer death at 10 years Categorical or continuous variable Prognostic significance retained after adjustment for clinical features Prognostic if no therapy, tam therapy, or chemohormonal therapy Prognostic for local recurrence also More accurately predicts outcome that Adjuvant! Predictive (B20 tamoxifen +/- CMF) High RS predictive of benefit from chemotherapy Paik et al. NEJM 2014, Paik et al. J Clin Oncol 2006, Bryant et al St.Gallen 2005

Prospectiely validated prognostic test for tamoxifen treated patients may also be used as continuous variable (Paik et al. NEJM, 2004) DRFS 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Low Risk (RS <18) Intermediate Risk (RS 18-30) High Risk (RS 31) 0 2 4 6 8 10 12 14 16 Years 338 pts 149 pts 181 pts Tamoxifen treated patients from NSABP B-14 (N=668) Performance exceeded standard measures of patient age, tumor size

Lower RS prognostic and predictive of tamoxifen benefit (B14 tamoxifen vs. placebo comparison by RS) (Paik et al. ASCO 2005, abstr 510) 1.0 1.0 0.8 0.8 0.6 0.6 DRFS DRFS 0.4 Low Risk (RS<18) 0.4 Int Risk (RS 18-30) 0.2 Placebo n=142 Tamoxifen n=171 0.0 0 2 4 6 8 10 12 14 16 Years p=0.04 0.2 Placebo n=69 Tamolxifen n=85 0.0 0 2 4 6 8 10 12 14 16 Years p=0.02 1.0 0.8 DRFS 0.6 0.4 High Risk (RS 31) 0.2 Placebo n=99 Tamoxifen n=79 0.0 0 2 4 6 8 10 12 14 16 Years p=0.82

RS and ER Expression Modestly Correlated (Paik et al. ASCO 2005, abstr 510) High ER tumors can still have high RS 100 R 2 = 0.29 80 Recurrence Score 60 40 Hi Risk For ER of 13, RS can be low or high 20 Int Risk Low Risk 0 7 8 9 10 11 12 13 14 ER Expresssion by RT-PCR (relative to ref genes; log2)

Entire Cohort B20 Tamoxifen +/- CMF in ER+, Node-Negative Beast Cancer RS > 30 (Paik et al. J Clin Oncol 2006;24:3726-34 12

Trial Category from Table 1: A: Prospective (eg. TAILORx, RxPONDER, OPTIMA) B: Prospective using archived samples (eg. B14, B20, TransATAC, S8814, E2197) C: Prospective, observational registry (treatment not dictated) Siimon, Paik, Hayes, JCNI 2009 13

Rationale for Choosing Oncotype DX Level of Evidence Prospective validation (B14) & external validation studies (Kaiser) in tamoxifen treated patients Experience in other populations including patients treated with chemohormonal therapy (B20) and no therapy Clinical Utility Common disease type that is commonly overtreated Potential for result to influence treatment decisions Practical Considerations CLIA approved, commercially available No special processing required facilitates retrospective clinical use Builds on prior public-private partnership Extensive post-marketing experience and precedent for payor reimbursement

What trial design for TAILORx?

B20: Relationship Between RS as a Continuous Variable and Treatment with Tam or Tam + Chemotherapy Distant Recurrence at 10 Years 0.0 0.1 0.2 0.3 0.4 Tam Tam + Chemo Primary Study Group For Randomization Benefit from chemo 0 10 20 30 40 50 Recurrence Score Secondary Study Group 1 Secondary Study Group 2

Rationale for Changing RS Cutpoints in TAILORx and Excluding HER2+ Disease HER2+ tumors excluded because of efficacy of trastuzumab plus chemotherapy established in 2005 Most HER2+positive tumors had a high RS (>25) contributed to basis for picking upper threshold Lower threshold set at up to a 10% risk of distant recurrence at 10 years Reduced risk of undertreatment in subjects randomized to receive chemotherapy or not

10 year DRFS and DFS - TAILORx RS Ranges in B20 RS No. (%) <11 177 (27%) DRFS Tam T+ Chemo HR P Value 98% 95% 1.79 0.47 Tam T+ Chemo DFS HR P Value 77% 85% 0.61 0.12 11-25 297 (43%) 95% 94% 0.76 0.53 81% 76% 1.11 0.69 >25 195 (30%) 63% 88% 0.29 <0.00 01 53% 75% 0.29 0.01 Sparano & Paik. J Clin Oncol 2008

Methods: TAILORx Design & Ra7onale for RS Cutpoints Enrollment period: April 7, 2006 to October 6, 2010 (N=10,273 eligible) Key Eligibility Criteria Node-negative ER-pos, HER2-neg T1c-T2 (high-risk T1b) Age 18-75 years No PBI planned Recurrence Score = 11 7.3% distant recurrence rate at 10 years 95% CI 5%, 10% Recurrence Score = 25 16.1% distant recurrence rate at 10 years 95% CI 13%, 20% Sparano J A, and Paik S JCO 2008;26:721-728 19

TAILORx: Objectives & Statistical Plan Primary objective: Is ET inferior to chemo + ET in patients with a mid-range RS Create a tissue and specimen bank Statistical considerations for RS 11-25: Primary endpoint idfs (DRFI, RFI, OS secondary) Non-inferiority design (HR 1.332) - 5-year DFS rate from 90% (with chemo) to < 87% (without chemo) would be considered unacceptable one-sided type I error of 10%, 5% type II error Both the primary assigned treatment and secondary as treated comparisons need to be non-significant for a clear conclusion of non-inferiority of hormonal therapy alone Repeated confidence interval (RCI) methodology for early stopping in favor onf non-inferiority using the critical value from the O Brien-Fleming error spending rate function with an overall one-sided 2.5% error rate Screen ~10,046 for 4,390 pts with RS 11-25, assuming 2.5% non-adherence Full information expected after 835 DFS events (originally projected 2016) Statistical considerations for RS <11: Sample size driven by expected proportion with RS < 11 (N=1394 projected) 10 -year DRFI rate of 95% vs. < 93.5% (75 DRFI events for full information) one-sided test with type I error 2.5%, 85% power

Effect of Average Non-Adherence Rate on Sample Size and Projected Completion of Study No. Patients 14000 12000 10000 8000 6000 June 2009 7047 2657 7851 2960 January 2010 8802 3318 9937 3746 July 2010 11,306 4262 12,979 4711 4000 2000 4390 4891 5484 Assumed 6191 7044 Actual 8066 0 2.50% 5.00% 7.50% 10.00% 12.50% 15.00% Average Non-Adhderence Rates in 2 Randomized Arms Required no. of randomized patients, expected no. registry patients, and total patients

Schema showing Trial Assigning Individualized Op7ons for Treatment (TAILORx) design N=11,232 N=10,293 N=1629 N=1737 Sparano J A, and Paik S JCO 2008;26:721-728 N=6907 2008 by American Society of Clinical Oncology 22

Non-Adherence in Other Seminal Breast Cancer Trials Experimental Arm Standard Arm Non-Adherence Rates B06 E2190 Lumpectomy +/- RT 7% High-dose chemo 14% Mastectomy 11% Average = 9% Standard Rx 7% Average = 11% Practice changing results: B06: Lumpectomy/RT as effective as mastectomy E2190: High dose therapy not effective as thought

Distribution of Recurrence Score in Patients Enrolled in TAILORx and Outside of TAILORx TAILORx Participants Non-TAILORx Courtesy of Steve Shak, MD, Genomic Health

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Results: Patient Characteristics and Treatment RS < 11 RS 11-25 P Value No. eligible patients 1626 6897 Median age 58 years 55 years P<0.001 Post-menopausal 70% 64% P<0.001 Median tumor size 1.5 cm 1.5 cm N.S Histologic grade Low Intermediate High 34% 59% 7% 29% 57% 14% P<0.001 ER Expression > 99% > 99% N.S. PgR Expression 98% 92% P<0.001 Surgery Lumpectomy 68% 72% P<0.001 Endocrine Mastectomy therapy in low RS 32% group: AI in 59%, 28% tamoxifen in 34%, sequential tamoxifen-ai in 1%, OFS plus other therapy (3%), or other/unknown (3%) Chemotherapy given to 6 patients in low RS group: (1 of whom recurred) 26

Results: Kaplan Meier Plots and 5 Year Event Rates No. of events: 88 idfs events and 30 deaths within 5 years of registra7on, including 18 recurrences (10 distant as first event), 15 second primary breast cancers, 43 other second primary cancers, 12 deaths without another event 5 year idfs Rate 93.8% (95% CI 92.4%, 94.9%) 5 year DRFI Rate 99.3% (95% CI 98.7%, 99.6%) 5 year RFI Rate 98.7% (95% CI 97.9%, 99.2%) 5 year OS Rate 98.0% (95% CI 97.%, 98.6%) 27

Results: Multivariate Analysis Cox proportional hazards model with covariates including age (< 50 vs. 51-60 vs. 61-75 years), tumor size (2.1-5.0 cm vs. < 2 cm), histologic grade (high vs. intermediate vs. low), and surgery type (mastectomy vs. lumpectomy) Grade was the only covariate that showed a significant association with any endpoint examined, which was RFI (P=0.02), but not idfs or DRFI Grade DRFI RFI idfs OS All Grades 99.3 98.7 93.8 98.0 (98.7, 99.6) (97.9, 99.2) (92.4, 94.9) (97.1, 98.6) Low 99.8 99.8 95.8 98.7 (98.3,100.0) (98.3,100.0) (93.5, 97.3) (97.0, 99.4) Intermediate 99.0 98.2 93.6 97.9 (98.0, 99.5) (97.0, 99.0) (91.7, 95.1) (96.8, 98.7) High 100 98.7 91.3 97.3 (--,--) (91.1, 99.8) (83.9, 95.4) (91.9, 99.1)! 28

Other Selected Clinical Results, Cohort, and Population-Based Studies with Oncotype DX Recurrence Score

PlanB: Design HER2-negative primary breast cancer! Age<75 years! free margins! M0! pn+! pn0 high risk! pt>2! G2-3! upa/pai-1! HR-! age <35 years HR- HR+ R E C U R R E N C E S C O R E 0-3 LN and RS>11 or >/= 4 LN 0-3 LN and RS<11 R A N D O M I Z A T I O N Doc 75 C 600 x 6* E 90 C 600 x4 "Doc 100 x4* Endocrine therapy* endocrine therapy and RT according to national guidelines E: Epirubcin; Doc: Docetaxel; C: Cyclophosphamid 30

PlanB: Five-year disease-free survival in per-protocol population (no chemotherapy in pn0-1 RS 0-11) 5-Y DFS 94% 5-Y DFS 94% 5-Y DFS 84% N0 5-Y DFS 94% 5-Y DFS 95% 5-Y DFS 88% N1 94% 94% 84% 31

PlanB trial (HR+/HER2- population; 5-year median follow-up): Conclusions I! Excellent 5-year DFS (94%) in clinically high-risk patients (pn0 or pn1) with RS <12 treated by endocrine therapy alone! Overtreatment by chemotherapy likely in patients with RS 12-25 (pn0 or pn1) 32

ECC 2015 Poster Presentation from Israel with 5- Year Outcomes Clalit Health Services Registry Chemotherapy Use in Percentage RS < 18 1% RS 18-30 28% RS 31 85% Stemmer et al. ECC 2015. 33

Genomic Health SEER Database Using TAILORX cutpoints, the 5-year BCSM in HR+, node neg disease: RS < 11-0.4% (95% CI, 0.2 0.6%) (N=7281 18%) N=38,568 RS 11-25 - 0.7% (95% CI, 0.6 0.8%) (N = 26,462 66%) RS > 25-3.6% (95% CI, 3.0 4.4%) (N= 6,391-16%) Petkov et al. NPJ Beast Cancer 2016 54% 38% 8% 34

Chemotherapy Use and Clinical Outcomes in ER+, HER2-, Node -Negative Breast Cancer at MD Anderson Cancer Center (N=894 with RS 11-25) Barcenas et al. Cancer 2017 35

Shifting a Treatment Paradigm and Delivering Measurable Results 1 Oncotype DX Penetration / Chemotherapy Usage 70% 60% 50% 40% 30% 20% ODX Market Penetration for ER+ 10% Adjuvant Chemo Usage U.S. 0% 2007-T1 2007-T2 2007-T3 2008-T1 2008-T2 2008-T3 2009-T1 2009-T2 2009-T3 2010-T1 2010-T2 2010-T3 T = Trimester 1 Adjuvant Data is from OncoReport ICI T3 2010. Date on File, Genomic Health 2012 36

Chemotherapy Benefit in EBCTCG Metaanalysis: Implications for TAILORx RICHARD GRAY, PHD CLINICAL TRIALS SERVICE UNIT & EPIDEMIOLOGIC STUDIES UNIT OXFORD UNIVERSITY

EBCTCG: Recurrence by follow-up period by chemotherapy regimens CMF vs no cytotoxic (p13) Anth. vs no cytotoxic (p11) Taxane vs Anth. (P7) Lancet 2012; 379: 432 44 supplementary material

Chemotherapy benefit: If propor7onal reduc7ons in recurrence by year of follow-up also do not differ much in different categories of pa7ent then the meta-analysis results suggest that the reduc7ons in recurrence with modern chemotherapy are likely to be: About 50% in years 0-1 About 33% in years 2-4 About 15% in years 5-9 Greater than zero in years 10+ The analyses shown above are of 7me to breast cancer recurrence Non-breast cancer mortality and second non-breast primary cancers are included in TAILORx primary DFS outcome Neither are much affected by chemotherapy and so their inclusion will dilute treatment efficacy

TAILORx: Established and Potential Implications for Clinical Practice Oncotype DX Recurrence Score (21 gene assay) Analytic and clinical validity (prognosis) established in ER+, HER2- disease, and also in node-positive diease Provides prognostic information that is independent of clinicopathologic features Provides predictive information for chemotherapy benefit Some level 1 evidence supporting clinical utility in node-negative disease. in direction of sparing (~20-25%) rather than selecting (~5%) chemotherapy Population-based studies show impact on chemotherapy use in node negative disease Recommended in some clinical practice guidelines for node-negative, ER+, HER2- negative disease (ASCO, NCCN) Additional work needed to determine whether more may be spared chemo TAILORx - node-negative disease with a RS 11-25 RxPONDER, OPTIMA - node-positive disease with a RS 25 or lower 40