Update on New Perspectives in Endocrine-Sensitive Breast Cancer. James R. Waisman, MD

Transcription

1 Update on New Perspectives in Endocrine-Sensitive Breast Cancer James R. Waisman, MD

2 Nothing to disclose DISCLOSURE

3 TAILORx Oncotype Recurrence Score

4 TAILORx Study Design Sparano, J Clin Oncol 2008;26:

5 TAILORx Results: Association between continuous RS and 9 year distant recurrent rate stratified by age Sparano, ASCO 2018

6 TAILORx ITT Population: Potential Chemotherapy benefit in women < 50 yrs (N=2216) in RS Sparano, ASCO 2018

7 TAILORx Results: Summary Sparano, J Clin Oncol 2008;26:

8 TAILORx Subgroup Results In Patients >50 & 50 Years The prediction of chemotherapy benefit is largely binary at a Recurrence Score result of 26. The absolute reduction of distant recurrence at 9 years from chemotherapy for patients >50 years and 50 years is shown below. Age RS 0-10 RS RS RS RS >50 years No CT Benefit Large CT Benefit 50 years No CT Benefit ~1.6% CT Benefit ~6.5% CT Benefit Large CT Benefit Paik, J Clin Oncol. 2006; Sparano, J Clin Oncol. 2008; Sparano, NEJM 2018

9

10 SOFT and TEXT Designs

11 Randomization and Analyses in SOFT and TEXT Francis, NEJM 2018:379;2:

12 Characteristics of the Patients in SOFT and TEXT at Baseline According to Chemotherapy Status Francis, NEJM 2018:379;2:

13 Kaplan-Meier Estimates of Freedom from Distant Recurrence and of Overall Survival in SOFT Francis, NEJM 2018:379;2:

14 Estimates of Disease-free Survival, Freedom from Distant Recurrence, and Overall Survival Among Patients with HER2- Disease in the Combined SOFT and TEXT Population Francis, NEJM 2018:379;2:

15 von Minckwitz, NEJM on line June 5, 2017

16 APHINITY Study Design Adjuvant Chemotherpy Patients with HER2+ T>Ib, N0-3* Invasive dz LVEF > 50% No MI, gr 2 neuropathy, uncontrolled HTN, or prior CA + trastuzumab n=2404 Adjuvant Chemotherpy + trastuumab + pertuzzumab n=2400 Primary Endpoint: IDFS Secondary Endpoints: OS, DFS, DRFS, safety, HRQoL * After enrollment of 3655 randomized, N0 pts were no longer eligible. von Minckwitz, NEJM on line June 5, 2017

17 APHINITY Patient Characteristics von Minckwitz, NEJM on line June 5, 2017

18 APHINITY Invasive DFS von Minckwitz, NEJM on line June 5, 2017

19 APHINITY Invasive DFS by Nodal Status von Minckwitz, NEJM on line June 5, 2017

20 Forest Plot of Invasive-Disease-free Survival von Minckwitz, NEJM 2017;377;2:

21 APHINITY Conclusions The addition of pertuzumab to trastuzumab containing adjuvant therapy improved IDFS. Pertuzumab was associated with increased diarrhea. Is this practice changing? von Minckwitz, NEJM on line June 5, 2017

22 2 year follow-up fo ridfs 5 year follow-up fo ridfs Overall Survival ExteNET Study Design Neratinib 240 mg/d HER2+ Prior adj Trastuzumab + Chemo LN+ or non-pcr after neoadjuvant therapy Known ER/PR status R X 1year Placebo X 1 year Loperamide pre medications D1: 4 mg with neratinib then D1-3: 2 mg q4h D mg q6-8h Statistical Endpoints Primary: IDFS in ITT (n=2840) Chan, Lancet Oncology 2016; 17:

23 Neratinib

24 ExteNET Study 3 Year IDFS (n-2850) Chan, Lancet Oncology 2016; 17:

25 ExteNET Study 2 and 5 year cutoff Chan, Lancet Oncology 2016; 17: FDA Briefing Documents 5/24/17

26 Neratinib versus Placebo Total population Hormone-positive group Hormone-negative group Invasive disease-free survival in the intention-to-treat population (A), patients with hormone receptor-positive breast cancer (B), and patients with hormone receptornegative breast cancer (C) HR = hazard ratio Martin, Lancet Oncology 2017;18:

27 Subgroup Analysis of Invasive Disease-free Survival in the Intentionto-treat Population The vertical dashed line indicates a hazard ratio of 1:00--the null hypothesis value. Error bars represent 95% Cls. *Stratification factor. Martin, Lancet Oncology 2017;18:

28

29 Kaplan-Meier Estimates of Disease-free Survival and Overall Survival (1 of 2) Panels A and B show disease-free survival and overall survival, respectively, in the full analysis set (primary analysis). Tick marks indicate censored data. Masuda, NEJM 2017;376;22:

30 Kaplan-Meier Estimates of Disease-free Survival and Overall Survival (2 of 2) Panels C and D show disease-free survival and overall survival, respectively, in the subgroup of patients with triplenegative breast cancer (i.e., breast cancer that was negative for estrogen receptors, progesterone receptors, and HER2). Masuda, NEJM 2017;376;22:

31 Subgroup Analysis of Disease-free Survival in the Full Analysis Set Masuda, NEJM 2017;376;22:

32 New Recommendations From 2018 Focused Guideline Update Denduluri, JCO 2018:36(23):

33 Summary of Clinical Trial Data for CDK4/6 Inhibitors for HR+/HER2- Advanced Breast Cancer Shah, Oncology 2018;May;

34 Progression-free Survival Outcomes in Patient Subgroups Slamon, J Clin Oncol 2018;36:24;

35 Summary CDK 4/6 Inhibitors Palbociclib Ribociclib Abemaciclib Trials PALOMA MONALEESA MONARCH Dose/Schedule 125 mg/d D mg/d D mg bid PFS 1 st line therapy with letrozole PFS 2 nd line with fulvestrant PFS 24.8 v 14.4 mos. PFS 8.2 v 3.8 mos Toxicity Any grade Neutropenia 79% Diarrhea 19% 18 mo PFS 63% vs 42.8% Neutropenia 74% Diarrhea 35% PFS 16.4 v 9.3 mos. Neutropenia 46% Diarrhea 86% Turner, NEJM;2015;373: Sledge, JCO 2017;35:1-12

36 CDK4/6 Inhibitors as First line Therapy

37 CDK4/6 Inhibitors in Refractory Disease

38 Clinical Trials Including Premenopausal Breast Cancer Patients Treated with LHRH and Tamoxifen Tancredi, Oncologist 2018;23:

39 Clinical Trials With the Combination of LHRH and Aromatase Inhibitor Tancredi, Oncologist 2018;23:

40 Endocrine Therapy for Premenopausal Women with Hormone Receptor Positive Metastatic Breast Cancer First line Second line Third line OFS plus No prior treatment tam or AI fulvestrant AI + CDK4/6 fulvestrant + CDK4/6 AI + everolimus alternative ET Adjuvant tam +/- OFS Adjuvant AI + OFS AI fulvestrant AI + CDK4/6 Late relapse: AI fulvestrant AI + CDK4/6 fulvestrant + CDK4/6 AI + everolimus alternative ET fulvestrant + CDK4/6 AI + everolimus alternative ET Further endocrine treatment based upon type and activity of prior endocrine therapy as well as clinical assessment or chemotherapy Early relapse: fulvestrant fulvestrant + CDK4/6 AI + everolimus alternative ET (+/- CDK4/6) Tancredi, Oncologist 2018;23:

41 Management Algorithm for HR+/HER2- Advanced Breast Cancer First-line therapy a,b Tamoxifen or aromatase inhibitor c Aromatase inhibitor c / CDK4/6 inhibitor Fulvestrant/ CDK4/6 inhibitor d Second-line therapy a,b Fulvestrant/ CDK4/6 inhibitor Fulvestrant or tamoxifen Third-line therapy a,b,e,f Exemestane/everolimus or chemotherapy a Consider chemotherapy at each step if overt evidence of visceral crisis. b Consider clinical trials at each step. c Should be used with ovarian function suppression in premenopausal women. d Consider in first line for patients who meet inclusion criteria for PALOMA-3 or MONARCH-2. e Consider Additional or other endocrine therapies in patients with long duration of response to endocrine therapy. f If patient has not yet received CDK4/6 inhibitor abemaciclib alone. CDK4/6 = cyclin-dependent kinase 4 and 6 HR+/HER2- = hormone receptor-positive/human epidermal growth factor receptor 2-negative. Shah, Oncology 2018;May;

42 Novel Antiestrogens In Clinical Development Lartigue, OncPathways 2018;19:15;62-65

43 Breast Cancer Incidence Among BRCA1 Mutation Carriers by HRT Use A, Breast cancer incidence among BRCA1 mutation carriers who used any HRT compared with women who did not use HR. B, Breast cancer incidence among BRCA1 mutation carriers who used estrogen-alone HRT compared with women who used combined estrogen plus progesterone HRT. C, Breast cancer incidence among BRCA1 mutation carriers who used estrogen-alone HRT compared with women who used combined estrogen plus progesterone HRT, among women who underwent oophorectomy prior to age 45 years. Abbreviations: E, estrogen; HRT, hormone replacement therapy; PE, progesterone plus estrogen. Kotsopoulos, JAMA Oncol. 2018:4(8):

44 Thank you!