Endocrine Therapy 2017: Is There a Better Single Agent and when Should we Use it?

Transcription

1 Endocrine Therapy 2017: Is There a Better Single Agent and when Should we Use it? ET1 ET2 ET3 Targeted agent 1 Targeted agent 2 Hope S. Rugo, MD Director, Breast Oncology and Clinical Trials Education University of California San Francisco Helen Diller Family Comprehensive Cancer Center

2 Chemotherapy Historical Timeline of Therapies for HR + Advanced Breast Cancer Anthracyclines 1 Doxorubicin Epirubicin 1980s Taxanes 1 Paclitaxel Docetaxel 1990s Others 1 Capecitabine Gemcitabine Ixabepilone Eribulin Nab-paclitaxel 2000s Endocrine Therapy s Oophorectomy 2,3 SERMs 4 Tamoxifen Toremifene AIs 4 Anastrozole Letrozole Exemestane ERDs 5 Fulvestrant ERDs 5 High-dose fulvestrant * Targeting mtor, CDK4/6 HDAC AI, aromatase inhibitor; ERDs, estrogen receptor downregulators; HR + ; hormone-receptor positive; SERMs, selective estrogen receptor modulators * Marginal improvement over lower dose fulvestrant. 1. Advanced Breast Cancer Community Website. Available at: Accessed April 20, 2015; 2. Beatson GT. Lancet. 1896;2: ; 3. Beatson GT. Lancet. 1896;2: ; 4. Cohen MH, et al. Oncologist. 2001;6(1):4-11; 5. Faslodex [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2011.

3 Goals and Challenges: Treatment of Metastatic Breast Cancer Goals: Help patients to live as long as possible with the best quality of life Challenges Maintain quality of life, particularly in the first-line setting, with the least toxicity Control symptoms associated with disease Longer PFS in the first-line setting associated with bettter quality of life Considerations Avoid need for intravenous access Minimize clinic visits Minimize additional toxicity Guidelines Hormone therapy should be used in the first-line setting in hormone receptor positive advanced breast cancer except in the case of rapidly progressive visceral disease

4 HR+ MBC: Concordance Across International Guidelines ABC2 treatment guidelines for advanced breast cancer: 1,2 Endocrine therapy (ET) is the preferred option for hormone receptor positive disease, even in the presence of visceral disease, unless there is concern or proof of endocrine resistance or rapidly progressive disease needing a fast response ASCO Guidelines for Metastatic HR+ Breast cancer 3 Treatment should be administered until there is unequivocal evidence of disease progression as documented by imaging, clinical examination, or disease-related symptoms Use of combined endocrine therapy and chemotherapy is not recommended Patients should be encouraged to consider enrolling in clinical trials, including patients receiving treatment in first-line setting 1. Cardoso F, et al. Ann Oncol Wilcken N, et al. 2. Cochrane Database Syst Rev. 2003;2:CD Rugo HS, et al. J Clin Oncol. 2016;34:

5 AI vs fulvest AI vs AI + fulvest AI vs Tamoxifen Efficacy of AIs in 1 st -Line MBC Trial Treatment # Patients TTP/PFS, months ORR, % CBR, % Bonneterre et al 1 Anastrozole vs 340 Tamoxifen Nabholtz et al 1 Anastrozole vs 171 Tamoxifen Mouridsen et al 1 Letrozole vs 453 Tamoxifen Paridaens et al 1 Exemestane vs 182 Tamoxifen NR NR Chernozemsky et al 1 Exemestane vs Tamoxifen Mehta et al 2 Anastrozole vs Anastrozole + Fulvestrant NR NR Bergh et al 3 Anastrozole vs Anastrozole + Fulvestrant Robertson et al 4, 5 Anastrozole vs Fulvestrant Cardoso F, et al. Cancer Treat Rev. 2013;39:457-65; 2. Bergh J, et al. J Clin Oncol. 2012;30(16): ; 3. Mehta RS, et al. N Engl J Med. 2012;367(5): ; 4. Robertson JF, et al. Breast Cancer Res Treat. 2012;136(2): ; 5. Robertson JF, et al. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract S6-04.

6 Comparison of First Line AI ± 250 mg Fulvestrant Trials FACT SWOG 0226* No. Patients De novo metastatic disease Prior adjuvant chemotherapy 13% 39% 45% 33% Prior adjuvant tamoxifen 68% 40% Median PFS (mo) 10.2 vs 10.8 HR.72, p =.91 Median OS (mo) 38.2 vs 37.8 P =1.0 Mehta et al, NEJM 2012; Bergh et al, JCO Fulvestrant 500 mg IM on day 0 followed by 250 mg IM day 14 and 28 then 250 mg every 28 days *Significance maintained only in those with no prior adjuvant tamoxifen 13.5 vs 15 HR.8, p = vs 47.7 HR.81, p =.049

7 Dose Matters! CONFIRM: PFS and OS (50% events) Progression-Free Survival Hazard ratio (95% CI): 0.80 (0.68 to 0.94) P =.006 Fulvestrant 500 Fulvestrant 500 mg Proportion of Fulvestrant 250 mg patients alive Fulvestrant 250 % progressed Overall Survival Fulvestrant 500 mg Fulvestrant 250 mg HR (95% CI) 0.81 (0.69, 0.96) p-value Median time to death (months) Fulvestrant 500 mg 26.4 Fulvestrant 250 mg Time (months) a a Nominal value, cannot be claimed as statistically significant Patients at risk: 500 mg mg Fulvestrant 500 % died 75.3 Fulvestrant 250 Median TTP (months) Di Leo A et al. J Clin Oncol, 2010; JNCI Median OS (months) CBR: F % vs F % ORR: F % vs F %

8 FIRST Trial: Randomized Phase II Postmenopausal ER+ advanced, 1st line Anastrozole 1 mg/daily (n=103) Fulvestrant 500 mg days 0, 14, 28, and then q 28 days (n=102) Primary endpoint = clinical benefit (CB) rate Best OR Fulvestrant 500 mg n=102 (%) Anastrozole 1 mg n=103 (%) Clinical benefit CR 0 1 (1.0) P value for primary endpoint: PR 32 (31.4) 32 (31.1) SD 24 weeks 42 (41.2) 36 (35.0) Total with CB 74 (72.5) 69 (67.0) P value (HR) PFS (mo) (0.66) OS (mo) (HR 0.7) Robertson JFR et al. J Clin Oncol 2009; BCRT 2012,; Ellis et al, JCO 2015

9 Cochrane Analysis: PFS Fulvestrant Compared to other Hormone Therapy 4514 women, mostly given 250mg Conclusion: Fulvestrant should be given at the 500 mg dose. At 250 mg is safe and as effective as other hormone therapies. Current data does not support combination hormone therapy as superior to single agent therapy. Lee et al, Cochrane Database, 2017

10 What is the Best First-Line Hormone Therapy for Advanced Disease?: FALCON Postmenopausal women presenting with ER+ and / or PgR+ LA / MBC not previously treated with any hormonal therapy Randomisation 1:1 (n=450) Fulvestrant 500 mg + placebo Anastrozole + placebo Progression Survival PFS analysis at 306 progression events OS analysis at 50% Progression Survival One prior line of chemotherapy allowed. No HRT within 6 months Stratification: measurable vs non-measurable disease; locally advanced vs metastatic Ellis et al, ESMO 2016; Robertson et al, Lancet 2016

11 Patients and Primary PFS Results Tumor characteristics About 87% metastatic; 84% measurable disease Visceral disease: 59% (fulvestrant) & 51% (anastrozole) Past treatment 34-35% prior chemotherapy (adjuvant/metastatic) Ellis et al, ESMO 2016; Robertson et al, Lancet 2016

12 FALCON: PFS IN PATIENTS WITH OR WITHOUT VISCERAL DISEASE Forest plot for subset analysis: No difference among predefined subsets EXCEPT visceral disease HR (visceral disease) vs (non-visceral disease) No difference in OS to date Post hoc interaction test p<0.01; A circle represents a censored observation

13 FALCON: Secondary Endpoints Endpoint Fulvestrant (N=230) ORR a 46.1% (89 /193) a In patients with measurable disease at baseline Anastrozole (N=232) 44.9% (88 /196) Odds ratio (95% CI) 1.07 (0.72, 1.61) p=0.729 CBR 78.3% (180 /230) 74.1% (172 /232) 1.25 (0.82, 1.93) p=0.305 Median DoR 20.0 months 13.2 months - Safety No new safety signals or concerns Similar rate of arthralgia betweent the two arms 7-8/17: EU and US approve fulvestrant as first-line therapy for advanced HR+ breast cancer

14 Can we Identify Which Tumors are More Sensitive to Specific Hormone Therapy with NGS?

15 Schiavon et al (Turner lab), ScienceTranslationalMedicine 2015 ctdna to Identify Driver Mutations? Ultra high-sensitivity multiplex digital PCR assays for ESR1 mutations in ctdna Evaluated ESR1 mutations in 171 women with MBC High concordance with contemporaneous tumor biopsies Found only in ER+ tumors previously exposed to AIs Prevalence varied depending on disease stage at time of exposure Adjuvant: 5.8% (3 of 52) Metastatic: 36.4% (16 of 44), P = In a patient with serial sampling, ESR1 mutation was selected during AI treatment to be the dominant clone

16 ESR1 mutated ESR1 wild type ESR1 wild type Fribbens C, et al. J Clin Onc. 2016;34(25):2961-8

17 Putting the Data Into Context: Populations in Recent Phase III 1 st -line Trials PALOMA-2 1 (n=666) MONALEESA-2 2 (n=668) SWOG (n=707) FALCON 4 (n=462) Disease Free Interval De novo MBC < 12 mo > 12 mo 37% 22% 40% 34% 2% 64% 39% nil 61% (> 10 yr) 28% MBC 87 % LABC 18 % Prior Treatment Adjuvant Endocrine Rx Adjuvant Chemotherapy Chemotherapy for MBC 56% 40% nil 52% 43% nil 40 % 33 % nil nil 19 % 17 % Site of Disease Median PFS for AI control (95 % CI) Visceral Bone only 48% 23% 14.5 mo ( ) 59% 21% 14.7 mo ( ) 54 % 22 % 13.5 mo ( ) 55 % 10 % 13.8 mo (NR) 1. Finn R, et al. NEJM. 2016;375(20): ; 2. Hortobagyi G, et al. NEJM. 2016;375(18): ; 3. Mehta RS et al. N Engl J Med 2012;367:435-44; 4. Ellis et al, LBA14 ESMO 2016

18 Results: Recent Phase III First-Line Studies in HR+ MBC Study design Paloma-2 Finn et al, NEJM 2016 Letrozole/Pla vs Letrozole/Palbociclib No. of pts 666 No progression on AIs PFS 14.5 vs 24.8 mo HR 0.58 ( ) p< Monaleesa-2 Hortobagyi et al, NEJM 2016 Letrozole/Pla vs Letrozole/Ribociclib 668 No progression on AIs 16 vs 25.3 mo HR ( ); p= Falcon Robertson et al, Lancet 2016 Anastrozole/Pla vs Fulvestrant/Pla 462 No prior hormone therapy Lilly Press-release: A pre-planned interim analysis for Monarch 3 met its primary endpoint with a significant PFS advantage with abemaciclib/ai vs placebo/ai; ORR also increased (n=493) vs 16.6 mo. HR ( ); p= All oral Yes Yes No Subset difference No No 13.8 v 22.3 mo in n= 218 (47%) without visceral disease No difference in those with visceral disease

19 Study design Comparison of Trials in Patients with Progression on Prior NSAI PALOMA 3 Turner et al, NEJM 2015, SABCS 2016 Fulvestrant/pl a vs fulvestrant/pal bociclib MONARCH 2 Sledge et al, JCO 2017 Fulvestrant/pla vs fulvestrant/ abemaciclib BOLERO 2 Baselga et al, NEJM 2012, Yardley et al, Adv Ther 2013 Exemestane/pl a vs exemestane/e VE PreCOG Kornblum et al, SABCS 2016 Fulvestrant/ pla vs fulvestrant/e VE Patient # PFS (mo) p value (HR) 4.6 vs 11.2 (inv, updated) p<.0001 (HR 0.5) 9.3 vs 16.4 (inv) P< (HR 0.55) 3.2 vs 7.8 (inv) 4.1 vs 11 (central) p<.0001 (HR 0.38) 5.1 vs 10.4 p=.02 (HR 0.6) Differences between trial populations: chemotherapy for metastatic disease ~35%(paloma) versus none (monarch) AI in 86% vs 69%

20 Sequencing Strategy Stratify treatment based on: Clinical characteristics Soft tissue/bone vs visceral Prior treatment history First line therapy Combination therapy: fulvestrant and AI Dose matters! Appears inferior to full dose fulvestrant as a single agent Based on Falcon, combination therapy with AI and low dose fulvestrant is not the best treatment strategy A proposed model for sequential treatment? Cost and drug availability will always impact choices

21 Balancing Treatments in MBC: First-Line Therapy Fulvestrant AI plus CDKi Oral No Yes Compliance easily tracked Yes No Monthly and sometimes repeated blood draws No Yes Monthly clinic visits Yes Mostly yes Safety Goal of treatment: control symptoms, delay start of chemotherapy, maintain or improve QOL Optimal patients for fulvestrant alone as first line therapy: No prior endocrine therapy No visceral disesase Similar to AI alone More fatigue, grade 1 stomatitis, hair loss, other (QTc, LFTs, diarrhea) Cost ** *****

22 Optimal Sequencing of Endocrine Therapy in ER+ MBC 1 st line approach 2 nd line approach Delay Start of Chemotherapy OS A. Conventional endocrine mono-therapy B. Optimally selected endocrine mono-therapy AI alone 8 14 months Fulvestrant months Exemestane 3 4 months (ie. endo Rx naïve, non-visceral mets, biomarker) AI or fulvestrant + everolimus months Fulvestrant + CDK4/6 I 11.2 months AI + CDK4/6 i 7 9 months? AI + everolimus 7 9 months? A B C 2 nd line post Fulvestrant: responsive to 2 nd line combinations? C. Combination Endocrine Strategy AI + CDK4/6 i 24 months Fulvestrant months? PI3K inhibitors? AI + everolimus 7 11 months? 2 nd Line post CDK 4/6 inhibitors: still endocrine responsive and to what therapy? Cumulative Median Progression-Free Survival (PFS) in months Overall Survival (OS) Adapted from Johnston, SABCS 2016

23 Raising the Bar in the Treatment of Hormone Responsive Advanced Breast Cancer Thank you!