ASCO and San Antonio Updates

Transcription

1 ASCO and San Antonio Updates 30 th Annual Miami Breast Cancer Conference March 7-10, 2013 Debu Tripathy, MD Professor of Medicine University of Southern California Norris Comprehensive Cancer Center

2 Breakthroughs in Sentinel Nodes after Neoadjuvant Therapy Not as accurate, but can still be useful Radiation when is less OK? Hypofractionation and omission for low risk DCIS Adjuvant Therapy Refinements 5 vs 10 years of tamoxifen, comparisons of 3 rd generation regimens, therapy for local recurrences Advanced Breast Cancer HER2+ - new options; CDK inhibitors; first line chemo Emerging genomic picture of breast cancer New therapeutic targets

3 ACOSOG Z1071 Trial Design 1 Endpoint: False Neg Rate cn1 w/ 2 SNLs Examined ct0-4 cn1-2 M0 Node FNA or core biopsy + Any preoperative chemotherapy Enrolled N = 756 Underwent surgery with SLN identification and ALND Dual tracer encouraged SLN + ALND N = 687 SLN ID ed N = 637 (92.7%) Node (40%) Node (60%) SLN+ 326 SLN- 56 False Neg Rate 12.6% 78 with 1 SLN False negative rate 31.5% 310 with 3 SLNs False negative rate 9.1% Dual tracer False negative rate 10.8% Clip False negative rate 10.8% No Clip False negative rate 13.5% Boughey JC, et al. SABCS 2012, Abstr S2-1

4 SENTINA Trial - Design N=662 Axillary imaging used only if axillary physical exam was unclear N=360 N=715 N=592 N=123 Kuehn T, et al. SABCS 2012, Abstr S2-2

5 SENTINA Trial SLN Detection Rate Kuehn T, et al. SABCS 2012, Abstr S2-2

6 SENTINA Trial - False Negative Rate Kuehn T, et al. SABCS 2012, Abstr S2-2

7 % Local Failure +/- Radiation for Low Risk DCIS: RTOG 9804 Lumpectomy for DCIS Gr 1, 2 < 2 cm > 3mm margin N = % received Tam Radiation (50, 50.4 or 42.5 cgy over 25, 28 or 16 fractions) (N = 287) Observation (N = 298) Median Follow up = 6.46 years 5.0 No XRT XRT Ipsilateral Contralateral 33% failures invasive No difference in survival Difference in Gr 1/2, not Gr 3/4 toxicities McCormick B, et al. ASCO 2012, Abstr 1004

8 UK START Trials 10 Year Follow-up Haviland JS, et al. SABCS 2012, Abstr S1-4

9 UK START Trial B Patients Free of Physician- Judged Marked to Moderate Skin Effects Haviland JS, et al. SABCS 2012, Abstr S1-4

10 UK START Trial B Local-Regional Relapse 40 cgy in 15 fractions/3 weeks is now standard in UK for all patients with invasive breast cancer (NICU Guidance 2009) Haviland JS, et al. SABCS 2012, Abstr S1-4

11 ATLAS Trial ~5 vs. ~10 Years of Tamoxifen Recurrence Cancer Mortality Cumulative Event 5 years 10 years HR P value Endometrial cancer 1.6% 3.1% Endometrial cancer mortality 0.2% 0.4% Davies C, et al. SABCS 2012, Abstr S1-2

12 Longer Periods of Tamoxifen: Estimates of Benefit Davies C, et al. SABCS 2012, Abstr S1-2

13 AZURE Trial: Is Adjuvant Benefit Divergent Based On Age or Estrogen Levels? Stage II/III Breast Cancer N = 3,360 R Standard therapy Standard therapy + Zoledronate 4 mg 6 doses 8 doses 5 doses Q3-4 wks Q 3 mos Q 6 mos Months Subset being Compared Hazard Ratio (95% CI)* P - Value 50 years of age (N=1626) 1.16 ( ) > 50 years of age (N=1733) 0.85 ( ) Bone: pre, peri and unknown menopause 0.86 ( ) Bone: > 5 years post menopause 0.96 ( ) Other: pre, peri and unknown menopause 1.32 ( ) Other: > 5 years post menopause 0.70 ( ) * Invasive disease-free recurrence on zoledronate vs placebo Heterogeneity between specified patient subgroups <0.001 Marshall H, et al. ASCO 2012, Abstr 503

14 Treatment Effects on First IDFS Recurrence Outside Bone by Menopausal Status Menopausal Group Odds Ratio Pre, Peri and unknown menopause > 5 yrs postmenopause HR: 0.70 (95% CI: ) HR: 1.32 (95% CI: ) TOTAL: 6% +/- 8 Z =.79, P = (heterogeneity) = 14.00; P = <.001 Adjusted for imbalances in ER, lymph node status, and T stage Marshall H, et al. ASCO 2012, Abstr 503

15 CALOR* Trial: Adjuvant Chemotherapy for Local-Regional Recurrence (median f/u 5 years) Early Stage Breast Cancer Loco-regional recurrence Rendered free of disease with surgery Chemotherapy (N=85) (4-6 months multi-agent recommended) Observation (N=77) Hormonal, radiation and trastuzumab allowed for both arms Chemo Observ P value 41% Disease-Free 5 years 69% 57% ER-Negative 67% 35% ER-Positive 70% 69% % Overall 5 years 88% 76% 0.02 ER-Negative 79% 69% 0.12 ER-Positive 94% 80% 0.12 * IBCSG 27-02, NSABP B-37, BIG 1-02 Aebi S, et al. SABCS 2012, Abstr S3-2

16 Adjuvant Chemotherapy Options FEC 100 Paclitaxel/ Docetaxel Dose dense AC Paclitaxel AC weekly paclitaxel CEF FEC 100 A/E CMF CAF AC Docetaxel TAC x 6 TC AC Paclitaxel FEC 50 FAC CMF AC A+ Docetaxel TAC x 4 Arrows indicated direct comparisons from randomized trials Benefits not drawn to scale

17 NSABP B-38 Schema (n=4894, med FU 5.3 yrs) TAC q 3 wk All arms pegfilgrastim or filgrastim N+ AC q 2 wk P q 2 wk ER positive: hormonal therapy for 5 yrs after chemo AC q 2 wk PG q2 wk 80% ER+ 65% 1-3+ nodes P = paclitaxel 175 mg/m2 G = gemcitabine 1000 mg/m2 Swain S, et al, ASCO 2012, LBA#1000

18 Disease-Free Survival NSABP B-38 Disease-Free Survival Treat N Events P-value* (vs AC PG) TAC AC P AC PG # at risk Years since Randomization * Stratified log-rank test adjusting for randomization factors Swain S, et al, ASCO 2012, LBA#1000

19 Survival, Toxicity and Conclusions Overall survival no different between arms More deaths on treatment in the TAC arm than AC/P or AC/PG (13/5/7, p=0.2) Addition of gemcitabine did not improve outcome DD AC/P similar to TAC o More FN, anemia, diarrhea, less neuropathy with TAC Swain S, et al, ASCO 2012, LBA#1000

20 HERA 2-Year Trial: Study Design Study Details Study Sites: Global (33 countries) Primary endpoint Disease-free survival: o 1-year trastuzumab vs. observation o 2-year trastuzumab vs. observation Secondary endpoint Disease-free survival Study Design HER2-positive invasive EBC (N ~ 5000) Surgery + (neo)adjuvant chemotherapy ± radiotherapy Nodal status, adjuvant chemotherapy regimen, hormone receptor status and endocrine therapy, age, region Randomization Stratification Arm 1 Arm 2 Arm 3 o 1-year trastuzumab vs. 2-year trastuzumab o Overall survival 1 years trastuzumab 8 mg/kg 6 mg/kg 3-weekly schedule (n ~ 1700) 2 year trastuzumab 8 mg/kg 6 mg/kg 3-weekly schedule (n ~ 1700) Observation (n = ~1700) Piccart-Gebhart MJ, et al. SABCS 2012, Abstr S5-2

21 Disease-free survival (%) HERA 2-Year Trial: DFS Results % 81.6% 86.7% 75.8% 81.0% 76.0% Trastuzumab 2 years Trastuzumab 1 year Pts Events HR (2 vs 1) 95% CI p-value 2 years ( ) year Years from randomization No. at risk Trastuzumab 2 years Trastuzumab 1 year Gelber R et al. ESMO 2012 Piccart-Gebhart MJ, et al. SABCS 2012, Abstr S5-2

22 Cardiac Events Primary or secondary = EF < 50% or 10% below baseline, but not NYHA III or IV heart failure Piccart-Gebhart MJ, et al. SABCS 2012, Abstr S5-2

23 PHARE Trial: Study Design Study Details Study Sites: France (~150 sites) Primary endpoint (non-inferiority) Disease-free survival o 6 months of trastuzumab vs. 1 year of trastuzumab Study Design HER2-positive EBC (N ~ 3500) Surgery + (neo)adjuvant chemotherapy ± radiotherapy Trastuzumab x 6 mos Any chemo adjuvant regimen 50% sequential 50% concurrent Stratification Chemotherapy and trastuzumab timing: sequential vs. concurrent, Hormonal therapy, Recruiting center Arm 1 Randomization Arm 2 6 months trastuzumab No further trastuzumab Pivot X, et al. SABCS 2012, Abstr S5-3

24 PHARE Study: Disease Free Survival Probability Events HR 95%CI p-value H 12m 176 H 6m ( ) Months At risk H-12m H 6m H-12m H-6m * Cox model stratified by ER status and concomitant chemotherapy Pivot X et al. ESMO 2012 Pivot X, et al. SABCS 2012, Abstr S5-3

25 Primary Endpoint Scenarios A Equivalent B Superior C PHARE trial D Non Inferior E HR Inferior Trial did not meet non-inferiority endpoint Longer follow-up and other trial results needed for final conclusions Pivot X, et al. SABCS 2012, Abstr S5-3

26 Proportion progression-free EMILIA Trial: T-DM1 vs. Capecitabine + Lapatinib Progression-Free Survival by Independent (IRC) and Investigator (INV) Review IRC INV Cap + Lap T-DM1 Cap + Lap T-DM1 HR=0.650 (95% CI, 0.55, 0.77) P< HR=0.658 (95% CI, 0.56, 0.77) P< Time (mos) No. at risk by independent review: Cap + Lap T-DM Unstratified HR by independent review=0.66 (P<0.0001). Blackwell K, et al. ASCO 2012, Abstr 1

27 Proportion surviving Overall Survival: T-DM1 vs. Capecitabine + Lapatinib % 78.4% 64.7% Median (mos) No. events Cap + Lap T-DM Stratified HR=0.68 (95% CI, 0.55, 0.85) P < Efficacy stopping boundary P= or HR= % Time (mos) No. at risk: Cap + Lap T-DM Verma S, et al. NEJM 2012

28 CALGB NCCTG N063H - CTSU An Open Label Phase III Trial of First Line Therapy for Locally Recurrent or Metastatic Breast Cancer - - N = 900 (planned) Strata: Adj taxanes ER/PR status Exp 1 Control Exp 2 nab-paclitaxel 150 mg/m 2 weekly + bevacizumab 10 mg/kg q 2 wks 2 paclitaxel 90 mg/m 2 weekly + bevacizumab 10 mg/kg q 2 wks 1 ixabepilone 16 mg/m 2 weekly + bevacizumab 10 mg/kg q 2 wks 3 All chemotherapy was given on a 3 week on, one week off schedule Patients could discontinue chemotherapy and continue bevacizumab alone - after 6 cycles if stable or responding disease Restage every 2 cycles until disease progression 1. Miller et al, N Engl J Med, Gradishar et al, J Clin Oncol, Dickson et al, Proc ASCO Rugo H, et al. ASCO 2012, Abstr CRA 1002

29 CALGB Progression-Free Survival By Treatment Arm Proportion Progression-Free Paclitaxel Nab-paclitaxel Ixabepilone Comparison HR P-value 95% CI nab vs. pac Pac Nab ixa vs. pac 1.53 < Ixa Months From Study Entry Agent N Median PFS Paclitaxel Nab-Paclitaxel Ixabepilone Rugo H, et al. ASCO 2012, Abstr CRA 1002

30 Eribulin vs. Capecitabine in Earlier Lines for MBC MBC or unresect LABC < 3 cm chemo lines (< 2 for MBC) Prior anthra/taxane Eribulin 1.4 mg/m 2 d 1, 8 q 3 wk Capecitabine 1250 mg/m 2 bid d1-14 q 3 wk PFS (IR) Erib 4.1 mo Cape 4.2 mo ORR (IR) Erib 11% Cape 12% Kaufman P, et al. SABCS 2012, Abstr S6-6

31 Eribulin vs. Capecitabine OS HR by Subsets Kaufman P, et al. SABCS 2012, Abstr S6-6

32 Rb as Master-Regulator of the R-point Finn RS, et al. SABCS 2012, Abstr S1-6

33 Randomized Phase 2 Design Postmenopausal, ER+/HER2-, No Prior Therapy for MBC Part 1 Part 2 ER+, HER2 BC R A N D O M I Z A T I O N 1:1 PD mg QD a + Letrozole 2.5 mg QD Letrozole 2.5 mg QD ER+, HER2 BC with CCND1 amp and/or loss of p16 R A N D O M I Z A T I O N PD mg QD a + Letrozole 2.5 mg QD 1:1 Letrozole 2.5 mg QD N = 66 N = 99 Stratification Factors Disease Site (Visceral vs Bone only vs Other) Disease-Free Interval (>12 vs 12 mo from end of adjuvant to recurrence or de novo advanced disease) Finn RS, et al. SABCS 2012, Abstr S1-6

34 Progression-Free Survival Probability Progression-Free Survival PD LET (n = 84) LET (n = 81) Number of Events (%) 21 (25) 40 (49) Median PFS, months (95% CI) Hazard Ratio (95% CI) 26.1 (12.7, 26.1) 0.37 (0.21, 0.63) P value < (5.6, 12.6) Time (Month) Finn RS et al. SABCS 2012 Abstr S1-6 Number of patients at risk PD991+LET LET

35 HER2 Somatic Mutations in 25 Patients 8 publications, total of 1499 patients (estimated incidence of 1.7%) 20% of mutations at AA 309 or % of mutations from Bose R, et al. SABCS 2012, Abstr S5-6

36 HER2 Mutations Differentially Activate HER2 Signaling Bose R, et al. SABCS 2012, Abstr S5-6

37 Colony formation of HER2 Mutants inhibited by HER1/2 Kinase Inhibitor Neratinib Multi-center Phase II Trial with Neratinib Planned Bose R, et al. SABCS 2012 Abstr S5-6

38 Please view the SABCS Poster Display during the Welcome Reception from 6-7 pm in the Exhibit Hall Discussion to follow at 7pm in the General Session Room moderated by Drs. Pat Borgen and Hope Rugo.