Neoadjuvant & Treatment of Early Stage Breast Cancer

Transcription

1 Neoadjuvant & Treatment of Early Stage Breast Cancer Jan 2014 Edith A. Perez, M.D. Deputy Director at Large, Mayo Clinic Cancer Center Serene M. and Frances C. Durling Professor of Medicine Group Vice Chair, Alliance for Clinical Trials in Oncology Director, Mayo Clinic Breast Cancer Translational Genomics Program Mayo Clinic

2 DISCLOSURES No conflicts of interest to disclose

3 CME Question #1 The neoaltto study showed that the 20% improvement in pathcr in the combination arm translated into improvements in EFS and OS, compared to single anti-her2 Rx A. YES B. NO

4 CME Question #2 The CALGB (Alliance) trial demonstrated an improvement in DFS for patients with TNBC who received neoadjuvant carboplatin added to T-AC compared to those who received T-AC A. YES B. NO

5 HER2+

6 Association between event-free survival and pathological complete response to neoadjuvant lapatinib, trastuzumab or their combination in HER2-positive breast cancer. Survival follow-up analysis of the NeoALTTO study (BIG 1-06) Martine Piccart-Gebhart, Andrew P Holmes, Evandro de Azambuja, Serena Di Cosimo, Ramona Swaby, Michael Untch, Christian Jackisch, Istvan Lang, Ian Smith, Fran Boyle, Binghe XU, Carlos Barrios, Richard Gelber, Holger Eidtmann, José Baselga On behalf of the NeoALTTO Study Team

7 pcr CORRELATES WITH BETTER EFS IN SUBSETS OF BC INCLUDING HER2+ BC A FDA led Meta analysis (N=11,955 patients / 1,989 HER2+) No Trastuzumab Trastuzumab pcr rates (%) Cortazar; Lancet 2013 (in press)

8 STRATEGY A Dual HER2 Blockade STRATEGY B EGF (N=296) NeoALTTO (N=455) Cherlob (N=119) LPT (N=78) NSABP B-41 (N=529) CALGB (N= 305 ) ALTTO (N=8381) Advanced Disease PFS and OS (2 trials) Neoadjuvant pcr (3 trials) Non significant pcr (2 trials) Adjuvant setting ? Cleopatra (N=808) NeoSPHERE (N=417) APHINITY (N=4805)

9 NeoALTTO: Study Design Invasive operable HER2+ BC T > 2 cm (inflammatory BC excluded) LVEF 50% N=450 Stratification: T 5 cm vs. T > 5 cm ER or PgR + vs. ER & PgR N 0-1 vs. N 2 Conservative surgery or not R A N D O M I Z E lapatinib paclitaxel trastuzumab paclitaxel lapatinib trastuzumab paclitaxel 6 w + 12 w S U R G E R Y F E C X 3 lapatinib trastuzumab lapatinib trastuzumab 34 weeks 52 weeks of anti-her2 therapy

10 N= % pcr in the Breast NEOALTTO 1ary Endpoint: Breast pcr All HR - positive HR - negative Lapatinib (L) Trastuzumab (T) L + T Baselga J et al; SABCS 2010; Lancet 2012

11 NeoALTTO SABCS 2013 Presentation Pre-specified analysis at 3 years after the last breast cancer surgery Median clinical follow-up 3.77 yrs (95% CI ) Median survival follow-up 3.84 yrs (95% CI ) Note: Clinical cut-off data on 26 May 2013; database freeze on 13 November 2013

12 SAFETY ANALYSES N = 448 patients who received at least 1 study drug dose

13 CARDIAC SAFETY % of cardiac events Any cardiac event Primary cardiac event Lapatinib (L) Trastuzumab (T) L + T Note: No major cardiac dysfunction was observed in the neoadjuvant phase. One patient in eachgroup presented a LVEF <50% and a decrease of >10% from baseline (Baselga et al 2012)

14 STUDY DRUG ADMINISTRATION N = 455 patients randomized

15 NeoALTTO LAPATINIB CONTAINING ARMS: Lapatinib completion Randomized Started Discontinued Completed Neoadj phase Started Adj therapy Discontinued Completed Adj phase N = 154 N = 151 N = 49 N = 102 N = 115 N = 16 N = 99 LAPATINIB ALONE 100% 98% Adv event 32 Progression 3 Other 14 66% 75% Adv event 5 Recurrence 4 Other 7 64% LAPATINIB + TRASTUZUMAB N = 152 N = 149 N = 57 N = 92 N = 116 N = 17 N = % 98% Adv event 34 Progression 1 Other 22 61% 76% Adv event 11 Recurrence 1 Other 5 65% This presentation is the intellectual property of the presenter. Contact martine.piccart@bordet.be for permission to reprint and/or distribute

16 NeoALTTO TRASTUZUMAB CONTAINING ARMS Trastuzumab completion TRASTUZUMA ALONE Randomized Started Discontinued Completed Neoad phase Started Adj phase Discontinued Completed Adj phase N = 149 N = 148 N = 10 N = 138 N = 137 N = 16 N = % >99% Adv event 2 Progression 4 Other 4 93% 92% Adv event 6 Recurrence 5 Other 5 81% TRASTUZUMAB + LAPATINIB N = 152 N = 149 N = 12 N = 137 N = 141 N = 21 N = % 98% Adv event 7 Progression 1 Other 4 90% 93% Adv event 9 Recurrence 2 Other 10 79% This presentation is the intellectual property of the presenter. Contact martine.piccart@bordet.be for permission to reprint and/or distribute

17 NEOALTTO EFFICACY RESULTS N = 455 patients randomized

18 Definitions used in NEOALTTO pcr No invasive disease in the breast and axilla (pt 0/is pn 0 ) EFS events For patients who underwent 1ary breast cancer surgery (N=427) Post surgery breast cancer recurrences, 2nd primary cancers and death For patients who did not undergo 1ary breast cancer surgery (N=28) Regional or distant progression or 2nd primary cancer during neo-adjuvant treatment or death OS events Death

19 NEOALTTO: EFS & OS Analyses Analyses of EFS and OS by arm are underpowered; intended to be descriptive. Assuming a HR of 0.78 for the combination, NeoALTTO: power of approx 20% Follow-up analysis for 2ary endpoints Event-free survival (EFS) by arm (L+ T vs. T) & (L vs. T) Overall survival (OS) by arm (L+ T vs. T) & (L vs. T) EFS and OS by pcr Analysis was adjusted for the stratification factors (tumor size, nodal status, HR status and candidate status for conservative surgery)

20 Distribution of the Stratification Factors by Treatment Arm L + T (N = 152) L (N = 154) T (N = 149) TOTAL (N = 455) Receptor Status Positive 77 (50.7%) 80 (51.9%) 75 (50.3%) 232 (51.0%) Negative 75 (49.3%) 74 (48.1%) 74 (49.7%) 223 (49.0%) Tumor size(cm) 5 89 (58.6%) 92 (59.7%) 93 (62.4%) 274 (60.2%) >5 63 (41.4%) 62 (40.3%) 56 (37.6%) 181 (39.8%) Lymph Node Status N0/1 128 (84.2%) 129 (83.8%) 126 (84.6%) 383 (84.2%) N2+, Nx or missing 24 (15.8%) 25 (16.2%) 23 (15.4%) 72 (15.8%) Breast Conservation Not a Candidate for Conservation Rx 106 (69.7%) 107 (69.5%) 112 (75.2%) 325 (71.4%) Candidate for Conservation Rx 46 (30.3%) 47 (30.5%) 37 (24.8%) 130 (28.6%) This presentation is the intellectual property of the presenter. Contact martine.piccart@bordet.be for permission to reprint and/or distribute

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35 NEOALTTO CONCLUSIONS (I) Patients who achieved pcr had significantly better EFS and OS compared with no pcr from the landmark irrespective of the treatment arm pcr was prognostic The NeoALTTO trial was powered to detect pcr differences, but underpowered to detect moderate differences in EFS and OS Too few pts to determine whether pcr is predictive??

36 NeoALTTO Conclusions (II) 20% improvement in pcr for the dual arm did not translate into improvement in EFS or OS for the overall group At approx 4-yr median follow-up, dual HER2 blockade appears to provide superior benefit (pcr, EFS, OS) in pts with HER2+ / HRnegative tumors. Follow-up analysis planned in 2.5 yrs AEs were consistent with known safety profile of lapatinib and/or trastuzumab

37 Triple Negative

38 Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant weekly paclitaxel followed by dosedense AC on pcr rates in TNBC: CALGB/Alliance WM Sikov, DA Berry, CM Perou, B Singh, C Cirrincione, S Tolaney, CS Kuzma, TJ Pluard, G Somlo, E Porte, M Golshan, JR Belloni, D Collyar, OM Hahn, LA Carey, C Hudis, EP Winer for the CALGB/Alliance

39 CALGB/Alliance 40603: Background Triple-negative Breast Cancer (TNBC) ~20% of invasive breast cancers More common in African-Americans, Hispanics, younger women, BRCA1 mutation carriers High grade, ER and PR <1%, HER2-negative Despite advances in adjuvant chemotherapy, still has the worst prognosis, stage for stage Early recurrences (<3 years), visceral and CNS Median OS for metastatic disease <1 year

40 CALGB/Alliance 40603: Background TNBC Neoadjuvant Chemotherapy pcr rate with standard (includes anthracycline and taxane) meta-analysis 34%; I-SPY 33% Cortazar et al SABCS 2012; Esserman et al JCO 2012

41 CALGB/Alliance 40603: Background pcr is prognostic TNBC Neoadjuvant Chemotherapy Cortazar et al SABCS 2012

42 CALGB/Alliance 40603: Background TNBC Gene expression analysis HER2 Basal Luminal Proliferation Over-expression of basal-like (CK 5, 6, 17, EGFR, c-kit, αb crystallin, etc.) and proliferation genes

43 CALGB/Alliance 40603: Background TNBC Biologic heterogeneity 60-70% of TNBC display basal-like pattern Does this predict response to treatment? Should the other 30-40% be treated differently? Are there other prognostic or predictive markers? What is the impact of recent analysis suggesting that there are 7 distinct subtypes within TNBC on treatment choice? Lehmann et al JCI 2011

44 CALGB/Alliance 40603: Study Design Standard regimen Weekly paclitaxel followed by dose dense AC Based on results from adjuvant studies CALGB 9344 CALGB 9741 ECOG 1199 Henderson et al JCO 2003; Citron et al JCO 2003; Sparano et al NEJM 2008

45 CALGB/Alliance 40603: Study Design Standard regimen weekly paclitaxel and ddac Addition of carboplatin Activity of platinum analogs in BRCA+ cancers Similar gene expression patterns between cancers in BRCA carriers and sporadic TNBC High pcr rates in pilot studies adding cisplatin or carboplatin to standard NAC Byrski et al JCO 2010; Gronwald et al ASCO 2009 ; Sikov et al JCO 2009; Frasci et al Ann Oncol 2009

46 CALGB/Alliance 40603: Study Design Standard regimen Addition of carboplatin Addition of bevacizumab Significant improvements in RR + TTP with chemotherapy in advanced breast cancer, including TNBC - E2100, confirmed by metaanalysis Miller et al NEJM 2007; O Shaughnessy et al SABCS 2009

47 CALGB/Alliance 40603: Study Design Standard regimen Addition of carboplatin Addition of bevacizumab Significant improvements in RR + TTP with chemotherapy in advanced breast cancer, including TNBC - E2100, confirmed by metaanalysis While no improvement in OS seen in MBC, could enhanced response translate to improved RFS and OS in (neo)adjuvant setting? Miller et al NEJM 2007; O Shaughnessy et al SABCS 2009

48 CALGB/Alliance 40603: Study Design Standard regimen Addition of carboplatin Addition of bevacizumab Correlative studies Required tumor biopsies (both frozen and fixed) If residual disease present, sample at surgery Optional Pharmacogenomics DNA sequencing of tumor vs. germline (TCGA)

49 CALGB/Alliance 40603: Schema Paclitaxel 80 mg/m 2 wkly x 12 ddac x 4 2 X 2 Randomization Paclitaxel 80 mg/m 2 wkly x 12 ddac x 4 Bevacizumab 10 mg/kg q2wks x 9 Paclitaxel 80 mg/m 2 wkly x 12 ddac x 4 Carboplatin AUC 6 q3wks x 4 Paclitaxel 80 80mg/m 2 weekly wkly x x 12 ddac x 4 Carboplatin AUC 6 q3wks x 4 Bevacizumab 10 mg/kg q2wks x 9 Surgery XRT No Adjuvant Systemic Treatment

50 CALGB/Alliance 40603: Eligibility Invasive breast cancer Clinical Stage II-III (except T4d inflammatory BC) ER + PR <10%, HER(-) (IHC 0-1+ or FISH <2.0) ANC >1000, platelets >100,000, creatinine <1.5 mg/dl, bilirubin < 1.5 x ULN, ALT < 2.5 x ULN No contraindication to treatment with bevacizumab Baseline evaluation including breast MRI (if not feasible, US for tumor measurement) US of axilla (FNA or bx of suspicious LN rec). Pre-treatment SLN sampling permitted in clinical N0

51 CALGB/Alliance 40603: Objectives Primary To determine whether the addition of carboplatin and/or bevacizumab increases the rate of pcr in the breast (T0/is Nany) in Stage II-III TNBC

52 CALGB/Alliance 40603: Objectives Primary To determine whether the addition of carboplatin and/or bevacizumab increases the rate of pcr in the breast (T0/is Nany) in Stage II-III TNBC To determine whether the addition of carboplatin and/or bevacizumab increases the rate of pcr in the breast (T0/is Nany) in patients with basal-like breast cancers, as determined by gene expression array

53 CALGB/Alliance 40603: Objectives Secondary To determine whether the addition of carboplatin and/or bevacizumab increases the rate of pcr in the breast and axilla (T0/is N0) in Stage II-III TNBC To determine whether the addition of carboplatin and/or bevacizumab increases the rate of pcr in the breast and axilla (T0/is N0) in patients with basal-like breast cancers, as determined by gene expression array

54 CALGB/Alliance 40603: Objectives Secondary To assess the toxicity of the control and experimental regimens To assess the impact of bevacizumab on the incidence of post-surgical complications To determine whether there is an interaction between the impact of carboplatin and bevacizumab on pcr rates RFS and OS Evaluate RCB as a predictor of RFS, TFF, OS

55 CALGB/Alliance 40603: Objectives Secondary To assess the toxicity of the control and experimental regimens To assess the impact of bevacizumab on the incidence of post-surgical complications To determine whether there is an interaction between the impact of carboplatin and bevacizumab on pcr rates To measure RFS and OS To evaluate RCB as a predictor of RFS, TFF and OS

56 CALGB/Alliance 40603: Objectives Correlative Science Identifications of biomarkers (in tissue and/or blood) predictive of pathologic response to the standard regimen or to the addition of carboplatin and/or bevacizumab Surgery and Radiation Oncology Substudies Practice pattern studies to see how baseline T and N stage and response to neoadjuvant treatment influence treatment decisions, including use of BCS, extent of axillary dissection, administration of PMXRT and extended nodal XRT

57 CALGB 40603: Patient Characteristics Patients enrolled 454 (over 36 months) Original accrual goal 362 Accrual goal raised to 445 when a higher than expected percentage of baseline biopsies were inevaluable for subtype assignment To ensure a minimum of 268 basal-like tumors evaluable for pathologic response

58 CALGB 40603: Pt Characteristics (n=443) Age Overall P AC (P AC)+ B PCb A C (PCb AC) +B N <40 23% 21% 28% 19% 23% % 59% 57% 57% 67% >60 17% 19% 15% 23% 10% Premenopausal 54% White 72% (8% Hispanic) Black - 22% Asian 3% ; Other/Multiracial/Unknown 5%

59 CALGB 40603: Patient Characteristics Age, Menopausal status, Race Clinical Stage II: 67.7% Stage III: 32.3% This presentation is the intellectual property of William Sikov, MD. Contact at for permission to reprint or distribute.

60 CALGB (Alliance) 40603: Pt Characteristics Age, Menopausal status, Race Stage, grade Receptor analysis ER negative(<1%): 92.8%; ER low (1-10%): 6.1% PR negative: 94.8%: PR low: 3.6% HER2: IHC 0-1+: 73.6% IHC 2+/FISH(-): 10.6% IHC not done/fish(-) 15.8%

61 ~85% of the samples are basal-like N = 212

62 Treatment delivery CALGB/Alliance Drug P AC (P AC)+B PCb AC (PCb AC)+B Paclitaxel doses 86% 82% 61% 68% 9-10 doses 4% 6% 23% 20% AC 4 doses 91% 88% 88% 80% Carboplatin 4 doses Bevacizumab 8-9 doses NA NA 83% 76% NA 69% NA 62%

63 CALGB/Alliance Grade > 3 hematologic toxicities P AC (P AC)+B PCb AC (PCb AC)+B Leukocytes 12% 13% 13% 25% Neutrophils 7% 9% 31% 30% Hemoglobin 0% 2% 4% 5% Platelets 4% 3% 20% 26% Febrile neutropenia Documented infection 7% 9% 12% 24% 2% 6% 1% 4%

64 CALGB/Alliance Grade > 3 Non-hematologic toxicities (>3%) P AC (P AC)+B PCb AC (PCb AC)+B Fatigue 10% 12% 10% 20% Hypertension 2% 12% 0% 9% N/V 4%/2% 4%/2% 3%/2% 8%/4% Mucositis 2% 0% 1% 4% Hypokalemia 3% 1% 6% 2% PSN 2% 6% 7% 4% Pain 3% 6% 3% 13% Thrombosis 1% 7% 0% 2%

65 CALGB/Alliance 40603: SAEs P AC (P AC)+B PCb AC (PCb AC)+B Total (#pts) FN during AC N/V/dehydration Bleeding/clotting 0/1 2/6 0/0 4/4 Infections No deaths were reported during study treatment Surgical complications most often hematoma/seroma: Without Bev 6.5% With Bev 11.7% Delayed surgical complications - wound healing Without Bev 1% With Bev 4%

66 CALGB/Alliance Consort diagram Patients enrolled Withdrew before starting treatment - 11 Patients started treatment 443 Withdrew before surgery - 10 Patients eligible for surgery Did not undergo surgery - 6 Patients assessable for pcr - 427

67 CALGB/Alliance No Carboplatin Carboplatin 46% (40-53%) 60% (54-66%) 1-sided p value: pcr breast (ypt0/is Nany) Evaluable patients

68 CALGB/Alliance No Carboplatin Carboplatin 46% (40-53%) 60% (54-66%) 1-sided p value: No Bevacizumab Bevacizumab 48% (41-54%) 59% (52-65%) 1-sided p value: pcr breast (ypt0/is Nany) Evaluable patients

69 CALGB/Alliance No Carboplatin Carboplatin 46% (40-53%) 60% (54-66%) pcr breast (ypt0/is 1-sided Nany) p value: Evaluable patients No Bevacizumab Bevacizumab 48% (41-54%) 59% (52-65%) 1-sided p value: P AC (P AC)+B PCb AC (PCb AC)+B 42% 50% 53% 67%

70 CALGB/Alliance No Carboplatin Carboplatin pcr breast (ypt0/is Nany) Basal-like pts only No Bevacizumab Bevacizumab P AC (P AC)+B PCb AC (PCb AC)+B

71 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013 CALGB/Alliance No Carboplatin Carboplatin 41% (35-48%) 54% (48-61%) 1-sided p value: pcr breast + axilla (ypt0/is N0) -Evaluable patients This presentation is the intellectual property of William Sikov, MD. Contact at wsikov@lifespan.org for permission to reprint or distribute.

72 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013 CALGB/Alliance No Carboplatin Carboplatin 41% (35-48%) 54% (48-61%) 1-sided p value: pcr breast + axilla (ypt0/is N0) -Evaluable patients No Bevacizumab Bevacizumab 44% (38-51%) 52% (45-58%) 1-sided p value: This presentation is the intellectual property of William Sikov, MD. Contact at wsikov@lifespan.org for permission to reprint or distribute.

73 CALGB/Alliance No Carboplatin Carboplatin 41% (35-48%) 54% (48-61%) 1-sided p value: pcr breast + axilla (ypt0/is N0) -Evaluable patients No Bevacizumab Bevacizumab 44% (38-51%) 52% (45-58%) 1-sided p value: P AC (P AC)+B PCb AC (PCb AC)+B 39% 43% 49% 60%

74 CALGB/Alliance No Carboplatin Carboplatin pcr breast + axilla (ypt0/is N0) Basal-like pts only No Bevacizumab Bevacizumab P AC (P AC)+B PCb AC (PCb AC)+B

75 CALGB/Alliance 40603

76 CALGB/Alliance RCB 0 + RCB I No Carboplatin Carboplatin 56% 67% No Bevacizumab Bevacizumab 55% 68% P AC (P AC)+B PCb AC (PCb AC)+B 51% 61% 59% 75%

77 CALGB/Alliance 40603: Discussion Support findings from GeparSixto (pcr breast + axilla) Chemo/B Chemo/B + Cb & (n = 222) 43% 60% GeparSixto* (n=315) 44% 64% & includes only patients who received Bevacizumab *Chemo/B = P 80 mg/m 2 + NPLD 20 mg/m 2 wkly + Bev 15 mg/kg q3wks +/- carboplatin AUC wkly x 18 weeks Von Minckwitz et al ASCO 2013

78 CALGB/Alliance 40603: Discussion Support findings from GeparSixto (pcr breast + axilla) Chemo/B Chemo/B + Cb & (n = 222) 43% 60% GeparSixto* (n=315) 44% 64% & includes only patients who received Bevacizumab *Chemo/B = P 80 mg/m 2 + NPLD 20 mg/m 2 wkly + Bev 15 mg/kg q3wks +/- carboplatin AUC wkly x 18 weeks? Optimal Cb dose/schedule:auc 6 q3wks or AUC 2 wkly? Will this translate into RFS and/or OS benefits? Addition of biologic agents, such as PARP inhibitor

79 CALGB/Alliance 40603: Discussion Support findings from GeparQuinto NSABP B-40 failed to demonstrate a significant pcr benefit with bevacizumab in TNBC subset Chemo Chemo + Bev (n = 443) 44% 52% GeparQuinto* (n = 663) 28% 39% NSABP B-40 & (n = 320) 47% 52% *pcr = ypt0 N0 & pcr = ypt0/is Nany Von Minckwitz et al NEJM 2012; Bear et al NEJM 2012

80 CALGB/Alliance 40603: Summary Addition of carboplatin increased Incidence of grade >3 hematologic toxicities Skipped chemo doses, dose modifications and delays Addition of bevacizumab increased Incidence of grade >3 HTN, thrombosis, pain and documented infection Immediate and delayed surgical complications Patients who received both carboplatin and bevacizumab had higher incidences of Febrile neutropenia (24% vs. 9%), fatigue

81 CALGB/Alliance 40603: Summary Addition of carboplatin increased pcr breast by 14%, p= pcr breast and axilla by 13%, p= Addition of bevacizumab increased pcr breast by 11%, p= pcr breast and axilla by 8%, p= With both carboplatin and bevacizumab 25% increase in pcr breast 21% increase in pcr breast + axilla 75% achieved pcr breast + axilla or RCB I

82 CALGB/Alliance 40603: Discussion What to do in practice? -- Carbo, Bev Different that the Alliance neoadjuvant, and the German neoadjuvant trials. BEATRICE trial failed to show improvement in IDFS in TNBC with a year of adjuvant bevacizumab Relatively lower risk patient population - 30% stage I, 63% node-negative Await results from ECOG 5103 Cameron et al Lancet Onc 2013

83 Hormone Receptor +

84 ALTERNATE: Neoadjuvant for ER+ Anastrozole x 4.5 yrs b i o p s y Anastrozole x 6 mo Fulvestrant x 6 mo (A+F) x 6 mo S U R G E R Y Fulvestrant x 1.5 yrs Anastrozole x 3 yrs (A+F) x 1.5 yrs Anastrozole x 3 yrs Biopsy at week 4 & 12 Ki67 > 10% Adjuvant chemotherapy and endocrine therapy Preoperative chemotherapy SURGERY Adjuvant systemic therapy maximum n= st phase (n=400 in each arm) 2 nd phase (an additional 540 in each arm)

85 CME Question #1 The neoaltto study showed that the 20% improvement in pathcr in the combination arm translated into improvements in EFS and OS, compared to single anti-her2 Rx A. YES B. NO

86 CME Question #2 The CALGB (Alliance) trial demonstrated an improvement in DFS for patients with TNBC who received neoadjuvant carboplatin added to T-AC compared to those who received T-AC A. YES B. NO

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