Integrating the New with the Old Recent Advances in Adjuvant Systemic Treatment Strategies for Breast Cancer

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1 Integrating the New with the Old Recent Advances in Adjuvant Systemic Treatment Strategies for Breast Cancer Kathy S. Albain, M.D., FACP Professor of Medicine Loyola University Chicago Stritch School of Medicine Cardinal Bernardin Cancer Center

2 Integrating the New with the Old the Year in Review Selected systemic therapy results from San Antonio 2010, St. Gallen 2011, ASCO 2011, and the Oxford Overview for early stage disease T H E M E S Targeting therapy to subsets defined by biology standard pathologic criteria and multigene assays Neoadjuvant models advances and controversy Status of the new paradigm of second generation neoadjuvant consortia studies Presurgical window model Our greatest challenge

3 Selected Adjuvant Therapy Clinical Trials What s New from the Oxford Overview and Individual Trial Updates

4 Postmenopausal, Node+, ER+ Disease-Free Survival S8814 (INT 0100) Disease-Free Survival by Randomized Treatment Group Stratified* log-rank p = Treatment Group Events/n 10 year DFS & 95% CI CAF, then Tamoxifen (CAF-T) 216/566 60% (55%,64%) CAF + Tamoxifen (CAFT) 242/550 53% (49%,58%) Tamoxifen alone (T) 179/361 48% (42%,53%) N at risk CAF-T CAFT T Years from Registration *stratified by nodes, PgR status and time from surgery Albain KS et al. Lancet 2009

5 Martin M, et al. PSABCS 2010

6 Adjuvant TAC vs FAC Node Negative Breast Cancer Analyses of Overall and Disease-free Survival Martín M et al. NEJM 2010;363:

7 Subgroup Analyses of DFS among Patients with Central Pathology Review: No Benefit to TAC if HER2+ (any ER) Martín M et al. NEJM 2010;363:

8 Targeting Therapy to Subsets Defined by Biology St. Gallen 2011, Standard Pathologic Criteria and Multigene Assays

9 Breast Cancer Subtypes

10 PAM50 Intrinsic Subtypes Present and Clinically Significant for Prognosis within both ER+ and ER- Tumors, with Heterogeneity in HER2+(clinical) Group (N0, no systemic adjuvant treatment) Parker et al. J Clin Oncol 2009

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12 St. Gallen 2011: Shorthand Determination of Breast Cancer Subtypes Intrinsic Subtype Surrogate Definition Luminal A Luminal B1 Luminal B2 HER2 over-expression ER and/or PgR(+), HER2(-) Ki-67 low (<14%)* ER and/or PgR(+), HER2(-) Ki-67 high ER and/or PgR(+), HER2(+) Any Ki-67 ER and PgR absent, HER2(+) Basal-like * Using PAM5O cutpoint from Cheang et al. JNCI 2009 Triple negative ductal (not medullary, adenoid cystic) Annals Oncol. In Press, 2011

13 Subtype Type of therapy Notes Luminal A Luminal B (HER2 negative) Luminal B (HER2 positive) HER2 positive (non luminal) Endocrine therapy alone Cytotoxics + endocrine therapy Cytotoxics + anti-her2 + endocrine therapy Cytotoxics + anti-her2 Few require cytotoxics (e.g. high nodal status). Inclusion and type of cytotoxics may depend on level of endocrine expression, perceived risk and patient preference. No data are available to support the omission of cytotoxics in this group. Patients at very low risk may be observed without treatment Triple negative (ductal) Special histological types * A. Endocrine responsive B. Endocrine non responsive Cytotoxics Endocrine therapy Cytotoxics Annals Oncol. In Press, 2011 Medullary and apocrine carcinomas may not require any adjuvant cytotoxics (if node negative).

14 Subtype Type of therapy Notes Luminal A Luminal B (HER2 negative) Luminal B (HER2 positive) HER2 positive (non luminal) Endocrine therapy alone Cytotoxics + endocrine therapy Cytotoxics + anti-her2 + endocrine therapy Cytotoxics + anti-her2 Few require cytotoxics (e.g. high nodal status). Inclusion and type of cytotoxics may depend on level of endocrine expression, perceived risk and patient preference. No data are available to support the omission of cytotoxics in this group. Patients at very low risk may be observed without treatment Triple negative (ductal) Special histological types * A. Endocrine responsive B. Endocrine non responsive Cytotoxics Endocrine therapy Cytotoxics Annals Oncol. In Press, 2011 Medullary and apocrine carcinomas may not require any adjuvant cytotoxics (if node negative).

15 21 Gene Recurrence Score (RS) <=.>")" Genomic Grade 7%3"-.8-+9)+0%&, 5&9)$%:-"0;;; High Risk Driven by Proliferation Genes!"#$%&'" ()*+,-&)". /!"0&0%$),"1!"#$%&'" 23"4+. /5")0&%&'&%61 BUT only RS tested in phase III trials: N0 (NSABP B20) N+ (SWOG 8814) Modified from C. Sotiriou SABCS 09 and Sotiriou and Pusztai, NEJM 2009

16 S8814 CAFT vs T Node Positive Breast Cancer Specific Survival by RS S8814D: BC Specific Survival Low Risk (RS < 18) Treatment Tamoxifen only (n=55; 4 BC deaths) CAF-T (n=91; 10 BC deaths) Stratified log-rank test p = 0.56 at 10 years S8814 E: BC Specific Survival Intermediate Risk (RS 18-30) Treatment Tamoxifen only (n=46; 11 BC deaths) CAF-T (n=57; 10 BC deaths) Stratified log-rank test p = 0.89 at 10 years Years since registration Years since registration S8814 F: BC Specific Survival High Risk (RS 31+) Treatment Tamoxifen only (n=47; 20 BC deaths) CAF-T (n=71; 18 BC deaths) Stratified log-rank test p = at 10 years Years since registration Interaction p = Albain, KS et al. Lancet Oncology 2010

17 S1007 RxPONDER Launched January, 2011 (Medical Oncology Investigators: Gonzalez-Angulo A-M,PI; Hortobagyi G; Albain K)

18 NSABP B-47 Evaluating Trastuzumab Efficacy across Low HER2 5%-$%&H&,$%&+).I6 (!E.)+*$#.0%$%:0!"#$%!"#$%&'&()*+(,-,$*.

19 ADJUVANT CHEMOTHERAPY Improving on Anthracycline Benefit by Metronomic Schedule?

20 S0221: Updated Interim Analysis: Anthracycline Question Disease-Free Survival Disease-Free Survival by Delivery of AC 5-year DFS: AC weekly 79% vs. AC q 2 wk 82% HR = 1.15 (95% CI ) AC weekly vs. AC q 2 wk p=0.16 AC q 2 weeks x 6 (n=1,342; 183 events) AC Weekly (n=1,320; 202 events) Years since registration q2wk: more myelosuppression/cardiac toxicity qwk: more stomatitis, dermatologic toxicity Budd, et al. PASCO 2011

21 S0221: Revised Schema for Remaining 534 Patients Stage I-III Breast Cancer R A N D O M I Z E Doxorubicin 60 mg/m2 Cyclophosphamide 600 mg/m2 Peg-filgrastim q 2 weeks x 4 Doxorubicin 60 mg/m2 Cyclophosphamide 600 mg/m2 Peg-filgrastim q 2 weeks x 4 Paclitaxel 175 mg/m2 Peg-filgrastim q 2 wks x 6 Paclitaxel 80 mg/m2 Weekly x 12 Budd, et al. PASCO 2011

22 On Abandoning Adjuvant Anthracyclines?

23 Time Trends in Type of Chemotherapy: Medicare Cohort: Patients 66+ (N=5511) Giordano, et al. PASCO 2011

24 Time Trends in Type of Chemotherapy: Private Insurance Cohort: Patients <65 (N=30,658) Giordano, et al. PASCO 2011

25 Insights Use of anthracycline-based chemotherapy has fallen dramatically Due to TC enthusiasm Will we see rise in BC mortality down the road? See thoughtful and comprehensive review of this topic by Dr. I. Craig Henderson in Oncology, February 2011

26 3 New Studies on More Adjuvant Chemotherapy Can We Add to the A-C-T Backbone?

27 FinXX Overall Survival % 95.3% 92.6% 89.7% TX/CEX T/CEF % HR = 0.73 (95% CI: ) P = Patients at risk: T + CEF TX + CEX Years Joensuu H, et al. PSABCS 2010

28 FinXX Biological Subtype and RFS 100 ER+ and/or PR+, HER2-100 ER+ and/or PR+, HER P = HR = 0.91 n = P = HR = 1.11 n = 163 T/CEF TX/CEX ER- and PR-, HER ER- and PR-, HER P = HR = 0.91 n = P = HR = 0.48 n = Joensuu H, et al. PSABCS 2010

29 USON Phase III Adjuvant Doxorubicin/Cyclophosphamide followed by Docetaxel ± Capecitabine - OS by Subgroup (planned analysis) 2$%"9+-6 O## 5:I9-+:J O## F$'+-0.O2!YZ F$'+-0.O2!Z STU.2B =;WX =;TCM=;S@ 8+0&%&'".#64J3.)+*"0 = CMN KL <S@ C@TX TWC =;WS =;NXMC;@W =;W= =;N<M=;SS =;<< =;LSMC;@N!$," @=X =;W@ C;XC =;TW =;LLM=;X< =;WSML;<T =;@CMC;TN (![89!.0%$%:0 V"9$%&'" 8+0&%&'" SLN CWWX =;WL =;<C =;LLM=;ST =;LTMC;CC?(!@.-","J%+-.0%$%:0 8+0&%&'" V"9$%&'" C;== =;WW =;L@M@;NT =;LXM=;S= Z-&J#"G)"9$%&'".P2 \"0 V+ <X= CXNC =;W@ =;<@ =;LCM=;SL =;LXMC;C= &&236&&7&&&&&&&4&&&8&5&9&6&&&&72 /*-*)0&)*(1% O Shaughnessy et al. PSABCS 2010, abstr S4-2.

30 NSABP B-40 Tissue for Biomarkers Tissue for Biomarkers Operable Breast Cancer R T T X T G T T X T G T T X T G T T X T G A C A C A C A C A C A C A C A C A C A C A C A C S UR G E R Y B +/- X 10 +/- B B B B B B Endpoints: pcr, ccr, DFS, gene expression patterns Baer, et al. PASCO 2011

31 NSABP B-40 Pathologic Complete Response (Breast and Nodes) 40 U.J2!.]P-"$0%.D.V+*"0^ N=393 N=390 N= Chi-square test: T!AC vs. TC!AC (p=0.443) T!AC vs. TG!AC (p=0.726) T-AC TX-AC TG-AC Baer, et al. PASCO 2011

32 Conclusions Addition Trials Toxicities not insignificant when 4 th drug added Exploratory analyses in 2 studies showed benefit to adjuvant capecitabine in triple negative No data to support adding 4 th drug to A/C/T backbone in clinical practice Could inclusion of patients with indolent, ER+ disease mask a stronger signal for the additional drug?

33 Neoadjuvant Models Advances, Promise and Controversy Bevacizumab HER2 Targeted Strategies

34 von Minckwitz et al. PSABCS 2010

35 *HR=1.47 in triple negative von Minckwitz et al. PSABCS 2010

36 NSABP B-40 Tissue for Biomarkers Tissue for Biomarkers Operable Breast Cancer R T T X T G T T X T G T T X T G T T X T G A C A C A C A C A C A C A C A C A C A C A C A C S UR G E R Y +/- B x10 +/- B B B B B B Endpoints: pcr, ccr, DFS, gene expression patterns Baer, et al. PASCO 2011

37 NSABP B-40 Pathologic Complete Response (Breast and Nodes) U.J2!.]P-"$0%.D.V+*"0^ V_TXX V_TXN W/O BEV No Bev BEV Bev 0 0 OR = 1.27 p=0.09 (significant if breast-only pcr) Baer, et al. PASCO 2011

38 NSABP B-40 Pathologic Complete Responses (Breast) for HR+ and TN Breast Cancer U.J2!.]P-"$0%^ N=349 N= N=243 N= W/O BEV No bev BEV Bev 0 0 HR+ HR+ TNBC TNBC OR = 1.70 p=0.008 OR = 1.17 p=0.44 Interaction p = Baer, et al. PASCO 2011

39 Summary Bevacizumab Trials: Not Ready for Clinical Use Disappointing results overall in 2 trials to date, with discordant results in subsets Impact on OS and DFS unknown Await long-term follow-up of these 2 trials, plus others recently completed/in progress (BETH, BEATRICE, SWOG, E5103, B-46) Need biomarkers to tailor therapy

40 Promise and Controversies Regarding the Neoadjuvant Approach Can rapidly determine tumor response using pcr as the primary endpoint Patients who achieve a pcr have better outcomes However, in large phase III trials in all comers (unselected for a target), regimens with higher pcr rates did not achieve better overall DFS and OS, the gold standards for FDA drug approval Need to target new neoadjuvant strategies to biologic subsets that otherwise would not have achieved a pcr without the new agent (eg: the NOAH trial overall survival predicted by pcr)

41 NOAH Trial: Preoperative Chemo +/- Trastuzumab for LABC Path CR Breast/Nodes Chemo + trast 38% Chemo only 19% Gianni L, et al; Lancet 2010

42 Anti-HER2 therapies: single (a, b, c, e) or dual (a+b, a+e, b+c) blockade Lapatinib

43 R Three New Neoadjuvant Trials HER2+ Presented at SABCS 2010 Trastuzumab +docetaxel Pertuzumab + docetaxel Pertuzumab + trastuzumab + docetaxel NEO- SPHERE n~400 Pertuzumab + trastuzumab R Trast Lapatinib Trast/lap Trastuzumab + paclitaxel Lapatinib + paclitaxel Trast/lap + paclitaxel NEO- ALTTO n~450 R EC + trast Docetaxel + trastuzumab EC + lapatinib Docetaxel + lapatinib Slide courtesy E. Winer, SABCS 2010 Discussant GEPAR- QUINTO n~600

44 NeoSphere: pcr Rates Doubled by Dual HER2 Blockade plus Chemotherapy Trast Docetax el Pertuz - Docetaxel Trast - Pertuz Docetaxel Trast - Pertuz ITT (Overall) 29% 24% 46% 17% ER- 37% 30% 63% 27% ER+ 20% 17% 26% 6% Slide modified from esy E. Winer, SABCS 2010 Discussant Gianni, et al. PSABCS 2010

45 NeoSphere: pcr Rates Intriguing in Non-Chemotherapy Arm, Especially ER- Trast Docetax el Pertuz - Docetaxel Trast - Pertuz Docetaxel Trast - Pertuz ITT (Overall) 29% 24% 46% 17% ER- 37% 30% 63% 27% ER+ 20% 17% 26% 6% Modified from E. Winer, SABCS 2010 Discussant Gianni, et al. PSABCS 2010

46 Pathologic Response in NeoALTTO Best if Dual Blockade plus Paclitaxel Lapatinib + Paclitaxel Trastuzumab + paclitaxel Trast + Lap + paclitaxel Path CR (breast only) Path CR (breast and LN) 25% 20% 29% 28% 51% 47% Slide courtesy E. Winer, SABCS 2010 Discussant Baselga, et al. PSABCS 2010

47 pcr Disappointing for Lapatinib in Direct Comparison with Trastuzumab Single Blockade (both with taxane) Lapatinib Trastuzumab Neo-ALTTO GEPARQUINTO Inability to give planned doses of lapatinib ~35% in both studies Slide courtesy E. Winer, SABCS 2010 Discussant

48 Neoadjuvant HER2+ ASCO 2011 Guarneri, V (Cher-Lob) Abstract 507 Holmes, FA (US Oncology) Abstract 506 CT: wp x 12!FEC x 4 CT: FECx4! wp x12 + T R + L(1500!1000*) 24wks + T+L(1000!750*) *after amendment N=121/115 (recruited/analyzed) + T R + L(1250) 26wks + T+L(750!1000*) *during weekly paclitaxel N=100/78 (recruited/analyzed) Slide courtesy G. Von Minckwitz

49 Efficacy (pcr = ypt0/is ypn0) Guarneri, V Holmes, FA Guarneri, V et al. ASCO 2011 Abst 507 Holmes, FA et al. ASCO 2011 Abst 506 Slide courtesy G. Von Minckwitz

50 TBCRC 006: Neoadjuvant Lapatinib & Trastuzumab Without Chemotherapy Lapatinib (1000 mg/day) Trastuzumab (4 mg/kg load, 2 mg/kg qw) S u r g e r y (Endocrine Therapy Added if ER++) Bx ! ""#$ n=66 recruited /61 analyzed pcr ER(-) 46% ER(+) 21% Chang J, ASCO 2011, Abst. 505

51 Current Status of a New Paradigm of Second Generation Neoadjuvant Consortia Studies which Build In Prospective Translational Biologic Questions NeoBIG and I-SPY2

52 NEO-ALTTO (reported SABCS 2010) 450 women with HER2 positive BC (> 2cm) ALTTO Met Accrual Goals Spring, 2011 Biomarkers of efficacy/ resistance Surogate of long-term efficacy VALIDATION Slide courtesy M. Piccart, St. Gallen 2011

53 I-SPY2 TRIAL OPENED FOR ACCRUAL IN 2010

54 Summary of I-SPY2 Study Plan Paclitaxel * (12 weekly cycles) AC (4 cycles) Screening MRI Biopsy Blood Draw MUGA/ECHO CT/PET Consent #1 Screening Consent R A N D O M I Z E O N S T U D Y Consent #2 Treatment Consent Paclitaxel* + Investigational Agent A (12 weekly cycles) Paclitaxel* + Investigational Agent B (12 weekly cycles) MRI Biopsy Blood Draw MRI Blood Draw AC (4 cycles) AC (4 cycles) MRI Blood Draw * HER2 positive participants will also receive Trastuzumab. An investigational agent may be used instead of Trastuzumab. S U R G E R Y Tissue 54

55 I-SPY2 Agent Target Agent Chaperone Institution Figitumumab* (CP-751,871) Neratinib (HKI-272) ABT-888 AMG 386 IGFR Inhibitor Dr. Doug Yee University of Minnesota Pan ErbB Inhibitor PARP Inhibitor Angiogenesis Inhibitor Dr. John Park Dr. Hope Rugo Dr. Kathy Albain University of California, San Francisco University of California, San Francisco Loyola University * Figitumumab has just been withdrawn and will not be available for randomization. 55

56 Hanahan and Weinberg, Cell, 2011

57 CHALLENGES Efficient test of multiple promising new agents Maintain standard curative therapy or replace entirely by new agents at some point in the trial Identify who can avoid chemotherapy altogether Shrinking eligible patient pool due to frequency of the target as well as competing trials with exciting new therapies for one target, and many companies making the same drug/target

58 Use of the Presurgical Window Model to Screen New Agent Activity

59 Presurgical Window Approach for New Drug/Target Assessment in Early Breast Cancer What This Model Is and What It s Not Can use small number patients since endpoint is biomarker modulation only - NOT an efficacy trial Short time window, not standard neoadjuvant duration Thus, can justify new agents alone, since definitive surgery and standard adjuvant recommendations will follow shortly Challenges for patient acceptance (extra biopsies, short delay in surgery) Requires multidisciplinary buy-in prior to a standard surgical approach

60 Targeting Critical Cancer Cell Survival Pathways to Overcome Resistance to Standard Endocrine Treatment Breast tumor initiating cells (breast cancer stem cells) use Notch receptors/ligands with other pathways for self renewal, resulting in tumor proliferation and progression We showed that Notch inhibition with novel compounds - gamma secretase inhibitors (GSI) - potentiates the effects of tamoxifen in xenografts (Rizzo et al. Cancer Research, 2008) It is unknown whether GSI plus endocrine therapy result in modulation of Notch and other proliferation markers in human breast cancer The presurgical window setting is an ideal model to test this hypothesis Albain KS, et al. PSABCS 2010

61 MK ENDOCRINE THERAPY PRESURGICAL WINDOW STUDY SCHEMA ER+, Early Stage, All Ages Day 1 Core biopsy Tamoxifen 20 mg OR Letrozole 2.5 mg PO daily x 14 days Day 14 Core biopsy Tamoxifen 20 mg OR Letrozole 2.5 mg daily x 10 days plus MK mg PO 3 days on 4 days off 3 days on Day 25 Definitive surgery qrt-pcr Global gene expression profiling qrt-pcr Global gene expression profiling qrt-pcr Global gene expression profiling Biomarker candidates Albain KS, et al. PSABCS 2010 *ClinTrials.gov NCT

62 Working Hypothesis Endocrine Therapy + Gamma Secretase Inhibitor - A potential anti-tumor initiating cell effect and a role in overcoming endocrine resistance :%(;"<7 :%(;"<5 >5B D16E Albain KS, et al. PSABCS 2010

63 Integrating New Agents with Standard, Curative-Intent Therapy in Early Breast Cancer Conclusions We have come a long way with standard chemotherapy and endocrine therapy in phase III adjuvant clinical trial design, improving breast cancer mortality Biomarker correlative translational studies yielded refinement in who can avoid chemotherapy Neoadjuvant therapy designs need to select for relevant biology if they are to yield strategies that increase cures Early excitement with dual HER2 blockade The presurgical window model can be used to determine which new targeted therapies merit more expanded neoadjuvant trials