ASCO 2012: Breast Cancer Updates

1. ASCO 2012: Breast Cancer Updates Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Comprehensive Cancer Center

2. Outline • What’s new in the treatment of HER2 positive metastatic breast cancer? • Emilia - TDM1 compared to lapatinib/capecitabine • Blackwell et al, #LBA1 • MA.31 - Is lapatinib as good or better than trastuzumab? • Gelmon et al, #LBA671 • NSABP B-41 – lapatinib as neoadjuvant therapy • Robidoux et al, #LBA506 • Do bisphosphonates improve breast cancer outcome? • MA.27 – Impact of osteoporosis and osteoporosis therapy • Sheperd et al, #501 • AZURE – impact in postmenopausal women • Marshal, Coleman et al, #502

3. Outline (2) • DCIS • RTOG 9804 - does everyone with DCIS need radiation? • McCormick et al, #1004 • Evaluating chemotherapy combinations, doses • NSABP B-38 – adding gemcitabine, sequential versus combination chemotherapy in early stage disease? • Swain et al, #LBA1000 • CALGB 40502 – comparing microtubule toxins in the metastatic setting • Rugo et al, #CRA1002 • What is the role of maintenance chemotherapy for patients with metastatic disease? • Im et al, #1003 • Can we target the androgen receptor in TNBC? • Gucalp et al, #1006

4. HER2 Positive MBC • The problem • Despite high response rates, almost all patients eventually develop progressive disease • How can we overcome resistance that we don’t understand? • Data before pertuzumab and T-DM1: • Start with trastuzumab + chemotherapy/hormone rx • Continue HER2 directed therapy through progression • Capecitabine/lapatinib > capecitabine (Geyer et al) • Capecitabine/trastuzumab > capecitabine (von Minckwitz et al) • Lapatinib/trastuzumab > lapatinib (Blackwell et al)

5. T-DM1: Dual Mechanisms of Action Combined Targeted Therapy Trastuzumab Biologic Activity • Targeted Intracellular Delivery of DM1a • Blocks downstream HER2 signaling to inhibit proliferation of tumor cells • Flags HER2-positive tumor cells for destruction via antibody-dependent cell-mediated cytotoxicity • Inhibits HER2 shedding • T-DM1 binds to the HER2 receptor and is internalized • DM1 is released inside the cell, resulting in mitotic arrest and apoptosis • Systemic toxicity is limited due to low HER2 expression in normal tissues aDM1 is 25–500 fold more potent than taxanein cytotoxic assays.

6. T-DM1 selectively delivers DM1 to HER2-positive tumor cells • Targeted intracellular delivery of a potent antimicrotubule agent, DM1 • Spares normal tissue from toxicity of free DM1 • Trastuzumab-like activity by binding to HER2 T-DM1 binds to the HER2 protein on cancer cells HER2 Receptor-T-DM1 complex is internalized into HER2-positive cancer cell Potent antimicrotubule agent is released once inside the HER2-positivetumor cell

7. PDa PDa Phase II Randomized International Open Label Studyb • Stratification factors: World region, prior adjuvant trastuzumab therapy, disease-free interval • Primary end points: PFS by investigator assessment, and safety • Data analyses were based on clinical data cut of Nov 15, 2010 prior to T-DM1 crossover • Key secondary end points: OS, ORR, DOR, CBR, and QOL • Demographics imbalanced: 29 vs 34 % stage IV at diagnosis, 27 vs 18% exposed to prior trastuzumab, 40 vs 33% exposed to prior taxanes HER2-positive, recurrent locally advanced breast cancer or MBC (N=137) First line setting T-DM1 3.6 mg/kg q3w IV (n=67) 1:1 Trastuzumab 8 mg/kg loading dose; 6 mg/kg q3w IV + Docetaxel 75 or 100 mg/m2 q3w (n=70) Crossover to T-DM1 (optional) aPatients were treated until PD or unacceptable toxicity. bThis was a hypothesis generating study; the final PFS analysis was to take place after 72 events had occurred. Hurvitz et al, ESMO 2011

8. PFS by Investigator N=137 1.0 0.8 0.6 0.4 0.2 0.0 Trastuzumab + docetaxel (n=70) T-DM1 (n=67) Proportion progression-free Crossover allowed to TDM1 Significantly less toxicity with TDM1, better patient reported outcomes 0 2 4 6 8 10 12 14 16 18 20 Time (months) Number of patients at risk T+D 70 66 63 53 43 27 12 4 2 2 0 T-DM1 67 60 51 46 42 35 22 15 6 3 0 Hazard ratio and log-rank P value were from stratified analysis. Hurvitz SA, et al. Abstract 5.001. ESMO 2011.

9. Clinical Rationale for EMILIA • T-DM1 • Two single-arm phase 2 trials in patients who received ≥1 HER2-directed therapies for MBC • ORR: 25.9% (N=112)1 and 34.5% (N=110)2 • Capecitabine + lapatinib • Randomized phase 3 trial in patients who received prior trastuzumab • Median TTP longer with capecitabine + lapatinib (n=163) vs. capecitabine (n=161), no difference in OS • 8.4 vs. 4.4 months (HR=0.49; P<0.001)4 1Burris HA, et al. J Clin Oncol 2011; 2Krop I, et al. J Clin Oncol 2012; 3Hurvitz S, et al. ESMO 2011; 4Geyer CE, et al. N Engl J Med 2006.

10. EMILIA Study Design T-DM1 3.6 mg/kg q3w IV • HER2+ (central) LABC or MBC (N=980) • Prior taxane and trastuzumab • Progression on metastatic tx or within 6 mos of adjuvant tx PD 1:1 Capecitabine 1000 mg/m2 orally bid, days 1–14, q3w + Lapatinib 1250 mg/day orally qd PD • Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease • Primary end points: PFS by independent review, OS, and safety • Key secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression Blackwell et al, ASCO 2011

11. EMILIA - Demographics • 496 vs 495 randomized • Median age 53, 27% from U.S. • Prior therapy • All treated with prior taxane • 16% received prior trastuzumab for early stage disease • 57% received at least one year of prior trastuzumab, 88% prior treatment for MBC • 79% measurable disease, 53-57% HR+

12. Progression-Free Survival by Independent Review Subroup analysis: TDM1 superior regardless of line of therapy (1-3) and HR status No. at risk by independent review: Cap + Lap 496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0 T-DM1 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0 Unstratified HR=0.66 (P<0.0001).

13. Overall Survival: Interim Analysis Unstratified HR=0.63 (P=0.0005). NR=not reached.

14. Objective Response Rate (ORR) and Duration of Response (DOR) in Patients with Measurable Disease DOR ORR

15. Overview of Adverse Events aCap + Lap: CAD, multiorgan failure, coma, hydrocephalus, ARDS; aT-DM1: metabolic encephalopathy. bEvaluable pts: 445 (Cap + Lap); 481 (T-DM1). • Cap and Lap: More grade 3 diarrhea (21 vs 1.6%), hand foot syndrome (16 vs 0%) • TDM1: More transaminiitis (4 vs 1%), grade 3/4 thrombocytopenia (13 vs 0%)

16. Summary and Ongoing Trials • T-DM1 superior to cap/lap • PFS, interim OS, response, safety • Will clearly be a new standard in this setting • Approval expected towards the end of 2012 • Marianne (n=1092, untreated HER2+ MBC) • Three arms • Trastuzumab + taxane • TDM1 + pertuzumab • TDM1 plus placebo • Th3RESA (n=795) • Prior trastuzumab/lapatinib/anthra/taxane/cape • 2:1 randomization to TDM1 v TPC

17. Early Stage Trials • Post-neoadjuvant cooperative group • Neoadjuvant company sponsored • Adjuvant small tumors: ATTEMPT Trial • Tolaney PI (DFCI) Trastuzumab emtansine q 3 weeks x 17 N=375 3 Stage I BC HER2+ N=500 Randomize 3:1 Paclitaxel + Trastuzumab weekly x 12 Trastuzumab every 3 weeks x 13 N=125 1

18. Two Questions • Can lapatinib overcome trastuzumab resistance? • Doesn’t require externalized receptor • Can this agent overcome resistance mediated by alterations of the PI3K pathway? • Can dual targeting of the HER2 Receptor overcome resistance more effectively? • Maintains benefits of trastuzumab while targeting the pathway through an alternate mechansim

19. 1 1 2 2 1 Trastuzumab T 2 Lapatinib L L L L L L Downstream signaling pathways Cell proliferation Cell survival

20. MA.31/ EGF108919: Metastatic Disease Randomize EXPERIMENTAL ARM STANDARD ARM 24 Weeks: Lapatinib plus Taxane 24 Weeks: Trastuzumab plus Taxane Until PD: Lapatinib Until PD: Trastuzumab Primary Outcome: PFS Sample Size: ~ 600 (536 centrally confirmed HER2+ patients) Gelmon et al, LBA671, ASCO 2012

21. Progression Free Survival Centrally-confirmed HER2+ Analysis Median PFS TTAX/T= 13.7 months Median PFS LTAX/L = 9.0 months HR = 1.48 (95% CI = 1.15 – 1.92), P = 0.003 TTAX/T LTAX/L TTAX/T LTAX/L

22. Serious Adverse Events • ** Protocol Amendment after first 189 patients were randomized mandated primary GCSF prophylaxis for patients on docetaxel and lapatinib • Discontinuation rates significantly higher for lapatinib arm * Included as one of the adverse event terms within a single SAE report Gelmon et al, LBA671, ASCO 2012

23. GeparQuinto (N=615) Neo-Altto(N=455) Pertuzumab + trastuzumab: improved pCR (NeoSphere, Tryphaena) Baselga J et al. Lancet 2012 Untch M et al. Lancet Oncology 2012

24. NSABP B-41 Schema (n=529) Tissue for Biomarkers Tissue for Biomarkers SURGERY AC→ WP + T Operable Breast Cancer HER-2 neu Positive T > 2 cm Trastuzumab for a total of 1 year AC→ WP + L1250 R AC→ WP + T + L 750 WP=Weekly Paclitaxel Endpoints: pCR, cardiac events, DFS, OS WP: d 1, 8, 15 q 28 d x 4 • Robidoux et al, #LBA506

25. Results • pCR breast • 53% (T) vs 53% (L)vs 62% (TL) (P 0.095 for TL vs T) • pCR breast and nodes • 49% (T) vs 47% (L) vs 60% (TL) (p=0.056 TL vs T) • pCR based on HER2 (IHC 3+, n=421, 81%) • 55% (T) vs 53% (L) vs 71% (TL) (p=0.006 TL vs T) • Completion of protocol defined neoadjuvant Rx • 78% (T) vs 68% (L) vs 63% (TL) (p=0.01) • Toxicity similar except diarrhea and overall • Grade 3: 2% (T) vs 20% (L) vs 27% (TL) (p<0.001)

26. ALTTO Surgery Paclitaxel weekly or TCH Lapatinib Closed due to futility +/- Anthracycline containing CT Trastuzumab Lapatinib Trastuzumab Lapatinib 1 year Trastuzumab

27. Clinical Context • What does this data mean to our clinical practice? • TDM-1 is a new and effective treatment for HER2+ metastatic disease progressing on trastuzumab • Toxicities are unique but generally well tolerated • Likely to be FDA approved by the end of the year • Pertuzumab approved in the first-line setting in combination with trastuzumab/docetaxel (PFS 18.5 mo.) • Lapatinib is associated with more toxicity and less efficacy than trastuzumab in the first-line metastatic setting • Lapatinib/capecitabine is still an option for later line therapy or in special settings (low EF (?), brain metastases) Pertuzumab/Trastuzumab/Taxane Pertuzumab/Trastuzumab Lapatinib/ Capecitabine ? TDM-1 Multiple drugs in clinical trials: inhibitors of mTOR, HSP90, TKs, vaccines

28. Osteoporosis • Osteoporosis is characterized by decreased bone mineral density. • The increased bone resorption associated with osteoporosis may provide fertile “soil” for cancer growth. • Will osteoporosis or therapy for osteoporosis affect outcome in patients with early stage breast cancer?

29. Observational Studies of Bisphosphonate Use and Breast Cancer Incidence Rennert G, Pinchev M, Rennert HS JCO, 2010 June 12 Epub ahead of print Newcomb PA, Trentham-Dietz A, Hampton JM Bristish J of Cancer 2010;102:799-802 Chlebowski RT, Chen Z, Cauley JA, et al JCO 2010 June 12 Epub ahead of print

30. Osteoporosis: 17% (1294) • Osteoporosis therapy: 36% (2711) • 116 (0.2%) took raloxifene prior to study • 39 started after randomization • Of those with osteoporosis • 85% (1101) took osteoporosis therapy • Of those taking osteoporosis therapy • 25.6% (1610) did not report osteoporosis Shepherd LE et al, ASCO 2012, #501

31. EFS by Osteoporosis Therapy HR (Yes/No) = 0.70 p<.00001 Shepherd LE et al, ASCO 2012, #501

32. Conclusions • Patients with self-reported osteoporosis and osteoporosis therapy had a lower incidence of breast cancer relapse • Patients receiving osteoporosis therapy, regardless of report of osteoporosis, had a lower incidence of relapse • Limitations • Self reporting • Variations in osteoporosis therapy and duration • Event rate (9.2%) and distant relapse rate low (4.1%)

33. The seed and soil hypothesis 'While many researchers have been studying ‘the seed’, the properties of ‘the soil’ may reveal valuable insights into the ‘metastatic peculiarities’ in cancer cases.' The Distribution of Secondary Growths in Cancer of the Breast. The Lancet. 1889 Stephen Paget 1855–1926

35. AZURE: Study Design Accrual September 2003 - February 2006 Standard therapy 3,360 Breast Cancer PatientsStage II/III R Standard therapy + Zoledronic acid 4 mg 6 doses 8 doses 5 doses Q3-4 weeks Q 3 months Q 6 months No difference in disease free or invasive disease free survival (IDFS) Months6 30 60 Zoledronic acid treatment duration 5 years Coleman et al. N Engl J Med 2011; 365:1396-1405

36. AZURE: Invasive DFS and OS by Menopausal Status IDFS: Pre, Peri, and Unknown Menopause IDFS: > 5 Yrs Postmenopausal 1.0 1.0 0.8 0.8 Adjusted HR: 1.15(95% CI: 0.97-1.36; P = .11)288 vs 256 events Adjusted HR: 0.75(95% CI: 0.59-0.96; P = .02)116 vs 147 events 0.6 0.6 Proportion Alive and invasive Disease Free Proportion Alive and invasive Disease Free 0.4 0.4 Pts at Risk, n Pts at Risk, n ZOL: ZOL: 0.2 0.2 1162 1088 996 919 829 393 57 0 519 490 447 418 393 177 25 0 No ZOL: No ZOL: 1156 1092 995 920 853 388 47 0 522 482 431 396 368 156 21 0 0 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Time From Randomization (Mos) Time From Randomization (Mos) N=2318 N=1041 OS: Pre, Peri, and Unknown Menopause OS: > 5 Yrs Postmenopausal 1.0 1.0 0.8 0.8 Adjusted HR: 0.97(95% CI: 0.78-1.21; P = .81)161 vs 165 events Adjusted HR: 0.74(95% CI: 0.55-0.98; P = .04)82 vs 111 events 0.6 0.6 Proportion Alive Proportion Alive 0.4 0.4 Pts at Risk, n Pts at Risk, n ZOL: ZOL: 0.2 0.2 1162 1131 1078 1020 955 466 71 0 519 502 482 448 422 190 29 0 No ZOL: No ZOL: 1156 1123 1076 1032 963 446 60 0 522 509 475 441 401 177 26 0 0 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Time From Randomization (Mos) Time From Randomization (Mos) Coleman RE, et al. N Engl J Med. 2011;365:1396-1405.

37. Treatment Effects on First IDFS Recurrence Outside Bone by Menopausal Status Menopausal Group Odds Ratio Pre, Periand unknown menopause HR: 1.32 (95% CI: 1.09-1.59) > 5 yrs postmenopause HR: 0.70 (95% CI: 0.54-0.92) TOTAL: 6% +/- 8 Z = .79, P = .43 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 21 (heterogeneity) = 14.00; P = < .001 Adjusted for imbalances in ER, lymph node status, and T stage. No significant differences in bone recurrence by menopausal status or age

38. SABCS 2011

39. Conclusions • In this population of patients, primarily treated with adjuvant chemotherapy • No effect of zoledronate on breast cancer outcome in the unselected overall population • Suggestion of improved outcome in pts with >5 years of menopause, due to recurrence outside bone • Unplanned subset analysis of interest but not sufficient to influence patient care • Variable results in 7 published trials • Bisphosphonates should be used to prevent or treat bone loss in patients with breast cancer • Bisphosphonates should not be used only for the purpose of preventing breast cancer recurrence • Ongoing studies are evaluating the impact of denosumab on breast cancer outcome in women with early stage disease • D-Care, ABCSG-18 • UCSF phase II trial in pts with DTCs

40. RTOG 9804: Does Good Risk DCIS Always Need Radiation? • Common disease, low long-term risk • Primary goal of treatment is to prevent invasive IBTR • Clearly variable risk exist based on biology, age, extent of disease • We have transitioned from mastectomy to lumpectomy and radiation with essentially equivalent outcomes • Does everyone need radiation? McCormick et al, #1004

41. RTOG 9804: Eligibility and Schema No palpable mass, low or intermediate grade, < 2.5 cm, margins > 3 mm Age 1. < 50 2 ≥ 50 Final Path Margins Negative (re-excision) 3-9 mm  10 mm Mammographic/Pathologic Size of Primary 1. ≤ 1 cm 2. > 1 cm to ≤ 2.5 cm  Nuclei Grade 1. Low 2. Intermediate Tamoxifen Use 1. No 2. Yes N=585 Arm 1 Observation ± tamoxifen, 20 mg per day for 5 years Arm 2 Radiation therapy to the whole breast, ± tamoxifen, 20 mg per day for 5 years • Results at 5 years • Local failure in ipsilateral breast • 3.2 vs 0.4% • HR 0.14, p=0.0022 • 15 vs 2 events • DFS • Identical • HR 0.84, p=0.48 McCormick et al, #1004

42. Summary • In patients with good risk DCIS, the addition of radiation • Added little to local control • Added nothing to survival • Use of genomic tests, such as the GH DCIS score, may help refine treatment decisions • Longer follow-up of this trial will be interesting.

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

44. 1.0 0.8 0.6 Disease-Free Survival 0.4 0.2 0.0 0 1 2 3 4 5 Years since Randomization NSABP B-38 Disease-Free Survival Treat N Events P-value* (vs ACPG) TAC 1610 327 0.410 ACP 1618 294 0.388 ACPG 1613 320 # at risk 1610 1532 1424 1331 1217 719 1618 1554 1452 1348 1240 754 1613 1533 1453 1350 1244 730 * Stratified log-rank test adjusting for randomization factors

45. 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 • More FN, anemia, diarrhea, less neuropathy with TAC • This trial started in 2004 and completed accrual in 2007 • About 10 years from initial planning to negative results • We can no longer do large trials testing therapy based solely on extent of disease

46. - - Exp 1 1 N = 900 (planned) Strata: Adj taxanes ER/PR status Control Exp 2 - CALGB 40502 - NCCTG N063H - CTSU 40502 An Open Label Phase III Trial of Firstline Therapy for Locally Recurrent or Metastatic Breast Cancer nab-paclitaxel 150 mg/m2weekly + bevacizumab 10 mg/kg q 2 wks2 Restage q 2 cycles until disease progression paclitaxel 90 mg/m2weekly + bevacizumab 10 mg/kg q 2 wks1 Randomize 1:1:1 ixabepilone 16 mg/m2weekly + bevacizumab 10 mg/kg q 2 wks3 • 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 1. Miller et al, N Engl J Med, 2007 2. Gradishar et al, J Clin Oncol, 2009 3. Dickson et al, Proc ASCO 2006.

47. CALGB 40502 Progression-Free Survival By Treatment Arm paclitaxel nab-paclitaxel ixabepilone

48. CALGB 40502 Overall Survival paclitaxel nab-paclitaxel ixabepilone

49. ixa Dose Reductions by Cycle 3 All Cause Cumulative Discontinuation by Cycle 45% 15% 15% nab pac Cycle 3

50. Other AEs – Grade 3+ Sensory Neuropathy