1. Key Issues in the Management of Metastatic Breast Cancer Case 2 (HER2 positive), v5 - July 3, 2009 - to Abraxis Medical

2. First-Line Treatment of HER2-Positive ER-Negative Metastatic Breast Cancer Case

3. Case: History 47-year-old woman with invasive ductal carcinoma – 2.0 cm – Node negative – ER negative – HER2 positive Treated with lumpectomy, adjuvant chemotherapy with AC x 4, and radiation Treatment completed in June 2004

4. Case: Clinical Presentation In 2007, presents with nausea and RUQ pain CT abdomen: diffuse liver metastases; marker lesion 5.5 cm CT chest: multiple pulmonary lung nodules all <1.0 cm Lytic bony metastases through thoracic and lumbar spine Mildly elevated transaminases, normal bilirubin ECOG PS = 1 RUQ = right upper quadrant ECOG = Eastern Cooperative Oncology Group PS = performance status

5. Case: What Are the Treatment Options? 1.Taxane + trastuzumab 2.Vinorelbine + trastuzumab 3.Capecitabine + trastuzumab 4.Taxane + carboplatin + trastuzumab (TCH) 5.Other

6. Case: Evidence-Based Treatment Options Randomized data: with trastuzumab – Paclitaxel and doxorubicin/cyclophosphamide – Docetaxel – Taxane and platinum Phase II data: multiple agents + trastuzumab – Vinorelbine – Capecitabine – Gemcitabine – nab  -paclitaxel

7. Chemotherapy + Trastuzumab for MBC that Overexpresses HER2 Slamon DJ et al. N Engl J Med 2001;344:783-92. CT = chemotherapy KPS = Karnofsky performance status Slamon et al. N Engl J Med 2001 * Doxorubicin or epirubicin MBC HER2 overexpression No prior CT for MBC Measurable disease KPS >60% n = 469 MBC HER2 overexpression No prior CT for MBC Measurable disease KPS >60% n = 469 No previous anthracyclines Previous anthracyclines Trastuzumab + anthracycline* + cyclophosphamide (n = 143) Trastuzumab + anthracycline* + cyclophosphamide (n = 143) Anthracycline* + cyclophosphamide (n = 138) Trastuzumab + paclitaxel (n = 92) Trastuzumab + paclitaxel (n = 92) Paclitaxel (n = 96) RANDOMIZATIONRANDOMIZATION

8. Chemotherapy Alone (n = 234) Chemotherapy + Trastuzumab (n = 235) P Median survival (months) 20.325.10.046 1-year survival (%)67780.008 Median TTP (months)4.67.4<0.001 RR (%)3250<0.001 TTP = time to progression RR = response rate Slamon DJ et al. N Engl J Med 2001;344:783-92. Slamon et al. N Engl J Med 2001 First-Line Chemotherapy for HER2-Positive MBC Results

9. First-Line Chemotherapy for HER2-Positive MBC Progression-Free Survival Slamon DJ et al. N Engl J Med 2001;344:783-92. Slamon et al. N Engl J Med 2001

10. First-Line Chemotherapy for HER2-Positive MBC Cardiac Dysfunction Slamon DJ et al. N Engl J Med 2001;344:783-92. Slamon et al. N Engl J Med 2001 Anthracycline + Cyclophosphamide + Trastuzumab (n = 143) Anthracycline + Cyclophosphamide Alone (n = 135) Paclitaxel + Trastuzumab (n = 91) Paclitaxel Alone (n = 95) Cardiac dysfunction, symptomatic or not (n, %) 39 (27)11 (8)12 (13)1 (1) Cardiac dysfunction, NYHA class III or IV (%) 16321 Death due to cardiac dysfunction (n) 1100 NYHA = New York Heart Association

11. First-Line Chemotherapy for HER2-Positive MBC M77001: Design Marty M et al. J Clin Oncol 2005;23:4265-74. LVEF = left ventricular ejection fraction MBC HER2 positive No prior CT for MBC No prior taxanes Baseline LVEF >50% n = 186 MBC HER2 positive No prior CT for MBC No prior taxanes Baseline LVEF >50% n = 186 Trastuzumab 4 mg/kg loading dose then 2 mg/kg q wk until disease progression + docetaxel 100 mg/m 2 q 3 wk  6 cycles (n = 92) Trastuzumab 4 mg/kg loading dose then 2 mg/kg q wk until disease progression + docetaxel 100 mg/m 2 q 3 wk  6 cycles (n = 92) Docetaxel 100 mg/m 2 q 3 wk  6 cycles (n = 94) RANDOMIZATIONRANDOMIZATION

12. First-Line Chemotherapy for HER2-Positive MBC M77001: Results * Kaplan-Meier estimate Intent-to-treat population Trastuzumab + Docetaxel (n = 92) Docetaxel Alone (n = 94) P ORR (%)61340.0002 Median DR (months)11.75.70.009 Median TTP (months)11.76.10.0001 Median OS* (months)31.222.70.0325 Marty M et al. J Clin Oncol 2005;23:4265-74. ORR = overall response rate DR = duration of response TTP = time to progression OS = overall survival

13. First-Line Chemotherapy for HER2-Positive MBC M77001: Toxicity Marty M et al. J Clin Oncol 2005;23:4265-74. Trastuzumab + Docetaxel (n = 92) Docetaxel Alone (n = 94) Grade 3/4 leukopenia (%)2015 Grade 3/4 neutropenia (%)3222 Febrile neutropenia/ neutropenic sepsis (%) 2317 Asymptomatic decrease in LVEF ≥15% (%) 178 Symptomatic CHF (n)20 LVEF = left ventricular ejection fraction CHF = congestive heart failure

14. Stratification: – Prior chemotherapy o Adjuvant/neoadjuvant –Centre Primary efficacy end point: TTP 8 TH 8 TCH Docetaxel 100 mg/m 2 q 3 wk Docetaxel 75 mg/m 2 q 3 wk Carboplatin AUC: 6 mg/mL/min Trastuzumab* First-Line Chemotherapy for HER2-Positive MBC BCIRG 007: Taxane and Platinum Forbes JF et al. ASCO 2006:LBA516. Pieńkowski T et al. ESMO 2006:148PD. FISH = fluorescent in situ hybridization AUC = area under the curve TTP = time to progression HER2 positive by FISH n = 263 HER2 positive by FISH n = 263 * 4 mg/kg IV, day 1, cycle 1; 2 mg/kg IV weekly starting day 8; 6 mg/kg IV q 3 wk starting 3 wk after last chemotherapy

15. First-Line Chemotherapy for HER2-Positive MBC BCIRG 007: Results TH (n = 131) TCH (n = 132) Best overall response (n, %) CR24 (18)23 (17) PR71 (54)73 (55) SD/NC24 (18)20 (15) PD11 (8.4)11 (8.3) NE 1 (0.8) 5 (3.8) RR (CR + PR) (%) 72.5 (64.0–80) 72.7 (64.3–80.1) Clinical benefit rate (%) CR, PR, or SD for >24 wk 67.266.7 CR = complete response PR = partial response SD = stable disease NC = no change PD = progressive disease NE = not evaluable RR = response rate Forbes JF et al. ASCO 2006:LBA516.

16. First-Line Chemotherapy for HER2-Positive MBC BCIRG 007: Time to Progression Pieńkowski T et al. ESMO 2006:148PD. Intent-to-treat population

17. Randomized Trials: Trastuzumab Added to Chemotherapy in First-Line MBC Chemotherapyn RR (%)TTP (months) Chemo- therapy Chemo- therapy + Trastuzumab Chemo- therapy Chemo- therapy + Trastuzumab Docetaxel 1 18634616.111.7 Paclitaxel 2 18817413.06.9 Paclitaxel 3 12457756.810.0 Doxorubicin or epirubicin + cyclophosphamide 2 281 42 566.17.8 1. Marty M et al. J Clin Oncol 2005;23:4265-74. 2. Slamon DJ et al. N Engl J Med 2001; 344:783-92. 3. Gasparini G et al. Breast Cancer Res Treat 2007;101:355-65. RR = response rate TTP = time to progression

18. Phase II Trials 1.Vinorelbine + trastuzumab 2.Capecitabine + trastuzumab 3.Gemcitabine + trastuzumab 4.nab  -paclitaxel and trastuzumab

19. Phase II Trials: Trastuzumab Added to Chemotherapy in MBC Chemotherapy Line of Therapy nRR (%)TTP (months) Vinorelbine 1 First54685.6 Vinorelbine 2 Various4075 7.9 (first line) 3.7 (second/third line) Vinorelbine 3 First407817 Capecitabine 4 First4363Not reached Gemcitabine 5 Third64385.8 nab  -paclitaxel 6 First1764.7NR 1. Burstein HJ et al. J Clin Oncol 2003;21:2889-95. 2. Burstein HJ et al. J Clin Oncol 2001;19:2722-30. 3. Jahanzeb M et al. Oncologist 2002;7:410-7. 4. Xu L et al. SABCS 2006:2065. RR = response rate TTP = time to progression NR = not reported 5. O’Shaughnessy JA et al. Clin Breast Cancer 2004;5:142-7. 6. Mirtsching B et al. ASCO 2008:1118.

20. Case: What Are the Treatment Options? 1.Taxane + trastuzumab 2.Vinorelbine + trastuzumab 3.Capecitabine + trastuzumab 4.Taxane + carboplatin + trastuzumab (TCH)

21. Case: Treatment Docetaxel 100 mg/m 2 Trastuzumab – 4 mg/kg loading dose over 90 min; 2 mg/kg weekly maintenance dose over 30 min After 2 cycles: – Liver enzymes normalize – Patient feels better

22. Case: Duration of Chemotherapy Treatment + Trastuzumab Options: – Continue chemotherapy until patient has dose- limiting toxicities? – Continue chemotherapy until 2 cycles past best response? – Continue chemotherapy for 6 cycles total? – Other?

23. Case: Progress Treated with 4 cycles of docetaxel then dose reduced by 20% due to neutropenia – Total of 6 cycles – Dose-limiting sensory neuropathy and peripheral edema – CT abdomen: marker liver lesion reduced from 5.5 to 2.0 cm Continued on single-agent trastuzumab  5 months Increasing liver enzymes CT abdomen: progressive liver metastases

24. Case: Treatment Options 1.Stop trastuzumab and start vinorelbine 2.Stop trastuzumab and start capecitabine 3.Continue trastuzumab and start capecitabine 4.Initiate lapatinib + capecitabine

25. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S Trastuzumab beyond progression in human epidermal growth factor receptor 2–positive advanced breast cancer: a German Breast Group 26/ Breast International Group 03-05 study von Minckwitz G et al. J Clin Oncol 2009;27:1999-2006.

26. GBG-26: First Randomized Phase III Study to Investigate Continuation of Trastuzumab Primary end point: TTP Study closed early (IDMC) TTP = time to progression IDMC = independent data-monitoring committee * First-line treatment for MBC: n = 111; adjuvant treatment: n = 3 Progression under taxane + trastuzumab (n = 114*) or trastuzumab monotherapy/ trastuzumab + nontaxane (n = 42) Capecitabine 2500 mg/m 2 bid days 1–14 q 21 days + continuation of trastuzumab 6 mg/kg q 3 wk (n = 78) Capecitabine 2500 mg/m 2 bid days 1–14 q 21 days (n = 78) RANDOMIZATIONRANDOMIZATION von Minckwitz G et al. J Clin Oncol 2009;27:1999-2006.

27. GBG-26: Continuation of Trastuzumab Significantly Improves Response Rate OR = odds ratio CR = complete response PR = partial response SD = stable disease PD = progressive disease Population that received at least one cycle of allocated treatment Response to treatment not assessed: combination arm, 2.6%; capecitabine arm, 8.1% OR: 2.50 P = 0.0115 von Minckwitz G et al. J Clin Oncol 2009;27:1999-2006.

28. GBG-26: Progression-Free Survival Median TTP Capecitabine (X): 5.64 months (4.16–6.30) Capecitabine + trastuzumab (H): 8.16 months (7.25–11.21) Unadjusted HR*: 0.685 (0.482–0.974) P = 0.0338 (2-sided log rank) * Intent-to-treat population von Minckwitz G et al. J Clin Oncol 2009;27:1999-2006.

29. GBG-26: Overall Survival Median Overall Survival Capecitabine (X): 20.39 months (17.77–24.66) Capecitabine + trastuzumab (H): 25.48 months (19.02–30.69) Unadjusted HR*: 0.763 (0.477–1.220) P = 0.2570 (2-sided log rank) * Intent-to-treat population von Minckwitz G et al. J Clin Oncol 2009;27:1999-2006.

30. Lapatinib: Mechanism of Action Image: GlaxoSmithKline MAPK Akt Sos PI3K Shc Ras Raf MAPK Grb2 ATP P P Akt Proliferation pathway Survival pathway Normal activation by ATP Activation blocked by lapatinib Survival pathway Proliferation pathway ErbB1ErbB2 ErbB1ErbB2 Lapatinib

31. Phase III Trial of Capecitabine ± Lapatinib in Advanced or MBC Primary end point: TTP Secondary end points: PFS, OS, ORR, rate of clinical benefit, and safety Geyer CE et al. N Engl J Med 2006;355:2733-43. Geyer et al. N Engl J Med 2006 IHC = immunohistochemistry FISH = fluorescent in situ hybridization TTP = time to progression PFS = progression-free survival OS = overall survival ORR = overall response rate Stage IIIB or IIIC with T4 lesion, or MBC that has progressed HER2 positive (IHC 3+ or 2+ with FISH) Unlimited prior therapies, but no prior capecitabine Prior therapies must include: –Trastuzumab in metastatic setting –Anthracycline and taxane in either metastatic or adjuvant setting Stage IIIB or IIIC with T4 lesion, or MBC that has progressed HER2 positive (IHC 3+ or 2+ with FISH) Unlimited prior therapies, but no prior capecitabine Prior therapies must include: –Trastuzumab in metastatic setting –Anthracycline and taxane in either metastatic or adjuvant setting Lapatinib 1250 mg/day po Capecitabine 2000 mg/m 2 /day, days 1–14 q 21 days (n = 163) Median trastuzumab-discontinuation time = 5.3 wk Lapatinib 1250 mg/day po Capecitabine 2000 mg/m 2 /day, days 1–14 q 21 days (n = 163) Median trastuzumab-discontinuation time = 5.3 wk Capecitabine 2500 mg/m 2 /day, days 1–14 q 21 days (n = 161) Median trastuzumab-discontinuation time = 6.0 wk Capecitabine 2500 mg/m 2 /day, days 1–14 q 21 days (n = 161) Median trastuzumab-discontinuation time = 6.0 wk RANDOMIZATIONRANDOMIZATION

32. Phase III Trial of Capecitabine ± Lapatinib in Advanced or MBC: TTP Cameron D et al. Breast Cancer Res Treat 2008;112:533-43. Cameron et al. Breast Cancer Res Treat 2008 Weeks Cumulative progression free (%) Intention-to-treat population HR = hazard ratio CI = confidence interval TTP = time to progression (n = 198) (n = 201)

33. Phase III Trial of Capecitabine ± Lapatinib in Advanced or MBC: Overall Efficacy Independent assessment, intent-to-treat population * End points based on evaluation by the independent review committee under blinded conditions † Calculated with log-rank test ‡ Calculated with Fisher’s exact test End Point Lapatinib + Capecitabine (n = 198) Capecitabine Alone (n = 201) HR (95% CI) P Median TTP (months)6.24.3 0.57 (0.43–0.77) <0.00013* PFS 0.55 (0.4–0.74) <0.001 † ORR (%) (95% CI) 23.7 (18.0–30.3) 13.9 (9.5–19.5) 0.017 ‡ Clinical benefit (%) (CR + PR + SD ≥6 months) 29.317.40.008 ‡ Death (n) (%)55 (28)64 (32) Cameron D et al. Breast Cancer Res Treat 2008;112:533-43. Cameron et al. Breast Cancer Res Treat 2008 CR = complete response PR = partial response SD = stable disease HR = hazard ratio PFS = progression-free survival ORR = overall response rate CI = confidence interval

34. Toxicity Cameron D et al. Breast Cancer Res Treat 2008;112:533-43. Cameron et al. Breast Cancer Res Treat 2008 Patients (%) L = lapatinib C = capecitabine PPE = palmar plantar erythrodysesthesia

35. Summary Suppressing HER2 upon progression appears to continue to benefit – Either continue trastuzumab with a change in chemotherapy or switch to lapatinib

36. Case: Progress Continued trastuzumab – 4 mg/kg loading dose over 90 min; 2 mg/kg weekly maintenance dose over 30 min Started capecitabine 2000 mg/m 2 bid Tolerated therapy well PR after 2 cycles PR = partial response

37. Challenges for Physicians in Canada Treatment with trastuzumab beyond progression is not funded in many provinces Lapatinib is an oral drug; coverage is not yet certain* Capecitabine is an oral drug and is not covered in some provinces for patients <65 years without a drug plan * As of June 2009

38. HER2-Positive MBC Treatment Summary For women with HER2-positive MBC, trastuzumab + chemotherapy should be the treatment of choice – Choice of chemotherapy should be individualized based on clinical presentation Treatment options for patients who progress on trastuzumab: – Continuation of trastuzumab + other chemotherapeutic agents (phase II data) – Continuation of trastuzumab + capecitabine (phase III data) – Lapatinib + capecitabine (phase III data) – Chemotherapy alone

39. Treatment Summary No gold-standard treatment for MBC Individualize treatment based on tumour burden and patient characteristics Goals of treatment: – Prolong survival – Relieve symptoms with minimal treatment-related toxicities (integral part of overall care) Discuss clinical trials when appropriate

40. Key Issues in the Management of Metastatic Breast Cancer