Lapatinib in Breast Cancer

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Information about Lapatinib in Breast Cancer

Published on December 16, 2016

Author: DrShadSalimAkhterAkh

Source: slideshare.net

1. Lapatinib in Breast Cancer Prof. Shad Salim Akhtar MBBS, MD, MRCP(UK), FRCP(Edin), FACP(USA) Member ASCO, ESMO, UICC, AUICC Fellows Member Global Community Against Cancer UICC Consultant Medical Oncologist Chairman Board of Directors Hakim Sanaullah Cancer Centre Sopore, Kashmir, J & K

2.  38 years female mother of 3 children  Mastectomy, Axillary node dissection  Tumor characteristics  2.5 cms, 3/14 nodes involved No lymphovascular invasion, ER/PR -ve, Her- 2/neu +ve (FISH),  Adjuvant therapy  AC X 4  Paclitaxel X12 weeks  Trastazumab X 5 months

3. Right upper quadrant pain Severe headache CT scan abdomen Liver lesions consistent with metastasis 3 Liver biopsy Adenocarcinoma high grade, ER/PR -ve, Her-2/neu 3+(IHC) MRI brain Five lesions consistent with metastasis throughout brain WBRT given What next?

4. Metastatic Breast Cancer  Metastatic breast cancer  6% of all newly diagnosed cases  30% during the course of illness  Brain metastasis  Case series  10-16%  Autopsy series  20-30%  Population based estimates  5.1 % (Barnholtz-Sloan et al: JCO 2004; 22: 2865-72) Pestalozzi BC et al: Ann Oncol 2008;17:935-44

5. Survival & Site of Relapse Site of relapse Median surv (mons) Local alone Undefined Contra-lateral breast 30.2 Regional and local 20.6 Bone only 21.8 Visceral (excluding liver) 13.1 Liver only 5.4 Central nervous system 4.0 Goldhirsch A et al: J Clin Oncol 1988;6:89

6. Brain Metastasis Risk Factors Younger age at presentation Hormone receptor negative disease Visceral metastasis at relapse Lung Metastasis free interval <24 months Premenopausal at diagnosis Gori S et al: The Oncologist 2007; 12:766 Silmane K et al: Ann Oncol 2004; 15:1640

7. ErB2 Over-expression / Amplification & Brain Metastasis  Amplified or over-expressed  25% patients  Metastasis and Primary concordance  Near 97%  FISH more accurate than IHC  3 fold increased risk of metastasis to viscera (Kallioniemi OP et al:1991) Lear-Kaul KC et al:Arch Pathol Lab Med 2003; 127:1451-7 Receptor status Brain Breast Her-2/neu +ve 13 13 Her-2/neu -ve 16 15 Fuchs IB et al J Clin Oncol 2002; 20:4130-3

8. Brain Metastasis Risk Factors  Total number reviewed 9524  Node negative 42%  No anthracyclines, taxanes or trastuzumab  Time period 1978-99  Median follow up 13 years  Incidence of CNS relapse 5.2%  As first site of recurrence 1.3%  Pts with lung mets at relapse 16.4% Pestalozzi BC et al: Ann Oncol 2008;17:935-44

9. Factors Predicting CNS As First Recurrence Factor Incidence (10 yrs incidence) Her-2/neu positive disease 2.7% ER-ve Node positive disease 2.6% ER negative 2.3% Age <35 years 2.2% Node positive (>3 n) disease 2.2% Grade III tumor 2.2% Tumor size >2 cms 1.7% Pestalozzi BC et al: Ann Oncol 2008;17:935-44

10. Brain Metastasis Risk Factors Gabos Z et al: J Clin Oncol 2006; 24:5658 664 patients not treated with trastuzumab; med foll up 3.9 yrs

11. Incidence of Brain Metastasis Trastuzumab Treated Pts Melisko ME et al: Nature Clin Pract Oncol 2009; 6:25:33

12. Abbott NJ et al. (2006) Astrocyte–endothelial interactions at the blood–brain barrier Nat. Rev. Neuro. 7: 41–53 doi:10.1038/nrn1824 Figure 3 Pathways across the blood–brain barrier. Trastuzumab is a large molecule (145 Kda)

13. Why Do Pts with Trastuzumab Therapy Have Higher Incidence of Brain Mets?  Selection bias  Increased survival  Increased follow up time Therapy Brain Met Incidence Per 100 person-years of observation TZ+Ct 9.3-9.8% 16.1 CT 7% 15.7 Burstein HJ et al: Ann Oncol 2005; 16:1772-7

14. This is a view of Indian Administered Kashmir

15. Brain Metastasis Therapy Multiple large volume WBRT Median survival 4.5-6 months Longer than 1 yr survival Cognitive impairment No impact on systemic disease Nieder C et al: Am J Clin Oncol 1999; 22;573-79

16. Brain Metastasis-Therapy Isolated or low volume Surgical resection Stereotactic surgery  May follow WBRT  Improved local control and may be survival  Survival ? 1year Gerosa M et al: J Neurosurgery 2000; 97:515-24

17. Do we have a drug which works in Her- 2/neu +ve breast cancer with cerebral metastasis after failure of trastuzumab? L A P A T I N I B

18. Paul B et al: Am J Health-Syst Pharm 2008; 65:1703-10

19. Lapatinib  Orally active small molecule  Dual TK inhibitor, reversible  ErbB  ErbB2  Phase I studies  7% ORR in heavily pretreated MBC  Manageable side effects  Effective dose 175-1800 mg/day  Case reports  Shrinkage of CNS metastasis Stein SH et al: Eur J Cancer Suppl 3; 2005:78 (Abst#277) Spector NL et al: J Clin Oncol 2005:23:2502-12

20. Lapatinib Activity in Breast Cancer Cameron DA et al: Nature Clin Pract Oncol 2008:5:512-20 Similar to early trastuzumab trials ORR independent assess 1.4% Clinical benefit –6% 31% Clinical benefit

21. Phase II Trial Outcome  Modest clinical activity  Her-2/neu+ve disease progressing after TZ  No clinical activity in chemo refractory her- 2/neu negative disease  Time to response 12 weeks  Duration of response 28.4 weeks  Major side effects (grade 1-2)  Diarrhea  Skin rash Cameron DA et al: Nature Clin Pract Oncol 2008:5:512-20

22. Lapatinib -Phase II Trial Brain Metastasis Safety and efficacy in Her-2/neu +ve breast cancer new or progressive brain metastasis  Min 1 measurable lesion (1.0 cm dia) Lapatinib 750 mg BID Assessment  MRI every 8 wks & FDG-PET wk 1 & 8 Primary  Obj resp (CR+PR) in brain by RECIST Secondary  Safety, QOL, PET changes Lin NU et al: J Clin Oncol 2008; 26:1993-9

23. Efficacy of Lapatinib CNS Mets 39 patients Age 31-76 (52) yrs All developed brain mets on trastuzumab 37 progresses after prior radiation Median TTP was 3.0 months (95% CI, 2.3 to 3.7 months). For the patient with CNS objective response, TTP was 11.3 months. Lin NU et al: J Clin Oncol 2008; 26:1993-9

24. Lapatinib Overall Activity Clinical Category Response Number % CNS Overall response 1 2.6 Complete response 0 0 Partial response 1 2.6 Stable disease* 6 15.4 Non CNS Measurable disease 16 Overall response 4 25 Complete response 0 0 Partial response 4 25 Non measurable disease 23 Lin NU et al: J Clin Oncol 2008; 26:1993-9 * Stable disease at both CNS and Non CNS sites >16wks

25. Volumetric Changes in CNS Lesions Lin NU et al: J Clin Oncol 2008; 26:1993-9 PR 10-30% reduction >=30% reduction 34/39 pts in the study were analyzed TTP better if reduction >=10%

26. EGF105084: Phase II study of lapatinib for brain metastases in ErbB2+ breast cancer Lapatinib 750 mg b.i.d. Eligibility criteria: • Stage IV patients with ≥ 1 measurable lesion in the brain • Unequivocal evidence of new and/or progressive brain metastasis after WBRT or STS • IHC3+ or FISH gene amplification • Prior trastuzumab therapy Two Cohorts: 1.ECOG PS 0 or 1 and 1 or 2 trastuzumab- containing regimens 2.ECOG PS 2 or > 2 prior trastuzumab- containing regimens (Open label phase II study n = 220) Primary endpoint: CNS objective RR using volumetric MRI Secondary endpoints: Safety tolerability, neurological signs and symptoms, progression free and overall survival Lin NU et al: Clin Cancer Res 2009; 15:1452-9

27. EGF105084: extension arms Stratification: PS and number of prior trastuzumab- containing regimens Stratification: PS and number of prior trastuzumab- containing regimens Lapatinib Monotherapy 750 mg BID Lapatinib Monotherapy 750 mg BID PD Extension arms Extension arms Lin NU et al: Clin Cancer Res 2009; 15:1452-9 CT + Lap extra CNS PD with SD in CNS After 2006 Cap for CNS progression

28. Efficacy of Lapatinib Monotherapy Cohort A (94) Cohort B (143) Total (237) Complete response 0 0 0 Partial response 6 (6) 9 (6) 15 (6) Stable disease 41 (44) 47 (33) 88 (37) Progressive disease 39 (41) 69 (48) 108 (46) Unknown 6 (6) 9 (6) 15 (6) Median PFS * 2.73 2.07 2.40 Median survival * 9.56 5.49 6.37 Lin NU et al: Clin Cancer Res 2009; 15:1452-9 * Months

29. Lin NU et al: Clin Cancer Res 2009; 15:1452-9 19 patients 8% 50 (21%) patients

30. Duration of CNS response in Lap+Cap extension phase pts with >=20% reduction in tumor volume Lin NU et al: Clin Cancer Res 2009; 15:1452-9 Med PFS 18.4 wks

31. Volumetric Reduction in CNS Mets >20% reduction >50% reduction Yes No Yes No Number* 50 186 19 217 Med PFS 3.61 1.87 3.38 2.07 Number# 20 30 11 39 Med PFS 4.60 1.89 6.21 3.12 * Lapatinib monotherapy #Lapatinib and capecitabine Lin NU et al: Clin Cancer Res 2009; 15:1452-9 A volumetric reduction of 20% indicates improvement in PFS 19.7% patients in ext arm PFS >6 months

32. Brain MRI Baseline Week 8 Subject 000133 Lin et al, Abs. 1012, ASCO 2007

33. Here rests the greatest human being ever to walk on the earth: The Prophet Mohammed (PBUH) He brought hope for humanity

34. Lapatinib in Advanced Breast Cancer •324 women Her-2/neu +ve LABC/ MBC •Previous therapy •>= 4 cycles of chemotherapy +trastuzumab •Randomization •Lap 1250 mg od + /- Cap 2000 mg/m2 in 2 doses Geyer CE et al: N Eng J Med 2006; 355:2733-43

35. Lapatinib Efficacy End Points Geyer CE et al: N Eng J Med 2006; 355:2733-43 CNS as the first event Monotherapy group 11 Combination group 4

36. Trastuzumab Wash Out Geyer CE et al: N Eng J Med 2006; 355:2733-43

37. First Line MBC Leo DA et al: J Clin Oncol 2008:26:1-12 Her-2/neu Positive 86 All patients 579

38. Inflammatory Breast Cancer Cristonfanilli M et al: SABC 2006; Dec 14-17 (Abst#1)

39. Lapatinib with HT  1286 post menop HR positive MBC  212 international centres  No previous therapy  Letrozole + Lap (1500 mg) or placebo  Her-2 +ve pts (219) Median PFS 8.2 VS 3.0 months  This may be the first line therapy in future Fricker J: Lancet Oncology: 2009; 10:20 Data from Stephen Johnson, UK

40. Toxicity we fear

41. Lapatinib Toxicity Lin NU et al: J Clin Oncol 2008; 26:1993-9

42. Adverse events Vomiting Anorexia 3 15 9 Rash <1% G3 Gr 3 Gr 2 Gr 4 Gr 1 Patients% 10 20 30 40 50 60 70 0 Diarrhea 27 25 13 1 21 6 FatigueNausea 13 7 4 1 <1 ↓ LVEF 3 8 11 3 4 8 1% G2 Lin et al, Abs. 1012, ASCO 2007EGF105084 Lin NU et al: Clin Cancer Res 2009; 15:1452-9

43. Results of an analysis of rash in nine TYKERB clinical trials  Skin events were primarily grade 1/2 (53%)  Grade 3 skin events were 6%  Grade 4 Nil.  Most skin events developed early (Days 1–14) and were self-limiting  Med duration of skin events 25 days  87% skin events did not require dose adjustment or treatment interruption.  1% resulted in therapy discontinuation  Incidence of rash with TYKERB was less than that seen with other ErbB1 inhibitors

44. Cardiotoxicity  Cardiac muscle cells contain a range of cellular receptors including ErbB2  Inhibition of the ErbB2 pathway blocks the normal repair-and survival-signaling pathways, reversibly impairing cardiac maintenance without inducing direct cell death  Tykerb appears to be less cardiotoxic

45. Common Terminology Criteria for Adverse Events v3.0 (CTCAE) Adverse event Short name Grade 1 2 3 4 5 L V systolic dysfunc tion Left ventricular systolic dysfunction Asymptomatic; resting ejection fraction (EF) <50–60%, shortening fraction (SF) <24–30% Asymptomatic; resting EF <50– 40%; SF <24–15% Sympto matic CHF responsi ve to treatme nt; resting EF <40– 20%; SF <15% Refractory CHF or poorly controlled; EF<20%; intervention such as ventricular assist device or ventricular reduction surgery or heart transplant indicated Death

46. Hudis C: N Engl J Med 2007; 357:39-51

47. Effect of lapatinib on the heart Patients, n (%) *Patients presented with dyspnea, palpitations, and signs of CHF, and responded promptly to standard therapy with furosemide, corticosteroids and diuretics, or diuretics and nitroglycerin. † 12 patients remain blinded and are assumed to have received lapatinib for analysis purposes. 7 (0.2)51 (1.4)58 (1.6)† Total (N = 3,558) 4 (0.2)34 (1.5)38 (1.7) Neither A nor T (n = 2,201) 1 (0.1)12 (1.6)13 (1.7) Trastuzumab (with chemotherapy or after A) (n = 759) 2 (0.3)5 (0.8)7 (1.2)Anthracyclines (n = 598) Symptomatic LVEF decrease* Asymptomatic LVEF decrease Decreased LVEFPrior therapy Perez et al. Annals Oncol 17(suppl. 9) Abstract 1420. Presented at ESMO 2006 2.1% asymptomatic decline in LVEF. Med time to onset 83 days. Resolves completely in almost all

48. Ongoing Lapatinib Trials Cameron DA et al: Nature Clin Pract Oncol 2008; 5:512-20

49. Cameron DA et al: Nature Clin Pract Oncol 2008; 5:512-20 Ongoing Lapatinib Trials

50. Women with centrally determined HER2- positive invasive breast cancer (N = 8000 planned) Trastuzumab 8 mg/kg IV (loading dose)*  6 mg/kg every 3 wks for 1 yr ± Paclitaxel 80 mg/m2 IV once wkly x 12 Trastuzumab 8 mg/kg (loading dose)  6 mg/kg every 3 wks for 1 yr Lapatinib 1000 mg orally once daily x 51 wks ± Paclitaxel 80 mg/m2 IV once wkly x 12 Lapatinib 1500 mg orally once daily x 34 wks Lapatinib 1500 mg/kg orally once daily x 51 wks ± Paclitaxel 80 mg/m2 IV once wkly x 12 Trastuzumab 4 mg/kg IV (loading dose)  2 mg/kg once wkly x 11 ± Paclitaxel 80 mg/m2 IV once wkly x 12 Surgery, neoadjuvant anthracycline- based therapy for 4 cycles; LVEF ≥ 50 6-week wash-out ALLTO Trial Design *For concomitant dosing with paclitaxel, trastuzumab will be given on a weekly schedule (4 mg/kg IV loading dose followed by 2 mg/kg IV weekly). Trastuzumab will revert to the 3-weekly schedule (6 mg/kg without loading dose).

51. ALTTO endpoints Primary  Disease-free survival Secondary (Efficacy)  Overall survival  Time to recurrence  Time to distant recurrence  Incidence of CNS as first site of recurrence Secondary (Other)  Safety and tolerability  Translational research  Pharmacogenetics research

52. EGF Pathway  EGFR: transmembrane protein Extracellular Domain Transmembrane Domain Intracellular Domain Tyrosine Kinase Domain Adapted from: Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174.

53. EGF Pathway Shc PI3K Raf MEKK-1 MEK MKK-7 JNK ERK Ras mTOR Grb2 AKT Sos-1  EGFR activationEGFR activation mediates multiplemediates multiple processesprocesses Adapted from: Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174.

54. O’Shaughnessy J, et al. J Clin Oncol ASCO Annual Meeting Proceedings 2008; 26(Suppl.): Abstract 1015 and oral presentation ErbB1–ErbB1 ErbB1–p95 ErbB1–ErbB3 ErbB2–ErbB2 ErbB2–ErbB4 ErbB1–ErbB4 PTENPTEN Cell proliferation Cell survival Cell mobility and invasiveness PI3K Akt MUC4 PI3K Akt SOS RAS RAF MEKMAPK Transcription ErbB2–ErbB3 Masking of Her-2 by mucin-4 Increased signaling from other HER receptors Loss of PTEN (phosphatase and tensin homolog) Mutation in PI3K gene Increased IGF-receptor signaling Loss or absence of external domain of the receptor leading to truncated form of the receptor p95 Toamsello G et al:Expert Rev Anticancer Therapy 2008;12:1883

55. Lapatinib

56.  Her -2/neu +ve 78 pts  Trastuzumab therapy  38 before CNS relapse  29 after CNS relapse Park IH et al: Ann Oncol 2009; 20:56-62

57. Trastuzumab Beyond Progression  Her-2/neu + progressing on trastuzumab 78 pts in each arm Trastuzumab + C Capecitabine TTP 8.2 m 5.6 m ORR 48% 27% Von Minckwitz G et al: J Clin Oncol 2009; 1999-2006 291 pts Lapatinib Lap+Trastuzumab PFS 8.1 wks 12 wks Jehanzeb M: J Clin Oncol 2009; 27:1935 O’Shaughnessy J et al: J Clin Oncol 2008: 26:44s

58. Lapatinib  CYP34A effect on AUC  Inducers Decrease by 72%  Inhibitors Increase by 3-4 fold  Fat content in food (per 500 cals)  Low (5%) 3 fold increase  High (50%) 4 fold increase  Lower dose may decrease diarrhea Reddy N et al:Clin Pharm Ther 2007; 81:s16-7

59. Lapatinib Dose Finding Study  LABC or MBC  Untreated in mets setting  ErbB2-amplified  Lapatinib doses  1500 once daily  500 mg BID  138 patients randomized Gomez Hl et al: J Clin Oncol 2008; 26:18:2999-3005

60. Lapatinib Dose  Overall response rate  24%  Clinical benefit (CR, PR, SD for 24 weeks)  31%  Median time to response  7.9 weeks  PFS  4 months 63%  6 months 43%  Adverse events (primarily grade1,2)  Diarrhea, rash, pruritis and nausea Gomez Hl et al: J Clin Oncol 2008; 26:18:2999-3005

61. Lapatinib Dose VS Response Gomez Hl et al: J Clin Oncol 2008; 26:18:2999-3005

62. Gomez Hl et al: J Clin Oncol 2008; 26:18:2999-3005

63. Gomez Hl et al: J Clin Oncol 2008; 26:18:2999-3005

64. Lapatinib Dose “There were no significant differences in clinical activity or the AE profile between the dosing schedules" Gomez Hl et al: J Clin Oncol 2008; 26:18:2999-3005

65. Tale of Lapatinib Dose  Diarrhea dose related  Phase I trials  175-1800 mg/ day  OD or BID  Dose in Phase III trial (Geyer trial)  1250 mg/day  From phase I (Chu S et al)  Published 9 months after Geyer trial  Cost per month 2900 US$ Seruga B et al: J Clin Oncol 2008; 26:18:2940-2

66. South Asia Income Country < 1$/day < 2$/day India 44.2% 86.2% Bangladesh 29.1% 77.*% Pakistan 31.0% 84.7% Kurkure AP et al: UICC Strategies for South Asia 2006: 26

67. Private Institutions-the conflict? Patient autonomyPatient autonomy Profit

68. What Dose Lapatinib? 250 mg BD with food 5 250 mg tablets fasting Decrease the cost by 40% 1700 US$ Ratain MJ et al: J Clin Oncol 2007:25:3397-8 Ciccarese M et al: J Clin Oncol 2008; DOI:10.1200

69. Thank You

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