Her2 positive breast cancer: beyond trastuzumab

1
Her2 positive breast cancer beyond trastuzumab

• Caron Rigden, M.D.
• Grand Rounds 05.04.07

2
Case

• 63 y/o woman with osteoporosis but otherwise
  healthy
• 8/2005 inflammatory breast cancer
• Modified radical mastectomy
• 8.5 cm IDC
• moderate-poorly differentiated
• ER/PR negative HER2 amplified FISH
• 10/21 LN involved
• Stage IIIC

3

• AC x 2 cycles
• Chest wall bx progressive disease
• Therapy switched to weekly taxol with Herceptin
• for 12 weeks
• Maintenance Herceptin
• Radiation to chest and supraclavicular region
  from Jan-Feb 2006
• July 2006 recurrent chest wall disease
• Referral here August 2006

4

• Chest wall punch biopsy extensive lymphatic
  involvement by carcinoma
• ER/PR negative, HER2 positive by FISH
• CT of C/A/P negative for metastatic disease
• Started on lapatinib monotherapy phase II study
  for refractory LABC/MBC IBC

5
Trastuzumab

• Humanized anti-HER2 monoclonal antibody targeting
  the extracellular domain
• Approximately 20-25 breast cancer exhibit
  overexpression of HER2
• Revolutionized treatment HER2 overexpressing
  breast cancers by improving survival in
  metastatic setting and improving outcomes in the
  adjuvant setting

6
Trastuzumab Resistance

• Majority of metastatic patients who initially
  respond to trastuzumab will develop resistance
  within one year of treatment initiation
• Adjuvant setting 15 of patients relapse despite
  trastuzumab-based therapy

7
Potential mechanisms of resistanceNahta, Rita
et al. Breast Cancer Research 2007

• Truncated HER2 without extracellular domain (p95)
• Therapeutic agent cannot recognize the molecule
  target disrupted interaction between HER2 and
  trastuzumab (MUC4 overexpression sterically
  hinders antibody binding)
• Compensatory signaling increased signaling from
  HER family members
• Compensatory signaling increased signaling from
  other receptor types (ILGF-R)
• Altered downstream signaling (PTEN deficiency
  correlated with resistance in clinical samples)
• Competition for binding therapeutic agent
  (increased circulating HER2 ECD)

8
Novel therapeutic strategies

• Small molecule tyrosine kinase inhibitors
• Pertuzumab humanized HER2 monoclonal antibody
  sterically blocks dimerization of HER2 with EGFR
  and HER3.
• mTOR inhibitors
• Histone Deacetylase inhibitors (hsp90 as target)

9
Theoretical advantages of TKIs compared with
trastuzumab

• Inhibitor of one TK alone may not be as effective
  as inhibiting heterodimers containing both
  EGFR/HER2
• Truncated forms (lacking extracellular domains)
  of EGFR and HER2 have been identified (ie p95)
• Compensatory signaling may be overcome (ILGFR)

10
Tyrosine Kinase Inhibitors blocking HER-2 kinase
in clinical developmentSpector, Neil et al.
Breast Cancer Research 2007
11
Lapatinib (Tykerb)

• Oral small molecule TKI
• Dual inhibitor
• ErbB-1 and ErbB-2

12
Overview of Phase II and III Clinical Trials With
Lapatinib
13
Overview of Phase II and III Clinical Trials With
Lapatinib
14
Overview of Phase II and III Clinical Trials With
Lapatinib
15
Overview of Phase II and III Clinical Trials With
Lapatinib
16
Overview of Phase II and III Clinical Trials With
Lapatinib
17
Lapatinib in Refractory Metastatic Setting

• EGF20002 (n 78) phase II ( Blackwell KL et al.
  JCO 2005 Abstract 3004)
• progressed on 1-2 prior herceptin containing
  regimens
• Lapatinib 1500 mg/day
• 16 week PFS 22
• EGF20008 (n 140) phase II (Burnstein H et al.
  Ann Oncol 2004 Abstract 1040)
• Prior anthracycline, taxane, and capecitabine
• Lapatinib 1500 mg/day
• 16 week PFS 13

18
Lapatinib plus Capecitabine for HER2-Positive
Advanced Breast Cancer
Charles E. Geyer, M.D., John Forster, M.Sc.,
Deborah Lindquist, M.D., Stephen Chan, M.D., C.
Gilles Romieu, M.D., Tadeusz Pienkowski, M.D.,
Ph.D., Agnieszka Jagiello-Gruszfeld, M.D., John
Crown, M.D., Arlene Chan, M.D., Bella Kaufman,
M.D., Dimosthenis Skarlos, M.D., Mario Campone,
M.D., Neville Davidson, M.D., Mark Berger, M.D.,
Cristina Oliva, M.D., Stephen D. Rubin, M.D.,
Steven Stein, M.D., and David Cameron, M.D.
N Engl J Med Volume 355(26)2733-2743 December
28, 2006
19
Study Design

• Progressive HER2 MBC/LABC
• Previous tx with an anthracycline, taxane, and
  trastuzumab
• No prior capecitabine
• Stratification
• disease site and stage of disease

N 528 planned
20
Study Design

• Lapatinib 1250 mg po qd continuously
• Capecitabine 2000mg/m2/d
• D1-14 q3 weeks

• Progressive HER2 MBC/LABC
• Previous tx with an anthracycline, taxane, and
  trastuzumab
• No prior capecitabine
• Stratification
• disease site and stage of disease

R A N D O M I Z E

• Capecitabine 2500 mg/m2/d
• D1-14 q3 week cycle

Patients stayed on treatment until disease
progression or toxicity, then followed for
survival
N 528 planned Enrollment began 3.2004
21
Study Design

• Primary end point TTP
• Secondary end points
• Progression free survival
• Overall survival
• Overall response rate
• Rate of clinical benefit (CR/PR/stable disease
  for 6 months)
• Safety

22
Study Design

• Efficacy (based upon RECIST) assessed under
  independent blinded review
• Assessed every 6 weeks for the first 24 weeks,
  then every 12 weeks thereafter

23
Eligibility

• HER2-positive ICH 3 or IHC 2 (confirmed by
  FISH)
• Locally advanced breast cancer (T4 and Stage
  IIIB/IIIC disease) or metastatic breast cancer
• Progression after treatment with regimens
  including an anthracycline, a taxane, and
  trastuzumab in either the adjuvant/metastatic
  setting.
• Measurable disease by RECIST
• ECOG 0-1
• Normal LVEF by institutions normal range
• CNS metastases allowed if clinically stable for
  at 3 months after discontinuation of
  corticosteroids and anticonvulsant therapy

24
Ineligibility

• Prior treatment with capecitabine however, prior
  treatment with fluorouracil was permitted
• Preexisting heart disease or conditions that may
  affect gastrointestinal absorption

25
Cardiac Monitoring

• Echocardiogram/MUGA
• Cardiac event
• Any decline in EF that was symptomatic
• Asymptomatic decline gt20 from baseline to a
  level below institutions lower limit of normal
• Lapatinib d/cd any symptomatic events (Grade 3
  or 4)
• Lapatinib held for asymptomatic events and could
  be resumed at 1000 mg if EF returned to normal
  range

26
Results

• November 2005 reached planned number events for
  interim analysis
• March 2006, IDMC recommended reporting results
  and providing lapatinib to the capecitabine
  monotherapy group after the primary endpoint TTP
  had been met
• No safety/tolerability concerns were noted

27
most metastatic
most had prior taxane, anthracycline,
and trastuzumab
Median number wks (42 and 44)
Median number wks (5.3 and 6)
28
(No Transcript)
29
Geyer CE et al. N Engl J Med 20063552733-2743
30
Adverse events resulting in treatment
discontinuation Combo (13) Mono (12)
31
Results

• No symptomatic cardiac events, and therapy was
  not withheld because of decline in cardiac
  function

Update March 2007 FDA approval
32
CNS as site of first progression
33
Conclusion

• Lapatinib plus capecitabine is superior to
  capecitabine alone in women with HER2-positive
  advanced breast cancer that has progressed after
  treatment with regimens that included an
  anthracycline, a taxane, and trastuzumab
• Well tolerated with infrequent, asymptomatic,
  reversible declines in EF
• Observation made of decreased number of brain
  metastases in the lapatinib arm
• These results provide the impetus for trials of
  lapatinib in earlier treatment of HER2 positive
  breast cancer.

34
Lapatinib for Brain Metastases in Her2
CancerLin et al. ASCO 2006 NCI-CTEP 6969 trial

• Background
• approximately 30 of Her2-positive breast cancer
  patients develop CNS metastases
• Numeric increase in CNS as first site of relapse
  in adjuvant trials of trastuzumab
• Trastuzumab does not cross the blood brain
  barrier
• XRT/SBS effective, but no effective treatment
  exists beyond progression
• Unknown if lapatinib crosses into the CNS

35
Lapatinib for Brain Metastases in Her2
CancerLin et al. ASCO 2006 NCI-CTEP 6969 trial

• Eligibility
• Her 2
• New/progressive measurable (gt 1 cm) brain
  metastases
• Treatment Lapatinib 750 mg po BID
• Primary Endpoint ORR (PR CR)
• Assessment RECIST criteria by MRI

36
Lapatinib for Brain Metastases in Her2
CancerLin et al. ASCO 2006 NCI-CTEP 6969 trial

• N 39 patients (accrual 9/04-9/05)
• Mean age 52
• All developed CNS disease while on Herceptin
• 38 progressed after WBXRT
• Toxicity
• Diarrhea (21)
• Fatigue (16)
• Rash (5)

37
Lapatinib for Brain Metastases in Her2
CancerLin et al. ASCO 2006 NCI-CTEP 6969 trial

• Median duration of treatment 3 cycles
• Most common reason for discontinuation tx
  progressive CNS disease
• Based upon RECIST criteria
• 2 patients PR
• 1 patient had response, but did not meet RECIST
• 5 patients SD gt 16 weeks
• Median TTP 3.2 months
• Did not meet hypothesized level of activity based
  upon RECIST gt 4 objective responses needed
• Preliminary evidence to suggest a possible
  clinical effect warranting further investigation

38
Lapatinib monotherapy for refractory IBCSpector
et al. ASCO 2006

• Rationale early Phase I data showed good
  response in
• patients with IBC
  Her2 often amplified in IBC
• Patients recurrent or refractory to prior
  anthracycline
• treatment
• Primary Objective ORR
• Secondary Objective to identify a tumor profile
  predicting
• 
  an increased likelihood to response

39
Lapatinib monotherapy for refractory IBCSpector
et al. ASCO 2006
Tumor biopsy central review
Cohort A ErbB2
Cohort B ErbB1/ErbB2-
Lapatinib 1500 mg/day
Clinical Evaluation Recist and chest
wall/skin photography
40
Spector et al. ASCO 2006
41
Lapatinib monotherapy for refractory IBCSpector
et al. ASCO 2006
Results pending for 17 of patients in Cohort B
42
Lapatinib monotherapy for refractory IBCSpector
et al. ASCO 2006

• Most toxicity grade 1 or 2 skin or GI
• Biomarker analysis suggests
• Correlation of ErbB2 IHC 3/FISH positivity with
  response
• Responders more likely to be p-ErbB2 positive
• Coexpression of ILGF-R as well as PTEN deficiency
  does not appear to preclude response

43
Lapatinib monotherapy for IBCSpector et al. ASCO
2006

• Summary
• Lapatinib monotherapy clinically active in
  heavily pretreated IBC patients
• Well tolerated
• ErbB2 overexpression but not ErbB1 expression,
  predicts sensitivity to lapatinib in IBC.
• High ErbB2, p-ErbB2 predict for clinical response
  in this group of patients, illustrating selecting
  patients based on biology versus histology alone,
  to maximize clinical efficacy

44
Neoadjuvant paclitaxel and lapatinib for newly
diagnosed IBCCristofanilli et al. SABC 2006
Breast Cancer Res Treat 2006

• lapatinib 1500 mg/day
  paclitaxel 80 mg/m2/weekly x 12 weeks

45
Lapatinib First-line Treatment in Metastatic
Breast Cancer

• Locally advanced/metastatic
• Randomized 500 mg bid or 1500 mg qd
• No grade 3 or 4 toxicity
• ORR 24
• 6 month PFS 43
• No difference in efficacy or toxicity between the
  two groups
• Stein SH et
  al. Eur J Cancer 2005 3 (supp) 78
• Gomez et al.
  JCO 2005 23 (16 supp)
• Gomez et al.
  Breast Cancer Res Treat 2006 100 (supp1)S69
  (abstract 1090)

46
Cardiac function in 2,812 patients treated with
lapatinibPerez et. al ASCO 2006

• Evaluated 2,812 patients treated with lapatinib
  in 18 phase I-III clinical trials in breast
  cancer and other malignancies
• Methods LVEF monitored with ECHO/MUGA q8 wks
• Cardiac Risks Collected age, prior known
  cardiac disease, previous exposure to
  mediastinal/left-sided xrt
• Data Collected for LVEF if
• gt grade 3 toxicity
• gt 20 decline relative to baseline and below
  institutions lower limit of normal

47
Cardiac function in 2,812 patients treated with
lapatinibPerez et. al ASCO 2006

• 1.3 (37/2812) experienced decline LVEF
• 22/37 monotherapy 15/37 combination
• 68 female
• median age 59
• 68 within 9 weeks of initiating treatment
• 57 of cases resolved/improved
• 50 of cases resumed lapatinib
• Average duration of treatment 5 weeks
• (0.1) 4/37 patients were symptomatic
• 92 (34/37) had confounding factors (ie exposure
  to AC, XRT)
• Overall rarely symptomatic and generally
  reversible incidence lower than the incidence of
  asymptomatic LVEF decreases observed in the
  general population or those treated with
  trastuzumab.
• Lapatinib trials excluded patients with LFEF lt
  50 at baseline, thus potentially biasing the
  data.

48
Examples of Ongoing Trials

• Refractory Metastatic
• TrastuzumabLapatinib vs. Laptinib (Phase III)
• Lapatinib in brain metastases (Phase II)
• First-Line advanced
• PaclitaxelLapatinib vs. LapatinibPlacebo (Phase
  III)
• LetrozoleLapatinib vs. LetrozolePlacebo (Phase
  III)
• PaclitaxelTrastuzumabLapatinib vs.
  PaclitaxelTrastuzumbaPlacebo (Phase III)
• FulvestrantLapatinib vs. FulvestrantPlacebo
  (Phase III)

49
Examples of Ongoing Trials

• Adjuvant Setting
• BIG/NCCTG (N 8000)
• Trastuzumab (1 yr) vs. Lapatinib (1 yr) vs.
  TrastuzumabLapatinib (1 yr) vs. Sequential
  Trastuzumab -gt Lapatinib (1 yr)
• TEACH (N 3000)
• Lapatinib (1 yr) vs. Trastuzumab (1yr)

50
Conclusion

• Lapatinib effective in Her2 positive breast
  cancer
• Approved with capecitabine in metastatic patients
  refractory to anthracyclines, taxanes, herceptin
• Ongoing trials will provide more direction
• Adjuvant studies interesting
• oral
• ? brain penetration
• appears to have minimal cardiac toxicity

51
References

• Perez, E.A. et al. Results of an analysis of
  cardiac function in 2,812 patients treated with
  lapatinib. JCO 2006 24(18S) 583.
• Spector N.L. et al. EGF103009, a phase II trail
  of lapatinib monotherapy in patients with
  relapsed/refractory inflammatory breast cancer.
  JCO 2006 24 (18S) 502.
• Lin, N.U. et al. Phase II trial of lapatinib for
  brain metastases in patients with HER2 breast
  cancer. JCO 2006 24 (18S) 503.
• Moy, Beverly and Goss, Paul. Lapatinib Current
  Status and Future Directions in Breast Cancer.
  Oncologist 2006 11 1047-1057.
• Geyer, Charles et al. Lapatinib plus
  Capecitabine for HER2-Positive Advanced Breast
  Cancer. NEJM 2006 355 2733-43.
• Nahta, Rita et al. Molecular Mechanisms of
  Trastuzumab Resistance. Breast Cancer Research
  2006 8 215.
• Spector, Neil. Her2 therapy Small Molecule
  Her-2 tyrosine kinase inhibitors. Breast Cancer
  Research 2007, 9 205.