02 Verma Treatment Duration444444444.ppt

treatment

1. Treatment duration
in HER2-positive breast cancer:
when to stop?
Shail Verma
Ottawa Regional Cancer Centre
Ottawa, Canada

2. Duration of anticancer therapy:
current understanding of known agents
Adjuvant
–randomised controlled trials of hormonal therapy
(e.g. tamoxifen 10 vs 5 years)
–randomised controlled trials of chemotherapy
(e.g. CMF 12 vs 6 cycles, 6 vs 3 cycles)
Metastatic
–defined by progression (e.g. hormonal agents)
–defined by progression and toxicity
(e.g. anthracyclines – cardiotoxicity; taxanes –
neuro, oedema, fatigue)
Patient preference

3. Current knowledge on
HER2-targeted therapy
Overexpression of HER2 is an early event in the
development of breast cancer and is maintained
throughout the course of the disease
HER2 signalling plays an important role in tumour
development/growth and is associated with high risk
and poor prognosis
The (pre-clinically) proven synergies of Herceptin
®

with various chemotherapeutic agents provides
rationale for different approaches to the disease

4. Herceptin
®
randomised clinical trials:
efficacy
CR
PR
H0648g (paclitaxel subgroup)
Slamon et al, 2001*
M77001
Extra et al, 2003
TTP = 6.9 months
TTP = 10.6 months
*All patients
60
50
40
30
20
10
0
P
a
t
i
e
n
t
s

(
%
)
7
54
8
34

5. Treatment duration
Treatment until progression is the basis of clinical
trials and has provided data showing significant
patient benefit
There have been tremendous advances in the
treatment of metastatic breast cancer but
residual/progressive disease remains a problem to
contend with

6. Continuous suppression of HER2
signalling helps control tumour growth
Pietras R, et al. Oncogene 1998;17:2235–49
2,000
1,500
1,000
500
0
Treatment day
0 10 20 30 40 50 60 70
Control
Herceptin
®
T
u
m
o
u
r

v
o
l
u
m
e

(
m
m
3)
Herceptin
®
withdrawn

7. Current knowledge on
HER2-targeted therapy: resistance
Resistance?
–clinical
–cellular
Level IV/V evidence
–anecdotal reports of responses to different
schedules and doses
–responses to rechallenge
Resistance to Herceptin
®
, cytotoxics or both?
Immunological phenomenon?

8. Emerging issues regarding
HER2-targeted therapy
ECD/serum HER2 measures correlate
with response?
1
Does treatment induce alterations in
HER2 expression?
2,3
1
Ghani F, et al. Proc Am Soc Clin Oncol 2003;22:32 (Abstract 129)
2
Dowsett M, et al. Proc Am Soc Clin Oncol 2003;22:3 (Abstract 7)
3
Lipton A, et al. Proc Am Soc Clin Oncol 2003;22:3 (Abstract 8)

9. The safety profile of Herceptin
®
enables
long-term administration
Adverse events commonly associated with
chemotherapy are rare with Herceptin
®
Most frequent side effects are infusion-related, seen
with initial doses and rarely thereafter
No evidence of cumulative toxicity
Clinically significant side effects of Herceptin
®
can be
managed using supportive standard therapy
Cook-Bruns N. Oncology 2001;61(Suppl. 2):58–66

10. Hypotheses on duration of
HER2-targeted therapy
HER2-positive disease should always be treated
with Herceptin
®
, at least until progression
There is a good rationale that treatment beyond
progression provides further benefit to
these patients

11. Herceptin
®
beyond progression:
current data and ongoing prospective trial
Extension study of patients treated in the pivotal trial
by Slamon et al
1,2
Two retrospective analyses of patients who received
multiple lines of Herceptin
®

–multinational study of 105 patients
3
–a Greek multicentre review of 80 patients
4

Prospective trial started in Q3/2003 comparing
single-agent Xeloda
®
versus Xeloda
®
plus Herceptin
®

in patients progressing after Herceptin
®
1
Slamon D, et al. N Engl J Med 2001;344:783–92
2
Tripathy D, et al. Breast Cancer Res Treat 2000;64:32 (Abstract 25)
3
Gelmon K, et al. Clin Breast Cancer 2004. In press
4
Fountzilas G, et al. Clin Breast Cancer 2003;4:120–5

12. Herceptin
®
beyond progression:
extension study
235 out of 469 patients in the pivotal trial of Slamon
et al., were treated with Herceptin
®
plus chemotherapy
(AC or paclitaxel)
93 of these 235 patients participated in an
extension study after progression on Herceptin
®

plus chemotherapy
1
Herceptin
®
retreatment consisted of
–Herceptin
®
plus chemotherapy – 76% of patients
(paclitaxel, vinorelbine, docetaxel, 5-FU)
–Herceptin
®
monotherapy – 24% of patients
1
Tripathy D, et al. Breast Cancer Res Treat 2000;64:32 (Abstract 25)

13. Herceptin
®
beyond progression:
extension study (cont’d)
Efficacy (subsequent treatments)
–overall response rate = 11%
–clinical benefit rate = 22%
–duration of response = 6.7 months
Safety (subsequent treatments)
–occurrence of adverse events similar to
pivotal trial
–cardiac dysfunction in 2% (1 symptomatic case)
Tripathy D, et al. Breast Cancer Res Treat 2000;64:32 (Abstract 25)

14. Herceptin
®
beyond progression:
retrospective review
Multinational study of 105 patients
–retrospective case analysis of patients having
had at least two Herceptin
®
-containing regimens
for MBC
–treatment in 13 centres
–HER2 IHC 3+ and/or FISH+ in 89/105 cases
Gelmon K et al. Clin Breast Cancer 2004. In press

15. Herceptin
®
regimens administered
beyond progression
No. of patients
Agent 1st regimen 2nd regimen
None 27 11
Taxane 50 21
Vinorelbine 2 33
Other 26 38

Gelmon K, et al. Clin Breast Cancer 2004. In press

16. Response rates to Herceptin
®
treatment
beyond progression
Gelmon K, et al. Clin Breast Cancer 2004. In press
Similar response rates to the first and second Herceptin
®
treatment
45
40
35
30
25
20
15
10
5
0
Monotherapy Plus taxane
Plus vinorelbine Total
O
b
j
e
c
t
i
v
e

r
e
s
p
o
n
s
e

(
C
R
+
P
R
)
(
%

o
f

p
a
t
i
e
n
t
s
)
1st regimen 2nd regimen
(Herceptin
®
retreatment)
ND

17. Median time to progression (TTP)
weeks (range)
Regimen n 1st regimen n 2nd regimen
Herceptin
®
monotherapy 27 23 (3–73) 10 30.5 (18–68)
Herceptin
®
+ taxane 45 24 (0–79) 20 24 (3–72)
Herceptin
®
+ vinorelbine – – 33 26 (3–108)

Time to progression:
first and second Herceptin
®
regimen
Median survival from initiation of the first Herceptin
®
regimen was 29.0 months (95% CI: 22.7–56.0)
Gelmon K, et al. Clin Breast Cancer 2004. In press

18. Herceptin
®
beyond progression:
retrospective review
Greek multicentre review of 80 patients
–retrospective case analysis of patients having
received multiple lines of Herceptin
®
treatment in
four centres
–no exclusion for previous chemotherapy,
radiotherapy, or hormonal treatment
–HER2 IHC 3+ in 91% of the cases
Fountzilas G et al. Clin Breast Cancer 2003;4:120–5

19. Herceptin
®


regimen
No. of
patients
ORR
(CR+PR)

SD
Median TTP
(months) (range)
Second 80 19 (24%) 22 (28%) 5.2 (0.5–1.7)
Third 49 7 (14%) 12 (24%) 3.5 (0–18.3)
Fourth 26 5 (19%) 8 (31%) 4.9 (0.3–21.8)
Fifth 12 1 (8%) 3 (25%) 3.9 (0.3–12.5)
Sixth 2 – – 0.8 (0.5–16.8)
Seventh 1 – – 1.1 (0.8–6.3)

Comparable responses seen for at least three subsequent
Herceptin
®
regimens after progression on the first Herceptin
®
treatment
Response rates to Herceptin
®
treatment
beyond progression
Fountzilas G et al. Clin Breast Cancer 2003;4:120–5

20. Patients may respond repeatedly to Herceptin
®
-

containing regimens
–a third of the patients responding to an initial Herceptin
®

regimen had a second response to a subsequent
Herceptin
®
regimen
1
Patients who fail a Herceptin
®
-containing regimen can
respond to a subsequent Herceptin
®
regimen
–nine of 21 patients who responded to the second had
not responded to the first Herceptin
®
regimen
1
–in the study by Fountzilas et al.,

four patients who
progressed during second therapy responded to
further regimens
2

Herceptin
®
beyond disease progression:
additional findings
1
Gelmon K, et al. Clin Breast Cancer 2004. In press
2
Fountzilas G, et al. Clin Breast Cancer 2003;4:120–5

21. Retrospective studies of Herceptin
®

beyond disease progression: summary
Responses to the second and subsequent
Herceptin
®
regimens demonstrate Herceptin
®
activity
beyond progression
Changing concomitant chemotherapy while
continuing Herceptin
®
may be an effective approach
Herceptin
®
treatment beyond progression is feasible
and well tolerated
randomised studies are needed to clarify the role of
Herceptin
®
treatment beyond progression

22. Herceptin
®
beyond progression:
prospective study (MO17038)
Randomised multinational trial
438 patients planned; >60 centres (Germany, Austria)
Recruitment started in Q4/2003
Patients who have progressed on
Herceptin
®
+ taxane (n=438)
Herceptin
®

8mg/kg loading  6mg/kg q3w
+ Xeloda
®

2,500mg/m
2
days 1–14 q3w
until PD
Xeloda
®

2,500mg/m
2
days 1–14 q3w
until PD
(n=219) (n=219)

23. Treatment duration in HER2-positive
breast cancer: when to stop?
Herceptin
®
should at least be administered until
disease progression
–shown to improve survival
–well tolerated in general
–no evidence of cumulative toxicity
Retrospective studies suggest efficacy for Herceptin
®

beyond disease progression
–treatment beyond progression is feasible, but still an
open question
–responses were seen in subsequent Herceptin
®
regimens after
initial responses as well as in prior treatment failures
–duration of treatment with Herceptin
®
is being addressed in a
randomised prospective study