Title: New optimism for patients with cancer
1New optimism for patients with cancer
- As cancer therapy evolves, new regimens and novel
agents that target specific cellular processes
allow a more optimistic prognosis for many
patients - Bortezomib and tipifarnib are two new targeted
treatments for hematologic malignancies
2Bortezomib
- A proteasome inhibitor
- Has shown good efficacy as a single agent and in
combination in patients - with relapsed multiple myeloma
- as initial treatment, including prior to
autologous stem cell transplantation - Has been studied as monotherapy and in
combination with standard treatments, such as
dexamethasone, chemotherapy, and with newer
agents such as the IMiDs, thalidomide and
lenalidomide - Is well-tolerated, including in combination
3Clinical course of multiple myeloma
Survival (years)
0
5
1
2
3
4
Diagnosis to death
34 years
- Relapsed disease
- Transient response to therapy
12 years
- Relapsed and refractory
- Resistant to all therapy
- Universally fatal
69 months
4Bortezomib a potent first-in-class proteasome
inhibitor
Dipeptidyl boronic acidderivative
Cross-section of b-ring
(reversible inhibitor of chymotryptic active site
of proteasome ? subunit)
Janssen-Cilag 2003
5Bortezomib
6Summary of bortezomib data in relapsed/refractory
MM
1. Abstracts in Blood 2005106 (ASH 2005) 2.
Blood 2005105305865
7Response to bortezomib by prognostic factor and
line of treatment
gt1 prior treatment and MM refractory to prior
treatment resulted in lower responses to
bortezomib
Richardson et al. ASCO 2005 Sonneveld et al. IMW
10, Sydney, 2005
8Bortezomib higher response rates in second-line
therapy than later therapy
CR
nCR
PR
100
P0.0035
80
Plt0.0001
60
Proportion of patients ()
45
40
34
26
32
20
13
21
0.5 nCR
23
6
7
13
0
6
2
6
Bortezomib
Dex
Bortezomib
Dex
1 prior line of therapy
gt1 prior line of therapy
Sonneveld et al. IMW 10, Sydney, 2005
9Single-agent bortezomib active in newly
diagnosed MM
- Well tolerated safety profile similar to
previous studies - Neuropathy frequently prevalent at baseline
- Stem cells successfully harvested from 13
patients 12 received transplants
Richardson et al. Blood 2004104100a (abstract
336)Jagannath et al. Haematologica 200590(Suppl
1)148 (abstract P0.725)
10Bortezomib dexamethasone in newly diagnosed MM
-
Data available for 46/52 patients - Stem cell collection adequate for all patients
(median CD34 cells 6.7 x 106/kg range 233)
median 2 collections required (range 14) - Well tolerated AEs mainly grade 1/2
- PN 6 grade 3, 8 grade 2
- 1 grade 4 GI
- Results form basis for IFM Phase III trial of
bortezomib Dex vs VAD
Harousseau et al. Haematologica 200590(Suppl
1)148(abstract P0.724)
11Bortezomib combination protocols in previously
untreated patients
VEL Bortezomib VELCADE 1. Abstracts in
Blood 2005106 (ASH 2005) 2. Abstract in Blood
2004104 (ASH 2004)
12MPV response rates (n53)Analysis of best
response achieved so far
1st cycle MPV
Best response median 3 cycles
Mateos et al. Blood 2005106 (Abs 786) ASH 2005
13Adverse events from APEX (all patients)
Deaths within 30 days after last dose 69 of
310 patients on bortezomib reported symptoms of
PN at baseline
SUMMIT/CREST PN grade 3, 13
Thrombocytopenia grade 3, 30
Richardson et al. N Engl J Med 2005352248798
14Tipifarnib
- A specific inhibitor of farnesyltransferase
- Clinical trials in patients with high-risk acute
leukemias and myelodysplastic syndromes have
demonstrated good efficacy with tipifarnib, even
in patients with poor prognosis and elderly,
poor-risk patients
15Tipifarnibtargeted farnesyltransferase inhibitor
- Oral formulation
- Potent and selective inhibitor of farnesylation
- Key enzyme involved in multiple tumor-promoting
pathways - Essential for the functioning of signal
transduction cascades associated with cell
proliferation - Potent inhibitor of malignant cell line
proliferation
16Farnesyltransferase
- Key enzyme in many pathways
- Farnesylated proteins
- Ras (H-, K-, N-)
- Rho (B,E)
- Lamins (A, B)
- Centromere-binding proteins
-
-
Blocking FTase has therapeutic potential
17Phase II trial of tipifarnib efficacy
Response confirmed ?28 days after initial response
Relapsed Refractory Total
(n135)
(n117)
(n252)
CR 7 (5) 4 (3) 11 (4) Confirmed
CR 2 (1) 1 (1) 3 (1) SD (gt8
weeks) 8 (6) 5 (4) 13
(5) Total 15 (11) 9 (8) 24 (10)
Harousseau et al. Presented at ASH 2003
18Targeted therapy
- Is among the most exciting new development in
cancer treatment - Specifically attacks the malignancy for improved
efficacy and overall safety - Underscores an important shift in the treatment
paradigm for multiple myeloma and other
hematologic malignancies a shift from
empirical chemotherapeutic regimens with
significant side effects towards rational,
targeted, effective therapies with improved
tolerability