new optimism for patients with cancer n as cancer therapy evolves, new regimens and novel agents...
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New optimism for patients with New optimism for patients with cancer cancer
As cancer therapy evolves, new regimens As cancer therapy evolves, new regimens and novel agents that target specific and novel agents that target specific cellular processes allow a more optimistic cellular processes allow a more optimistic prognosis for many patientsprognosis for many patients
Bortezomib and tipifarnib are two new Bortezomib and tipifarnib are two new targeted treatments for hematologic targeted treatments for hematologic malignancies malignancies
BortezomibBortezomib
A proteasome inhibitorA proteasome inhibitor
Has shown good efficacy as a single agent and in Has shown good efficacy as a single agent and in combination in patientscombination in patients
– with relapsed multiple myelomawith relapsed multiple myeloma
– as initial treatment, including prior to autologous as initial treatment, including prior to autologous stem cell transplantationstem cell transplantation
Has been studied as monotherapy and in combination Has been studied as monotherapy and in combination with standard treatments, such as dexamethasone, with standard treatments, such as dexamethasone, chemotherapy, and with newer agents such as the IMiDs, chemotherapy, and with newer agents such as the IMiDs, thalidomide and lenalidomide thalidomide and lenalidomide
Is well-tolerated, including in combination Is well-tolerated, including in combination
Diagnosis to death
Relapsed disease• Transient response
to therapy
Relapsed and refractory• Resistant to all therapy• Universally fatal
Survival (years)
1–2 years
3–4 years
0 51 2 3 4
6–9 months
Clinical course of multiple myelomaClinical course of multiple myeloma
Janssen-Cilag 2003
Dipeptidyl boronic acidDipeptidyl boronic acidderivativederivative
(reversible inhibitor of chymotryptic active site (reversible inhibitor of chymotryptic active site of proteasome of proteasome subunit) subunit)
2
Chymo-tryptic
site
Post-glutamyl
site
Trypticsite
1
33
44
5
66
77
Bortezomib
Cross-section of Cross-section of -ring-ring
H N B
N H
O
O
OHN
N
OH
Bortezomib: a potent first-in-class Bortezomib: a potent first-in-class proteasome inhibitorproteasome inhibitor
Bortezomib
X
X
X
Summary of bortezomib data Summary of bortezomib data in relapsed/refractory MMin relapsed/refractory MM
1. Abstracts in Blood 2005;106 (ASH 2005) 2. BloodBlood 2005;105:3058–65 2005;105:3058–65
RegimenRegimen PhasePhase nn CR + PRCR + PR CR + nCRCR + nCR ReferenceReference
Single-agent bortezomib Single-agent bortezomib (APEX)(APEX) IIIIII 331331 43%43% 16%16% Richardson Richardson
((2547254711))
+ low-dose IV melphalan+ low-dose IV melphalan I/III/II 2222 53%53% 5%5% Popat (2555Popat (255511))
+ oral cyclophosphamide+ oral cyclophosphamide IIII 5050 82%82% 12%12% Kropff (2549Kropff (254911))
+ steroids+ steroids IIII 3030 60%60% 6%6% Suvannasankha Suvannasankha (2562(256211))
+ pegylated + pegylated
liposomal doxorubicinliposomal doxorubicin II 4242 73%73% 36%36% OrlowskiOrlowski22
Response to bortezomib by Response to bortezomib by prognostic factor and line of treatmentprognostic factor and line of treatment
Richardson et al. ASCO 2005; Sonneveld et al. IMW 10, Sydney, 2005
n is shown by the number on each bar
CR+PR 45%
CR+PR 34%
>1 prior treatment and MM refractory to prior treatment resulted in lower responses to bortezomib
Bortezomib: higher response rates in Bortezomib: higher response rates in second-line therapy than later therapysecond-line therapy than later therapy
1 prior line of therapy1 prior line of therapy >1 prior line of therapy>1 prior line of therapy
Pro
po
rtio
n o
f p
atie
nts
(%
)
6 2 6
6 7
32
23
21
13
0
2020
4040
6060
8080
100100
BortezomibBortezomib DexDex BortezomibBortezomib DexDex
4545
2626
PP=0.0035=0.0035
3434
1313
PP<0.0001<0.0001
0.5 nCR0.5 nCR
CRCR nCRnCR PRPR
Sonneveld et al. IMW 10, Sydney, 2005
Single-agent bortezomib active in Single-agent bortezomib active in newly diagnosed MMnewly diagnosed MM
Well tolerated: safety profile similar to previous studies Well tolerated: safety profile similar to previous studies – Neuropathy frequently prevalent at baselineNeuropathy frequently prevalent at baseline
*Stem cells successfully harvested from 13 patients: 12 received transplants*Stem cells successfully harvested from 13 patients: 12 received transplants
Richardson Richardson et alet al..
RR (CR+PR), n=28RR (CR+PR), n=28 45%45% (67% including MR) (67% including MR)
Jagannath Jagannath et alet al.*.*
RR (CR+nCR+PR)RR (CR+nCR+PR) (23 pts evaluable) (23 pts evaluable)
41%41% (after 2 cycles), 11% CR+nCR (after 2 cycles), 11% CR+nCR
85%85% (after addition of Dex), (after addition of Dex), 20% CR+nCR 20% CR+nCR
Richardson et al. Blood 2004;104:100a (abstract 336)Jagannath et al. Haematologica 2005;90(Suppl 1):148 (abstract P0.725)
Bortezomib + dexamethasone Bortezomib + dexamethasone in newly in newly diagnosed MMdiagnosed MM Data available for 46/52 patientsData available for 46/52 patients
Stem cell collection adequate for all patients (median CD34+ cells Stem cell collection adequate for all patients (median CD34+ cells 6.7 x 106.7 x 1066/kg; range 2–33); median 2 collections required (range 1–4) /kg; range 2–33); median 2 collections required (range 1–4)
Well tolerated: AEs mainly grade 1/2 Well tolerated: AEs mainly grade 1/2 – PN: 6% grade 3, 8% grade 2PN: 6% grade 3, 8% grade 2– 1 grade 4 GI1 grade 4 GI
Results form basis for IFM Phase III trial of bortezomib + Dex vs VADResults form basis for IFM Phase III trial of bortezomib + Dex vs VAD
After SCTAfter SCT
RR after 4 cyclesRR after 4 cycles 75% 75% (n=48)(n=48)
92%92%(n=42)(n=42)
CR + VGPRCR + VGPR 31%31% 52%52%
PRPR 35%35% 33%33%
MRMR 8%8% 7%7%
Harousseau et al. Haematologica 2005;90(Suppl 1):148(abstract P0.724)
Bortezomib combination protocols Bortezomib combination protocols
in previously untreated patientsin previously untreated patientsStudy Study NN RegimenRegimen CR/nCRCR/nCR CR+PRCR+PR ToxicityToxicity
Cavenagh Cavenagh (2554(255411)) 1919
PADPAD
VEL (1.0 mg/mVEL (1.0 mg/m22) + Adria + ) + Adria + Dex Dex → → SCTSCT
17%17% 89%89%
Gr 1-2 PN 16%, no Gr 3-4 PNGr 1-2 PN 16%, no Gr 3-4 PN6 Gr3 events: abnormal liver 6 Gr3 events: abnormal liver function; thrombocytopenia, function; thrombocytopenia, neutropenia, hyperglycemia, neutropenia, hyperglycemia, sepsis, anxietysepsis, anxiety
Harousseau Harousseau (1490(149022)) 4848
HD DexHD Dex
VEL + high dose Dex VEL + high dose Dex → → SCTSCT
21%21% 67%67% 1 Gr3 PN, others 1 Gr3 PN, others ≤ Gr2≤ Gr2
Wang (784Wang (78411)) 3636VTDVTD
VEL+ Thal + Dex VEL+ Thal + Dex → → SCTSCT31%31% 89%89%
Infection (3), orthostatic Infection (3), orthostatic hypotension (1), DVT (2) Gr 3 hypotension (1), DVT (2) Gr 3 PN (reversible) (3) PN (reversible) (3)
Barlogie (1154Barlogie (115411))162162
TT3TT3
VEL + DT-PACE VEL + DT-PACE →→ SCT x2 SCT x2 →→ VDT-PACE + VDT-PACE +
Thal dexThal dex
81%81%
at 12 at 12 mosmos
NANA6 treatment related deaths,6 treatment related deaths,Other toxicity not different Other toxicity not different from DT-PACEfrom DT-PACE
Mateos (786Mateos (78611)) 6060VMPVMP
VEL + M + P (Days 1 VEL + M + P (Days 1 – – 4)4)39%39% 85%85%
Gr 3-4: GI Gr 3-4: GI <<15%; PN 15%; 15%; PN 15%; anemia 12%, neutropenia anemia 12%, neutropenia 39%, thrombocytopenia 46%39%, thrombocytopenia 46%
*VEL: Bortezomib – VELCADE® 1. Abstracts in Blood 2005;106 (ASH 2005) 2. Abstract in Blood 2004;104 (ASH 2004)
MPV response rates (n=53)MPV response rates (n=53)Analysis of best response achieved so Analysis of best response achieved so farfar
1st cycle MPV
72%
0%
10%
20%
30%
40%
50%
60%
70%
CR IF- CRIF+ PR MR SD
6% 2%
64%
6%
24%
Best response: median 3 cycles
85%
28%
11%
45%
13%
0%
10%
20%
30%
40%
50%
60%
70%
CR IF- CR IF+ PR SDMateos et al. Blood 2005;106 (Abs 786) ASH 2005
Adverse events from APEX (all patients) Adverse events from APEX (all patients) Bortezomib(n=331) %
Dexamethasone (n=332) %
AEs ≥ grade 3 61 44
AEs grade 4 14 16
Serious AEs 44 43
PN* ≥ grade 3 8** 1
Thrombocytopenia ≥ grade 3 30** 6
Discontinuation due to AEs 37 29
Deaths on study† 14 (4%) 25 (8%)
Richardson et al. N Engl J Med 2005;352:2487–98
†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%
TipifarnibTipifarnib
A specific inhibitor of farnesyltransferaseA specific inhibitor of farnesyltransferase
Clinical trials in patients with high-risk Clinical trials in patients with high-risk acute leukemias and myelodysplastic acute leukemias and myelodysplastic syndromes have demonstrated good syndromes have demonstrated good efficacy with tipifarnib, even in patients efficacy with tipifarnib, even in patients with poor prognosis and elderly, poor-risk with poor prognosis and elderly, poor-risk patients patients
Tipifarnib:Tipifarnib:targeted farnesyltransferase inhibitortargeted farnesyltransferase inhibitor
Oral formulationOral formulation Potent and selective inhibitor of farnesylationPotent and selective inhibitor of farnesylation
– Key enzyme involved in multiple tumor-promoting pathwaysKey enzyme involved in multiple tumor-promoting pathways
– Essential for the functioning of signal transduction cascades Essential for the functioning of signal transduction cascades associated with cell proliferationassociated with cell proliferation
Potent inhibitor of malignant cell line proliferationPotent inhibitor of malignant cell line proliferation
NH2
Cl
N
Cl
ON N
FarnesyltransferaseFarnesyltransferase
Key enzyme in many pathwaysKey enzyme in many pathways
Farnesylated proteinsFarnesylated proteins Ras (H-, K-, N-)Ras (H-, K-, N-) Rho (B,E)Rho (B,E) Lamins (A, B)Lamins (A, B) Centromere-binding proteinsCentromere-binding proteins
Blocking FTase has therapeutic potentialBlocking FTase has therapeutic potential
Response confirmed Response confirmed 28 days after initial response28 days after initial response
CRCR 7 (5%) 4 (3%)7 (5%) 4 (3%) 11 (4%)11 (4%)
Confirmed CRConfirmed CR 2 (1%) 1 (1%) 2 (1%) 1 (1%) 3 (1%)3 (1%)
SD (>8 weeks)SD (>8 weeks) 8 (6%) 5 (4%)8 (6%) 5 (4%) 13 (5%)13 (5%)
TotalTotal 15 (11%) 9 (8%)15 (11%) 9 (8%) 24 (10%)24 (10%)
(n=135)(n=135) (n=117)(n=117)
RelapsedRelapsed RefractoryRefractory TotalTotal
(n=252)(n=252)
Phase II trial of tipifarnib: efficacyPhase II trial of tipifarnib: efficacy
Harousseau et al. Presented at ASH 2003
Targeted therapyTargeted 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