CARFILZOMIB IFM MARS 2015
Jan 01, 2016
Single-Agent Activities of 129 Drugs in MM Sorted by Best ResponseKortuem et al.Clin Lymphoma Myeloma Leuk. Author manuscript; available in PMC 2014 August 01.
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OHN
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Rationale for Clinical Development of Carfilzomib in Cancer
Demo SD Cancer Res. 2007; Kuhn DJ Blood. 2007; Kirk, CJ ASH 2008 (Abstract 2765); Arastu-Kapur ASH 2008 (Abstract 2657)
PeptideSelective for proteasome chymotrypsin-like activity
EpoxyketoneSpecific and irreversible
target inhibition
Selective Inhibition• Targets one subunit within the proteasome• Minimal inhibition of off-target proteases
Prolonged Inhibition• Irreversible mechanism → delays recovery• Consecutive day dosing with >80% maximum
inhibition
Overcomes Bortezomib Resistance• Tumor cell lines and myeloma cells in vitro• Human tumor xenograft models
Carfilzomib (CFZ)
Duration of Proteasome Inhibition
In Vitro(HT-29 tumor cell line)
0 4 8 120
20
40
60
80
100
BTZ
CFZ
Time (hr)
Pro
tea
so
me
Ac
tiv
ity
(% o
f c
on
tro
l)
In Vivo(rat/mouse adrenal)
0 24 48 720
20
40
60
80
100BTZ
(D1/D4)
CFZ(D1/D2)
Time (hr)
% p
rote
as
om
e i
nh
ibit
ion
D8 D9
0
Week:
D15 D16
1 2 3
28-daycycle
80
D1 D2
Rest period (12 days)
4
Carfilzomib in relapsed multiple myeloma
• 20 mg/m2 IV push cycle 1 D1 and 2• 27 mg/m2 IV push cycle 1 (D8) – cycle 12
- Progressive disease required at study entry
- Relapsed from ≥ 2 prior lines of therapy Must include BTZ Must include THAL or LEN
- Refractory to last regimen
Siegel DS, et al. Blood. 2012;120(14):2817-2825.
Baseline Demographics and Clinical Characteristics (N = 266)
Overall survival in response-evaluable patients (n = 257) treated with single-agent carfilzomib
Overall Survival
Siegel DS, et al. Blood. 2012;120(14):2817-2825.
Carfilzomib is approved in US
On July 20, 2012, FDA granted accelerated approval to carfilzomib injection, for the treatment of patients with Multiple Myeloma
who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent,
and have demonstrated disease progression on or within 60 days of the completion of the last therapy.
FOCUS phase 3
Randomized
Relapsed / refractory MM
Progression on last therapy
Prior exposure to IMids, bortezomib
Carfilzomib Days1,2,8,9,15,16 : 27mg/m2
vs Best Supportive Care
28
Carfilzomib, Lenalidomide, and Dexamethasone vs Lenalidomide and
Dexamethasone in Patients withRelapsed Multiple Myeloma:
Interim Results from ASPIRE, a Randomized, Open-Label, Multicenter
Phase 3 Study
A. Keith Stewart, S. Vincent Rajkumar, Meletios A. Dimopoulos, Tamás Masszi, Ivan Spicka, Albert Oriol, Roman Hájek, Laura Rosiñol, David S. Siegel, Georgi G. Mihaylov, Vesselina Goranova-Marinova, Péter Rajnics, Aleksandr Suvorov, Ruben Niesvizky, Andrzej Jakubowiak, Jesus F. San Miguel, Heinz Ludwig, Naseem Zojwalla, Margaret E. Tonda, Biao Xing,
Philippe Moreau and Antonio Palumbo
ASPIRE Study Design
29
RdLenalidomide 25 mg Days 1–21
Dexamethasone 40 mg Days 1, 8, 15, 22
KRdCarfilzomib 27 mg/m2 IV (10 min)
Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)
Lenalidomide 25 mg Days 1–21
Dexamethasone 40 mg Days 1, 8, 15, 22
Randomization
N=792
Stratification:
•β2-microglobulin
•Prior bortezomib
•Prior lenalidomide
After cycle 12, carfilzomib given on days 1, 2, 15, 16
After cycle 18, carfilzomib discontinued
28-day cycles
Patient and Disease Characteristics at BaselineIntent-to-Treat (ITT) Population (N=792)
30
CharacteristicKRd
(n=396)
Rd
(n=396)
Median age, years (range)
≥65 years, %
64 (38–87)
46.7
65 (31–91)
52.5
ECOG performance status, %
0–1
2
89.9
10.1
91.2
8.8
Cytogenetic risk category by FISH, %
High
Standard
Unknown
12.1
37.1
50.8
13.1
42.9
43.9
Mean creatinine clearance, mL/min (SD)
≥50 mL/min, %
85.0 (28.9)
93.4
85.9 (30.2)
90.4
Serum β2-microglobulin
≥2.5 mg/L, % 80.6 80.6
ECOG, Eastern Cooperative Oncology Group; FISH, fluorescence in situ hybridization; SD, standard deviation.
Patient and Disease Characteristics at Baseline (continued)ITT Population (N=792)
31
CharacteristicKRd
(n=396)
Rd
(n=396)
Presence of neuropathy at baseline, % 36.4 34.6
Number of prior regimens, median (range) 2 (1–3) 2 (1–3)
Prior therapies, %
Transplant
Bortezomib
Non-responsive to prior bortezomib*
Lenalidomide
Any IMiD
Refractory to prior IMiD in any prior regimen
Bortezomib and IMiD
Non-responsive to prior bortezomib* and refractory to prior IMiD
54.8
65.9
15.2
19.9
58.8
21.5
36.9
6.1
57.8
65.7
14.6
19.7
57.8
22.2
35.1
6.8
*Non-responsive is defined as less-than-minimal response to any bortezomib-containing regimen, disease progression during any bortezomib-containing regimen, or disease progression within 60 days after the completion of any bortezomib-containing regimen.
Primary Endpoint: Progression-Free SurvivalITT Population (N=792)
32
1.0
0.8
0.6
0.4
0.2
0.0
Pro
port
ion
Sur
vivi
ngW
ithou
t P
rogr
essi
on
KRdRd
0 6 12 18 24 30 36 42 48Months Since Randomization
KRd Rd(n=396) (n=396)
Median PFS, mo 26.3 17.6HR (KRd/Rd) (95% CI) 0.69 (0.57–0.83)P value (one-sided) <0.0001
No. at Risk:KRd
Rd396 332 279 222 179 112 24 1396 287 206 151 117 72 18 1
Primary Endpoint: Progression-Free Survival by Subgroup
33
KRd RdIntent-to-treat group (n) (n) Overall 396 396Subgroup Age, years 18–64 211 188 ≥65 185 208 Risk group by FISH High-risk 48 52 Standard-risk 147 170 ß2-microglobulin, mg/L
<2.5 68 71 ≥2.5 324 319 Prior treatment with bortezomib No 135 136 Yes 261 260 Prior treatment with lenalidomide No 317 318 Yes 79 78 Non-responsive to bortezomib in any prior regimen No 336 338 Yes 60 58 Refractory to IMiD in any prior regimen No 311 308 Yes 85 88
HR (95% CI)
HR1.000.750.500.25 1.25 1.50 1.75
Favors RdFavors KRd
PFS by Risk Group
34
KRd(n=396)
Rd(n=396)
Risk Group by FISH
NMedian, months
NMedian, months
HRP-value
(one-sided)
High 48 23.1 52 13.9 0.70 0.083
PFS by Risk Group
35
KRd(n=396)
Rd(n=396)
Risk Group by FISH
NMedian, months
NMedian, months
HRP-value
(one-sided)
High 48 23.1 52 13.9 0.70 0.083
Standard 147 29.6 170 19.5 0.66 0.004
Secondary Endpoints: Response
36
P<.0001
P<.0001
sCR 14.1% vs 4.3%
P<.0001
Median duration of response was 28.6 months in the KRd group and 21.2 months in
the Rd group
Secondary Endpoints: Interim Overall Survival AnalysisMedian Follow-Up 32 Months
37
Median OS was not reached; results did not cross the prespecified stopping
boundary (P=0.005) at the interim analysis
1.0
0.8
0.6
0.4
0.2
0.0
Pro
port
ion
Sur
vivi
ng
KRdRd
0 6 12 18 24 30 36 42 48
Months Since Randomization
KRd Rd(n=396) (n=396)
Median OS, mo NE NEHR (KRd/Rd) (95% CI) 0.79 (0.63–0.99)P value (one-sided) 0.018
No. at Risk:KRd
Rd396 369 343 315 280 191 52 2396 356 313 281 237 144 39 3
Adverse Events (AEs), Treatment Discontinuations, and DeathsSafety Population (n=781)
38
CategoryKRd
(n=392)
Rd
(n=389)
Median treatment duration, weeks (range) 88.0 57.0
Any AE, %
Grade ≥3 treatment-emergent AE
96.9
83.7
97.2
80.7
Treatment discontinuations, %
Discontinuation due to disease progression
Discontinuation due to AE
69.9
39.8
15.3
77.9
50.1
17.7
Serious AE, % 59.7 53.7
Deaths within 30 days of last dose, %
Deaths due to disease progression
Deaths due to AEs
7.7
0.5
6.9
8.5
1.3
6.9
Other AEs of InterestSafety Population (n=781)
39
AE, %KRd (n=392) Rd (n=389)
All Grade Grade ≥3 All Grade Grade ≥3
Dyspnea 19.4 2.8 14.9 1.8
Peripheral neuropathy* 17.1 2.6 17.0 3.1
Hypertension 14.3 4.3 6.9 1.8
Acute renal failure* 8.4 3.3 7.2 3.1
Cardiac failure* 6.4 3.8 4.1 1.8
Deep vein thrombosis 6.6 1.8 3.9 1.0
Ischemic heart disease* 5.9 3.3 4.6 2.1
Pulmonary embolism 3.6 3.1 2.3 2.3
Second primary malignancy* 2.8 2.3 3.3 2.8
*Grouped term.
Health-Related Quality-of-Life
40
EORTC Global Health Status improved in the KRd group vs the Rd group over 18 cycles of treatment (P=0.0001)
70
65
60
55
50
EORT
C Q
LQ-C
30 G
loba
l Hea
lth S
tatu
s/Q
ualit
y-of
-Life
Sco
re
Cycle 1(Baseline) Assessment Time Point (Day 1)
Carfilzomib group
Control group
Cycle 3 Cycle 6 Cycle 12 Cycle 18
Endeavour phase 3
RandomizedRelapsed / refractory MM (1-3 prior lines of therapy)
Bortezomib-dex vs carfilzomib (56 mg/m2)-dex
Until progression
PFS : 18 vs 9 months
Champion / Arrow
Escalade de dose weekly carfil-dex
70 mg/m2
Phase 3 randomisée :
Kd weekly 70 vs Kd biweekly selon endeavor
Effect of CMP, Carfilzomib (CFZ) plus Melphalan – Prednisone (MP), on response rates in elderly
patients with newly diagnosed multiple myeloma:results of a phase I/II trial
Cyrille Touzeau, Brigitte Kolb, Cyrille Hulin, Denis Caillot, Lofti Benboubker, Mourad Tiab, Xavier Leleu, Murielle Roussel, Carine Chateleix, Michel Attal, Thierry Facon, Philippe Moreau
Abstract # 8513
- MELPHALAN (oral) : D1 to D4 : 9 mg /m2/day
- PREDNISONE (oral) : D1 to D4 : 60mg /m2/day
- CARFILZOMIB (30 min-IV)
C1 -> D1-2: 20 mg/m²/day -> D8-9, 22-23, 29-30: 20 or 27 or 36 or 45 mg/m²/day (cohort 1, 2, 3, or 4)
C2 to C9 -> D1-2, 8-9, 22-23, 29-D30: 20 or 27 or 36 or 45 mg/m²/day (cohort 1, 2, 3, or 4)
9 cycles
CFZ – MP : study design
-> ORR : 91%-> At least VGPR : 56%
RESPONSE RATES (66 patients)
Best Response Patients n (%)
CR 4 (6%)
VGPR 33 (50%)
PR 23 (35%)
SD 6 (9%)
PD 0
median number of cycles = 7 (1-9)21 patients (31%) still on therapy