CARFILZOMIBIFM MARS 2015

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.

HN

NH

OHN

O

O

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N

O O

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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)

Clin Cancer Res 2009;15:7085

% 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

No neurotoxicity !!

- 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)

Siegel DS, et al. Blood. 2012;120(14):2817-2825.

Best Overall Responses (n = 257)

Siegel DS, et al. Blood. 2012;120(14):2817-2825.

Best Overall Responses (n = 257)

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.

Duration of response (CBR) : 8.3 months

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

Carfilzomib earlier in the course of the disease ?

Jakubowiak; Cancer Treatment Reviews 40 (2014) 781–790

Jakubowiak; Cancer Treatment Reviews 40 (2014) 781–790

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

0 10 20 30

Time (in months)

0.0

0.2

0.4

0.6

0.8

1.0

Kapla

n-Meie

r Esti

mate

Clarion phase 3

Randomized

Frontline elderly Carfil-MP vs VMP