carfilzomib

1. Carfilzomib
Dr. Govind Kendre
Seth G.S. medical college& KEM hospital,
Parel, Mumbai

2. Need for Novel Drugs for Relapsed Multiple Myeloma
 Despite advances, myeloma remains an incurable disease with nearly all patients
experiencing relapse and progression in spite of salvage therapy
 Tumours typically recur more aggressively after each relapse, leading to decreased
duration of response & ultimately culminating in the development of treatment-
refractory disease
 Relapsed-refractory disease is associated with shortened survival times (median OS
of 9 months)
 Therapeutic options for patients with advanced stage disease, including those
relapsed after multiple prior lines of therapy and those with refractory disease, are
limited and lead to significant toxicity and transient responses
 There is thus a need for newer agents for relapsed-refractory multiple myeloma with
improved response rates and depth of responses for better outcomes
8/25/2017 2

3. Multiple Myeloma –
Relapsing Disease with poor outcomes in Relapsed/Refractory MyelomaM-ProteinLevel
MGUS or Indolent
Myeloma
Active
Myeloma
Remission
Relapse
Frontline
Therapy
Second- or Third-Line
Therapy
Remission duration decreases
with each line of therapy
//
//
Asymptomatic Symptomatic Relapsing Refractory
Frontline
Treatment
Relapsed Myeloma Relapsed/Refractory
Myeloma
Expected Survival (Months) 20 – 50 14 – 16 6 – 10
Sensitivity to Therapy Sensitive Less Sensitive/Resistant Resistant
Treatment Limitations/Co-
morbidities
Peripheral
Neuropathy (~15%
at diagnosis)
>80% incidence of peripheral
neuropathy
Compromised marrow reserve
Intolerant to or
ineligible for
available therapy

4. Improvement in Survival in MM
Melphalan
1958
Corticosteroids
1962 2015
Elotuzumab
Daratumumab
Panobinostat
Ixazomib
Pomalidomide
Carfilzomib
2012 2013
Bortezomib
Lenalidomide
2002
ASCT
Thalidomide
19991983
Median OS
<12mo
1971-1998 2001-2005 2006-2011 2015-
?
29.9mo
64mo
72mo
1958
48/25/2017

5. Carfilzomib
8/25/2017 5

6. Carfilzomib
• Carfilzomib is a next-generation selective,
irreversible, proteasome inhibitor
• Carfilzomib acts by 20S Proteosome
inhibition
8/25/2017 6

7. SITE OF ACTION
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8. 8/25/2017 8

9. Mechanism of action
8/25/2017 9

10. Indications
Carfilzomib is indicated
In combination with
dexamethasone
for the treatment of patients
with relapsed or refractory
multiple myeloma who have
received one to three lines
of therapy
In combination with
lenalidomide plus
dexamethasone
for the treatment of patients
with relapsed or refractory
multiple myeloma who have
received one to three lines
of therapy
As a single agent
for the treatment of
patients with relapsed or
refractory multiple myeloma
who have received one or
more lines of therapy
8/25/2017 10

11. Carfilzomib: Administration
Carfilzomib 28-Day Cycle
1 2 3 4 5 6 7
8 9 10 11 12 13 14
15 16 17 18 19 20 21
22 23 24 25 26 27 28
Cycle 1: 20 mg/m2
Cycle 2+: 27 mg/m2 or 56 mg/m2
Pt Education
 Instruct pts to monitor and report symptoms
(eg, dyspnea, fatigue, anemia,
thrombocytopenia, TLS)
 Teach pt measures to prevent infection.
Administration: IV over 10 or 30 mins based on dose
‒ Approved for 2 consecutive days/wk for 3 wks but multiple
studies give weekly dosing (ensure adherence to treatment
schedule)
Premedication: 4-mg dexamethasone before each dose
Hydration: 250-500 mL IV saline before carfilzomib for all doses
in cycle 1 and in subsequent cycles (monitor for fluid overload)
Prophylaxis: decrease risk of herpes zoster reactivation with
acyclovir
Monitor: signs of infection, blood counts (renal, liver function),
TLS (consider uric acid–lowering drugs); cardiac eval: to prevent
new onset or worsening of preexisting cardiac failure (eg, CHF,
pulmonary edema, decreased ejection fraction) Patients With
Renal Impairment :No starting dose adjustment is required in patients
with baseline mild, moderate, or severe renal impairment or patients on
chronic dialysis. Since dialysis clearance of KYPROLIS® (carfilzomib)
concentrations has not been studied, the drug should be administered
after the dialysis procedure
Contraindication:Carfilzomib should not be administered during
pregnancy or breast feeding
8/25/2017 11

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13. 8/25/2017 13

14. 8/25/2017 14

15. PX-171-003-A01
(Phase II)
PX-171-003-A12
(Phase II)
PX-171-0043
Cohort 1
(Phase II)
Patient population
Relapsed/refractory
(≥2 prior therapies including
BTZ + IMiD)
Relapsed/refractory
(99.6% prior BTZ)
Relapsed/refractory
(1-3 prior therapies, including
BTZ)
N
46
(42 evaluable for efficacy)
266
(257 evaluable for efficacy) 35
Treatment arms CFZ 20 mg/m2 CFZ 20/27 mg/m2 CFZ 20 mg/m2
Primary endpoint ORR: 16.7% ORR: 23.7% ORR: 17.1%
Carfilzomib—Key Clinical Trials in Relapsed/Refractory MM Patients with
Prior Bortezomib
Abbreviations: BTZ, bortezomib; CFZ, carfilzomib; IMiD, immunomodulatory drug; ORR, overall response rate.
1. Jagannath S, et al. Clin Lymphoma Myeloma Leuk. 2012;12:310-318. 2. Siegel DS, et al. Blood. 2012;120: 2817-2825.
3. Vij R, et al. Br J Haematol. 2012;158:739-748.
8/25/2017 15

16. PX-171-0041
Cohort 1
(Phase II)
PX-171-0041
Cohort 2
(Phase II)
Patient population Relapsed/refractory
(BTZ naive)
Relapsed/refractory
(BTZ naive)
N 59 70
(67 evaluable for efficacy)
Treatment arms CFZ 20 mg/m2 CFZ 20/27 mg/m2
Primary endpoint ORR: 42.4% ORR: 52.2%
Carfilzomib—Key Clinical Trials in Bortezomib-Naive
Relapsed/Refractory MM Patients
Abbreviations: BTZ, bortezomib; CFZ, carfilzomib; ORR, overall response rate.
1. Vij R, et al. Blood. 2012;119:5661-5670.
8/25/2017 16

17. 003-A1
(N=266)Study Population
Carfilzomib on days 1, 2, 8, 9, 15 and 16
every 28 days
20 mg/m2 in Cycle 1
and 27 mg/m2 (10min infusion)
from Cycle 2 and beyond
(maximum 12 cycles)
Relapsed from ≥2 prior lines of therapy
• Must include BTZ
• Must include THAL or LEN
Refractory to last regimen
Study 003-A1: Phase 2b Study of Single-Agent Carfilzomib in Relapsed and Refractory
Multiple Myeloma
 Primary endpoint: ORR
 IMWG response criteria (IRC assessed)
 Secondary endpoints
 CBR (ORR+ MR), DOR, OS, PFS, TTP, safety
Siegel D, et al. Blood. 2012; 120:2817-25.
8/25/2017 17

18. Study 003: Single Agent Anti-tumor Activity (Safety population; N=266)
CBR, clinical benefit response; CR, complete response; DCR, disease control rate; MR, minor response
* CR IRC determined; 11 patients had unconfirmed response
Adapted from Siegel D, et al. Blood. 2012; 120:2817-25.
0.4
4.9
17.7
12.8
30.5
25.9
0
5
10
15
20
25
30
35
CR*
(n=1)
VGPR
(n=13)
PR
(n=47)
MR
(n=34)
SD
(n=81)
PD
(n=69)
PercentageofPatients
ORR = 23%
CBR = 36%
DCR = 66%
DOR: 7.8 mo (≥ PR) and 8.3 mo (≥ MR)
Subset analyses of higher risk populations showed similar response rates
8/25/2017 18

19. Study 003: Summary of Response and OS
N ORR % (95% CI) OS months (95% CI)
Safety population 266 22.9 (18.0-28.5) 15.4 (12.5-19.0)
Response evaluable population 257 23.7 (18.7-29.4) 15.6 (13.0-19.2)
Refractory to bortezomib and lenalidomide 169 15.4 (10.3-21.7) 11.9 (8.4-14.7)
Refractory or intolerant to bortezomib and
lenalidomide
214 20.1 (14.9-26.1) 13.2 (10.6-16.6)
Siegel D, et al. Blood. 2012; 120:2817-25; KYPROLIS® [package insert]. South San Francisco, CA: Onyx
Pharmaceuticals, Inc; 2012.
8/25/2017 19

20. Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma Patients Treated
with Carfilzomib
Event, %
Patients (N=526), %
All Gradesa Grade 3 Grade 4
Fatigue 55.5 7.2 0.4
Anemia 46.8 21.1 1.3
Nausea 44.9 1.3 0
Thrombocytopenia 36.3 13.1 10.3
Dyspnea 34.6 4.8 0.2b
Diarrhea 32.7 0.8 0.2
Pyrexia 30.4 1.3 0.4
URTIc 28.3 3.2 0
Headache 27.6 1.3 0
Cough 26.0 0.2 0
Blood creatinine increased 24.1 2.5 0.2
Lymphopenia 24.0 16.0 2.1
Edema peripheral 24.0 0.6 0
Vomiting 22.2 1 0
Constipation 20.9 0.2 0
Neutropenia 20.7 9.5 0.8
Back pain 20.2 2.9 0
Insomnia 17.9 0 0
Chills 16 0.2 0
aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0, bOne event was Grade 5 severity,
cUpper respiratory tract infection, dAspartate aminotransferase
Event, %
Patients (N=526), %
All Gradesa Grade 3 Grade 4
Arthralgia 15.8 1.3 0
Muscle spasms 14.4 0.4 0
Hypertension 14.3 2.9 0.4
Asthenia 13.9 2.3 0.2
Hypokalemia 13.7 2.7 0.6
Hypomagnesaemia 13.5 0.4 0
Leukopenia 13.5 5.1 0.2
Pain in extremity 13.3 1.3 0
Pneumonia 12.7 9.9 0.6b
ASTd increased 12.5 2.9 0.2
Dizziness 12.5 1.0 0.2
Hypoesthesia 12.2 0.6 0
Anorexia 12.0 0.2 0
Pain 12.0 2.3 0.2
Hyperglycemia 11.8 3.0 0.6
Chest wall pain 11.4 0.6 0
Hypercalcemia 11.0 2.5 1.5
Hypophosphatemia 10.5 4.6 0.6
Hyponatremia 10.3 5.9 0.6
Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%),
cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each).
208/25/2017

21. 8/25/2017 21
carfilzomib monotherapy was effective even in patients with relapsed/refractory MM who have been
heavily pretreated – 22.9% ORR with carfilzomib in patients with a median of 5 lines of therapy – 7.8-
month DoR
Objective responses and clinical benefit were durable, as demonstrated by the DoR.
Carfilzomib demonstrated clinically meaningful single-agent activity in a heavily treated patient
population.
Study 003-A1 Conclusion

22. Phase III Studies: Combination Studies
• ASPIRE Study
• ENDEAVOR Study
8/25/2017 22

23. ASPIRE : Phase III Study
Evaluate the safety and
efficacy of carfilzomib with
lenalidomide and weekly
dexamethasone as
compared with lenalidomide
and weekly dexamethasone
alone in patients with
relapsed multiple myeloma
Objective
Key Inclusion criteria
• Patients with relapsed multiple
myeloma
• Measurable disease
• 1-3 prior therapies
Key Exclusion criteria
• Refractory to previous
bortezomib or lenalidomide
• Grade ≥ 3 peripheral neuropathy
• NYHA Class III or IV heart failure
Study Population
(n=792)
Primary: Progression-free
survival
Secondary: Overall Survival,
rate of overall response
(partial response or better),
duration of response,
health-related quality
of life, and safety
Endpoints
Stewart AK, et al. N Engl J Med 2015;372:142-52.8/25/2017 23

24. ASPIRE Study: Treatment Schedule
R
A
N
D
O
M
I
Z
A
TI
O
N
Cycles 1 and higher (28
days each)
Cycles 1 –12
(28 days each)
Cycles 13 –18
(28 days each)
Cycles 19 and higher
(28 days each)
Dexamethasone 40 mg PO or IV
Days 1, 8, 15, 22
Lenalidomide 25mg PO
Days 1-21Rd
KRd
Dexamethasone 40 mg PO or IV
Days 1, 8, 15, 22
Carfilzomib 20 mg/m2 IV
Days 1 and 2 (Cycle 1)
Carfilzomib 27 mg/m2 IV
Days 8, 9, 15, 16 (Cycle 1) and
Days 1, 2, 8, 9, 15, 16 (Cycles 2-12)
Lenalidomide 25mg PO
Days 1-21
Dexamethasone 40 mg
PO or IV
Days 1, 8, 15, 22
Carfilzomib 27 mg/m2 IV
Days 1, 2, 15, 16
Lenalidomide 25mg PO
Days 1-21
Dexamethasone 40
mg PO or IV
Days 1, 8, 15, 22
Lenalidomide 25mg
PO
Days 1-21
FOLLOWUP
1:1
Treatment continued until withdrawal of consent, disease
progression, or the occurrence of unacceptable toxic effects
Stewart AK, et al. N Engl J Med 2015;372:142-52.
KRd: Carfilzomib, lenalidomide, dexamethasone; Rd:
Lenalidomide, dexamethasone
8/25/2017 24

25. ASPIRE Study: Progression-Free Survival in ITT Population
Median PFS was 8.7 months longer in the Carfilzomib group than in the control group
Stewart AK, et al. N Engl J Med 2015;372:142-52.
Benefit with respect to PFS in the Carfilzomib group was observed across all subgroups
8/25/2017 25

26. ASPIRE Study: Overall Survival
Median overall survival was not reached in either group after a median follow
up of 32 months ; A trend in favor of the carfilzomib group was observedNE: Not estimable
Stewart AK, et al. N Engl J Med 2015;372:142-52.8/25/2017 26

27. ASPIRE Study: Treatment Responses
Stewart AK, et al. N Engl J Med 2015;372:142-52.8/25/2017 27

28. ASPIRE Study: HRQoL
Addition of carfilzomib to lenalidomide and dexamethasone achieved superior health-
related quality of life compared with lenalidomide and dexamethasone alone
Stewart AK, et al. N Engl J Med 2015;372:Suppl Appendix
8/25/2017 28

29. ASPIRE Study: Safety
• Median duration of treatment
• 88.0 weeks (range, 1.0 to 185.0) in the carfilzomib group and 57.0 weeks
(range, 1.0 to 201.0) in the control group
• Treatment discontinuation
• 69.9% in the carfilzomib group and 77.9% in the control group
• Mainly due to disease progression (39.8% and 50.1%) or adverse events
(15.3% and 17.7%)
• Dose reduction due to AEs
• In the carfilzomib group: 11.0% for carfilzomib and 43.4% for lenalidomide
• In the control group: 39.1% for lenalidomide
Stewart AK, et al. N Engl J Med 2015;372:142-52.
8/25/2017 29

30. ASPIRE Study: Safety
Stewart AK, et al. N Engl J Med 2015;372:142-52.8/25/2017 30

31. ASPIRE Study: Severe & Serious Adverse Events
• Adverse events of grade 3 or higher were reported in 83.7% of patients in the
carfilzomib group and 80.7% of patients in the control group
• Serious adverse events were reported in 59.7% in the carfilzomib group and 53.7%
in the control group
• In each treatment group, 6.9% of patients died owing to adverse events
• Overall, 14 deaths were reported as treatment-related: 6 in the carfilzomib group
and 8 in the control group
• Adverse events leading to more than 2 deaths (carfilzomib group vs control group)
• Myocardial infarction (3 vs 1)
• Cardiac failure (1 vs 3)
• Sepsis (3 vs 2)
Stewart AK, et al. N Engl J Med 2015;372:142-52.8/25/2017 31

32. 8/25/2017 32
1 in 3 patients receiving KRd had a CR (32%
[KRd] vs 9% [Rd])
>2 years’ median PFS in patients receiving
KRd (26.3 months [KRd] vs 17.6 months [Rd])
About 9 in 10 patients responded to KRd
treatment (87% [KRd] vs 67% [Rd])
QoL was improved (started in cycle 1 and
continued through cycle 18)
Summary

33. ASPIRE Conclusion
The addition of carfilzomib to lenalidomide and dexamethasone in
patients with relapsed multiple myeloma resulted in statistically
significant and clinically meaningful improvement in the primary
endpoint, PFS, as compared to Rd.
Secondary endpoints were supportive of the primary endpoint,
including strong evidence of longer OS, higher ORR, and improved
HRQoL in the KRd arm.
Adverse events were generally consistent with the known toxicity
profiles of lenalidomide, and dexamethasone.
8/25/2017 33

34. ENDEAVOR Study
Phase 3 study to
compare the efficacy
and safety of
carfilzomib and
dexamethasone with
bortezomib and
dexamethasone in
patients with relapsed
or refractory
multiple myeloma
Objective
N=929
Key Inclusion criteria
• Patients with relapsed or
refractory multiple myeloma
• Measurable disease
• 1-3 prior therapies
• LVEF of ≥40%
Key Exclusion criteria
• Refractory to previous
bortezomib or carfilzomib
• Grade ≥ 2 peripheral
neuropathy
• MI within past 4 months
• NYHA Class III or IV heart
failure
Study Population
Primary:
Progression-free survival
Secondary:
• Overall Survival
• Rate of overall
response (partial
response or better)
• Duration of response,
• Incidence of grade 2 or
higher peripheral
neuropathy events,
and safety
Endpoints
Dimopoulos MA, et al. Lancet Oncol 2016; 17: 27–388/25/2017 34

35. ENDEAVOR Study: Treatment Schedule
R
A
N
D
O
M
I
Z
A
T
I
O
N
Kd, n=464
Vd, n=465
FOLLOWUP
1:1
Treatment continued until disease progression, withdrawal of
consent, or the occurrence of unacceptable toxic effects
Carfilzomib
20/56 mg/m2 IV D1,2, 8, 9, 15, 16
(30min infusion)
Dexamethasone
20 mg PO or IV D1, 2, 8, 9, 15, 16,
22, 23
28-day cycle
Bortezomib
1.3 mg/m2 IV or SC D1, 4, 8, & 11
Dexamethasone
20 mg PO or IV D1, 2, 4, 5, 8, 9,
11, 12
21-day cycle
Kd: Carfilzomib-dexamethasone; VD: Bortezomib-dexamethasone
Dimopoulos MA, et al. Lancet Oncol 2016; 17: 27–388/25/2017 35

36. ENDEAVOR: Carfilzomib Double PFS compared to Bortezomib
Moreau P, et al. ASH 2015. Abstract 729.
N = 929
Inclusion Criteria:
• Relapsed MM (primary refractory
disease excluded)
• 1-3 prior regimens
(Prior V or K if response occurred
with no discontinuation due to
toxicity)
Stratified By:
 Prior PI therapy
 Prior lines of treatment
 ISS stage
 Planned route of bortezomib
(SQ/IV)
Until PD or unacceptable toxicity
• Carfilzomib (K)
• Cycle 1: 20 mg/m2 (d1,2)
• Escalated to 56 mg/m2 (d 8, 9,15,16 &subsequent cycles)
• Dexamethasone (d) 20mg (d1,2,8,9,15,16,22,23)
• 28-day cycle
• Bortezomib (V) 1.3 mg/m2 IV or SC (d1,4,8,11)
• Dexamethasone (d) 20 mg (d1,2,4,5,8,9,11,12)
• 21-day cycle
1 Prior Line ≥ 2 Prior Lines
PFS(Proportion)
Months Since Randomization
PFS(Proportion)
Months Since Randomization
HR (95% CI): 0.45 (0.33–0.61) HR (95% CI): 0.60 (0.47–0.78)
Kd: 22.2 mos
Vd: 10.1 mos
Kd: 14.9 mos
Vd: 8.4 mos
1.0
0.8
0.6
0.4
0.2
0.0
0 6 12 18 24 30
1.0
0.8
0.6
0.4
0.2
0.0
0 6 12 18 24 30
8/25/2017 36

37. Adverse Events (AEs), Treatment Discontinuations, and Deaths
Safety Population (n=919)
Category
Kd
(n=463)
Vd
(n=456)
Median treatment duration, weeks (range) 40 (1–108) 27 (1–106)
AE, %
Any grade AE
Grade ≥3 AE
Serious AE
98
73
48
98
67
36
Dose reduction due to an AE, % 23 48
Treatment discontinuations, %
Discontinuation due to disease progression
Discontinuation due to AE
25
14
36
16
On-study deaths, %
Deaths due to disease progression
Deaths due to AEs
1
4
1
3
Kd, carfilzomib and dexamethasone; Vd, bortezomib and dexamethasone.
8/25/2017 37

38. Nonhematologic AEs Occurring in ≥20% of Patients in Either Group
Safety Population (n=919)
AE, %
Kd (n=463) Vd (n=456)
All grade Grade ≥3 All grade Grade ≥3
Nonhematologic AEs (preferred term)
Diarrhea 31 4 38 8
Fatigue 29 5 29 7
Dyspnea 29 5 13 2
Pyrexia 28 2 14 1
Constipation 15 <1 27 2
Peripheral neuropathy 9 1 27 5
Insomnia 25 2 26 2
Cough 25 0 14 <1
Hypertension 25 9 9 3
Peripheral edema 22 1 17 1
Asthenia 20 4 16 3
AE, adverse event; Kd, carfilzomib and dexamethasone; Vd, bortezomib and dexamethasone.
8/25/2017 38

39. • Rates of grade ≥3 hypertension (9% vs 3%), dyspnea (5% vs 2%), cardiac failure
(5% vs 2%), and acute renal failure (4% vs 3%) were higher in the Kd group
compared with the Vd group
• However, this could be managed well with slower infusion of the drug
• Grade ≥2 PN rates were significantly lower in the Kd group than in the Vd group
(6% vs 32%) despite 79% of Vd patients receiving subcutaneous bortezomib
throughout their treatment
• Although Kd patients remained on study treatment longer (40 weeks vs 27
weeks), treatment discontinuation due to AEs and on-study deaths due to AEs
were comparable between groups
• Kd was superior to Vd regardless of prior bortezomib exposure
AE, adverse event; Kd, carfilzomib and dexamethasone; PN, peripheral neuropathy; Vd, bortezomib and dexamethasone.
ENDEAVOUR
8/25/2017 39

40. 8/25/2017 40
Median PFS was doubled (18.7 months [Kd] vs 9.4
months [Vd])
In bortezomib-treated patients, the risk of progression
was reduced by 44% (HR 0.56) with Kd vs Vd
Nearly 4 in 5 patients responded to Kd treatment
(76.9% [Kd] vs 62.6% [Vd])
DoR was doubled (21.3 months [Kd] vs 10.4 months
[Vd])
Summary

41. ENDEAVOR
Conclusion
first head-to-head study
comparing 2 proteasome
inhibitors
Treatment with carfilzomib and
dexamethasone resulted in a
clinically meaningful and statistically
significant decrease in risk of
progression or death compared with
combined bortezomib and
dexamethasone therapy.
The benefit was consistent across
prespecified subgroups, including
prior bortezomib exposure and by
age.
ORR and DoR were significantly
higher with carfilzomib and
dexamethasone, resulting in an
improvement in duration and depth
of response.
Although rates of ≥Grade 3
hypertension, dyspnoea, and cardiac
failure were higher in the carfilzomib
arm, the rate of ≥Grade 2 PN was
significantly lower, patients remained
on study treatment longer, and
discontinuations due to AEs and on-
study deaths were comparable
8/25/2017 41

42. Beyond Endeavor: Recapture Response: 56 mg/m2
• Chari et al
• 13 pts progressed on Car 27 mg/m2 retreated at 56 mg/m2
• Refractory to len, pom, bort, and carf
• ORR 42%: 5/12 pt had a > PR
• Small numbers but proof of principle
• HTN noted needing additional therapy in 4 pt, No cardiac signals
• Important option to consider challenging patients progress on
lower dose Carfilzomib based therapies
• S1304 Study: Car 56 vs 27 further data about optimal dosing
8/25/2017 42

43. 8/25/2017 43
Thank you