Debate: Should we change the standard of care to Carfilzomib? nuchanan areethamsirikul

1. Should We Change
A New Standard of Care to
Carfilzomib?
Nuchanan Areethamsirikul, M.D.
Wattanosoth Hospital

2. Carfilzomib
• Second-generation proteasome inhibitor
• Tetrapeptide Epoxyketone
• Highly selective and irreversible proteasome binding
• Minimal off-target effect  less neurotoxicity
Kortuem KM et al. Blood 2013.7;121(6):893-7.

3. Single Agent Carfilzomib Pivotal Trial : 003-A1
Carfilzomib
20 mg/m2 days 1, 2, 8, 9, 15, 16
every 28 days
N = 46
MM: Progressive disease
> 2 prior therapy lines
including bortezomib, thalidomide
or lenalidomide,
an alkylating agent,
and anthracycline alone or in
combination
Carfilzomib
Dose escalation to 27 mg/m2
after cycle 1 up to 12 cycles
N = 266
Phase II; N= 266; Median of 5 prior therapies
Primary Endpoint: ORR 23.7%, ≥VGPR 5.3%
Secondary Endpoints:
• Clinical benefit rate (≥minimal response) 37%
• Median DOR 7.8 months
• Median PFS 3.7 months
• Median OS 15.6 months
Siegel DS, et al. Blood. 2012;120:2817-25.

4. ASPIRE : KRd vs Rd in Relapsed MM
Stewart AK et al. N Engl J Med. 2015 Jan 8;372(2):142-52.
Phase 3
open label,
multicenter, RCT
N = 792
Prior Rx 1-3 lines
KRd
Carfilzomib 20/27 mg/m2 D 1, 2, 8, 9, 15 , 16
Len 25 mg D1-21
Dex 40 mg D 1, 8, 15, 22
After cycle 12, K given on D 1,2,15,16
After cycle 18, K discontinued
Rd
Len 25 mg D1-21
Dex 40 mg D 1, 8, 15, 22

5. ASPIRE : Treatment Responses
Stewart AK et al. N Engl J Med. 2015 Jan 8;372(2):142-52.

6. ASPIRE : Progression Free Survival
Stewart AK et al. N Engl J Med. 2015 Jan 8;372(2):142-52.

7. ASPIRE : Overall Survival
Stewart AK et al. N Engl J Med. 2015 Jan 8;372(2):142-52.

8. ENDEAVOR : Kd vs Vd in Relapsed MM
N = 929
• Prior Rx 1-3
lines
• Prior Rx with
V or K was
allowed if
- PR to prior Rx
- 6 mo PI-free
interval
- Not D/C due to
toxicity
Kd
Carfilzomib 20/56 mg/m2 D 1, 2, 8, 9, 15, 16
Infusion in 30 mins
Dex 20 mg D 1, 2, 8, 9, 15, 16, 22,23
q 28 days until PD
Vd
Bortezomib 1.3 mg/m2 D 1, 4, 8, 11
Dex 20 mg D 1, 2, 8, 9, 11, 12
q 21 days until PD
Dimopoulos MA et al. EHA meeting 2015. Abstract LB2071.

9. ENDEAVOR: Treatment Response
Dimopoulos MA et al. EHA meeting 2015. Abstract LB2071.

10. ENDEAVOR: PFS and OS
Dimopoulos MA et al. EHA meeting 2015. Abstract LB2071.
• Double median PFS in Kd arm compared to Vd
• Subgroup analysis, favor Kd in all subgroups – high ISS, prior
bortezomib and IMIDs exposure, high risk cytogenetics,
age≥75 yo

11. Carfilzomib in Renal Insufficiency Patient
• Phase II PX-171-005, single agent carfilzomib in RRMM
• Dose : 15/20/27 mg/m2 ; n = 50
• No difference in carfilzomib clearance among patients with
various degree of renal impairment
• Carfilzomib is predominantly cleared through extra-renal
pathway
Badros AZ et al. Leukemia. 2013;27(8):1707-14.
Group Renal function status CrCl (mL/min) ORR
1 Normal >80 18%
2 Mild impairment 50-80 27%
3 Moderate impairment 30-<50 22%
4 Severe Impairment <30 25%
5 Chronic dialysis - 38%

12. Carfilzomib & High Risk Cytogenetics
• 27% high risk cytogenetics (del17p, t(4;14), t(14,16) by FISH, del
13 or hypodiploidy by metaphase)
• ORR were similar in patient with high- and standard-risk
cytogenetics (26% vs 25%, P=0.85)
• Comparable efficacy in patient who had isolated t(4;14) 
median OS 16 mo
• Del 17p had the greatest negative impact  ORR 17%, OS 7 mo
• Carfilzomib can at least overcome the adverse impact of t(4;14)
Jakubowiak AJ et al. Leukemia. 2013;27(12):2351a-6.
PFS OS

13. Carfilzomib & High Risk Cytogenetics
• PFS benefit was demonstrated in patient with high risk
cytogenetics who had carfilzomib combination treatment in
phase 3 studies
• ASPIRE study, median PFS 23.1 vs 13.9 mo; HR 0.70, 95%CI 0.43-1.16;
P=0.083
• Endeavor study, HR 0.65, 95% CI 0.45-0.92
Stewart AK et al. N Engl J Med. 2015 Jan 8;372(2):142-52.
Dimopoulos MA et al. EHA meeting 2015. Abstract LB2071.

14. Carfilzomib & Peripheral Neuropathy (PN)
Dimopoulos MA et al. EHA meeting 2015. Abstract LB2071.
• PN is a common side effect of bortezomib, up to 57%
• Less PN with weekly bortezomib dosing and subcutaneous
route  still ~ 38% experienced PN from phase III study
• Very low incidence of PN in carfilzomib (all gr 14-17%,
gr 3-4 1%)
• Allow more drug combination option, more tolerable in
elderly patients and allow longer treatment duration

15. Cardiovascular/Pulmonary toxicities
• Multiple factors Multiple comorbidities, age related CV-
risk, chronic anemia, amyloidosis, prior anthracycline Rx
• 74% of patient had a history of cardiovascular events
• No different overall mortality rate (7%) in patients who had
baseline cardiac risk factor or not
• 14% Hypertension (mainly gr 1-2); ≥50% had Hx of HTN
• Cardiac failure rate is similar (6-8% in phase II; 5-6% in phase
III) to the rate reported in bortezomib (8%)
• Majority of dyspnea was low grade and transient
• Dose reduction/treatment discontinuation were uncommon
(1%/4% for cardiac AEs and 1%/1% for pulmonary AEs)
Siegel et al. Haematologica. 2013;98(11):1753-61.
Stewart AK et al. N Engl J Med. 2015 Jan 8;372(2):142-52.
Dimopoulos MA et al. EHA meeting 2015. Abstract LB2071.

16. Ongoing Carfilzomib Studies In Upfront Setting
Study Phase Patient N ORR/≥VGPR PFS/OS
Median
F/U (mo)
CYKLONE1
Ib/II
ASCT 64 91%/59% 2yr PFS 76%
2 yr OS 96%
17.5
CMP2
I/II
Elderly 72 90%/58%
PFS 21 mo
Estimated
3 yr OS 80%
22
KRd3 II ASCT 53 98%/78% - 17
KTd4 II ASCT 91 90%/68% 3yr PFS 72% 23
CLARION
KMP vs VMP
III Elderly 882 - - -
1 Mikhael JR et al. Br J Haeatol. 2015;169(2);219-27. 2 Moreau P et al. Blood. 2015;125(20):3100-4.
3 Zimmerman TM et al. ASCO 2015. Abstract 8510. 4 Sonneveld P et al. Blood. 2015;125(3);449-56.

17. Conclusion
• Carfilzomib is a potent 2nd generation PI and becoming a
new standard of care in MM treatment
• Currently approved by US FDA for 2nd/3rd lines therapies
• Highly efficacious with PFS benefit in two phase 3 RCT
 superior to bortezomib in ENDEAVOR study
• Favorable safety profiles, well tolerated – less PN
• Safe to use in patient with renal impairment, includes
those who are on dialysis
• Carfizomib can at least overcome the negative impact of
some certain high risk cytogenetics
• Promising results from ongoing studies in front line
setting

18. Thank You