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Carfilzomib: new standard of care for myeloma
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.
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
Carfilzomib shows greater selectivity compare to bortezomib, without inhibiting off-target proteases
Despite the heavily pretreated nature of these patients, they achieved an ORR of 24%, had a duration of response that was nearly identical to that of pomalidomide, and had promising median PFS – 3.7 months – and OS – 15.6 months. These data suggest that this agent will improve the outcomes of patients with myeloma.
Had ASCT 74%, median cycle 4
Median OS for double refractory ~ 9 mon ( kumar et al)
RESULTS:
Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life.
CONCLUSIONS:
In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number
The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04).
20 mg/m2 only day 1,2 in cycle 1 only
Exclude gr3-4 PN or gr2 PN with pain; MI within 4 mo, CHF gr III-IV, EF<40%, CCr < 15
Median f/u of 11.2 mo
Carfilzomib dose and schedule doesn’t need to be adjusted in renal insufficiency patients
Efficacy was similar across all groups of renal function
AEs were similar among groups and
Carfilzomib can be safely administered
Median duration of response ~7.9 mo with ORR whole gr 26%
Trend toward shorter duration of median DOR (5.6 vs 8 mo) and PFS (3.5 vs 4.6 mo, P=0.06) in high risk group
OS is significantly shorter in high risk group (9.3 vs 19 mo, P=0.0003)
Comparable efficacy in patient who had isolated t(4;14) with ORR 64% vs 24% and PFS of 5 mo vs… mo and median OS 16 mos boths
Less PN with weekly dosing (28% 8%) and subcutaneous route (166%)
Graph gr>/= 2 PN
Gr3-4 cardiac ae 10%, failure was most common
12% of cardiac AE occurred within day one of dosing
