Optimal Use of Newly Approved Agents – Carfilzomib and Pomalidomide

Lymphoma-Myeloma Symposium

October 2013

Scottsdale, ArizonaScottsdale, Arizona Rochester, MinnesotaRochester, Minnesota Jacksonville, FloridaJacksonville, Florida

Joseph Mikhael, MD, MEd, FRCPC, FACPStaff Hematologist, Mayo Clinic Arizona

Disclosures

• I do not have any relevant financial relationships with any commercial interests.

Objectives

1. Review recent and critical data on the use of carfilzomib and pomalidomide

2. Provide practical advice as to the optimal use of these agents in clinical practice

Treatment sequence

Induction Consolidation

Front line treatment

Post consolidation

Maintenance

Rescue

Relapsed

OLD VADDEX

SCTNothing

PrednisoneThalidomide

Few options

NEW

Thal/Dex VD

Rev/DexCyBorD

VTDVRD

SCTVD/VRD

NothingThalidomide?Bortezomib?Lenalidomide

BortezomibLenalidomideThalidomideCarfilzomib

Pomalidomide

Carfilzomib: A Novel Agent Designed to Promote Selective and Sustained Proteasome Inhibition

• Carfilzomib is a next-generation, selective proteasome inhibitor• Potent and sustained target suppression• Improved antitumor activity• Minimal off-target activity with low neurotoxicity

5

HN

NH

O HN

O

O

NHO

NO O

O

EpoxyketoneTetrapeptide

Adapted from: Kuhn DJ, et al. Blood. 2007;110:3281-3290.

Neuropathy Was Infrequent and Not Dose LimitingPooled data from single-agent studies (003 / 004 / 005)

• Peripheral neuropathy occurred infrequently across all single-agent studies*

• Only 6 patients (1.2%) experienced a Grade 3 PN event

• No Grade 4 PN events

• Only 1 patient had drug discontinued for PN (study 004; BTZ-treated arm)

6Adapted from: Singhal S, et al. ASH 2010. Abstract 1954 (poster presentation).*Includes the terms peripheral neuropathy, neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy

N=505

Did not experience peripheral neuropathy

Grade 3 PN (1.2%)

Grade 1/2 PN (13.4%)

Carfilzomib Single-Agent Activity

7

BTZ-naïve patients*

Response Rate 20/27 mg/m2 (N=53)*

CR 0%

VGPR 17%

PR 38%

MR 8%

SD 26%

PD 11%

ORR 55% CBR

62%

0.4%

5.1%

18.7%

10.1%

34.6%

26.8%

0

5

10

15

20

25

30

35

CR* (n=1)

VGPR (n=13)

PR (n=48)

MR (n=26)

SD (n=89)

PD (n=69)

Responses in Bortezomib-Refractory Immunomodulator-Exposed Patients (Response-

Evaluable Population, N=257)

ORR = 24%

CBR = 34%

DOR (≥ PR) and (≥ MR) = 8.3 mo

8

Phase III ASPIRE Trial

9

Randomized 1:1

N = 700

Stratification

• Prior bortezomib

• Prior lenalidomide

• β2m

Primary End Point: PFS

• Carfilzomib 27 mg/m2 IV Day 1, 2, 8, 9, 15, 16 (20 mg/m2 on Days 1, 2 of Cycle 1)

• Lenalidomide 25 mg PO Days 1–21

• Dexamethasone 40 mg PO or IV on Days 1, 8, 15, 22

• Lenalidomide 25 mg Days 1–21

• Dexamethasone 40 mg PO or IV on Days 1, 8, 15, 22

Cycle = 28 days

Cycle = 28 days

β2m = beta-2-microglobulin. US NIH, 2011.

Carfilzomib - Upfront

1. Carfilzomib-Lenalidomide Dexamethasone (CRD) in newly diagnosed

2. Cyclophosphamide – Carfilzomib – Thalidomide – Dex (CYCLONE) in newly diagnosed

Stem cell collection

≥PR

CRd Cycles 9–24

CRdInduction

CRdMaintenance

CRd Cycles 1–4 CRd Cycles 5–8

ASCT

LEN Cycles 25+

Lenalidomide (off protocol)

Transplant-eligible

Transplant-eligible and --ineligible patients

•Assessments on D1 and 15 of C1 and D1 thereafter using modified IMWG Criteria with nCR•Cycles 1–8

• CFZ Days 1–2, 8–9, 15–16 at assigned doses1

• LEN 25 mg Days 1–21• DEX 40 mg weekly Cycles 1-4, 20 mg weekly Cycles 5–8

•Cycles 9–24• CFZ on Days 1–2 and 15–16 only• CFZ, LEN, DEX at last best tolerated doses•After Cycle 4, pts could undergo stem cell collection and then continue CRd with the

option to proceed to ASCT

Until disease progression or unacceptable toxicity

Treatment Schema

1. Jakubowiak AJ, et al. Blood. 2011;118: abstract 631. ASCO 2012 Slides courtesy of Dr. Jakubowiak

Responses

51%

Change from baseline

67%

81%

Pat

ien

ts (

%)

N= 53; median 12 cycles (range 1–25)

Initial Response Best Response

ASCO 2012 Slides courtesy of Dr. Jakubowiak

Results From the Phase II Dose Expansion of Cyclophosphamide, Carfilzomib, Thalidomide and

Dexamethasone (CYCLONE) in Patients with Newly Diagnosed Multiple Myeloma

#445

J. Mikhael, C. Reeder, E. Libby, L. Costa, A. Mayo, L. Bergsagel, F. Buadi, N. Pirooz, J. Lubben, AC. Dueck, AK. Stewart

Scottsdale, ArizonaScottsdale, Arizona Rochester, MinnesotaRochester, Minnesota Jacksonville, FloridaJacksonville, Florida

Newly Diagnosed: CYCLONE Phase I/II

Carfilzomib

Cyclophosphamide

Thalidomide

Dexamethasone

Newly Diagnosed MM

ResponsePFS

ToxicityStem cell harvest

ResponsePFS

ToxicityStem cell harvest

4%

26%

22%

48%

CRVGPRPRMR

Results Levels 0 and 1– Response n=27

• Overall Response 96%

CR 7 VGPR 13 PR

6MR 1

≥ VGPR 74%

Carfilzomib - Practical

• Highly effective and very well tolerated

• Beware of tumor lysis hence dosing schedule

• Cardiac issue present but mostly mitigated by fluid management

• Issues of weekly dosing being explored

• Lack of neuropathy very attractive

• Upfront uses increasing

Structurally similar, but functionally different both qualitatively and

quantitatively

Molecular Structure of Thalidomide, Lenalidomide and Pomalidomide

Molecular Structure of Thalidomide, Lenalidomide and Pomalidomide

Myeloma Pomalidomide Summary

18

Lacy Pom/Dex1-3 reg

Lacy Pom/DexLen ref

RichardsonPom+/- dex

MM-002

PR 63% 32% 28%

MR 82%* 47% 52%

Median 3 prior regimens

Median 4-6 prior regimens

Pomalidomide in 350 Relapsed Patients: Change in the Measurable Parameter From Baseline

19

MM-003 Design: POM + LoDEX vs. HiDEXRefractory MM Pts Who Have Failed BORT and LEN

(n = 302)

POM: 4 mg/day D1-21 +

LoDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1, 8, 15, 22

Follow-Up for OS and SPM

Until 5 Years Post Enrollment

(n = 153)

HiDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1-4, 9-12, 17-20

28-day cycles

PD* orintolerable AE

PD* Companion trialMM-003C

POM 21/28 days

Stratification•Age (≤ 75 vs. > 75 yrs)

•Number of prior Tx ( 2 vs. > 2)

•Disease population

Thromboprophylaxis was indicated for those receiving POM or with DVT history

*Progression of disease was independently adjudicated in real-timeDimopoulos Blood 2012, 120(21): LBA-6

MM-003: Key Eligibility Criteria• All pts had to be refractory to last therapy

• At least 2 prior therapies• ≥ 2 consecutive cycles of LEN and BORT (alone or in combination)

• Adequate prior alkylator therapy (SCT or ≥ 6 cycles or PD following ≥ 2 cycles)

• All pts must have failed LEN and BORT • Pt progressed on or within 60 days

• Pt with PR must have progressed within 6 months

• Intolerant to BORT

• Refractory or relapsed and refractory disease• Primary refractory: never achieved > PD to any therapy

• Relapsed and refractory: relapsed after having achieved ≥ SD for ≥ 2 cycles of Tx to at least one prior regimen and then developed PD ≤ 60 days of completing their last therapy

Dimopoulos Blood 2012, 120(21): LBA-6

MM-003: Patient Disposition*

*As of final PFS analysis, Sept 7, 2012.

POM + LoDEX(n = 302)

RANDOMIZATION 2:1

(N = 455)

HiDEX(n = 153)

PD

Discontinued 75% PD: 49%AE: 6%Death: 10%Withdrawal: 3%Lost to follow-up: 1%Other: 6%

25%Ongoing Tx

Discontinued 55%PD: 35%AE: 7%Death: 6%Withdrawal: 2%Lost to follow-up: 1%Other: 4%

45%Ongoing Tx

29% Pts received POM

after PD on HiDEX

Dimopoulos Blood 2012, 120(21): LBA-6

Based on adjudicated data; IMWG criteria

MM-003: Progression-Free Survival ITT Population

0 4 8 12 160.0

0.2

0.4

0.6

0.8

1.0

Progression-Free Survival (months)

Pro

po

rtio

n o

f P

atie

nts

Median PFS

POM + LoDEX (n = 302) 3.6 months

HiDEX (n = 153) 1.8 months

HR = 0.45P < .001

Dimopoulos Blood 2012, 120(21): LBA-6

MM-003: Overall SurvivalITT Population

NE, not estimable

Overall Survival (months)

0.0

0.2

0.4

0.6

0.8

1.0

0 4 8 12 16

Pro

po

rtio

n o

f P

atie

nts

Median OS (95% CI)

POM + LoDEX (n = 302) Not Reached (11.1-NE)

HiDEX (n = 153) 7.8 months (5.4-9.2)

HR = 0.53P < .001

29% of pts received POM after progression on HiDEX

Dimopoulos Blood 2012, 120(21): LBA-6

MM-003: Ongoing Evaluation of Response ITT Population

Response based on IMWG criteria, except for MR (based on EBMT criteria)* KM median, patients with ≥ PR onlyNE, not estimated due to too few responders

Response, % POM + LoDEX (n=302)

HiDEX (n=153)

P value

ORR (≥ PR) 21 3 < .001

VGPR 3 1 —

≥ MR 37 8 —

≥ SD 81 60 —

Median DOR*, m (95% CI)10.1

(6.2 – 12.1)NE —

As of Nov 9, 2012• PFS of ≥ MR in POM + LoDEX: 8.5 months

Dimopoulos Blood 2012, 120(21): LBA-6

Pomalidomide - Practical

• Similar to lenalidomide with slightly less myelotoxicity and fatigue

• Dosing range 2-4mg

• Thromboprophylaxis necessary

• Feasible in combination

Selecting Therapy

• Both are highly active agents

• Class switch a consideration

• Useful even when progressing on same class agent

• Convenience and toxicity is important

• Most MM patients will ultimately see both drugs