Update on novel combinations for relapsed/refractory disease: “Coming soon”

1

Tomer M. MarkDepartment of Medicine, Division of Hematology /

OncologyWeill-Cornell Medical College /

New York Presbyterian Hospital, New York, NY, USA

Lymphoma & Myeloma 2012

Disclosures

2

Research Funding: Celgene Inc.; Onyx Inc.

Speakers Bureau: Celgene Corp; Millenium Inc.; Sanofi-Aventins Inc.; Onyx Inc.

Membership on an entity's advisory committees: Celgene Corp. There is no FDA indication for pomalidomide or elotuzumab at this time.

Off-label uses of bortezomib and lenalidomide are discussed.

“Novel Agents”

• New drugs not yet available on the market– Elotuzumab

• Single-agent• In combination with bortezomib• In combination with lenalidomide

– Pomalidomide• Single-agent• In combinations

3

Natural History of MM:

Asymptomatic

20

50

100

Refractory Relapse MGUS* or

SmolderingMyeloma

Active Myeloma

Plateau Remission

Symptomatic

Relapse

Therapy

~60,000~20,000 New cases

in U.S.2

~11,000 Annual

deaths in U.S.2

Prevalence in the U.S.

M P

rote

in (

g/l

)

*Monoclonal gammopathy of uncertain significance

Therapy Therapy

Myeloma after bortezomib and lenalidomide

5

• What is the outlook for MM refractory to both bortezomib and an IMiD?– Retrospective study of 286 pts treated at nine sites

T0 = time eligibility met

Kumar et al., 2012, Leukemia, 26, 149-157

Elotuzumab: Background

• Elotuzumab (HuLuc63) is a humanized monoclonal IgG1 antibody targeting human CS1, a cell surface glycoprotein

• CS1 is highly and uniformly expressed on >95% of primary MM cells– Restricted expression on

NK cells– Little to no expression on

normal tissues– May promote adhesion to

bone marrow stroma

• Acts primarily through NK cell-mediated ADCC

Hsi et al, 2008; Tai et al, 2008;

PC in cecum Plasmacytoma

LPL PC in marrow

Elotuzumab: single agent experience

• Phase 1 study: doses 0.5-20mg/kg every two weeks, n = 54

• Median # prior tx: 4.5; len (82%), thal (80%), bort (82%)

• No objective responses seen; 9 pts (26.5%) with SD.

• MTD not seen

Zonder et al., 2012, Blood, 120, 552-9.

7

Elotuzumab: MM xenograft model

• The combination of elotuzumab and bortezomib worked better than either agent alone…

8van Rhee F et al. Mol Cancer Ther 2009;8:2616-2624

Elotuzumab + Bortezomib:

9

Jakubowiak A J et al. JCO 2012;30:1960-1965

©2012 by American Society of Clinical Oncology

Phase 1 study• N = 28, median 2 prior tx (64% prior bort, 39% prior len, 43% refractory

to last tx)• Elo: (5,10,20 mg/kg); bortezomib 1.3mg/m2 IV; (no dexamethasone).• DLT assessed in cycle 1; no MTD was found

Elo + Bort + Dex: efficacy

10

Response All pts Prior Bort Bort Refr (n=3)

Prior Len Refractory to last tx

ORR 48% 45% 0 42% 45%

CR 7% 0 0 8% 9%

PR 41% 45% 67% 33% 36%

MR 15% 0 0 8% 18%

SD 30% 45% 0 33% 27%

PD 7% 9% 33% 17% 9%

• 2/3 patients refractory to bort with PR• Favorable results compared to Phase III APEX study.

APEX(n=333)

38%

6%

32%

---

---

---

Richardson P. et al. Blood. 2008. 110(10): 3557-60.

• Median TTP = 9.36m• APEX median TTP = 6.2m

11

Kaplan-Meier analysis of time to disease progression.

Jakubowiak A J et al. JCO 2012;30:1960-1965©2012 by American Society of Clinical Oncology

Elo + Bort: Most Common Adverse Events

• 71% (20/28) pts had at least 1 infusion reaction, incl nausea, dyspnea, chills, dizzyness, headache, vomiting, rash – all Grade 1 or 2; One grade 3 hypersensitivity rxn

12

Adverse Event All Grades (%) Grade 3 / 4 (%)

Fatigue 82 14

Anemia 71 14

Diarrhea 71 0

Thrombocytopenia 68 11

Hyperglycemia 61 11

Nausea 61 0

Neutropenia 50 11

Elotuzumab: xenograft model

13

• The combination of elotuzumab and lenalidomide worked better than either agent alone…

Lonial S et al. Blood. 2009;114:432

Lonial S et al. JCO 2012;30:1953-1959

©2012 by American Society of Clinical Oncology

Elotuzumab + Lenalidomide / Dex in RRMM

Phase 1 study• N = 29, median 3 prior tx (69% prior bort, 21% prior len)• Elo: (5,10,20 mg/kg); len 25mg 21/28d, dex 40mg weekly• DLT assessed in cycle 1; no MTD was found

Elo + Len + Dex: efficacy

15

Response All pts Len-naïve Prior thal Prior bort Refractory to last tx

ORR 82% 95% 94% 75% 83%

CR 4% 5% 0 5% 0

VGPR 29% 32% 44% 20% 33%

PR 50% 59% 50% 50% 50%

SD 11% 5% 6% 15% 17%

PD 7% 0 0 10%

MM-009 MM-010

61% 60%

14% 16%

10% 9%

37% 36%

31% 30%

3% 2%

• 6 with prior len: 1 CR, 1 VGPR

Kaplan-Meier estimate of time to disease progression for the 20-mg/kg cohort (n = 22).

Lonial S et al. JCO 2012;30:1953-1959

©2012 by American Society of Clinical Oncology

Elo + Len + Dex: Most Common Adverse Events

• 89% (25/28) pts had at least 1 infusion reaction, incl nausea, dyspnea, chills, dizzyness, sweating, cough, rash

• 2 pts withdrew for tox: 1 pt with stridor, 1 with anaphylaxis

17

Adverse Event All Grades (%) Grade 3 / 4 (%)

Fatigue 61 11

Anemia 46 7

Diarrhea 50 11

Nausea 43

Constipation 39 4

Neutropenia 39 36

Muscle Spasms 32

Future of elotuzumab

• Appears to enhance antitumor activity of both bortezomib and lenalidomide.

• Combination with Lenalidomide + low-dose dexamethasone: two phase III trials:– ELOQUENT-1: upfront treatment (CA204-006;

NCT01335399)– ELOQUENT-2 in RRMM (CA204-004;

NCT0123979)

• Combination with Bortezomib + low-dose dexamethasone Phase 1 / 2 trials.

18

Pomalidomide (CC-4047)

Thalidomide

Analog of thalidomide – 2nd generation IMiD– Equivalent anti-angiogenic activity– 8x greater stimulation of apoptosis– 15,000x greater inhibition of TNF-alpha production– Stimulates ADCC

Lenalidomide

Pomalidomide Mechanisms of Action:

– Anti-proliferative• Demonstrated upregulation of p23WAF1, inhibiting CDK

pathway, leading to G1/G0 arrest

– Pro-apoptotic• Enhanced sensitivity to Fas and TRAIL-induced

apoptosis

– Antiangiogenic• Decreased VEGF secretion

– Modulates bone resorption• Inhibition of differentiation of osteoclasts by down-

regulating PU.1

Phase 1 / Single Agent Studies

21

Regimen N Schedule Doses MTD (DLT)PR and better

PFS/DOR/OS, months

Schey et al. JCO 2004 (MM-001)

Pom 24 28/281,2,5, or

10mg2 mg

(neutropenia)54%

9.7/ - / 22.5

Streetly et al. BJH 2008 Pom 20 28/28

1,2,5, or 10 mg

5mg QOD(neutropenia)

50%10.5 / - /

33

Richardson et al. 2011(MM-002)

Pom +/- Dex 38 21/28 2 to 5mg 4 mg(neutropenia)

25%5.0 /5.0 /

19.9

Response to Pomalidomide / Dexamethasone In Previously Treated MM (Phase 2 studies)

§ Responses assessed by the investigator.Dex, dexamethasone; PR, partial response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; Pom, pomalidomide; VGPR, very good PR.

Study # of prior Regimens

N Pom schedule (dose)

ORR, %

Lacy MQ, et al.1 2 60 28/28 (2 mg) 63

Lacy MQ, et al.2

(Len-refractory)4 34 28/28 (2 mg) 32

Leleu X, et al. 3

IFM 2009-02(Double refractory)

4 43 21/28 (4 mg) 42

4 41 28/28 (4 mg) 39

Richardson P, et al.4 MM-002

5 113 21/28 (4 mg) 34§

5 10821/28 (4 mg)

(no dex)13§

Lacy MQ, et. al.5

(Double refractory)6 35 28/28 (2 mg) 25

6 35 28/28 (4 mg) 29

1. Lacy MQ, et al. J Clin Oncol. 2009;27:5008-14. 2. Lacy MQ, et al. Leukemia. 2010;24:1934-9.

3. Leleu X, et al. IMW 2011;P-148..4. Richardson P, et al. Blood. 2011;118:[abstract 634].

5. Lacy MQ, et al. Blood. 2011;118:2970-5.

IFM 2009-02

23

Until Progression (relapse or refractory)

- Simon two stage design

- 22 IFM centres

- 92 pts included

- N=84 evaluable

STOP #1/DMC – TOLERANCERule: acceptable

STOP #2 DMC - EFFICACYRule: 4 PR and better/arm

Simon stage 1 17 pts per arm

Simon stage 2 40 pts per arm

6 pts per arm

Arm B – Cycle 28 days• Pomalidomide 4mg oral/d, d 1–28 Dexamethasone 40mg oral/w, 1, 8, 15, 22

• Aspirin/LMWH

Arm A – Cycle 21 days•Pomalidomide 4mg oral/d, 1–21 Dexamethasone 40mg oral/w, 1, 8, 15, 22• Aspirin/LMWH

Patient Characteristics at entry into IFM2009-02

24

Arm 21/28 (N = 43) 28/28 (N = 41)

Median age, years (range) 54 (39-78) 53 (36-69)

Gender ratio (M/F) 2 2

Neuropathy (all grades), N (%) 34 (79) 25 (61)

DVT/PE prophylaxis, N(%) LWMH 10 (23) 8 (19.5)

VKA 7 (16) 4 (10)

T(4;14), N(%) 0 3 (7)

Del17p, N(%) 5 (12) 4 (10)

Prior line of therapy, N (range) 4 (1-8) 4 (1-8)

Thalidomide, N (%) 20 (46.5) 24 (58.5)

Lenalidomide, N (%) (100) (100)

Bortezomib, N (%) (100) (100)

DVT: Deep Veinous Thromboembolism/PE: Pulmonary Embolism; LWMH: Low Weight Molecular Heparin; VKA: Vitamin K antagonist

Response (ITT - Central lab)

25

Arm 21/28N=43

28/28N=41

Number of cycle, median 5 5

ORR (PR and better), N(%) 18 (42) 16 (39)

sCR 0 0

CR 1 (2) 0

VGPR 3 (7) 2 (5)

PR 14 (32.5) 14 (34)

Stable disease, N(%) 20 (46.5) 21 (51)

Progression, N(%) 5 (12) 1.7 (10)

Time to best response, months (range) 2 (1-9) 1.7 (1-9)

Time To Progression (TTP)

Median follow-up is 6.5 months (arm A 21/28) and 7 months (arm B 28/28)

26

Perc

ent w

ithou

t pro

gres

sion

0.00

0.25

0.50

0.75

1.00

Days0 50 100 150 200 250 300 350 400

Arm O/N Median, months Range

21/28 19/43 7 (4 - )

28/28 16/41 9.7 (4 - )

O/N: observed number / total number

Lessons from Phase 2 Studies

• Activity present in lenalidomide-refractory patients– ORR 32% in len-refractory– ORR 25% in both len and bortez-refractory

• 4 mg daily is NOT better than 2mg• 4 mg daily is NOT better than 4mg 21/28

days• ORR correlates with # of prior lines of

therapy

Toxicities in Phase 2 studies

Toxicity Lacy 2009 (n=60)

Lacy 2010 (len refractory)

(n=34)Lacy 2011 (double - refractory

RRMM), n=70Leleu 2010 (IFM 2009-02)

n=84

2 mg 4 mg4 mg 21/28

days4 mg 28/28

days

Hematological (%) 23.5* 26.5*

Neutropenia 32 29 51 65

Thrombocytopenia 3 9 32 31

Anemia 5 12 26 26

Non-hematological (%) 23* 13* 12* 9*

Fatigue 17 9 9 9

Pneumonia 8 3 31 3

Hyperglycemia 5 3 9 3

Peripheral neuropathy

2 0 0 3

Thomboembolic complications

2 0

* No breakdown of grade 3 or 4 adverse events reported

ClaPD (Clarithromycin, Pomalidomide, Dexamethasone) Therapy in Relapsed or

Refractory Multiple Myeloma

Tomer M. Mark1, Melissa Rodriguez1, Manan Shah1, Ryann Quinn1, Jessica Campbell1, Ramsey Abdullah1, Roger Pearse1, Faiza

Zafar1, Karen Pekle1, Patrice Mignott1, David Jayabalan1, Scott A. Ely2, Morton Coleman1, Selina Chen-Kiang2, Ruben Niesvizky1

1Department of Medicine, Division of Hematology and Oncology; and 2Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA

ASH 2011

Rationale for Clarithromycin

• Treatment in newly diagnosed, symptomatic MM with BiRD (clarithromycin, lenalidomide, dexamethasone) in a phase 2 trial yielded:

– N = 72, 90.3% ≥ partial response (PR), 38.9% complete response1

• Clarithromycin:

– slows hepatic clearance of dexamethasone leading to greater corticosteroid exposure2–4

– acts as a weak immunomodulatory agent5,6

• A case-control study showed superior clinical outcomes for BiRD versus lenalidomide plus low-dose dexamethasone.7

5. Takizawa H, et al. Biochem Biophys Res Commun. 1995;210:781-6.6. Matsuoka N, et al. Clin Exp Immunol. 1996;104:501-8.

7. Gay F, et al. Am J Hematol. 2010;85:664-9.

1. Niesvizky R, et al. Blood. 2008;111:1101-9. 2. Garey KW et al. Chest. 2000;118:1826-7. 3. Fost DA, et al. J Allergy Immunol. 1999;103:1031-5.4. Spahn JD, et al. Ann Allergy Asthma Immunol. 2001;87:501-5.

Study Design

A single-center, phase 2 study of clarithromycin combined with Pomalidomide+Dexamethasone in RRMM

p.o., orally; b.i.d., twice a day; RRMM, relapsed, refractory MM.

1 2 8 9 15 16 21 22 28Day

Dex 40mg PO

Dex 40mg PO

Dex 40mg PO

Dex 40mg PO

Pomalidomide 4 mg PO

Clarithromycin 500mg PO BID

Key Patient Eligibility Criteria

Inclusion criteria Exclusion criteriaAge > 18 years Nonsecretory MM

Relapsed or progressive MM after at least 3 prior therapeutic treatments/regimens for MM

History of thromboembolic event within the past 6 months prior to enrollment

Must have been previously treated with lenalidomide

Unable to take prophylactic anticoagulation or antiplatelet therapy

Adequate bone marrow, liver, and renal function

Patient Baseline Characteristics

Median (range) N = 46

Age, years 65 (41–87)

Sex 21 male, 25 female

β2-Microglobulin, mg/L 3.4 (1.2–12.4)

Albumin, g/dL 3.6 (1.8–4.5)

Lactate dehydrogenase, U/L 171 (131–447)

Hemoglobin, g/dL 10.4 (7.5–13.5)

Creatinine, mg/dL 0.9 (0.44–2.5)

Calcium, mg/dL 9.15 (7.9–11.5)

Number of prior therapies 5 (3–15)

Baseline MM Stage and Cytogenetic Abnormalities

n (%)

Durie-Salmon stage, N = 46

Ia 25 (54)

IIa 16 (35)

IIb 3 (7)

IIIa 2 (4)

International Staging System stage, N = 33

I 14 (42)

II 11 (33)

III 8 (24)

Cytogenetics*, N = 44

Standard risk 20 (45)

High risk 24 (55)

*Standard risk, n (%), defined by the presence of one or more of the following: t(11;14): 4(16); hyperdiploidy, 12(46); FISH del 13q14, 12(46); no abnormality: 5(19).High risk, n (%), defined by the presence of one or more of the following: del 17p: 5(19); karyotype del 13q: 3(12); amp 1q/ del 1p: 5(19);

t(14;20): 1 (6); t(14;16): 1(6); t(4;14): 1(6); or other complex cytogenetic abnormalities.

Prior Therapy History (N = 46)

Refractory: disease that is nonresponsive while on therapy, or progresses within 60 days of last therapy. Relapsed: previously treated myeloma that progresses and requires initiation of salvage therapy but does not meet the definition of refractory MM.ASCT, autologous stem cell transplantation.

33 patients (71%) were refractory to both lenalidomide and bortezomib.

Results

46 patients completed at least 1 cycle of ClaPD.

– median number of cycles received was 6 (range 2–10)

– median study follow-up was 9.4 months (range 3.2–14.4)

In responding patients, median time to PR was 1.5 cycles (range 1–7)

Best Response (IMWG Criteria)

n (%) Overall(N = 46)

ORR (≥ PR) 27 (60)

sCR 3 (7)

VGPR 9 (20)

PR 15 (33)

MR 3 (7)

SD 7 (15)

PD 9 (20)

IMWG, International Myeloma Working Group; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.

Treatment History With Len/Bort Did Not Influence Response to ClaPD

37

Best Response (IMWG Criteria)

n (%) Overall(N = 46)

Lenalidomide refractory(N = 38)

Lenalidomide and bortezomib refractory

(N = 33)

ORR (≥ PR) 27 (60) 24 (63) 20 (61)

sCR 3 (7) 3 (8) 3 (9)

VGPR 9 (20) 7 (18) 5 (15)

PR 15 (33) 14 (37) 12 (36)

MR 3 (7) 2 (5) 2 (6)

SD 7 (15) 4 (11) 3 (9)

PD 9 (20) 8 (21) 8 (24)

IMWG, International Myeloma Working Group; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.

25

50

75

100

100 200 300

No

pro

gres

sion

(%

)Time (days)

00

PFS by Cytogenetic Risk

Standard riskHigh risk

Results

Median PFS: 8.13 months At latest analysis, adverse cytogenetics did not appear to influence the risk of progression

(log-rank P = 0.40)

25

50

75

100

100 200 300

No

pro

gres

sion

(%

)

Time (days)

00

PFS

No. of patients at risk: 46 33 17 0

No. of patients at risk:Standard risk 20 16 8 0High risk 24 15 8 0

25

50

75

100

100 200 300

No

pro

gres

sion

(%

)

Time (days)

00

25

50

75

100

100 200 300

No

pro

gres

sion

(%

)Time (days)

00

RelapsedDouble-refractory

PFS by Len history PFS by Len/Bort history

RelapsedRefractory

Results

At latest analysis, lenalidomide history did not statistically influence the risk of

progression (log-rank P = 0.14)

Similarly, a history of being refractory to both bortezomib and lenalidomide did not

statistically influence the risk of progression (log-rank P = 0.97)

Bort, bortezomib; Len, lenalidomide.

No. of patients at risk:Relapsed 8 4 2 0Refractory 38 29 15 0

No. of patients at risk:Relapsed 13 9 6 0Double- 33 24 11 0refractory

25

50

75

100

100 200 300

Sur

viva

l (%

)

Time (days)

00

OS

25

50

75

100

100 200 300

Sur

viva

l (%

)

Time (days)

00

OS by Cytogenetic Risk

Standard riskHigh risk

Median survival has not been reached. After median follow-up time for survival of

9.4 months, 39 patients (85%) are alive

Adverse cytogenetics did not appear to influence risk of death as of last study

follow-up (log-rank P = 0.48)

Results

No. of patients at risk: 46 45 37 20 4

No. of patients at risk:Standard risk 20 20 17 9 2High risk 24 23 18 11 2

400400

Grade 3/4 Adverse EventsAdverse event, n (%) Grade 3* Grade 4

Anemia 6 (13) 2 (4)

Thrombocytopenia 6 (13) 8 (17)

Neutropenia 15 (32) 6 (13)

Febrile neutropenia 5 (11) 1 (2)

Lymphopenia 11 (24) 5 (11)

Hypoglycemia 5 (11) 4 (9)

*Occurring in ≥ 10% of patients.

Two patients withdrew from study, both due adverse events: – 1 due to grade 3 fatigue – 1 due to grade 4 muscular weakness

There was no treatment-related mortality

Conclusions

• ClaPD is a highly effective regimen for heavily treated relapsed or refractory MM patients.

• ClaPD demonstrates clinical activity in patients with advanced MM who have received multiple prior therapies, including many who are refractory to both lenalidomide and bortezomib.

• PFS in patients treated with ClaPD is sustained for > 6 months in the majority of patients.

Conclusions

• High-risk cytogenetics did not impact PFS or OS in patients treated with ClaPD.

• A history of being refractory to prior lenalidomide or double-refractory to lenalidomide and bortezomib did not influence PFS in patients treated with ClaPD.

• Discontinuation due to adverse events was low (2 patients).

Pomalidomide Summary

• Pomalidomide is:– 2nd generation IMiD– Has anti-proliferative, anti-angiogenic, and IMiD

properties– Primary toxicities are similar to lenaliomide:

• Myelosuppression• Venous thromboses

– Active as a single agent– Synergizes with dexamethasone– Active in MM that is lenalidomide-refractory– Active in MM that is double-refractory– Less active as number of prior lines of therapy increases

44

Thank you

45