Ash 2014 update

ASH 2014 UPDATE

DR. RAJKUMAR M.D., D.M

CONSULTANT MEDICAL ONCOLOGIST

GURU CANCER CENTER

OVERVIEW

1. CHRONIC MYELOID LEUKEMIA

2. MULTIPLE MYELOMA

3. CHRONIC LYMPHOCYTIC

LEUKEMIA

4. FOLLICULAR LYMPHOMA

CHRONIC MYELOID LEUKEMIA

Early analysis of the randomized, open-label EPIC trial

Terminated early due to safety concerns in ponatinib clinical program (arterial thrombotic events)

Endpoints: BCR-ABLIS < 10% at 3 mos; MMR, MR4, MR4.5; CCyR rates; safety

Phase III EPIC: Ponatinib vs Imatinib in Pts

With Newly Diagnosed Ph+ CP-CML

Lipton JH, et al. ASH 2014. Abstract 519.

Pts with newly

diagnosed

Ph+ CP-CML

(N = 307)

Stratified by Sokal risk score:

low (< 0.8) vs

intermediate (0.8 to ≤ 1.2) vs

high (> 1.2) Ponatinib 45 mg/day orally

(n = 155)

Imatinib 400 mg/day* orally

(n = 152)

Dose modification allowed in both arms for management of AEs

*Dose escalation allowed for suboptimal response up to 800 mg/day (400 mg BID)

EPIC: Ponatinib vs Imatinib in Pts With

Newly Diagnosed CP-CML: Results

None of the prospectively defined endpoints could be analyzed due to trial termination

Deeper, more rapid response rates with ponatinib vs imatinib

– < 10% BCR-ABL transcripts at 3 mos overall

– Ponatinib: 94%

– Imatinib: 68%

– Significantly higher number of patients achieved MMR, MR4, MR4.5 with ponatinib vs imatinib in all risk groups

– Greater rate of molecular responses at 3, 6, 9, 12 mos with ponatinib vs imatinib

– Higher percentage of CCyR with ponatinib vs imatinibLipton JH, et al. ASH 2014. Abstract 519.

EPIC: Ponatinib vs Imatinib in Newly

Diagnosed Ph+ CP-CML: Conclusions

EPIC: ponatinib showed significantly improved efficacy vs imatinib in pts with newly diagnosed CP-CML, but with increased toxicity

< 10% BCR-ABL at 3 mos overall

– Ponatinib: 94%

– Imatinib: 68%

Better molecular response rates with ponatinib vs imatinib across all Sokal risk categories and time periods

Patients experienced greater number of AEs in ponatinib arm

– More grade 3/4 AEs and serious AEs

– More vascular occlusive events

Lipton JH, et al. ASH 2014. Abstract 519.

PACE: Effect of Early Response to

Ponatinib on Outcomes in Pretreated Pts

Objective: subset analysis (n = 267) of association between early landmark responses with ponatinib and long-term outcomes in heavily pretreated pts (more than 90% ≥ 2 TKIs) with CP-CML in phase II PACE trial

Assessment of responses at 3, 6, and 12 mos

– Molecular: BCR-ABLIS ≤ 0.1% (MMR), ≤ 1%, ≤ 10%

– Cytogenetic: MCyR, ≤ 35% Ph+ metaphases; CCyR, ≤ 0% Ph+ metaphases

Outcomes: PFS, OS, MR4.5

Median follow-up: 38.4 mos (range: 0.1-48.6)

Mueller M, et al. ASH 2014. Abstract 518.

≤ 1% BCR-ABL by 3 mos associated with longer 2-yr PFS, OS vs BCR-ABL > 1% at 3 mos

Molecular response at 3 mos directly correlated with MR4.5 over time

Response at 3 and 6 mos associated with significant improvement in 2-yr PFS and OS


Ponatinib: 2-Yr PFS, OS

Outcome 2-Yr PFS

Probability, %

P Value 2-Yr OS

Probability, %

P Value

3 mos

MMR 97

.0006

97

.0324No MMR 67 84

6 mos

MMR 95

< .0001

95

.0428No MMR 65 88

12 mos

MMR 93

.0010

100

.0089No MMR 74 93



Ponatinib: Conclusions

Early MMR in BCR-ABL with ponatinib in heavily pretreated pts with CP-CML correlated with improved long-term outcomes

– 2-yr PFS and OS significantly associated with positive 3-mo, 6-mo, and 12-mo cytogenetic and molecular responses


Early Predictors of Survival in Pts With

CML Treated With Imatinib

Background: BCR-ABLIS > 10% at 3 and 6 mos current threshold to assess pt response and determine treatment course

Current analysis: prognostic significance of 3-mo and 6-mo BCR-ABLIS vs 0.5 log reduction of BCR-ABL* at 3 mos from baseline according to sensitivity and specificity of BCR-ABL landmarks in pts with imatinib-treated CML in CML-Study IV

– BCR-ABL landmarks applied to pts with later disease progression (accelerated phase, blast phase, or death)

– Measured: 8-yr PFS

Hanfstein B, et al. ASH 2014. Abstract 156.

*Calculated from BCR-ABL ratio at 3 mos and at diagnosis.

Prognostic Markers for Safely Halting TKI

Therapy in Pts With CP-CML: EURO-SKI

Background: prospective trials suggest imatinib therapy may be sustainably and safely discontinued in CML pts with deep and durable MR (MR4; BCR-ABL <0.01% for at least 1 yr)

EURO-SKI study: define prognostic markers to identify patients most likely to retain deep molecular responses after stopping TKI therapy

Planned interim analysis: after 200 pts available with eligible molecular results at 6 mos

Eligible pts: CP-CML in confirmed deep MR (BCR-ABL < 0.01% for > 12 mos) while on TKI therapy ≥ 3 yrs

Primary endpoint: assessment of duration of MR after discontinuing TKI

Mahon FX, et al. ASH 2014. Abstract 151.

Loss of MMR by TKI duration: > 8 yrs, 29/86 pts (34%); ≤ 8 yrs, 60/114 (53%) Loss of MMR by MR4 duration: > 5 yrs, 32/92 pts (35%); ≤ 5 yrs, 57/108 (53%) Conclusion: ~ 60% of pts with CP-CML with initial stable, deep MR are likely to remain

in TFR after treatment is stopped

100

80

60

40

20

0

EURO-SKI: Molecular RFS at 18 Mos

Previous TKI Duration MR4 Duration


Mos From TKI Discontinuation

P = .0122

Mos From TKI Discontinuation0 6 12 18 24 30

P = .007

Mole

cula

r R

FS

(%

)

100

80

60

40

20

0

0 6 12 18 24 30

Mole

cula

r R

FS

(%

)> 8 yrs: 65%

≤ 8 yrs: 47%

> 5 yrs: 65%

≤ 5 yrs: 46%

EURO-SKI: Conclusion

EURO-SKI study suggests ~ 60% of pts with CP-CML with deep, durable MR (MR4; BCR-ABL <0.01% for at least 1 yr) on TKIs are likely to remain in remission after TKIs are stopped


MULTIPLE MYELOMA

Updated IMWG Criteria For Diagnosis of

Multiple Myeloma

*C: Calcium elevation (> 11 mg/dL or > 1 mg/dL higher than ULN)R: Renal insufficiency (creatinine clearance < 40 mL/min or serum creatinine > 2 mg/dL)A: Anemia (Hb < 10 g/dL or 2 g/dL < normal)B: Bone disease (≥ 1 lytic lesions on skeletal radiography, CT, or PET-CT)

Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

MGUS

M protein < 3 g/dL

Clonal plasma cells in BM < 10%

No myeloma defining events

Smoldering Myeloma

M protein ≥ 3 g/dL (serum) or ≥ 500 mg/24 hrs (urine)

Clonal plasma cells in BM 10% - 60%

No myeloma defining events

Multiple Myeloma

Underlying plasma cell proliferative disorder

AND 1 or more myeloma defining events

≥ 1 CRAB* feature

Clonal plasma cells in BM ≥ 60%

Serum free light chain ratio ≥ 100

>1 MRI focal lesion

FIRST: Lenalidomide/Dexamethasone vs

MPT in NDMM SCT-Ineligible Pts

Random

ized 1

:1:1

Arm B

Rd18

Arm C

MPT

Len + LoDex 18 cycles (72 wks)

Lenalidomide 25 mg Days 1-21/28

LoDex 40 mg Days 1, 8, 15, 22/28

Mel + Pred + Thal 12 cycles[2] (72 wks)

Melphalan 0.25 mg/kg Days 1-4/42

Prednisone 2 mg/kg Days 1-4/42

Thalidomide 200 mg Days 1-42/42

PD

, O

S,

and

su

bse

qu

en

t a

nti-M

M T

x

PD

or

unaccepta

ble

toxic

ity

Active treatment + PFS follow-up phase

Pts > 75 yrs: LoDex 20 mg Days 1, 8, 15, 22/28; Thal 100 mg Days 1-42/42;

Mel 0.2 mg/kg Days 1-4. Stratification: age, country, and ISS stage.

Len + LoDex Continuously

Lenalidomide 25 mg Days 1-21/28

LoDex 40 mg Days 1, 8, 15, 22/28

Arm A

Continuous Rd

1. Hulin C, et al. ASH 2014. Abstract 81. 2. Facon T, et al. Lancet. 2007;370:1209-1218. 3. Hulin C, et al.

J Clin Oncol. 2009;27:3664-3670. 4. Benboubker L, et al. N Engl J Med. 2014;371:906-917

Phase III

(N = 1623)

FIRST Trial: PFS by Age Stratification

Hulin C, et al. ASH 2014. Abstract 81. Reproduced with permission.

Aged 75 Yrs or Younger

100

80

60

40

20

0

Pts

(%

)

0 6 12 18 24 30 36 42 48 54 60

PFS (Mos)

HR (95% CI)Rd vs MPT: 0.68 (0.56-0.83)Rd vs Rd18: 0.68 (0.55-0.83)Rd18 vs MPT: 1.01 (0.84-1.21)

Rd Rd18MPT

Median,Mos27.421.321.8

46% (Rd)

25% (Rd18)

23% (MPT)

Aged Older Than 75 Yrs

100

80

60

40

20

0

Pts

(%

)

0 6 12 18 24 30 36 42 48 54 60

PFS (Mos)


Rd Rd18MPT

Median,Mos21.219.419.2

35% (Rd)

19% (Rd18)22% (MPT)

FIRST Trial: OS by Age Stratification


Aged 75 Yrs or Younger

100

80

60

40

20

0

Pts

(%

)

0 6 12 18 24 30 36 42 48 54 60

OS (Mos)


Rd Rd18MPT

3-Yr OS, %747067

Aged Older Than 75 Yrs

100

80

60

40

20

0

Pts

(%

)

0 6 12 18 24 30 36 42 48 54 60

OS (Mos)


Rd Rd18MPT

3-Yr OS, %635854

FIRST Trial: Grade 3/4 Adverse Events

Grade 3/4 Treatment-

Emergent AE, %

Dose for Pts Aged ≤ 75 Yrs Dose for Pts Aged > 75 Yrs

Continuous

Rd

(n = 347)

Rd18

(n = 348)

MPT

(n = 357)

Continuous

Rd

(n = 185)

Rd18

(n = 192)

MPT

(n = 184)

Hematologic in ≥ 10% of pts

Neutropenia 28 25 47 28 29 40

Anemia 18 12 20 19 23 17

Thrombocytopenia 8 9 13 9 7 7

Leukopenia 5 6 11 4 5 8

Nonhematologic

Infection 29 21 16 29 23 20

Cardiac disorders 12 6 6 12 9 13

Fatigue 6 8 5 9 10 8

Peripheral sensory neuropathy

1 1 10 1 0 8

Cataracts 7 3 < 1 3 2 1

DVT and/or PE 8 5 6 7 6 4


FIRST Trial: Conclusions

Continuous Rd improved PFS vs MPT or 18 cycles of Rd for newly diagnosed MM regardless of age

– Median and 3-yr PFS both extended with continuous Rd vs MPT or Rd18 whether pts were younger or older than 75 yrs of age

– 3-yr OS extended with continuous Rd vs MPT whether pts were younger or older than 75 yrs of age

– Analysis of FIRST results based on age consistent with overall trial results

Toxicity profile of Rd similar among pts 75 yrs of age or younger and older than 75 yrs of age

Hulin C, et al. ASH 2014. Abstract 81.

Modified Lenalidomide/Bortezomib/

Dexamethasone in ASCT-Ineligible NDMM

Phase II trial exploring utility of modified RVD (RVD lite); N = 30

– Lenalidomide: single daily oral dose of 15 mg Days 1-21

– Bortezomib: 1.3 mg/m2 SC once weekly Days 1, 8, 15, 22

– Dexamethasone: 20 mg twice weekly if ≤ 75 yrs or once weekly if > 75 yrs

RVD lite resulted in 90% ORR (≥ PR), ≥ VGPR: 53%

– 3 pts discontinued study after <1 cycle due to worsening adrenal insufficiency; rash attributed to lenalidomide; unrelated

AEs manageable and well tolerated in an older population

– Grade 3 AEs in ≥ 5%: hypophosphatemia (32%), rash (12%), mood disorder (9%)

– Grade 4 AEs: hypoglycemia (3%), neutropenia (3%), corneal ulcer (3%)

O’Donnell E, et al. ASH 2014. Abstract 3454.

Phase III Trial Comparing MPT-T vs MPR-R

in SCT-Ineligible Pts with NDMM

Joint study of the Dutch-Belgian Cooperative Trial Group for Hematology Oncology and the Nordic Myeloma Study Group

MPR

Melphalan 0.18 mg/kg on Days 1-4 +

Prednisone 2 mg/kg on Days 1-4 +

Lenalidomide 10 mg on Days 1-21

(n = 319)

MPT

Melphalan 0.18 mg/kg on Days 1-4 +

Prednisone 2 mg/kg on Days 1-4 +

Thalidomide 200 mg on Days 1-28

(n = 318)

R Maintenance

Lenalidomide 10 mg

on Days 1-21 q28d

until PD

T Maintenance

Thalidomide

100 mg/day

until PD

Stratified by

center and ISS

28-day cycles x 9

Ra

nd

om

iza

tio

n 1

:1

Zweegman S, et al. ASH 2014. Abstract 179.

Granulocyte-colony stimulating factor administered if absolute neutrophil count < 0.5 x 109 cells/L or in

event of febrile neutropenia during a cycle.

MPT-T vs MPR-R: Efficacy Analysis

Median follow-up: 33.6 mos

ORR similar between arms: 81% MPT-T vs 83% MPR-R

No significant difference in PFS or OS


OutcomeMPR-R

(n = 319)MPT-T

(n = 318)HR (95% CI) P Value

ORR (on protocol), % 83 81

CR 13 10

VGPR 32 38

PR 39 33

Median PFS, mos 22 20 086 (0.72-1.04) .12

Median OS, mos NR NR 0.79 (0.61-1.03) .08

2-yr OS, % 84 73

3-yr OS, % 69 64

4-yr OS, % 55 52

MPT-T vs MPR-R: Safety Analysis

*Primarily due to peripheral neuropathy in thalidomide arm, hematologic toxicity in lenalidomide arm


Treatment Outcome, % MPR-R MPT-T

≤ 75 Yrs > 75 Yrs ≤ 75 Yrs > 75 Yrs

Completed 6 induction cycles 68 73 76 77

Initiated maintenance therapy 59 58 57 39

Discontinued maintenance 43 88

Due to AEs* 24 31 67 69

Median duration of maintenance, mos

(range)

16 (0-53) 15 (1-52) 5 (0-49) 5 (0-44)

MPT-T associated with significantly higher rate of grade ≥ 2 neuropathy (45% vs 8%; P < .0001); higher rate of grade 3/4 hematologic AEs (including neutropenia [63% vs 27%], thrombocytopenia [28% vs 8%], and anemia [14% vs 5%]) vs MPR-R

ASPIRE: Phase III Trial Comparing Len/

Dexamethasone ± Carfilzomib in R/R MM

Randomized, open-label, multicenter phase III trial

KRd* (n = 396)

Carfilzomib 27 mg/m2 IV

Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)

Lenalidomide 25 mg Days 1-21

Dexamethasone 40 mg Days 1, 8, 15, 22

Rd (n = 396)

Lenalidomide 25 mg Days 1-21

Dexamethasone 40 mg Days 1, 8, 15, 22

Stratified by β2-microglobulin, prior

bortezomib, and prior lenalidomide

*After cycle 12, carfilzomib given on Days 1, 2, 15, 16. After cycle 18, carfilzomib discontinued.

Stewart AK, et al. ASH 2014. Abstract 79.

Pts with symptomatic

R/R MM after 1-3 prior

treatments with ≥ PR

to ≥ 1 prior regimen

(N = 792)

28 day cycles

ASPIRE: PFS in ITT Population (Primary

Endpoint)KRd Rd

(n = 396) (n = 396)

Median PFS, mos 26.3 17.6

HR (KRd/Rd) (95% CI) 0.69 (0.57-0.83)

P value (1 sided) < .0001

1.0

0.8

0.6

0.4

0.2

0.0

Pro

port

ion S

urv

ivin

g

Without

Pro

gre

ssio

n

KRd

Rd

0 6 12 18 24 30 36 42 48Mos Since Randomization

Stewart AK, et al. ASH 2014. Abstract 79. Reproduced with permission.

Risk Group by

FISH

KRd (n = 396) Rd (n = 396) HR P Value

n Median PFS, Mos n Median PFS, Mos

High 48 23.1 52 13.9 0.70 .083

Standard 147 29.6 170 19.5 0.66 .004

ASPIRE: Interim OS Analysis

OS results did not meet prespecified statistical boundary (P = .005) at interim

AEs consistent with previous studies; no unexpected toxicities observed

– Grade ≥ 3 cardiac failure and ischemic heart disease: 3.8% and 3.3% in KRd arm vs 1.8% and 2.1% in Rd arm, respectively

KRd Rd

(n = 396) (n = 396)

Median OS, mos NR NR

HR (KRd/Rd) (95% CI) 0.79 (0.63-0.99)

P value (1 sided) .018

Median follow-up: 32 months

1.0

0.8

0.6

0.4

0.2

0.0

Pro

port

ion S

urv

ivin

g

KRd

Rd

0 6 12 18 24 30 36 42 48Mos Since Randomization

Stewart AK, et al. ASH 2014. Abstract 79. Reproduced with permission.

ASPIRE: Conclusions

PFS significantly improved by 8.7 mos in pts treated with KRd vs Rd relapsed/refractory MM (HR: 0.69; P < .0001)

– Median PFS of 26.3 mos with triplet combination unprecedented in this setting

Interim OS analysis reveals trend favoring KRd

Increased ORR with KRd vs Rd: 87.1% vs 66.7%

– More pts achieved CR or better with triplet: 31.8% with KRd vs 9.3% with Rd

Acceptable safety profile observed with KRd

KRd potentially new standard of care for treatment of relapsed MM

Stewart AK, et al. ASH 2014. Abstract 79.

CLL

CLL10 (Phase III): Final Analysis of FCR vs

BR in Pts With Advanced CLL

Eichhorst B, et al. ASH 2014. Abstract 19

FCR

Fludarabine 25 mg/m2 IV Days 1-3

Cyclophosphamide 250 mg/m2 Days 1-3

Rituximab 375 mg/m2 IV Day 0, cycle 1

Rituximab 500 mg/m2 IV Day 1, cycles 2-6

BR

Bendamustine 90 mg/m2 IV Days 1-2

Rituximab 375 mg/m2 Day 0, cycle 1

Rituximab 500 mg/m2 IV Day 1, cycles 2-6

Pts with untreated,

active CLL without

del(17p) and good

physical fitness

(CIRS ≤ 6, creatinine

clearance ≥ 70 mL/min)

(N = 564)

Primary endpoint: noninferiority of BR vs FCR for PFS HR (λBR/FCR) < 1.388

1.0

0.8

0.6

0.4

0.2

0

FCR vs BR in Pts With Advanced CLL:

PFS


Cum

ula

tive

Su

rviv

al

ITT PFS = Primary Endpoint

PFS in IGHV-Matched Population (n = 398; FCR = 201; BR = 197)

0 12 24 36 48 60

Median PFSFCR: 55.2 mosBR: 41.7 mos

P < .001HR: 1.626C

um

ula

tive S

urv

ival

1.0

0.8

0.6

0.4

0.2

0

0 12 24 36 48 60

Median PFSFCR: NRBR: 43.1 mos

P < .005HR: 1.565

1.0

0.8

0.6

0.4

0.2

0

FCR vs BR in Pts With Advanced CLL: OS


0 12 24 36 48 60

Cum

ula

tive S

urv

ival

Mos to Event (OS)

OS at 36 MosFCR: 90.6%BR: 92.2%

P = .897

FCR vs BR in Pts With Advanced CLL:

Conclusions

BR showed inferiority with PFS and CR rate compared with FCR in the final analysis

Lower rates of neutropenias and severe infections in elderly pts associated with BR

FCR is still standard therapy for fit pts, whereas BR may be considered in fit, elderly pts as an alternative


RESONATE-17: Phase II Ibrutinib in

del(17p) Relapsed/Refractory CLL/SLL CLL/SLL

– Relapsed/refractory disease after 1-4 prior therapies

– del(17p)13.1 in peripheralblood*

– ECOG PS 0-1

– Measurable nodal disease

Primary endpoint: ORR

Secondary endpoints

– DoR

– Safety

– Tolerability

Exploratory endpoints

– PFS

– OSO’Brien SM, et al. ASH 2014. Abstract 327.

Ibrutinib 420 mg/day PO

(N = 144)

*Confirmed by FISH.

Until unacceptable toxicity or disease progression

Primary analysis 12 mos after last enrolled pt

Ibrutinib in del(17p) Relapsed/Refractory

CLL/SLL: Main Findings Best response (ORR + PR-L) by IRC (no 2nd confirmatory CT scan) was 74%

(95% CI: 66% to 80%)

Median DOR was not reached at median follow-up of 11.5 mos; 12-mo DOR was 88.3%

O’Brien SM, et al. ASH 2014. Abstract 327.

Median PFS (Not Reached) Median OS (Not Reached)100

80

60

40

20

00 121 2 3 4 5 6 7 8 9 10 11

Mos

PF

S (

%)

100

80

60

40

20

00 121 2 3 4 5 6 7 8 9 10 11

Mos

OS

(%

)

Ibrutinib in del(17p) Relapsed/Refractory

CLL/SLL: Conclusions

Ibrutinib showed efficacy with favorable risk–benefit profile in pts with del(17p) CLL/SLL

12-mo PFS: 79%, consistent with previous study of 26-mo PFS (75%)

PFS outcomes in this relapsed/refractory setting favorable compared with previous results for frontline FCR regimen or alemtuzumab in del(17p) CLL (median PFS: 11 mos)

Safety profile consistent with known profile for ibrutinib

O’Brien SM, et al. ASH 2014. Abstract 327. Byrd JC, et al. N Engl J Med. 2013;369:32-42.

Primary outcome:

– CR/CRu rate assessed at Wk 23, defined according to NCI criteria

– Response assessment

Treatment-naive pts with grade 1, 2, 3A FL,

in need of therapy

(N = 154)

Rituximab 375 mg/m2 on Day 1 of Wks 1-4, 12-15 +

Lenalidomide 15 mg/day*

(n = 77)

Rituximab 375 mg/m2 on Day 1 of Wks 1-4, 12-15

(n = 77)

*Lenalidomide started 14 days before first administration of rituximab and continued until 14 days after

last rituximab dose.

Stratified by

FL grade 1-2 vs 3a

Bulky vs no bulk

FLIPI score 1, 2 vs ≥ 3

First restaging

Wk 10

Second restaging

Wk 22-24

Kimby E, et al. ASH 2014. Abstract 799.

Phase II Rituximab + Lenalidomide vs

Rituximab Monotherapy in Untreated FL

Rituximab + Lenalidomide vs Rituximab in

Untreated FL: Overall Response


ITT population PP population

90

80

70

60

50

40

30

20

10

010%

35%

45%

13%

62%

75%

25%

36%

36%

45%

61%

82%

R(n = 77)

R + Lenalidomide

(n = 77)

R + Lenalidomide

(n = 77)

R(n = 77)

Wk 10 Wk 23

P < .0001P = .002

PRCR/CRu

Pts

(%

)

90

80

70

60

50

40

30

20

10

0

Pts

(%

)

11%

37%

48%

17%

67%

28%

38%

45%

42%

83%

66%

87%

R(n = 65)

R + Lenalidomide

(n = 60)

R + Lenalidomide

(n = 60)

R(n = 65)

Wk 10 Wk 23

P < .0001 P = .003

PRCR/CRu

Rituximab + Lenalidomide vs Rituximab

Monotherapy in Untreated FL: Conclusions

Addition of rituximab to lenalidomide associated with significantly more CRs vs rituximab alone in untreated FL (36% vs 25%, respectively)

Comparison with existing single-arm studies confounded by differences in pt characteristics and treatment schedules

Neutropenia was the most common grade 3/4 AE with rituximab + lenalidomide; more grade 3/4 AEs seen with combination

– Continuous dosing may contribute to lenalidomide toxicity

According to investigators, further follow-up needed to determine if better response translates to improvement in PFS, OS, and time to next treatment


Comparing CTLA-4 and PD-1

PD-1 CTLA-4

Biological function Inhibitory receptor Inhibitory receptor

Expression on Activated T cells, B cells, NK cells

TILs in different tumor types

T cells at the time of initial response

to antigen (activated CD8+ T cells)

Major role Limits T-cell activity in peripheral

tissue after inflammatory response

Limits autoimmunity

Regulates the early stage of T-cell

activation

Ligands PD-L1 (B7-H1/CD274)

PD-L2 (B7-CD/CD273)

B7.1 (CD80)

B7.2 (CD86)

Mechanism of action After ligand binding:

Recruits inhibitory phosphatase,

SHP-2

Decreases expression of cell

survival protein Bcl-xL

Inhibits kinases (PI3K/AKT) involved

in T-cell activation

After ligand binding:

Binding with PI3K, phosphatases

SHP-2 and PP2A

Blockade of lipid-raft expression

Blockade of microcluster formation

Merelli B, et al. Crit Rev Oncol Hematol. 2014;89:140-165.

PD-L2–mediated

inhibition of TH2 T cellsStromal PD-L1

modulation of T cells

Reprinted from Clinical Cancer Research. 2013;19(5):1021-1034. Sznol M, et al. Antagonist antibodies to PD-1 and B7-H1

(PD-L1) in the treatment of advanced human cancer. With permission from AACR.

Blockade of PD-1 Binding to PD-L1 (B7-

H1) and PD-L2 (B7-DC) Revives T Cells

PD-L1 expression on tumor cells is induced by γ-interferon

In other words, activated T cells that could kill tumors are specifically disabled by those tumors

PD-1

PD-L1

PD-L2

T-cell receptor

MHC-1

CD28

Shp-2

B7.1

IFN-γ–mediated

upregulation of

tumor PD-L1PD-L1/PD-1–mediated

inhibition of tumor cell killing

Priming and

activation of

T cells

Immune cell

modulation of T cells

Tumor cell

IFN-γR

IFN-γ

Tumor-associated

fibroblast M2

macrophage

Treg

cell

Th2

T cell

Other NFκB P13K

CD8+ cytoxic

T lymphocyte

T-cell polarization

TGF-β

IL-4/13

Can you generate

tumor-killing T cells?

Dendritic

cell

Antigen priming

Can the T cells

get to the tumor?

T-cell trafficking

Can the T cells

see the tumor?

Peptide-MHC

expression

Can the T cells

be turned off?

Inhibitory cytokines

Can the T cells

be turned off?

PD-L1 expression

on tumor cells

CTLA-4 and PD-1/PD-L1 Checkpoint

Blockade for Cancer Treatment

Immune checkpoint blockade includes agents targeting the negative regulators CTLA-4 and PD-1

CTLA-4 attenuates the early activation of naive and memory T cells in the lymph nodes

– Agents targeting CTLA-4 include ipilimumab and tremelimumab

In contrast, PD-1 modulates the effector phase of T cell activity in peripheral tissues via interaction with PD-L1 and PD-L2

– Agents targeting PD-1 include nivolumab and MK-3475

– Agents targeting PD-L1 include MPDL3280A and MEDI4736

Kyi C, et al. FEBS Lett. 2014;588:368-376

CTLA-4 and PD-1/PD-L1 Checkpoint

Blockade for Cancer Treatment

Immune checkpoint blockade includes agents targeting the negative regulators CTLA-4 and PD-1

CTLA-4 attenuates the early activation of naive and memory T cells in the lymph nodes

– Agents targeting CTLA-4 include ipilimumab and tremelimumab

In contrast, PD-1 modulates the effector phase of T cell activity in peripheral tissues via interaction with PD-L1 and PD-L2

– Agents targeting PD-1 include nivolumab and MK-3475

– Agents targeting PD-L1 include MPDL3280A and MEDI4736

Kyi C, et al. FEBS Lett. 2014;588:368-376

PD-1 and PD-L1 Antibodies Currently

in Phase III Development

Agent Class Disease State

Anti–PD-L1

MPDL3280A Engineered IgG1 NSCLC[1]

MEDI-4736 Modified IgG1 NSCLC[2]

Anti–PD-1

Nivolumab IgG4 Melanoma,[3] NSCLC,[4] RCC[5]

MK-3475

(pembrolizumab)

IgG4 (humanized) Melanoma,[6] NSCLC[7,8]

1. ClinicalTrials.gov. NCT02008227. 2. ClinicalTrials.gov. NCT02125461. 3. ClinicalTrials.gov. NCT01844505.

4. ClinicalTrials.gov. NCT01673867. 5. ClinicalTrials.gov. NCT01668784. 6. ClinicalTrials.gov. NCT01866319.

7. ClinicalTrials.gov NCT01905657. 8. ClinicalTrials.gov. NCT02142738.

Health & Medicine

Ash 2014 update