West Immunotherapy, Vaccines for Lung Cancer Mage-A3, Stimuvax, and Lucanix

Vaccine Strategies: MAGE-A3, Stimuvax, and Lucanix

Howard (Jack) West, MD

Swedish Cancer Institute

Seattle, WA

February, 2014

Disclosures

• Consultant:

– Genentech/Roche

– Celgene

– Novartis

– Foundation Medicine

MAGE-A3

Vansteenkiste, ASCO 2007, JCO 2013

• Tumor-specific

• 30-50% of NSCLC

• IHC testing

Biomarker Selection in NSCLC:

Predictive Gene Signature & DFI

- 5 -

MAGE-A3 as Adjuvant Non-Small Cell LunG CanceR ImmunoTherapy

Powered for efficacy

No chemo

MAGE-A3 ASCI PlaceboPowered for efficacy

Phase III Study - MAGRIT

MAGE-A3 ASCI Placebo

Randomization

Pathological stage IB, II, IIIA

Resected MAGE-A3 (+) NSCLC

Up to 4 cycles of

platinum-based chemo

Randomization

Chemo

>6000 screened for MAGE-A3 to enroll > 2000

Results expected 2H2014

Stimuvax (L-BLP25, Tecemotide)

Presented by: Charles Butts, M.D.6

Adjuvant = Monophosphoryl lipid A (MPL®)

The adjuvant supports T-cell response by inducing pro-inflammatory cytokines (via TLR4 stimulation)

Antigen = BLP25 lipopeptide

The amino acids of the lipopeptide provide antigenic epitopes for T cells

MUC1 mucin

Structural lipids = cholesterol, DPPC, and DMPG

Further enhancement of antigen delivery/uptake into APCs and immune reaction

G S T A P P A H G V T S A P D T R P A P

S T A P P A H G V T S A P D T R P A P G S T A P P - Lys (PAL) G

Mucinous glycoprotein overexpressed or

abnormally glycosylated in epithelial

malignancies

Rand Phase 2 of BLP-25 vs. Placebo

Stage IIIB (no MPE)


MPE/Stage IV

N = 171, stage IIIB or IV NSCLC

Prior chemo CR/PR/SD

Overall, median OS 17.4 vs. 13 mo, HR .739, p = 0.112

Butts, J Clin Oncol, 2005

Presented by: Charles Butts, M.D.

Day −3 i.v.

cyclophosphamide /

saline

6-weekly treatment

Randomize

2:1

Unresectable

NSCLC

stage IIIA/B

No progression

following

chemo/RT*

L-BLP25

+ BSC

Placebo

+ BSC

Disease

progression

Survival

follow-upWeekly treatmentScreening

Study design of EMR 63325-001 (START)

s.c. administrations L-BLP25/placebo

Primary endpoint: Overall survival

Key secondary endpoints:

• Time to symptom progression (TTSP)

as measured by the Lung Cancer

Symptom Scale (LCSS)

• Time to progression (TTP, investigator assessment)

• Safety

*Chemo/RT ≥2 cycles of platinum-based chemotherapy and radiation ≥50 Gy

Randomization strata:

• Stage IIIA vs. IIIB at first diagnosis

• CR/PR vs. SD to initial chemo/RT

• Concurrent vs. sequential chemo/RT

• Geographical region

The primary analysis (OS) was adjusted for

these four variables.


353

757

188

429

Placebo

L-BLP25

410

829

285

617

127

301

108

255

88

204

59

128

33

73

18

33

4

8

0

0

At risk (N)

L-BLP25

(N=829)

Placebo

(N=410)

Median OS 25.6 mo 22.3 mo

Adjusted HR 0.88 (95% CI 0.75‒1.03)

p=0.123*

Median

follow-up39.9 mo 37.7 mo

9

OS

rate

(%

)Primary endpoint: Overall survival

*Two-sided, strata and multiplicity adjusted


Imaging intervals according to institutional standards

226

513

90

205

Placebo

L-BLP25

410

829

144

329

58

144

49

122

42

96

25

60

15

30

9

13

3

5

0

0

At risk (N)

10

*Two-sided, adjusted for strata

TT

P r

ate

(%

)Secondary endpoint: Time to progression

L-BLP25

(N=829)

Placebo

(N=410)

Median TTP 10.0 mo 8.4 mo

Hazard ratio 0.87 (95% CI 0.75‒1.00)

p=0.053*


0.86 (0.67, 1.11)

0.90 (0.74, 1.09)

0.79 (0.58, 1.09)

0.91 (0.71, 1.17)

0.95 (0.73, 1.22)

0.85 (0.65, 1.11)

0.91 (0.75, 1.10)

0.78 (0.64, 0.96)

1.11 (0.86, 1.43)

Favors L-BLP25

Stage IIIA (N=487) 27.6 vs. 23.1

Stage IIIB (N=752) 23.7 vs. 20.9

NA and Aus. (N=321) 34.1 vs. 21.7

W. Europe (N=475) 24.2 vs. 22.3

Rest of world (N=443) 21.8 vs. 22.7

Stable disease (N=396) 20.4 vs. 17.8

Obj. response (N=843) 27.8 vs. 23.9

Concurrent (N=806) 30.8 vs. 20.6

Sequential (N=433) 19.4 vs. 24.6

Stage

Region

Response

to chemo/

RT

Chemo/ RT

type

Median OS (months)

L-BLP25 vs. Placebo

HR* (95% CI)

Favors placebo

11

OS: Subgroup analyses by randomization strata

*Not adjusted for strata

Overall survival: Concurrent chemo/RT


227

499

118

295

Placebo

L-BLP25

268

538

186

412

73

205

62

176

54

147

40

89

26

51

16

24

4

7

0

0

At risk (N)

12

L-BLP25

(N=538)

Placebo

(N=268)


Hazard ratio 0.78 (95% CI 0.64‒0.95)

p=0.016*

OS

rate

(%

)


Overall survival: Sequential chemo/RT


126

258

70

134

Placebo

L-BLP25

142

291

99

205

54

96

46

79

34

57

19

39

7

22

2

9

0

1

0

0

At risk (N)

13


OS

rate

(%

)

L-BLP25

(N=291)

Placebo

(N=142)


Hazard ratio 1.12 (95% CI 0.87‒1.44)

p=0.38*

Overview of adverse events


Preferred term

AE

L-BLP25

N=1,024

n (%)

Placebo

N=477

n (%)

Any 938 (91.6) 432 (90.6)

Any serious 303 (29.6) 151 (31.7)

Any grade 3/4 342 (33.4) 171 (35.8)

Any leading to death 46 (4.5) 35 (7.3)

Most frequent

adverse events

(>10 % in

L-BLP25 arm)

L-BLP25

N=1,024

n (%)

Placebo

N=477

n (%)

Cough 338 (33.0) 133 (27.9)

Dyspnea 238 (23.2) 112 (23.5)

Fatigue 197 (19.2) 102 (21.4)

Back pain 146 (14.3) 53 (11.1)

Nausea 140 (13.7) 39 (8.2)

Chest pain 135 (13.2) 45 (9.4)

Nasopharyngitis 128 (12.5) 44 (9.2)

Headache 124 (12.1) 54 (11.3)

Decreased

appetite

109 (10.6) 44 (9.2)

Arthralgia 108 (10.5) 34 (7.1)

Injection site

reactions

L-BLP25

(N=1,024)

Placebo

(N=477)

Any 176 (17.3) 56 (11.9)

Any Grade 3/4 0 (0) 0 (0)

Flu-like symptoms L-BLP25

(N=1,024)

Placebo

(N=477)

Any 391 (38.2) 158 (33.1)

Any Grade 3/4 15 (1.5) 8 (1.7)Injection-site reactions and flu-like symptoms

were identified by MedDRA PT search.

INSPIRE Trial (Asia)


Tecemotide

Placebo

Stage III

unresectable NSCLC

CR/PR/SD after >2

cycles platinum-based

doublet chemotherapy

with concurrent or

sequential RT

R

A

N

D

1

2

• N = 500

• Primary endpoint: overall survival

START2 Trial, just being initiated


Tecemotide

Placebo

Stage III

unresectable NSCLC

CR/PR/SD after >2



with concurrent RT

R

A

N

D

1

2

• N = 1002


Survival

Co-

hort N

Median

(months) 1-yr 2-yr 5-yr

All 75 14.5 55% 35% 20%

1 25 10.4 42% 21% 17%

2 26 21.8 67% 46% 21%

3 24 15.8 57% 39% 22%

Belagenpumatucel-L: Allogeneic whole tumor cell vaccine

Months

0 12 24 36 48 60 72

Su

rviv

al

0.0

0.2

0.4

0.6

0.8

1.0

Cohort 2

Cohort 1

Cohort 3

Data from March 2009

12/71 patients (17%) alive (Mar, 2009)

Survival range: 48 - 76 months

4 lost to follow up

2 stage II patients12 stage IIIA patients15 stage IIIB patients46 stage IV patients

Orig data - Nemunaitis, JCO 2006

– Four irradiated, cryopreserved NSCLC tumor cell lines

– Each gene-modified to block TGF-β2 secretion

N

Median

(months) 1-yr 2-yr 5-yr

SD, PR, or

CR

18 44 65% 59% 50%

PD 11 14 64% 36% 14%

BSC-SD,

PR, or CR

11 35% 8% <5%

BSC-PD 5 8% <5% <5%

Patients received one front-line, combination chemotherapy regimen: • with or without adjuvant chemotherapy• with or without radiation therapy

Overall survival of phase III-eligible patients

Time (Months)

0 12 24 36 48 60

Su

rviv

al

0.0

0.2

0.4

0.6

0.8

1.0

Patients who enrolled with SD/PR/CR

Patients who enrolled with PD

March 2009

8/16 patients (50%) currently alive

Survival range: 51 - 68 monthsMonths

BSC = best standard of careSD = stable disease; PR = partial response; CR = complete responsePD = progressive disease Orig data - Nemunaitis, JCO 2006

STOP trial of Belagenpumatucel vs. Placebo as Maintenance Therapy

Belagenpumatucel-L

Placebo

Stage IIIA/IIIB/IV NSCLC

CR/PR/SD after 4



start Rx 4-17 wks

after chemo

R

A

N

D

1

1

• N = 532, 42 with stage IIIA, 490 stage IIIB/IV (NOT all “wet” IIIB)


STOP trial of Belagenpumatucel vs. Placebo as Maintenance Therapy

• Overall results negative for OS benefit

– med OS 20.3 vs. 17.8 mo (HR 0.94)

– Minimal toxicity (grade 2 rash at most)

• Cox regression analysis (post hoc)

– Stage IIIB/IV pts starting within 12 weeks of prior chemo

med OS 20.7 vs. 13.4 mo (HR = 0.75, p = 0.083)

– Prior RT: med OS 40.1 vs. 10.3 mo (HR = 0.45, p = 0.014)

– Non-adeno, starting within 12 weeks of prior chemo >

med OS 19.9 vs. 12.3 mo (HR 0.55, p = 0.036)

• FDA notes interest in continued study in subgroups

Giaccone, ESMO 2013

Conclusions: Vaccines Have Potential for Efficacy with Excellent Therapeutic Index

• MAGE-A3: MAGRIT trial results awaited this year; have

potential to change standard of care for MAGE-A3

antigen-positive NSCLC in adjuvant setting

• START trial with tecemotide showed promising results

for patients who received concurrent chemo/RT– Await results of INSPIRE trial (Asia, START design)

– START2 trial of tecemotide after concurrent CT/RT being

initiated (N = 1002)

• Belagenpumatucel: Subsets identified as beneficiaries– Subsequent study? TBD

West Immunotherapy, Vaccines for Lung Cancer Mage-A3, Stimuvax, and Lucanix

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Transcript of West Immunotherapy, Vaccines for Lung Cancer Mage-A3, Stimuvax, and Lucanix