This document summarizes information about three cancer vaccines - MAGE-A3, Stimuvax (L-BLP25, Tecemotide), and Lucanix (Belagenpumatucel-L). It discusses past and ongoing clinical trials of these vaccines in non-small cell lung cancer (NSCLC), including trial designs, results, and potential efficacy in patient subgroups. Key information presented includes Phase 3 trial results for Stimuvax showing a possible survival benefit in patients receiving concurrent chemotherapy and radiation, and evidence that Belagenpumatucel-L may benefit certain NSCLC patient subgroups based on retrospective analyses.

1. Vaccine Strategies:
MAGE-A3, Stimuvax, and Lucanix
Howard (Jack) West, MD
Swedish Cancer Institute
Seattle, WA
February, 2014

2. Disclosures
• Consultant:
–
–
–
–
Genentech/Roche
Celgene
Novartis
Foundation Medicine

3. MAGE-A3
• Tumor-specific
• 30-50% of NSCLC
• IHC testing
Vansteenkiste, ASCO 2007, JCO 2013

4. Biomarker Selection in NSCLC:
Predictive Gene Signature & DFI

5. Phase III Study - MAGRIT
MAGE-A3 as Adjuvant Non-Small Cell LunG CanceR ImmunoTherapy
Resected MAGE-A3 (+) NSCLC
Pathological stage IB, II, IIIA
No chemo
Chemo
Randomization
Up to 4 cycles of
platinum-based chemo
MAGE-A3 ASCI
Placebo
Randomization
Powered for efficacy
MAGE-A3 ASCI
Powered for efficacy
>6000 screened for MAGE-A3 to enroll > 2000
Results expected 2H2014
-5-
Placebo

6. Stimuvax (L-BLP25, Tecemotide)
Mucinous glycoprotein overexpressed or
abnormally glycosylated in epithelial
malignancies
MUC1 mucin
GSTAPPAHGVTSAPDTRPAP
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
Antigen = BLP25 lipopeptide
The amino acids of the lipopeptide provide antigenic epitopes for T cells
Adjuvant = Monophosphoryl lipid A (MPL®)
The adjuvant supports T-cell response by inducing pro-inflammatory cytokines (via TLR4 stimulation)
Structural lipids = cholesterol, DPPC, and DMPG
Further enhancement of antigen delivery/uptake into APCs and immune reaction
6
Presented by: Charles Butts, M.D.

7. Rand Phase 2 of BLP-25 vs. Placebo
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
MPE/Stage IV
Stage IIIB (no MPE)
7
Butts,Presented by: Charles Butts, M.D.
J Clin Oncol, 2005

8. Study design of EMR 63325-001 (START)
Screening
Weekly treatment
6-weekly treatment
Survival
follow-up
Day −3 i.v.
cyclophosphamide /
saline
Unresectable
NSCLC
stage IIIA/B
No progression
following
chemo/RT*
L-BLP25
+ BSC
s.c. administrations L-BLP25/placebo
Randomize
2:1
Placebo
+ BSC
Disease
progression
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.
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
Presented by: Charles Butts, M.D.

9. Primary endpoint: Overall survival
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*
OS rate (%)
Median
follow-up
39.9 mo
37.7 mo
*Two-sided, strata and multiplicity adjusted
At risk (N)
Placebo
L-BLP25
9
410
829
353
757
285
617
Presented by: Charles Butts, M.D.
188
429
127
301
108
255
88
204
59
128
33
73
18
33
4
8
0
0

10. Secondary endpoint: Time to progression
Placebo
(N=410)
Median TTP
10.0 mo
8.4 mo
Hazard ratio
TTP rate (%)
L-BLP25
(N=829)
0.87 (95% CI 0.75‒1.00)
p=0.053*
*Two-sided, adjusted for strata
Imaging intervals according to institutional standards
At risk (N)
Placebo
L-BLP25
10
410
829
226
513
144
329
Presented by: Charles Butts, M.D.
90
205
58
144
49
122
42
96
25
60
15
30
9
13
3
5
0
0

11. OS: Subgroup analyses by randomization strata
Median OS (months)
L-BLP25 vs. Placebo
HR* (95% CI)
Stage IIIA (N=487)
23.7 vs. 20.9
0.90 (0.74, 1.09)
NA and Aus. (N=321)
34.1 vs. 21.7
0.79 (0.58, 1.09)
24.2 vs. 22.3
0.91 (0.71, 1.17)
Rest of world (N=443)
Response
to chemo/
RT
0.86 (0.67, 1.11)
W. Europe (N=475)
Region
27.6 vs. 23.1
Stage IIIB (N=752)
Stage
21.8 vs. 22.7
0.95 (0.73, 1.22)
Stable disease (N=396) 20.4 vs. 17.8
0.85 (0.65, 1.11)
Obj. response (N=843) 27.8 vs. 23.9
0.91 (0.75, 1.10)
Chemo/ RT Concurrent (N=806)
type
Sequential (N=433)
*Not adjusted for strata
11
Presented by: Charles Butts, M.D.
30.8 vs. 20.6
0.78 (0.64, 0.96)
19.4 vs. 24.6
1.11 (0.86, 1.43)
Favors L-BLP25
Favors placebo

12. Overall survival: Concurrent chemo/RT
Placebo
(N=268)
Median OS
30.8 mo
20.6 mo
Hazard ratio
0.78 (95% CI 0.64‒0.95)
p=0.016*
OS rate (%)
L-BLP25
(N=538)
*Two-sided, adjusted for strata
At risk (N)
Placebo
L-BLP25
12
268
538
227
499
186
412
Presented by: Charles Butts, M.D.
118
295
73
205
62
176
54
147
40
89
26
51
16
24
4
7
0
0

13. Overall survival: Sequential chemo/RT
Placebo
(N=142)
Median OS
19.4 mo
24.6 mo
Hazard ratio
1.12 (95% CI 0.87‒1.44)
p=0.38*
OS rate (%)
L-BLP25
(N=291)
*Two-sided, adjusted for strata
At risk (N)
Placebo
L-BLP25
13
142
291
126
258
99
205
Presented by: Charles Butts, M.D.
70
134
54
96
46
79
34
57
19
39
7
22
2
9
0
1
0
0

14. 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)
46 (4.5)
35 (7.3)
L-BLP25
(N=1,024)
Placebo
(N=477)
Any
176 (17.3)
56 (11.9)
0 (0)
0 (0)
L-BLP25
(N=1,024)
Placebo
(N=477)
391 (38.2)
8 (1.7)
Any Grade 3/4
Flu-like symptoms
Any
Any Grade 3/4
14
Cough
338 (33.0)
133 (27.9)
Dyspnea
238 (23.2)
112 (23.5)
Fatigue
197 (19.2)
102 (21.4)
146 (14.3)
53 (11.1)
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)
158 (33.1)
15 (1.5)
Placebo
N=477
n (%)
Nausea
Injection site
reactions
L-BLP25
N=1,024
n (%)
Back pain
Any leading to death
Most frequent
adverse events
(>10 % in
L-BLP25 arm)
Presented by: Charles Butts, M.D.
Injection-site reactions and flu-like symptoms
were identified by MedDRA PT search.

15. INSPIRE Trial (Asia)
• N = 500
Stage III
unresectable NSCLC
CR/PR/SD after >2
cycles platinum-based
doublet chemotherapy
with concurrent or
sequential RT
15
Presented by: Charles Butts, M.D.
2
R
A
N
D
1
Tecemotide
Placebo
• Primary endpoint: overall survival

16. START2 Trial, just being initiated
• N = 1002
Stage III
unresectable NSCLC
CR/PR/SD after >2
cycles platinum-based
doublet chemotherapy
with concurrent RT
2
R
A
N
D
1
Tecemotide
Placebo
• Primary endpoint: overall survival
16
Presented by: Charles Butts, M.D.

17. Belagenpumatucel-L: Allogeneic whole tumor cell vaccine
– Four irradiated, cryopreserved NSCLC tumor cell lines
– Each gene-modified to block TGF-β2 secretion
1.0
Survival
All
N
Median
(months)
1-yr
2-yr
5-yr
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%
0.8
Survival
Cohort
Cohort 1
Cohort 2
Cohort 3
0.6
22%
2 stage II patients
12 stage IIIA patients
15 stage IIIB patients
46 stage IV patients
0.4
0.2
0.0
0
12/71 patients (17%) alive (Mar, 2009)
Survival range: 48 - 76 months
4 lost to follow up
12
24
36
48
60
72
Months
Orig data - Nemunaitis, JCO 2006
Data from March 2009

18. Overall survival of phase III-eligible patients
N
Median
(months)
1-yr
2-yr
5-yr
SD, PR, or
CR
18
44
65%
59%
50%
PD
11
1.0
14
64%
36%
14%
BSC-SD,
PR, or CR
11
35%
8%
<5%
BSC-PD
5
0.8
8%
<5%
<5%
Patients received one front-line, combination
chemotherapy regimen:
• with or without adjuvant chemotherapy
• with or without radiation therapy
Survival
Patients who enrolled with SD/PR/CR
8/16 patients (50%) currently alive
Survival range: 51 - 68 months
BSC = best standard of care
SD = stable disease; PR = partial response; CR = complete response
PD = progressive disease
0.6
0.4
Patients who enrolled with PD
0.2
0.0
0
12
24
36
Months
Time (Months)
48
60
Orig data - Nemunaitis, JCO 2006
March 2009

19. STOP trial of Belagenpumatucel vs. Placebo as Maintenance Therapy
• N = 532, 42 with stage IIIA, 490 stage IIIB/IV (NOT all “wet” IIIB)
Stage IIIA/IIIB/IV
NSCLC
CR/PR/SD after 4
cycles platinum-based
doublet chemotherapy
1
R
A
N
D
1
start Rx 4-17 wks
after chemo
Belagenpumatucel-L
Placebo
• Primary endpoint: overall survival

20. 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

21. 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