Current Chemotherapy and the Future of Targeted Therapies presented by Lee Krug, MD, of Memorial Sloan-Kettering Cancer Center at the Mesothelioma Applied Research Foundation's conference in New York, NY on September 28, 2012. www.curemeso.org

1. CURRENT CHEMOTHERAPY
AND THE FUTURE OF
TARGETED THERAPIES
Lee M. Krug, M.D.

2. Current Chemotherapy Options
 Standard 1st line regimen pemetrexed plus cisplatin or
carboplatin
 Improves survival, but only by a few months on average
 Improves quality of life
 Limited data on the efficacy of 2nd line therapy
 Rechallenge with pemetrexed if good initial response and
significant time since initial treatment
 Other option is vinorelbine
 16% response rate in one phase II trial
 0% response rate, 40% stable disease in MSKCC retrospective
series

3. Approaches for Development of Novel
MPM Therapies
 Adjuvant: After surgery or combined modality
therapy
 First-line:
 Add new agent in combination with pemetrexed, cisplatin
 Develop new regimen
 Maintenance: After treatment with pemetrexed,
cisplatin to maintain response
 Second-line: At progression after 1st line therapy

5. VANTAGE 014: Vorinostat in
Patients With Advanced Malignant
Pleural Mesothelioma Who Have
Failed Prior Pemetrexed and
Either Cisplatin or Carboplatin
Therapy: A Phase 3, Randomized,
Double-Blind, Placebo-Controlled
Trial
Lee M. Krug,* Hedy L. Kindler, Hilary Calvert,
Christian Manegold, Anne S. Tsao, Dean
Fennell, Gregory M. Lubiniecki, Xing Sun,
Margaret Smith, Paul Baas
*Memorial-Sloan Kettering Cancer Center, New York City, USA

6. Histone Deacetylase Inhibitors:
Mechanism of Action
Epigenetic (Histones/Chromatin) Anticancer Effects
HAT
Decondensed
Ac Ac Ac Ac
chromatin
Ac Ac Ac Ac Decrease Decrease
HDAC
proliferation angiogenesis
HDACi
Increase
apoptosis
HDAC
Ac
Ac Transcription factors
Signaling proteins
Chaperone proteins
Ac Ac
Structural proteins
HAT Decrease Increase
cell motility differentiation
Nonepigenetic (Nonhistone Protein)
HAT: histone acetyltransferase; HDAC: histone deacetylase; HDACi: histone
deacetylase inhibitor
Adapted from Paik PK, Krug LM. J Thorac Oncol. 2010;5(2):275–279.

7. VANTAGE 014 Study Design
R Vorinostat 300 mg
A orally, twice per day
Stratification N 3 of 7 days in a
D 3-week cycle
• KPS (>80% vs ≤ 80%) O
• Histology (epithelioid vs other) M Placebo orally,
• Prior chemo regimens (1 vs 2)
I twice per day
Z 3 of 7 days in a
E 3-week cycle
Double blind
330 patients in each arm
125 centers in 23 countries participated
ClinicalTrials.gov identifier: NCT00128102

8. Overall Survival Curves
(ITT Population)
OS: overall survival; P: placebo; V: vorinostat

9. Overall Survival: At and After Third
Interim Analysis (ITT Population)
Interim analysis 3 After interim analysis 3
■ Test of interaction between survival effect and time of enrollment (before or after interim
analysis 3) has a 2-sided P value of 0.019
OS: overall survival; V: vorinostat; P: placebo

10. Conclusions
VANTAGE 014 was the largest randomized trial in
malignant pleural mesothelioma
No survival difference
Statistically significant, but clinically irrelevant
benefit in progression free survival
Excellent correlative data collection
• Pulmonary function tests
• Lung cancer symptom scale-mesothelioma
• Soluble mesothelin-related peptide
• Pathologic tissue samples

11. Abstract ID #: 109
Updated results of the Phase II clinical trial of the
anti-mesothelin monoclonal antibody Amatuximab
in combination with Pemetrexed and Cisplatin for
front line therapy of pleural mesothelioma and
correlation of clinical outcome with serum
mesothelin, MPF and CA-125

12. Background
Amatuximab (MORAb-009): Chimeric mAb to mesothelin
• Safety demonstrated in phase I clinical trial
• In pre-clinical studies synergistic with chemotherapy
Mesothelin:
• Is a cell surface glycoprotein expressed on mesothelial
cells of pleura, peritoneum and pericardium
• Highly expressed in epithelial mesothelioma
Mesothelin processing

13. K-M for Progression Free Survival
---- MORAb-009 + Pemetrexed + Cisplatin
ooo MORAb-009 + Pemetrexed + Cisplatin Censored
Subjects who progressed or died: 52
% Progression-Free
Subjects Censored: 25
Time from First MORAb-009 Dose (Months)

14. Summary of Results
• No added toxicity of amatuximab aside from
hypersensitivity / infusion reactions in about 20%.
• Overall response rate and progression free survival as
expected.
• The median overall survival of 14.8 months compares
favorably with historical controls
• Currently, 29/89 subjects still alive, and 5 of the 29 are
still on amatuximab
• Low baseline mesothelin, MPF and CA-125 levels each
correlate with improved median overall survival

15. Randomized Phase II Trial of
Pemetrexed/Cisplatin with or without
CBP501 in Patients with Advanced
Malignant Pleural Mesothelioma (MPM)
L.M. Krug, A.J. Wozniak, H.L. Kindler, R. Feld,
M. Koczywas, J.L. Morero, C. Rodriguez, H.J. Ross,
J.E. Bauman, S.V. Orlov, J.C. Ruckdeschel, A.C. Mita,
L. Fein, X. He, R. Hall, T. Kawabe , S. Sharma

16. CBP501 - Background
 CBP501 is a novel, synthetic drug MPKAP-K2 C-TAK1 CHK1
designed from the peptide sequence
of the cell cycle regulator CDC25C.1
CBP501 P
 CBP501 inhibits several kinases
involved in G2 arrest and thereby CDC25C CDC25C
affects DNA repair selectively in
malignant cells. 1 P
CDC2 CDC2
Cyclin B Cyclin B
G2 M
 CBP501 also enhances DNA damage by
increasing platinum concentration and DNA-
platinum adduct formation in tumor cells.2
1. Sha SK, et al. Mol Cancer Ther 2007;6:147-53.
2. Mine N, et al. Mol Cancer Ther 2011;10:1929-38.

17. CBP501 Randomized Phase II Trial
Study Design
Open-label, multicenter, randomized phase II study
conducted in USA, Canada, Argentina and Russia
Arm A:
R Pemetrexed 500 mg/m2
A 2 Cisplatin 75 mg/m2
Unresectable MPM N = 42
N CBP501 25 mg/m2
Chemo naïve D Q3 weeks
Stratify by: O
Histology M Arm B:
Performance Status 1
I Pemetrexed 500 mg/m2 N = 21
Z Cisplatin 75 mg/m2
E Q3 weeks
Primary endpoint: Progression free survival at 4 months in Arm A.
If ≥ 23 of the 42 patients remain free of progression more than 4 months, the
combination will be deemed worthy of further study.

18. CBP501: Response in Evaluable Patients
Chemo + CBP501 Chemo
Investigator Assessed N=39 N=20
Complete Response (CR), n (%) 0 (0) 1 (5)
Partial Response (PR), n (%) 11 (28) 3 (15)
Objective Response Rate (ORR), n (%) 11 (28) 4 (20)
(95% CI) (.15, .45) (.06, .44)
Stable Disease (SD), n (%) 21 (54) 11 (55)
Chemo + CBP501 Chemo
Independent Radiology Review
N=39 N=20
Complete Response (CR), n (%) 0 (0) 0 (0)
Partial Response (PR), n (%) 12 (31) 2 (10)
Objective Response Rate (ORR), n (%) 12 (31) 2 (10)
(95% CI) (.17, .48) (.01, .32)
Stable Disease (SD), n (%) 15 (39) 10 (50)
Based on modified RECIST and confirmed with f/u scan at least 4 weeks later

19. CBP501: Progression Free Survival
Investigator Assessed Independent Radiology Review
Chemo + CBP501
Chemo
Chemo + Chemo Chemo + Chemo
CBP501 CBP501
# censored 7 4 # censored 8 6
# events 33 19 # events 32 17
Median PFS (mo) 5.9 4.6 Median PFS (mo) 5.1 3.4
P=0.24 P=0.42
PFS > 4 mo, n (%) 27 (68) 13 (57) PFS > 4 mo, n (%) 25 (63) 9 (39)

20. CBP501: Conclusions
1. This trial met its primary endpoint.
2. Response rate and progression free survival
favored the triplet combination arm, but not
significantly.
3. No added toxicities were noted with the addition
of CBP501 aside from the infusion reactions
which were all grade 1-2.
4. Results from a randomized phase II trial in NSCLC
are anticipated shortly.

21. Evaluation of anti-tumor activity and tolerability
of GDC-0980, an oral PI3K/mTOR inhibitor,
administered QD in patients with advanced
malignant pleural mesothelioma (MPM)
Hedy L. Kindler1, Saoirse Dolly2, Johanna Bendell3, Lee M. Krug4,
Lawrence Schwartz5, Michael Rabin6, 8, Nina Tunariu7, Tanguy Y.
Seiwert1, Marjorie G. Zauderer4, Ann M. Young2, Jennifer Shouldis1,
J P. Marcoux6, David Kwiatkowski6, 8, Jennifer O. Lauchle9, Howard
Burris3, Andrew J. Wagner6, 8, Johann de Bono2
1University Of Chicago, 2The Institute of Cancer Research and Royal Marsden
Hospital, 3Sarah Cannon Research Institute,4Memorial Sloan-Kettering Cancer
Center, 5Columbia University Medical Center, 6Dana Farber Cancer
Institute, 7Radiology Department, Royal Marsden Hospital, 8Brigham and Women’s
Hospital, 9Exploratory Clinical Development, Genentech

22. PI3K and mTOR: Therapeutic targets in MPM
• The PI3K/Akt/mTOR pathway is frequently activated in MPM1
• Small molecules that inhibit PI3K signaling1,2, and/or the mTOR
pathway,2,3 have activity in preclinical MPM models4
• PTEN loss inversely correlates with survival in MPM patients5
Inhibiting both PI3K and
mTOR may result in
increased efficacy within
a tumor and broader
efficacy across tumors
with diverse molecular
mechanisms of PI3K
activation
1. Mikami et al, Oncol Rep, 2010
2. Altomare et al, Oncogene, 2005
3. Hoda et al, J. Thoracic Oncology, 2011
4. López-Lago et al, Mol. Cell. Biol, 2009
5. Opitz et al, Eur J Cardiothorac Surg, 2008

23. Tumor Response Per Modified RECIST
Modified RECIST measurements per independent radiographic review
*
*
*
*
* * *
PTEN
loss
* *
*
* Biomarker analyses performed PIK3CA
R88Q
Data cut-off 18 May 2012

24. Conclusions
• GDC-0980 has demonstrated encouraging activity in patients
with pleural mesothelioma:
 Most patients had tumor shrinkage
 About 15% had a partial response
• Hyperglycemia, pneumonitis, and rash are associated with
GDC-0980 dosing, consistent with other PI3K or mTOR
inhibitors in clinical trials
• Tolerability of GDC-0980 in mesothelioma patients is similar
to patients with other solid tumors
• PIK3CA mutation and PTEN alterations have been detected
in some pleural mesotheliomas
 Preliminary data suggests clinical activity is present in
tumors independent of these alterations
25

25. Ongoing Clinical Trials (Partial List)
Drug Line Phase Sponsor
Bevacizumab 1st with pem/cis II/III French Intergroup
Cediranib 1st with pem/cis RP II SWOG
NGR-hTNF 2nd line RP II MolMed
Pemetrexed Maintenance RP II Alliance
WT-1 vaccine Adjuvant RP II MSKCC, MD Anderson

26. Potential Future Clinical Trials
Drug Sponsor
BAY 94-9343 Bayer
GDC-0980 Genentech
MORAb 009 Morphotek
Nintedanib Boehringer Ingelheim
Tremelimumab MedImmune
VS-6063 Verastem

27. Final Thoughts
 Fortunately, a number of new agents are planned
for clinical trials in mesothelioma, particularly
targeting the biology of the disease
 Imperative for patients to participate in these trials
 Need to develop a Meso Trials Consortium to
ensure that trials are done expeditiously and in a
scientifically sound manner