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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
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CURRENT CHEMOTHERAPY
AND THE FUTURE OF
TARGETED THERAPIES
Lee M. Krug, M.D.
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
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
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
Ac Ac
Ac Ac
Epigenetic (Histones/Chromatin)
Nonepigenetic (Nonhistone Protein)
Anticancer Effects
Decrease proliferation
Decrease angiogenesis
Decrease cell motility
Increase apoptosis
Increase differentiation
Decondensed chromatin
Transcription factors
Signaling proteins Chaperone proteins Structural proteins
Histone Deacetylase Inhibitors:
Mechanism of Action
HDAC
HAT
HAT
HDAC
HAT: histone acetyltransferase; HDAC: histone deacetylase; HDACi: histone deacetylase inhibitor Adapted from Paik PK, Krug LM. J Thorac Oncol. 2010;5(2):275–279.
HDACi
Ac Ac Ac Ac
Ac Ac Ac Ac
R
A
N
D
O
M
I
Z
E Double blind
330 patients in each arm
125 centers in 23 countries participated
ClinicalTrials.gov identifier: NCT00128102
Vorinostat 300 mg
orally, twice per day
3 of 7 days in a
3-week cycle
Placebo orally,
twice per day
3 of 7 days in a
3-week cycle
Stratification
• KPS (>80% vs ≤ 80%)
• Histology (epithelioid vs other)
• Prior chemo regimens (1 vs 2)
VANTAGE 014 Study Design
Overall Survival Curves
(ITT Population)
OS: overall survival; P: placebo; V: vorinostat
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
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
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
Abstract ID #: 109
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
Background
K-M for Progression Free Survival %
Pro
gre
ssio
n-F
ree
Time from First MORAb-009 Dose (Months)
---- MORAb-009 + Pemetrexed + Cisplatin
ooo MORAb-009 + Pemetrexed + Cisplatin Censored
Subjects who progressed or died: 52
Subjects Censored: 25
• 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
Summary of Results
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
CBP501 - Background
CBP501 is a novel, synthetic drug
designed from the peptide sequence
of the cell cycle regulator CDC25C.1
CBP501 inhibits several kinases
involved in G2 arrest and thereby
affects DNA repair selectively in
malignant cells. 1
G2 M
P
Cyclin B CDC2 CDC2
P
CDC25C CDC25C
MPKAP-K2 C-TAK1 CHK1
CBP501
Cyclin B
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.
CBP501 Randomized Phase II Trial
Study Design
Unresectable MPM Chemo naïve Stratify by: Histology Performance Status
Open-label, multicenter, randomized phase II study conducted in USA, Canada, Argentina and Russia
RANDOMIZE
Arm A: Pemetrexed 500 mg/m2
Cisplatin 75 mg/m2
CBP501 25 mg/m2
Q3 weeks
Arm B: Pemetrexed 500 mg/m2
Cisplatin 75 mg/m2
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.
N = 42
N = 21
2
1
CBP501: Response in Evaluable Patients
Investigator Assessed
Chemo + CBP501
N=39
Chemo
N=20
Complete Response (CR), n (%) 0 (0) 1 (5)
Partial Response (PR), n (%) 11 (28) 3 (15)
Objective Response Rate (ORR), n (%)
(95% CI)
11 (28)
(.15, .45)
4 (20)
(.06, .44)
Stable Disease (SD), n (%) 21 (54) 11 (55)
Independent Radiology Review Chemo + CBP501
N=39
Chemo
N=20
Complete Response (CR), n (%) 0 (0) 0 (0)
Partial Response (PR), n (%) 12 (31) 2 (10)
Objective Response Rate (ORR), n (%)
(95% CI)
12 (31)
(.17, .48)
2 (10)
(.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
CBP501: Progression Free Survival
Investigator Assessed Independent Radiology Review
Chemo + CBP501 Chemo
Chemo + CBP501
Chemo
# censored 7 4
# events 33 19
Median PFS (mo) 5.9 4.6 P=0.24
PFS > 4 mo, n (%) 27 (68) 13 (57)
Chemo + CBP501
Chemo
# censored 8 6
# events 32 17
Median PFS (mo) 5.1 3.4 P=0.42
PFS > 4 mo, n (%) 25 (63) 9 (39)
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.
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
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
Tumor Response Per Modified RECIST Modified RECIST measurements per independent radiographic review
PIK3CA
R88Q
PTEN
loss
Data cut-off 18 May 2012
*
* *
* * * *
* *
*
* Biomarker analyses performed
• 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
Conclusions
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
Potential Future Clinical Trials
Drug Sponsor
BAY 94-9343 Bayer
GDC-0980 Genentech
MORAb 009 Morphotek
Nintedanib Boehringer Ingelheim
Tremelimumab MedImmune
VS-6063 Verastem
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
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