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

http://www.imig2012.org/

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