Prognostic Factors for MPM in 2012

• Two Major well studied and validated scoring systems are those from CALGB and from EORTC, both derived from phase II chemotherapy trial data in this disease.

• CALGB treated 337 patients over a 10 year period. The MST ranged from 3.9-9.8 months with 1 year survival between 14% and 50%

Prognostic Factors for MPM in 2012 (Cont.)

• Six prognostic subgroups were generated from the CALGB data base with MST of 1.4-13.9 months The latter had patients with ECOG 0, age <49 years, and Hb =/>146. The worst MST was seen in patients with ECOG 1 or 2 and WBC >15.6

• Older age, worse PS, non-epithelial histology, chest pain, weight loss, low HB, high platelet or WBC and high LDH all predict for shorter survival

Prognostic Factors for MPM in 2012 (Cont.)

• The EORTC had data on 204 adults with MPM treated on 5 phase II trials over 9 years. The overall MST was 8.4 months

• Poor prognosis was associated with a poor PS, high WBC, probable/possible histologic diagnosis of MPM, male gender, and sarcomatoid subtype

• They ended up with 2 prognostic groups with 1 year survival rates of 40% in the good risk group and 12% in the poor risk group.

Prognostic Factors in MPM in 2012 (Cont.)

• MRSP levels may be prognostic• The presence or absence of specific or groups of

genes may be prognostic• There are specific prognostic factors in patients

undergoing surgery for MPM. • 183 patients from Harvard had EPP and they

concluded epithelial histology, negative resection margins and no extrapleural nodes were all important for good prognosis with proven longer survival

Prognostic Factors in MPM in 2012 (Cont.)

• PET standard update value (SUV) is also important with an SUV >4 predicting a poor prognosis in MPM.

• Other factors are also under study.

Radiologic Measurement of MPM in 2012

• It is very difficult to assess response or progression in this disease on imaging

• Standard RECIST works poorly.• A Modified RECIST technique was suggested

using the same criteria for response or progression but multiple measurements on 3 separate CT sections with a minimum axial separation of 1 cm in which these measurements extend perpendicular to the chest wall or mediastinum

Radiologic Measurement of MPM in 2012 (Cont.)

• The modified RECIST measures tumour thickness on CT and has worked reasonably well in a number of chemotherapy studies but still only large changes in thickness can be detected.

• Automated and semi automated measurement methods are desirable

• Tumour volume techniques will be better

MPM – ChemotherapyClass # Pts Response Rate

Antimetabolites 247 18%

Anthracyclines 267 13%

Platinum salts 147 12%

Alkylating agents 99 7%

Vinca Alkaloids 116 3%

Biologics 94 13%Kindler, 2003

Anthracyclines in MPMAgent # trials # pts RR

Doxorubicin 1 51 14%

Epirubicin 2 68 12%

Mitoxantrone 2 62 5%

Liposomal Doxo 3 109 6%

Liposomal Dauno 1 14 0%

Dox/Dexrazoxane 1 10 0%

Kindler, 2003

Platinum compounds in MPM

Agent # trials # pts RR

Cisplatin 2 59 14%

HD Cisplatin 1 14 36%

Carboplatin 3 89 7–16%

ZD0473 1 41 0%

Antifolates in MPM

Agent # Trials # Pts RR

Trimetrexate 1 52 12%

Edatrexate 1 20 25%

Edatrexate/LV 1 40 16%

Methotrexate 3 78 41%

Pemetrexed 1 64 14%

Raltitrexed 1 24 21%

A brief historyA brief history

• Supportive CareSupportive Care

• Pemetrexed/CisplatinPemetrexed/Cisplatin

• Raltitrexed/CisplatinRaltitrexed/Cisplatin

Until 2003Until 2003

20032003

20052005

Novel targeted therapies

Pemetrexed + Cisplatin500 mg/m2 75 mg/m2

NS + Cisplatin 75 mg/m2

RANDOMIZE

Stratified by:

• PS, histology, gender, WBC, measurable disease

• baseline homocysteine

Phase III Trial:Pemetrexed/Cisplatin vs. Cisplatin

q21d

Design: Single-blind

1o endpoint: survival (HR 0.67)

2o endpoints: TTP, response, toxicity, PF, QoL, clinical benefit

Dexamethasone 4 mg BID x 3 days Folate, B12 supplementation 12/99

Vogelzang, 2003

Pemetrexed/Pemetrexed/Cisplatin vs. Cisplatin vs. Cisplatin

Primary endpoint: survival

• 94% power to detect hazard ratio of .67 in entire study

• 80% power to detect hazard ratio of .67 in FA/B12 group

FinalAnalysis

58 pts

59 pts

Cisplatin

168 pts

163 pts

No FA/B12 FA/B12

226 pts

222 pts

Pemetrexed + Cisplatin

RANDOMIZE

FA 350 – 1000 ucg qd

B12 1000 ucg IM q9w

Results: Pemetrexed/Cisplatin vs. Cisplatin

Pem/Cis Cis p value

N 226 222

RR 41% 17% <0.001

MST (m) 12.1 9.3 0.020

TTP (m) 5.7 3.9 0.001

MST = 12.1 mos

HR 0.77Logrank p-value 0.020

MST = 9.3 mos

0 5 10 15 20 25 30

100

Months

75

50

25

0

Method: Kaplan-Meier

Survival: All Eligible PatientsSurvival: All Eligible Patients%

Aliv

e

Pemetrexed + Cisplatin (n=226)Pemetrexed + Cisplatin (n=226)

Cisplatin (n=222)Cisplatin (n=222)

Response Rate 41% vs 17% (p<0.001)

Symptoms, Quality of Life, Lung FunctionSymptoms, Quality of Life, Lung Function

Raltitrexed in MPM

Fizazi, 2000

Phase I raltitrexed + oxaliplatin

17/48 6 PR (4 ref)

Fizazi, 2003

Phase 2 raltitrexed 3mg/m2 +oxaliplatin 130mg/m2 q21d

70 20% 7.8 (1st) 11 (2nd)

Baas, 2002 Phase 2 raltitrexed 3mg/m2 24 21% 7

EORTC Phase 3 cisplatin +/- raltitrexed

240 Accrual completed

Study N RR MST (m))

Raltitrexed/Cisplatin vs. Cisplatin

van Meerbeeck et al. 2005

8.8 m

11.4 m

Response rate 24% vs. 14%

Gemcitabine in MPM# trials # ptsRR MST (m)

Gem 1250 – 1500 mg/m2 3 57 0–31%

Gem 1000 – 1250 mg/m2 4 143 9-48% 9.5-11.2+ Cisplatin 80 – 100 mg/m2

Gem 1000 mg/m2 d1,8,15 1 50 26% 16.5+ Carboplatin AUC 5 q28d

Gem 1000 mg/m2 + 1 25 40% 13Oxali 80 mg/m2 d1,8 q21d

Vinorelbine in MPM

# pts RR MST

Vinorelbine 30 mg/m2 wkly 29 24% 10.6m

Vinorelbine + oxaliplatin 17 12%Steele, 2000

Vinorelbine vs MVP vs ASC ongoing in UK

Randomized phase II trial of Gemcitabine/Cisplatin +/-Bevacizumab

RANDOMI

Z ATION

Bevacizumab 15 mg/kg d1 q 21dGemcitabine 1250 mg/m2 d1, 8Cisplatin 75 mg/m2 d 1 x 6 cycles

Placebo 15 mg/kg d1 q 21dGemcitabine 1250 mg/m2 d 1, 8Cisplatin 75 mg/m2 d 1 x 6 cycles

N=53

N=53

Stratification: histology, PS

CR/PR/SD after 6 cycles: Bevacizumab/Placebo q21d

11oo endpt TTP, 2 endpt TTP, 2oo tox, RR, correlative tox, RR, correlative

Active Studies for Advanced MPM

• Phase II study of AZD2171 in MPM-run by Consortium-target 50 patients The endpoints are Safety and Efficacy

• A Phase III Randomized, Double-Blind, Placebo-Controlled Trial of Oral Suberoylanilide Hydroxamic Acid (SAHA-HDAC) in Patients with Advanced MPM-Previously treated with Systemic Chemotherapy-350 Patients (Survival Safety and Efficacy)

Active Studies for Advanced MPM (Cont.)

• A Phase IB, open label, multicenter study to investigate the effect of Oral LBH589 (HDAC) on dextromethorphan, a CYP2D6 substrate, and to assess the efficacy and safety of LBH589 in Patients with Advanced or metastatic NSCLC or MPM

• 24 patients with PK component will be studied

Active Studies for Advanced MPM (Cont.)

• A phase II Study of Sunitinib in Patients with Advanced MPM-57 patients in 2 cohorts (previous treatment cohort closed)-Survival, Safety and Tolerability are the endpoints

• Run by NCIC

Active Studies for Advanced MPM (Cont.)

• Phase I/II Study of a Triplet Combination of CBP501 (Cell Cycle G2 Abrogator), Pemetrexed and Cisplatin in Patients with Advanced Solid Tumours and in chemotherapy-naïve patients with MPM-42 patients (Phase I Study complete with MTD reached). The endpoints are Safety and Efficacy

Active Studies for Advanced MPM (Cont.)

• An Open-Label Clinical Trial of

MORAB-009 in combination with Pemetrexed and Cisplatin in Patients with Mesothelioma

• This is a monoclonal antibody against mesothelin