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Prognostic Factors for MPM in 2012

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.

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Prognostic Factors for MPM in 2012

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  1. 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%

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. 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

  7. 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

  8. MPM – Chemotherapy Class# PtsResponse Rate Antimetabolites 247 18% Anthracyclines 267 13% Platinum salts 147 12% Alkylating agents 99 7% Vinca Alkaloids 116 3% Biologics 94 13% Kindler, 2003

  9. Anthracyclines in MPM Agent# trials# ptsRR 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

  10. Platinum compounds in MPM Agent# trials# ptsRR Cisplatin 2 59 14% HD Cisplatin 1 14 36% Carboplatin 3 89 7–16% ZD0473 1 41 0%

  11. Antifolates in MPM Agent# Trials# PtsRR 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%

  12. A brief history • Supportive Care • Pemetrexed/Cisplatin • Raltitrexed/Cisplatin Until 2003 2003 2005 Novel targeted therapies

  13. Phase III Trial:Pemetrexed/Cisplatin vs. Cisplatin RANDOM I ZE • Stratified by: • PS, histology, gender, WBC, measurable disease • baseline homocysteine Pemetrexed + Cisplatin 500 mg/m2 75 mg/m2 q21d NS + Cisplatin 75 mg/m2 Dexamethasone 4 mg BID x 3 days Folate, B12 supplementation 12/99 Design: Single-blind 1o endpoint: survival (HR 0.67) 2o endpoints: TTP, response, toxicity, PF, QoL, clinical benefit Vogelzang, 2003

  14. Pemetrexed/Cisplatin vs. Cisplatin Pemetrexed + Cisplatin RANDOM I ZE 58 pts 168 pts 226 pts FA 350 – 1000 ucg qd B12 1000 ucg IM q9w No FA/B12 FA/B12 59 pts 163 pts 222 pts Cisplatin Final Analysis • 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

  15. Results: Pemetrexed/Cisplatin vs. Cisplatin

  16. HR 0.77 Logrank p-value 0.020 MST = 12.1 mos Survival: All Eligible Patients 100 Pemetrexed + Cisplatin (n=226) Cisplatin (n=222) Response Rate 41% vs 17% (p<0.001) 75 % Alive 50 MST = 9.3 mos 25 0 0 5 10 15 20 25 30 Months Method: Kaplan-Meier

  17. Symptoms, Quality of Life, Lung Function

  18. Raltitrexed in MPM Study N RR MST (m)

  19. Raltitrexed/Cisplatin vs. Cisplatin 11.4 m 8.8 m Response rate 24% vs. 14% van Meerbeeck et al. 2005

  20. Gemcitabine in MPM # trials # pts RR 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% 13 Oxali 80 mg/m2 d1,8 q21d

  21. 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

  22. Randomized phase II trial of Gemcitabine/Cisplatin +/-Bevacizumab Stratification: histology, PS R A N D O M I Z A T I O N Bevacizumab 15 mg/kg d1 q 21d Gemcitabine 1250 mg/m2 d1, 8 Cisplatin75 mg/m2 d 1 x 6 cycles N=53 1o endpt TTP, 2o tox, RR, correlative Placebo 15 mg/kg d1 q 21d Gemcitabine 1250 mg/m2 d 1, 8 Cisplatin75 mg/m2 d 1 x 6 cycles N=53 CR/PR/SD after 6 cycles: Bevacizumab/Placebo q21d

  23. 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)

  24. 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

  25. 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

  26. 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

  27. 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

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