11/21/2009. World Perspective on the Treatment of Mesothelioma: A few 2009 Highlights. Thierry M. Jahan, MD. But the incidence is rising

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1 Presenter Disclosures World Perspective on the Treatment of Mesothelioma: A few 2009 Highlights Personal financial relationships with commercial interests relevant to this presentation during the past 12 months: Research support: Eli Lilly, Genentech, Morphotek Consultant: Poniard Pharmaceuticals Thierry M. Jahan, MD Bonnie J. and Anthony Addario Endowed Chair in Thoracic Oncology UCSF Diller Family Comprehensive Cancer Center Thoracic Oncology Program Personal financial relationships with non-commercial interests (e.g., government or other nonprofit funding) relevant to this presentation, within past 12 months: NONE Relevant institutional financial interests: NONE Personal financial relationships with tobacco industry entities within the past 3 years: NONE Mesothelioma, why does it matter? But the incidence is rising Overall, relatively small number of cases/yr 2000~ 3000/yr in US Concentrated more in areas of high asbestos exposure: Mining towns (Western Australia 6.6/10 5, in men over 35) Harbors/areas with large shipyard activity (Seattle, San Francisco/Oakland, New Orleans, Honolulu) /10 5 Certain hotspots (Libby MT, Sarnia Canada, Cappadocia Turkey) Untreated survival is measured in months Treatment can prolong survival and improve QOL Copyright restrictions may apply. Price, B. et al. Am. J. Epidemiol

2 SMRP as a Mesothelioma Screening Tool Soluble Mesothelin-Related Protein (SMRP): Marker of mesothelial cell differentiation split product of mesothelin SMRP levels are elevated in pleural and peritoneal fluid of pts with MPM In several retrospective analysis, SMRP had % specificity and 84-89% sensitivity in diagnosing MPM (Robinson Lancet 2003, Davies AJRCCM 2009 ) SMRP utility was studied prospectively in pts exposed to asbestos (Park AJRCCM 2008): N=538 subjects, 15 (3%) had elevated SMRP Elevated SMRP pts underwent w/u no MPM diagnosed WCLC 2009 update-holeevoet al 2 groups of patients from Belgian companies with history of asbestos use and from population seen at the Occupational Diseases Fund in Brussels G1: pts without asbestos related radiographic changes (N= 93, med age= 51) G2: pts with BENIGN asbestos related pulmonary disease (N= 102, med age= 64) 59 with pleural plaques 33 with diffuse pleural thickening Pts were followed for 2 yrs, with yearly blood sampling: SM levels a level > 2.5nM is considered elevated Renal function/gfr Mean baseline SM values: G1: 0.89 nm +/ G2: 1.24 nm +/ G2 pts with levels > 2.5 nm (1 pt with highest elevation of SM als with low GFR) No mesothelioma (or other Ca) diagnosed in this population during f/u Screening for Mesothelioma Mesothelioma is clearly a disease that could use a good screen Diagnosis is almost always made at an advanced stage Therapeutic options are limited and morbid Med survival is under 1 yr Latency bet exposure and diagnosis is measured in decades, and that is a huge problem for screening! Who do you screen? When do you start? When do you intervene? Ideal test for this disease should allow you to risk stratify as well as intervene in a timely fashion Conclusions on utility of SMRP Value of SMRP as screening tool likely to be limited With high sens/spec SMRP is an excellent tool for the DIAGNOSIS of MPM 2

3 Induction Chemotherapy for resectable MM NEW TREATMENT DEVELOPMENTS Usual rationale: Easier to administer chemo pre-op than post op Potentially eradicates microscopic disease? Potentially downstages making it an easier surgery? Patient selection: All non metastatic MPM (including N2) with biopsy confirmed mesothelioma and decent organ function No prior surgery (other than for diagnostics) Treatment: Cis-platin 75 mg/m 2 d1, Pemetrexed 500 mg/m 2 d1 q 21 days 4 cycles Planned surgery: EPP Planned post op RT: 54 Gy to operated hemithorax Krug JCO 2009 Induction Chemotherapy for resectable MM Results Pem/Cis-P followed by EPP, RT 77 pts enrolled, 73% men, med age 63 (34-78) 74% of pts completed planned chemo (12% PD, 2.5% died) 57% completed surgery(5% PD, 2.5% peri operative deaths) 52% completed planned RT (5% PD, 2.5% died) Total treatment related mortality= 9% Med OS= 16.8 mo ITT pop Med PFS= 10.1 mo ITT pop Krug JCO 2009 Krug JCO

4 Survival Results Explored Median overall survival for total population: 16.8 mo Median survival for pts WITHOUT radiographic response: 13.9 mo Median survival for pts WITH radiographic response: 26.1 mo Med OS for those who completed ALL Rx (52%): 29.1 mo Krug JCO 2009 Conclusions on Induction Therapy Appears promising Patient choice seems critical, but not too different from choice of candidates for EPP: Good PS Good Physiology ADVANCED DISEASE TREATMENT UPDATE Phase I trial of neo-adjuvant dasatinib in patients with resectable MPM DASATANIB: Oral agent ATP competitive inhibitor against Src kinase, BCR-ABL, c-kit, PDGFR, and ephrin receptor kinases Low toxicity profile : fluid retention, pleural/pericardial effusion, prolonged QTc, skin rash, TLS (CML) TREATMENT PLAN: Surgically resectable patients Initially staged through extensive surgical sequence Then 4 wks of dasatanib 70 mg po BID Followed by planned EPP or P/D Radiographic/mol responders receive additional 2 yrs of dasatanib after adjuvant RT/Chemo TSAO WCLC

5 MDACC Protocol Funding: DOD, BMS (drug) Dasatanib induction Results and Conclusions ESS: Mediastinoscopy Laparoscopy VATS or US Bx Day Weeks Oral Dasatinib Therapy EPP or Pleurectomy N=14 Radiographic response after 4 weeks: 2 MR, 8 SD, 2 too early to evaluate Molecular response: 2pts with MR had de-phosphorylation of p-srctyr 419 Assess eligibility PET-CT +/-MRI Labs Pre-op cardiac PFT Informed Consent Day -5 Blood/ Tissue Platelets/ Pleural Effusion collection in OR Day 7 Visit Blood collection Clinical Exam Day 14 Visit Blood collection Clinical Exam Day 21 Visit Blood collection Clinical Exam Day Blood/ Tissue Platelets/ Pleural Effusion Collection in OR PET-CT Of 4 pts with SD: 1 had min de-phosphorylation of p-srctyr no change in p-src Tyr increased phosphorylation p-srctyr 419 CONCLUSIONS: Subpopulation of MPM patients that may derive clinical benefit from dasatinib. Modulation of p-srctyr 419 is a reasonable pharmacodynamic marker for dasatinib treatment MPM is very heterogeneous. Molecular profiling will be necessary to ultimately optimize targeted therapy in this disease. Phase I trial of neo-adjuvant dasatinib in patients with resectable MPM This was a window of opportunity trial - Tissue is obtained as part of the patients preoperative evaluation for pre intervention evaluation - Tissue is obtained post op can assess effectiveness of agent on target: p-src-tyr 419 phosphorylation status Src inhibition was associated with some clinical activity: - Pts with MR had highest decrease in Src phosphorylation This study helps validate Src as a target in MPM: - CALGB finished enrolling is looking at dasatanib in unresectable, relapsed MPM with following correlative endpoints: Src phosphorylation on PBMC VEGF, PDGF, CSF-1 (Src depdt. activ. of MAPKK), MSRP Archival tissue for EphA2, PDGFR-β and their phosphorylation status Ph II Pazopanib In newly dx/relapsed MPM Pazopanib: oral VEGFR-1,2,3 PDGFR-α/β c-kit inhibitor Administered at 800 mg/d x 21 Decision rule: > 14/28 with 6mo PFS to continue N= 34, med age= 73, 82% men, 44% pre treated, majority of all pts had PS 1-2, med f/u= 8.1 mo 65% of pts had a Gr 3 AE, 12% Gr 4 AE Prev. Treated ORR Med OS Med PFS 47% 5.0 mo 2.0 mo Un treated 63% 14.4 mo 5.4 mo Only 10/28 met 6 mo PFS requirement so study stopped Molina et all WCLC

6 A pilot Ph II trial of the 20S proteosome inhibitor Bortezomib in patients with relapsed MPM Inhibitor of the 20S subunit of proteosome complex, good preclinical activity to justify clinical use in pts with relapsed MPM 1 prior therapy, PS 0-1, adequate heme/hepatic/renal fn B=1.6 mg/m2 weekly x 4 every 5 wks x 4 cycles or until progression 1 o obj= response, 2 o obj= OS, PFS, toxicity, Simon 2 stg design with need for 2 responses in first 23 pts to continue on to 2 nd stage 87% men, 96% PS 0-1, med age % pleural, 70% epi, 9% sarc, 4% biphasic, 17% NOS A pilot Ph II trial of the 20S proteosome inhibitor Bortezomib in patients with relapsed MPM N= 23 pt 1 pt with PR, 3 ineligible for resp, 19 pts with PD Median OS= 6.1 mo, median PFS= 2.1 mo Only 1 response seen, but needed 2 to continue to 2 nd stage Conclusion: BZ as single agent has minimal activity Fennell et al WCLC different single agent trials, similar results: - Acceptable toxicity profile. - Modest-likely cytostatic activityof the agent tested - No further development warranted as single agents These drugs join a growing list of targeted agents with similar results in MPM A phase I trial of cisplatin-pemetrexed-imatinib mesylate in patients with unresectable MPM Agent Gefitinib Erlotinib Vatalanib Sorafenib Imatinib Sunitinib Pazopanib Bortezomib Dasatanib Author Govindan/CALGB Garland/SWOG Jahan/CALGB Jänne/CALGB Porta/Ali/Mathy Nowak Molina/ Mayo Fennell Tsao/MDA Inhibitor of BCR-ABL protein, c-kit receptor, PDGF-R Commonly Used in : - CML - GIST tumors - Dermatofibrosarcoma protuberans Tsao et al WCLC

7 Phase I Cisplatin-Pemetrexed-Imatinib mesylate Unresectable Mesothelioma Chemo-naive KPS > 70 Dose Escalation of Imatinib Mesylate Cohort 1: 300 mg Cohort 2: 400 mg Cohort 3: 600 mg Cisplatin 75 mg/m 2 Pemetrexed 500 mg/m 2 IV every 3 weeks Imatinib mesylate orally daily Primary endpoint: Safety/Toxicity, DLT/MTD Secondary endpoints: OS, TTP, RR, QOL Preliminary Results DLT reached in cohort 3: - Nausea/vomiting - Cardiac event MTD: cisplatin 75 mg/m 2, pemetrexed 500 mg/m 2, imatinib 600 mg po daily Tissue analysis of PDGFR and serum PDGF pending Patient Summary Phase I cisplatin-pemetrexed-gleevec (n=17) Histology Best response Duration of Response (months) Dose of Agents Phase I cisplatin-pemetrexed-imatinib mesylate Preliminary Conclusions 1 Sarcomatoid SD 4 C 60 P 500 G Sarcomatoid INEV INEV C 60 P 500 G Biphasic PD 2 C 60 P 500 G Sarcomatoid PD 1 C 60 P 500 G Epitheliod SD/MR 4 C 75 P 500 G Epitheliod SD 12 C 75 P 500 G Epitheliod INEV 1 C 75 P 500 G Biphasic SD 16 C 75 P 500 G Sarcomatoid Mix SD/PR 3 C 75 P 500 G Epitheliod PR 8 C 75 P 500 G Biphasic SD 9++ C 75 P 500 G Sarcomatoid PD 2 C 75 P 500 G 600 Cisplatin-pemetrexed and imatinib mesylate is reasonably tolerated and may have activity in certain MPM patients. The MTD is cisplatin 75 mg/m 2 + pemetrexed 500 mg/m 2 + imatinib mesylate 600 mg po daily. DLT was nausea/vomiting and a cardiac event Targeting PDGFR in combination with platinum-pemetrexed should be studied further in MPM. 13 Sarcomatoid INEV DLT - nausea C 75 P 500 G * Epitheliod PR Still receiving Tx* C 75 P 500 G Epitheliod INEV DLT - MI C 75 P 500 G Epitheliod SD Still on trial C 75 P 500 G Epitheliod SD Still on trial C 75 P 500 G 600 7

8 How do we move forward We need better/more abundant target validation: - Dr. Tsao s paradigm: using a novel drug as induction therapy gives her access to plenty of post-op tissue to evaluate effect of drug on targets We need better biomarkers-predictive and prognostic - Correlative science components of these trials are extremely important We need more investigation into resistance mechanisms - Dr. Fennell and colleagues are looking in to Bortezomib resistance as part of the correlative analyses with their trial 2009 was a rich year with continued intense efforts in mesothelioma research worldwide These efforts continue to be quite necessary The US government has yet to ban asbestos We need more trials combining cytotoxics PLUS targeted drug: - Most targeted drugs are primarily cytostatic - Combinations can usually be carried out at full doses for cytotoxics with little or no PK interaction or overlap in toxicity - Dr. Tsao s pem/cis/imatinib showed decent activity, when there a had been none previously in the published efforts with imatinib 8