1 Proceedings of UCLA Healthcare -VOLUME 18 (2014)- CLINICAL VIGNETTE New Results and Concepts in Systemic Treatment of Mesothelioma Olga Olevsky, M.D., Raymond Wong, Ph.D., and Robert Cameron, M.D. Malignant Mesothelioma is rare cancer that arises from the layer of mesothelial cells. Mesothelial cells usually line the surfaces of the lungs, heart, peritoneal cavity and tunica vaginalis. Most of the mesotheliomas (80%) are of pleural origin. Mesothelioma is a rare cancer with incidence of cases reported each year in the United States. Mesothelioma is strongly associated with exposure to asbestos. The tumor forms after asbestos particles are inhaled, and subsequently lodge in the lining of the airways and the lung. The latency period between the exposure and development of disease is at least 15 years, with risk persisting for decades. Most patients present in the 6-8 decade of life. Asbestos was used extensively in the past in this country, and is still used in other countries as an insulation material. Histologically, mesothelioma can be subdivided into three types. Epitheliod, sarcomatoid and biphasic. Traditionally the biphasic and sarcomatoid types have worse prognosis and survival than the epitheliod type. If the disease is localized to one hemithorax, the primary approach is pleurectomy and decortication followed by radiation. However, for more widespread or recurrent disease chemotherapy has been the mainstay of treatment. Almost all chemotherapeutic agents have been tried in mesothelioma. Prior to 2003 there was no standardized therapy. A meta analysis of 119 trials demonstrated that combination therapy, especially cisplatin based regimens, provided better response rate than single agent therapy. In 2003, two International Trials demonstrated that combination therapy with either pemetrexed or raltitrexed increases survival compared to single agent cisplatin. Both trials showed a significant increase in response rate, and no deleterious impact on quality of life. Pemetrexed is an antifolate that inhibits purine and pyrimidine synthesis. It inhibits key enzymes such as Thymidilate Synthase (TS), Dihyhydrofolate Reductase (DHFR) and Glycinamide Ribonucleotide Transferase (GARFT), which are required in DNA synthesis. Cisplatin acts by intercolating itself among the DNA bases, and thus inhibits DNA synthesis. Vogelzanget published the major US trail in 2003 comparing combined therapy to cisplatin alone. This phase III trial randomized 456 patients with unresectable mesothelioma who were chemotherapy naïve. 226 patients received cisplatin at 75 mg/m2 with pemetrexed 500m g/m2 on a 21-day schedule compared with 222 patients with cisplatin alone. This was the first trial to demonstrate superior Overall Survival (OS) (12.1 mos vs 9.3mos), Time To Progression (TTP) (5.7 mos vs 4.9 mos) and Response Rate (RR) (41.3% vs 16.7%) in the combination arm. The study established the combination of cisplatin 75mg/m2 and pemetrexed (500mg/m2) every 3 weeks as the new standard of care. 1 Similar results were achieved when antifolate raltitrexed was combined with cisplatin in a phase III EORTC trial 2,3. The current recommendation is to administer at least 4 courses of Cisplatin 75mg/m2+Pemetrexed 500 mg/m2. 4 If delayed response is seen and therapy is tolerated, treatment can be extended to 6 courses. When pemetrexed is used, folic acid and Vitamin B12 supplementation are required to decrease hematologic toxicity. The question whether carboplatin can be substituted for cisplatin was evaluated in an International Extended Access Program (EAP). This multicenter, nonrandomized, open label trial in chemotherapy naïve patients compared Pemetrexed + Cisplatin (n= 843) versus Pemetrexed + Carboplatin (n=861) 5. The overall Response Rate was 26.3% in the cisplatin arm, and 21.7% in the carboplatin arm respectively. Time to Progression (TTP) was 7 months in the cisplatin arm and 6.9 months in the carboplatin arm. One-year survival rates were comparable, 63.1% for cisplatin and 64% for carboplatin.
2 Therefore at this time, Cisplatin and pemetrexed is the regimen of choice, and the only FDA approved regimen. However substituting Carboplatin for Cisplatin may be acceptable. Another issue is whether patients can be retreated with pemetrexed at progression. In a Phase III trial conducted by Jassem, patients with progressive disease were randomized to best supportive care or second line pemetrexed (single agent). Significantly better response rate (18.7 vs 1.7%) and longer time to progression (3.7 mos vs 1.7 mos) were seen in patients retreated with pemetrexed, but there was no difference in overall survival 6. The role of maintenance therapy remains to be determined. The CALGB trial is an ongoing multicenter randomized phase II trial of maintenance pemetrexed vs observation 7. The goal of the trial is to determine whether maintenance therapy with pemetrexed improves PFS and OS. Patients are randomized to pemetrexed 500mg/m2 q 21 days vs observation alone, after completing four cycles of pemetrexed/cisplatin regimen. The trial is due to close December of The role of biomarkers has always been a challenging topic in the field of oncology. As we saw from the pivotal pemetrexed trial only 40 % of the patients responded to cisplatin/pemetrexed regimen. Several biomarkers were investigated in order to establish which patients will respond to the chemotherapy. The role of thymidilate synthase, which is the main enzyme in the synthesis of pyrimidines inhibited by pemetrexed, was examined in relation to response to pemetrexed. The role of Excision Repair Cross- Complementation Group 1 (ERCC1), a DNA damage repair gene in the nucleotide excision repair pathway, which removes cisplatin induced DNA adducts, was also evaluated to assess response to cisplatin. In an Italian Retrospective study 8, Righi collected data on 60 patients with confirmed MPM previously treated with pemetrexed and platinum (45 of 60) or single agent platinum (15 of 60). The investigators looked at Thymidialate Synthase and Excision Repair Cross- Complementation Group 1 (ERCC1). Gene expression levels were evaluated by Polymerase chain reaction (PCR). Protein levels were evaluated by Immunohistochemistry (IHC). In patients treated with pemetrexed, low Thymidilate Synthase protein levels (gold line) were predictive of improved time to progression (TTP) 17.9 vs 7.9 mos, as well as longer OS 30 vs 16.7 mos. Baseline TS values had no prognostic value in patients not treated with pemetrexed 8.. (Figure 1) Figure 1. Gold line: Low TS TS Blue line: High Excision repair cross- complementation group, ERCC1, was evaluated in patients treated with platinum based therapy. ERCC1 was a prognostic factor; patients with high ERCC1 levels had longer median survival than patients with lower ERCC1 protein expression, (30 months vs 19.7 months) regardless of the chemotherapy regimen employed. No correlation between ERCC1 levels and response to cisplatin or carboplatin was found 8. (Figure 2) Figure 2. Blue line: High ERCC1 Gold line: Low ERCC1. Other chemotherapy agents are still used in mesothelioma treatment.
3 Gemcitabine, is a nucleoside analogue of deoxycytidine, in which two fluorine atoms have been inserted into the deoxyribose ring. It competes for incorporation into DNA thereby inhibiting DNA synthesis. Prior to introduction of Pemetrexed, gemcitabine and cisplatin had been used as first line treatment in mesothelioma with responses between 12-48%. Patients with mesothelioma have very high levels of Vascular Endothelial Growth Factor ( VEGF). In a phase II trial, Anti-VEGF Antibody bevasizumab was added to cisplatin/ gemcitabine combination in first line patients with unresectable mesothelioma 9. Patients were randomised to receive Gemcitabine 1250 mg/m2 day 1, 8, Cisplatin 75 mg/m2 on day 1, bevasizumab 15 mg/kg on day 1, every 21 days for 6 cycles, or gemcitabine 1250 mg/m2 day 1, 8, Cisplatin 75 mg/m2 on day 1 and placebo on day 1. If they had stable disease at completion of 6 cycles, they received bevacizumab 15 mg/kg vs placebo every 21 days until progression. Unfortunately, addition of bevacizumab did not improve PFS or OS. PFS was 6.9 months in bevacizumab arm, and 6 months in placebo arm (P=0.88). OS was 15.6 months in bevacizumab arm and 14.7 in placebo arm. However, difference in OS was seen if patients were stratified by baseline VEGF levels. Patients with higher baseline VEGF levels had worse PFS and OS. VEGF levels were not different between responders and non-responders. At the beginning of the trial pemetrexed was not available, and now there is information about negative interaction between gemcitabine and bevacizumab. An ongoing MAPS Trial, a multicenter randomized phase III trial of pemetrexed cisplatin with or without bevacizumab, is addressing the question of bevacizumab therapy in patients with malignant pleural mesothelioma 10. As of April 30, 2012, 280 patients from 85 French Centers had been enrolled, with 8.9% difference in OS in patients receiving bevacizumab in addition to pemetrexed and cisplatin. Biomarker Analysis of Tissue Specimens is also ongoing. There is no standardized second line therapy, since there is no FDA approved agent or drug in clinical trials that has demonstrated a survival advantage. The following agents have completed phase II trials. Anti- angiogenic agents/tyrosine Kinase Inhibitors: Thalidomide, Sunitinib, Cedarinib, Sorafanib. Tyrosine Kinase Inhibitor Dasatinib. Histone Deacytylase inhibitor Vorinostat. An ongoing trial is evaluating CTLA-4 antibody, tremilumimab. A summary of the studies follows. NVALT was an open label randomized phase III study of maintenance thalidomide vs. placebo. Patients who completed 4 cycles of pemetrexed based therapy were randomized to receive either thalidomide 200 mg/day, or placebo. At 33 months, no difference was seen in survival or time to progression. More adverse events were reported in thalidomide group (neurosensory and cardiac) 11. Sorafenib is a potent inhibitor of the ras/raf/mek pathway, which also targets VEGFR and ckit. A phase II study was conducted in malignant mesothelioma patients who had received 0 to 1 prior chemotherapy regimens. Sorafenib 400 mg was administered orally twice daily continuously, vs placebo. Response rate was 6%, with no difference in OS (9.7 months/ OS 9.0 months) or PFS 3.6 months/ 5.1 months 12,13. Sunitinib is an antiangiogenic inhibitor of multiple tyrosine kinases in the VEGFR, PDGFR, c- kit, FLT-3 pathways. Second line Phase II study evaluated administration of intermittent sunitinib 50 mg daily for 28 days of 42 days. 53 patients were evaluated from July 2006-Dec % response rate was seen, with 65% disease stabilization. Median Time to Progression was 3.5 months. OS was 6.7 months 14. Cedirinib is an oral tyrosine kinase inhibitor of VEGF receptor family (VEGF receptors 1,2,3) that has been studied in two phase II clinical trials. SWOG Cediranib S included 54 patients and the University of Chicago Phase II Consortium, 51 patients 16. All patients previously treated with platinum-containing chemotherapy received Cedirinib 45 mg orally daily. The primary end point was objective response. Both trials demonstrated 9%-10% RR, 34% disease stabilization and modest PFS 2.6/1.8 months respectively. However grade 3/4 adverse events such as fatigue, hypertension, pulmonary embolism, angioedema, and reversible posterior leukoencephalopathy were observed.
4 Dasatinib is an aminothiazole analogue, an oral tyrosine kinase inhibitor which belongs to a family of SRC family kinases (SFKs), which also inhibits vascular endothelial growth factor (VEGF), and platelet-derived growth factor β (PDGFβ) receptor. Phase II study of dasatinib, in patients with previously treated malignant mesothelioma was conducted by the Cancer and Leukemia Group B Patients previously treated with chemotherapy were eligible. Biomarker Analysis included levels of vascular endothelial growth factor, platelet-derived growth factor b, colony stimulating factor 1 (CSF-1) and mesothelin-related protein, measured at baseline and during therapy. Dasatinib was administered at 50 mg orally daily and 46 patients were evaluated. Disease control rate was 32.6%, progression-free survival was 9.1 weeks, overall survival was 26.1 weeks. Grade 3 and 4 toxicities included fatigue (11%) and pleural effusion (9%). Survival was markedly longer in patients with lower pretreatment Colony stimulating factor 1 (CSF- 1) levels and in patients whose CSF-1 levels decreased from baseline during therapy. (Figure 3) Phase III trial of Vorinostat vs placebo 18. Vantage 014 was a multicenter phase III trial, that enrolled 660 patients with malignant mesothelioma, that were treated with no more than 2 prior therapies. They were randomized to receive Vorinostat 300 mg po bid for 3 days out of for 7 days, q 21 days until disease progression vs placebo. Primary outcome was progression free survival, secondary outcome was overall survival. No difference was seen on PFS (6.3 vs 6.1 weeks) or OS (31 vs 27 weeks). Immunotherapy with tremilumamab- CTLA 4antibody. There has been a long standing interest in stimulating the immune system to treat cancer. Immune response is the body s natural mechanism of defense against cancer cells. Clinical testing of immune stimulating cytokines led to low frequency of durable responses. Interferons and interleukens are immune stimulating cytokines that have activity in several cancers such as melanoma and renal cell carcinoma. Dendritic cells are antigen presenting cells. (Figure 4) They present processed tumor antigens to the T cell in the immune system. T cells are believed to be the main effectors of the immune system s antitumor response Figure 3 The potential role of Histone deacetylase inhibitor vorinostat. To carry out gene expression, a cell must control the coiling and uncoiling of DNA around histones proteins in the cell around which the DNA coils. This is accomplished with the assistance of histone acetylases (HAT) which acetylate the lysine residues in core histones leading to a less compact and more transcriptionally active chromatin. Histone deacetylases (HDAC), remove the acetyl groups from the lysine residues leading to the formation of a condensed and transcriptionally silenced chromatin. Preclinical data suggests that HDACs play a role in the malignant transformation of mesothelioma. HDAC inhibitor Vorinostat demonstrated some activity in a Phase I trial, which led to a large Figure 4 T cells recognize antigen presented by the dendritic cells when it is coupled with the Major Histocompatibility Complex (MHC) through their T- cell receptor. T cells generate an immune response by binding to a stimulatory receptor (B7) on the dendritic cell via the CD 28 receptor on the T cell. This activates the immune system, which results in increased production of activated T cells. Helper T cells secrete IL-2. Cytotoxic T cells (CTLAs) directly target and lyse tumor cells expressing the antigen presented to them. To avoid overactivation of the immune system, there is an increased expression
5 of the Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a transmembrane protein. CTLA-4 is expressed about 48 hours after T- cell activation. It competitively binds to B7, outcompeting stimulatory CD28 receptors. CTLA-4 binding provides dominant negative signaling and inhibits the immune response. Antibody to CTLA-4 prevents interaction with B7 and removes downregulation of the immune system. Blockade of this checkpoint provided the first evidence of improvement in OS in patients with metastatic melanoma 19. CTLA-4 blockade with Monoclonal Antibodies (MoAbs) blocks the inhibitory signal, thereby sustaining activation and proliferation of T cells. Two agents are available, both human MoAbs. Ipilimumab was approved by FDA in 2011 for treatment of metastatic melanoma. Tremelimumab is currently in clinical trial as second line therapy in patients with malignant pleural mesothelioma. A phase II, randomized, double- blind study comparing tremelimumab to placebo in secondor third- line treatment of subjects with unresectable Malignant Pleural Mesothelioma is currently open at UCLA. The study is planning to enroll 180 subjects who will be randomized 2:1 to receive tremelimumab or placebo. The primary objective is overall survival, and the secondary objectives include progression free survival, durable complete response, and a number of validated quality of life measures. Other outcomes include disease-related symptoms, pain symptoms, time to deterioration of disease-related symptoms, biomarker Analysis and their association with tremelimumab treatment and clinical outcome. Tumor assessments will be done with scans every three months and patient reported outcome assessments will be collected. In a recent publication Hassan et. al describe the use of a antibody conjugates against mesothelin in the treatment of mesothelioma. Mesothelin is an antigen that is expressed by the mesothelioma cells. An antimesothelin antibody fragment combined with a portion of Pseudomonas exotoxin A(S1P) has been developed to recognize mesothelin on the cancer cell and then destroy the mesothelioma cell. The limitation in the past has been generation of antibodies to the anti mesothelin protein after the first cycle of therapy, precluding further treatment with the compound. Hassan et al recently reported using a conditioning regimen of cyclophoshomide and pentostatin to eradicate T and B cells responsible for the antibody generation. Out of the 10 heavily pre-treated patients, 3 had major tumor regressions. 2 of the patients had responses lasting for 15 months, and 2 additional patients responded to cytotoxic chemotherapy after discontinuing the immunotoxin 20,21. Important changes in the management of mesothelioma have occurred in the past decade. Cisplatin/pemetrexed combination has been approved by the FDA, but the OS after the regimen is 12.1 months. Unfortunately there is no effective second line therapy that is FDA approved, and overall survival still remains dismal. Role of VEGF in first line treatment and maintenance is currently being investigated. Molecular-biologic studies are examining biomarkers and pathways. The role of immunotherapy is promising, with the anti CTLA-4 antibodies currently being studied. The role of immunoconjugates coupled with immune modulation appears to be promising and needs further study. REFERENCES 1. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol Jul 15;21(14): PubMed PMID: van Meerbeeck JP, Gaafar R, Manegold C, Van Klaveren RJ, Van Marck EA, Vincent M, Legrand C, Bottomley A, Debruyne C, Giaccone G ; European Organisation for Research and Treatment of Cancer Lung Cancer Group; National Cancer Institute of Canada. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol Oct 1;23(28): PubMed PMID: Ceresoli GL, Zucali PA, Favaretto AG, Grossi F, Bidoli P, Del Conte G, Ceribelli A, Bearz A, Morenghi E, Cavina R, Marangolo M, Parra HJ, Santoro A. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol Mar 20;24(9): PubMed PMID: Ellis P, Davies AM, Evans WK, Haynes AE, Lloyd NS; Lung Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-based Care. The use of chemotherapy in patients with advanced malignant pleural mesothelioma: a systematic review and practice guideline. J Thorac Oncol Jul;1(6): Review. PubMed PMID: Santoro A, O'Brien ME, Stahel RA, Nackaerts K, Baas P, Karthaus M, Eberhardt W, Paz-Ares L,
6 Sundstrom S, Liu Y, Ripoche V, Blatter J, Visseren-Grul CM, Manegold C. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaïve patients with malignant pleural mesothelioma: results of the International Expanded Access Program. J Thorac Oncol Jul;3(7): /JTO.0b013e31817c73d6. PubMed PMID: Jassem J, Ramlau R, Santoro A, Schuette W, Chemaissani A, Hong S, Blatter J, Adachi S, Hanauske A, Manegold C. Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma. J Clin Oncol Apr 1;26(10): /JCO PubMed PMID: Clinicaltrials.gov NCT Righi L, Papotti MG, Ceppi P, Billè A, Bacillo E, Molinaro L, Ruffini E, Scagliotti GV, Selvaggi G. Thymidylate synthase but not excision repair crosscomplementation group 1 tumor expression predicts outcome in patients with malignant pleural mesothelioma treated with pemetrexed-based chemotherapy. J Clin Oncol Mar 20;28(9): /JCO Epub 2010 Feb 22. PubMed PMID: Kindler HL, Karrison TG, Gandara DR, Lu C, Krug LM, Stevenson JP, Jänne PA, Quinn DI, Koczywas MN, Brahmer JR, Albain KS, Taber DA, Armato SG 3rd, Vogelzang NJ, Chen HX, Stadler WM, Vokes EE. Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma. J Clin Oncol Jul 10;30(20): /JCO Epub 2012 Jun 4. PubMed PMID: ; PubMed Central PMCID: PMC G. Zalcman, J. Margery, A. Scherpereel, P. Astoul, I. Monnet, B. J. Milleron, L. M. Paule, M. André, D. Moro-Sibilot, J. Mazieres on behalf of IFCT. IFCT- GFPC-0701 MAPS trial, a multicenter randomized phase II/III trial of pemetrexed-cisplatin with or without bevacizumab in patients with malignant pleural mesothelioma ASCO Annual Meeting Abstracts; Abstract 7020; 2012 imig meeting, Session IB Buikhuisen WA, Burgers JA, Vincent AD, Korse CM, van Klaveren RJ, Schramel FM, Pavlakis N, Nowak AK, Custers FL, Schouwink JH, Gans SJ, Groen HJ, Strankinga WF, Baas P. Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study. Lancet Oncol May;14(6): /S (13) Epub 2013 Apr 12. PubMed PMID: Dubey S, Jänne PA, Krug L, Pang H, Wang X, Heinze R, Watt C, Crawford J, Kratzke R, Vokes E, Kindler HL. A phase II study of sorafenib in malignant mesothelioma: results of Cancer and Leukemia Group B J Thorac Oncol Oct;5(10): /JTO.0b013e3181ec18db. PubMed PMID: ; PubMed Central PMCID: PMC Papa S, Popat S, Shah R, Prevost AT, Lal R, McLennan B, Cane P, Lang-Lazdunski L, Viney Z, Dunn JT, Barrington S, Landau D, Spicer J. Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy. J Thorac Oncol Jun;8(6): /JTO.0b013e31828c2b26. PubMed PMID: Nowak AK, Millward MJ, Creaney J, Francis RJ, Dick IM, Hasani A, van der Schaaf A, Segal A, Musk AW, Byrne MJ. A phase II study of intermittent sunitinib malate as second-line therapy in progressive malignant pleural mesothelioma. J Thorac Oncol Sep;7(9): /JTO.0b013e31825f22ee. PubMed PMID: Garland LL, Chansky K, Wozniak AJ, Tsao AS, Gadgeel SM, Verschraegen CF, Dasilva MA, Redman M, Gandara DR. Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509. J Thorac Oncol Nov;6(11): /JTO.0b013e e. PubMed PMID: ; PubMed Central PMCID: PMC Campbell NP, Kunnavakkam R, Leighl N, Vincent MD, Gandara DR, Koczywas M, Gitlitz BJ, Agamah E, Thomas SP, Stadler WM, Vokes EE, Kindler HL. Cediranib in patients with malignant mesothelioma: a phase II trial of the University of Chicago Phase II Consortium. Lung Cancer Oct;78(1): /j.lungcan Epub 2012 Jul 23. PubMed PMID: Dudek AZ, Pang H, Kratzke RA, Otterson GA, Hodgson L, Vokes EE, Kindler HL; Cancer and Leukemia Group B. Phase II study of dasatinib in patients with previously treated malignant mesothelioma (cancer and leukemia group B 30601): a brief report. J Thorac Oncol Apr;7(4): /JTO.0b013e c. PubMed PMID: ; PubMed Central PMCID:PMC Krug LM, Kindler HL, Calvert H, et al. VANTAGE 014: Vorinostat in patients with advanced malignant pleural mesothelioma (MPM) previously treated with pemetrexed and either cisplatin or carboplatin therapy: a phase III, rando-mized, doubleblind, placebo-controlled trial. ESMO 2011, abstract 3BA. 19. Kirkwood JM, Tarhini AA, Panelli MC, Moschos SJ, Zarour HM, Butterfield LH, Gogas HJ. Next generation of immunotherapy for melanoma. J Clin Oncol Jul 10;26(20): /JCO Review. PubMed PMID: Hassan R, Miller AC, Sharon E, Thomas A, Reynolds JC, Ling A, Kreitman RJ, Miettinen MM, Steinberg SM, Fowler DH, Pastan I. Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. Sci Transl Med Oct 23;5(208):208ra /scitranslmed PubMed PMID: Salgia R, Sattler M. A new hope for precision medicine. Sci Transl Med Oct 23;5(208):208fs /scitranslmed PubMed PMID: Submitted on November 18, 2013
Activity of pemetrexed in thoracic malignancies Results of phase III clinical studies of pemetrexed in malignant pleural mesothelioma and non-small cell lung cancer show benefit P emetrexed (Alimta) is
Clinical Trials for Patients with Malignant Pleural Mesothelioma Lee M. Krug, M.D. Memorial Sloan-Kettering Cancer Center New York, New York Challenges in MPM Clinical Trials Mesothelioma is a rare disease,
Report on New Patented Drugs - Alimta Under its transparency initiative, the PMPRB publishes the results of the reviews of new patented drugs by Board Staff, for purposes of applying the PMPRB s Excessive
Mesothelioma 2014 Paul Baas Department of Thoracic Oncology The Netherlands Cancer Institute Amsterdam Disclosures Grants from Pfizer and Roche Advisor for MSD and Verastem Once upon a time. http://amlbenzene.net/diseases-asbestos.htm
Moda Health Plan, Inc. Medical Necessity Criteria Subject: Alimta (pemetrexed) Page 1 of 6 Origination Date: 08/13 Revision Date(s): 12/13, 12/14, 04/2015 Developed By: Medical Criteria Committee Effective
Maintenance therapy in in Metastatic NSCLC Dr Amit Joshi Associate Professor Dept. Of Medical Oncology Tata Memorial Centre Mumbai Definition of Maintenance therapy The U.S. National Cancer Institute s
+ Anti-PD1 Agents: Immunotherapy agents in the treatment of metastatic melanoma Claire Vines, 2016 Pharm.D. Candidate + Disclosure I have no conflicts of interest to disclose. + Objectives Summarize NCCN
Vandetanib (Zactima) for advanced or metastatic non-small cell lung cancer December 2007 This technology summary is based on information available at the time of research and a limited literature search.
40 Second-Line Chemotherapy Nick Pavlakis and Nicholas J. Vogelzang Chemotherapy trials for malignant pleural mesothelioma have almost exclusively focused on chemotherapy-naive patients. Until 2000, the
NEW CLINICAL RESEARCH OPTIONS IN PANCREATIC CANCER IMMUNOTHERAPY Alan Melcher Professor of Clinical Oncology and Biotherapy Leeds CANCER IMMUNOTHERAPY - Breakthrough of the Year in Science magazine 2013.
AHFS Final Determination of Medical Acceptance: Off-label Use of Bevacizumab in Combination with Chemotherapy for the Treatment of Metastatic Breast Cancer Previously Treated with Cytotoxic Chemotherapy
Abstract No. 4501 Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Results from a Phase III randomized, open-label, multicenter trial R. Motzer, D.
Cancer Treatments Subcommittee of PTAC Meeting held 18 September 2015 (minutes for web publishing) Cancer Treatments Subcommittee minutes are published in accordance with the Terms of Reference for the
The Use of Kinase Inhibitors: Translational Lab Results Targeting Specific Cell Signaling Pathways for the Treatment of Malignant Peritoneal Mesothelioma Sheelu Varghese, Ph.D. H. Richard Alexander, M.D.
Treatment of Malignant Pleural Mesothelioma 13th Perspectives in Lung Cancer March 10, 2012 Paul Baas, MD, PhD The Netherlands Cancer Institute Advisor for Merck Sharp Dohme Advisor for Pfizer Teaching
Update on Clinical Trials and Foundation Funded Grants Mary Hesdorffer, MS, APRN-BC Medical Liaison Meso Foundation www.curemeso.org Delivering the Diagnosis Delivering the Diagnosis Day 1 Taking control
REPORT PERSPECTIVES IN LUNG CANCER 2010 AMSTERDAM Valerie Van Damme, Isabelle Wauters, Johan Vansteenkiste Univ. Hospital Leuven and Leuven Lung Cancer Group Introduction Perspectives in Lung Cancer (PILC)
Advances in Treatment of Malignant Pleural Mesothelioma: A Reason for Hope Daniel H. Sterman, M.D. Associate Professor of Medicine and Surgery Co-Director, PENN Mesothelioma and Pleural Program University
Mesothelioma Applied Research Foundation www.curemeso.org Board of Directors Michael Becich PhD Gen. Steven Blum Lee Krug MD David Ettinger MD Axel Ranier Richard Mosca Erica Iacono Terry Lynch Hanne Minz
What is the Optimal Front-Line Treatment for mrcc? Michael B. Atkins, MD Deputy Director, Georgetown-Lombardi Comprehensive Cancer Center The Case for Immunotherapy in mrcc 1. Achieves patient s goal 2.
Generic (Trade Name): Manufacturer: Gefitinib (Iressa ) formerly referred to as ZD1839 AstraZeneca NO. 52 JANUARY 2004 Indication: Current Regulatory Status: Description: Current Treatment: Cost: Evidence:
PROSPETTIVE FUTURE NEL TRATTAMENTO MEDICO DEL mrcc Cinzia Ortega Dipartimento di Oncologia Medica Fondazione del Piemonte per l Oncologia I.R.C.C.S. Candiolo Future strategies in mrcc Improve therapeutic
Management of stage III A-B of NSCLC Hamed ALHusaini Medical Oncologist Global incidence, CA cancer J Clin 2011;61:69-90 Stage III NSCLC Includes heterogeneous group of patients with differences in the
Targeting angiogenesis in NSCLC: Clinical trial update Martin Reck Lung Clinic Grosshansdorf Grosshansdorf, Germany This presentation was selected by the 15 th World Conference on Lung Cancer Program Committee
Turkish Journal of Cancer Volume 34, No.1, 2004 19 Is the third-line chemotherapy feasible for non-small cell lung cancer? A retrospective study MUSTAFA ÖZDO AN, MUSTAFA SAMUR, HAKAN BOZCUK, ERKAN ÇOBAN,
Risk Management Plan PEMETREXED Powder for concentrate for Solution for infusion Pemetrexed is also indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non small cell
Mesothelioma: The standard of care Jan.email@example.com Brussels, March 7, 2009 take home messages PILC 2006 All patients should receive adequate palliation of dyspnea and pain before starting chemotherapy
Malignant Pleural Mesothelioma: State of the art and projects Rolf Stahel, MD University Hospital Zurich, Switzerland Chemotherapy of malignant pleural mesothelioma Chemotherapy provides symptom relief
Determination of Biomarker Response in a Phase II Window of Opportunity Study of Defactinib (VS 6063), a Focal Adhesion Kinase (FAK) Inhibitor, in Patients with Resectable Malignant Pleural Mesothelioma
Metastatic Breast Cancer 201 Carolyn B. Hendricks, MD October 29, 2011 Overview Is rebiopsy necessary at the time of recurrence or progression of disease? How dose a very aggressive treatment upfront compare
WHITE PAPER Biomarker Trends in Breast Cancer Research Jason Hill, PhD, Associate Director, External Science Affairs, Quintiles Quintiles examines the novel drug combinations and mechanisms of action that
Lung Cancer International Volume 2015, Article ID 590148, 7 pages http://dx.doi.org/10.1155/2015/590148 Research Article Malignant Pleural Mesothelioma Outcomes in the Era of Combined Platinum and Folate
COMPENDIA TRANSPARENCY TRACKING FORM DATE: MAY 2015 PACKET: 111 DRUG: INDICATION: Vinorelbine Tartrate Malignant pleural mesothelioma COMPENDIA TRANSPARENCY REQUIREMENTS 1 Provide criteria used to evaluate/prioritize
Pharmacogenomic Approaches Luis Paz-Ares Hospital Universitario Virgen del Rocio Seville, Spain Pharmacogenetics & Pharmacogenomics Medicine tailored to the individual Genetic information, including the
Medication Policy Manual Policy No: dru213 Topic: Alimta, pemetrexed Date of Origin: May 12, 2010 Committee Approval Date: February 17, 2015 Next Review Date: February 2016 Effective Date: March 1, 2015
Malignant pleural mesothelioma Florian Honeyball, 1 Michael Boyer, 1 Nico van Zandwijk, 2 and Steven C Kao. 1,2 1. Department of Medical Oncology, Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney,
Introduction Objective Methods Results Conclusion 2 Malignant pleural mesothelioma (MPM) is the most common form of mesothelioma a rare cancer associated with long latency period (i.e. 20 to 40 years),
Malignant Pleural Mesothelioma Rolf Stahel, MD University Hospital Zurich, Switzerland Luzerne, 14.1.2012 Mesothelioma Questions 1 The following statement about pleural mesothelioma is correct 1) Dyspnoe
GENETIC PROFILES AND TARGETED TREATMENT OF CANCER - PERSONALIZED MEDICINE Branko Zakotnik MD, PhD Department of Medical Oncology Institute of Oncology Ljubljana 1 I have no conflict of interest to declare
Gemcitabine, Paclitaxel, and Trastuzumab in Metastatic Breast Cancer Review Article  December 01, 2003 By George W. Sledge, Jr, MD  Gemcitabine (Gemzar) and paclitaxel show good activity as single
Malignant Pleural Mesothelioma Joseph Friedberg, MD Hedy Lee Kindler, MD Lee Krug, MD Kenneth Rosenzweig, MD Epidemiology of Mesothelioma Incidence: 2,500 3,000 cases year in the US 5,000 cases per year
New Trends & Current esearch in the Treatment of Lung Cancer, Pt. II Howard (Jack) West, MD President & CEO, GACE Medical Director, Thoracic Oncology Program Swedish Cancer Institute Seattle, WA Cancer
CABOZANTINIB VERSUS EVEROLIMUS IN PATIENTS WITH ADVANCED RENAL CELL CARCINOMA: RESULTS OF A RANDOMISED PHASE III TRIAL (METEOR) This late-breaking abstract was presented on 26 th September 215 in Presidential
Perspective Precision oncology: identifying predictive biomarkers for the treatment of metastatic renal cell carcinoma Parth K. Modi 1, Nicholas J. Farber 1, Eric A. Singer 1,2 1 Division of Urology, Rutgers
CD22 Antigen Is Broadly Expressed on Lung Cancer Cells and Is a Target for Antibody-Based Therapy Joseph M. Tuscano, Jason Kato, David Pearson, Chengyi Xiong, Laura Newell, Yunpeng Ma, David R. Gandara,
Non-Small Cell Lung Cancer in East tasia Chia-Chi (Josh) Lin, MD, PhD 林 家 齊 Director of Phase I Center, e Department of Oncology, National Taiwan University Hospital Clinical Associate Professor, Department
Department of Veterans Affairs Health Services Research & Development Service Treatment of Metastatic Non-Small Cell Lung Cancer: A Systematic Review of Comparative Effectiveness and Cost-Effectiveness
Cancer patients waiting for potentially live-saving treatments in UK 29 May 2005 UK patients are waiting too long for new treatments, according to a 'Dossier of Delay' compiled by information charity CancerBACUP.
Kasr El-aini J. Clin. Oncol. nucl. med. vol., no. 3-4, Jul.-oct. 006:4-47 NEMROCK Original Article Phase II Trial of Cisplatin and Vinorelbine as First-line Therapy in Malignant Pleural Mesothelioma Salah
Treatment of Metastatic Non-Small Cell Lung Cancer: A Systematic Review of Comparative Effectiveness and Cost Effectiveness Investigators: Paul G. Shekelle, MD, PhD, Director Alicia R. Maher, MD Clinical
Targeted Therapy What the Surgeon Needs to Know AATS Focus in Thoracic Surgery 2014 David R. Jones, M.D. Professor & Chief, Thoracic Surgery Memorial Sloan Kettering Cancer Center I have no disclosures
Page: 1 of 6 IMPORTANT REMINDER This Clinical Policy has been developed by appropriately experienced and licensed health care professionals based on a thorough review and consideration of generally accepted
CHEST Recent Advances in Chest Medicine Malignant Pleural Mesothelioma An Update on Biomarkers and Treatment Mandira Ray, MD; and Hedy Lee Kindler, MD Although the insulating properties of asbestos have
Comparing Immunotherapy with High Dose IL-2 and Ipilimumab Michael K Wong MD PhD FRCPC firstname.lastname@example.org Disclosures Speaker s Bureau, Advisory Boards, Consultant: Prometheus Bristol Myers Squibb Novartis
Corporate Medical Policy Ado-Trastuzumab Emtansine (Trastuzumab-DM1) for Treatment of File Name: Origination: Last CAP Review: Next CAP Review: Last Review: ado_trastuzumab_emtansine_(trastuzumab-dm1)_for_treatment_of_her-2_positivemalignancies
LEUKEMIA LYMPHOMA MYELOMA Advances in Clinical Trials OUR FOCUS ABOUT emerging treatments Presentation for: Judith E. Karp, MD Advancements for Acute Myelogenous Leukemia Supported by an unrestricted educational
Avastin in breast cancer: Summary of clinical data Worldwide, over one million people are diagnosed with breast cancer every year 1. It is the most frequently diagnosed cancer in women 1,2, and the leading
ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials) 3 Integrated Trials Testing Targeted Therapy in Early Stage Lung Cancer Part of NCI s Precision Medicine Effort in
Pharmacogenomic markers in EGFR-targeted therapy of lung cancer Rafal Dziadziuszko, MD, PhD University of Colorado Cancer Center, Aurora, CO, USA Medical University of Gdansk, Poland EMEA Workshop on Biomarkers,
Future Directions in Clinical Research Karen Kelly, MD Associate Director for Clinical Research UC Davis Cancer Center Outline 1. Status of Cancer Treatment 2. Overview of Clinical Research at UCDCC 3.
Journal of the Egyptian Nat. Cancer Inst., Vol. 19, No. 1, March: 61-70, 2007 Assessment of Survival and Clinical Benefit in Malignant Pleural Mesothelioma (MPM) Patients Treated with Gemcitabine and Carboplatin
Trials in Elderly Melanoma Patients (with a focus on immunotherapy) Where we were Immunotherapy Trials: past and present Relevance for real world practice Where we are SIOG October 2012 James Larkin FRCP
ASX ANNOUNCEMENT 3 August 2011 ABN 53 075 582 740 BNC105 CANCER CLINICAL TRIALS REACH KEY MILESTONES CLINICAL PROGRAM TO BE EXPANDED Data from renal cancer trial supports progression of the trial: o Combination
Non-interventional study Avastin in Metastatic Breast Cancer ML 21165 / 2007 Clinical Study Report Synopsis ROCHE ML21165 / WiSP Project RH09 / V. 1.0 / 24.06.2013 ROCHE ML21165-2 - Name of Sponsor Roche
Transcript Details This is a transcript of a continuing medical education (CME) activity accessible on the ReachMD network. Additional media formats for the activity and full activity details (including
Bearz et al. BMC Research Notes 2012, 5:482 RESEARCH ARTICLE Open Access Re-challenge with pemetrexed in advanced mesothelioma: a multi-institutional experience Alessandra Bearz 1,9*, Renato Talamini 2,
Your Immune System & Lung Cancer Treatment Immunotherapy and Lung Cancer Immunotherapy is quickly developing as an important approach to treating many forms of cancer, including lung cancer. Immunotherapy
Corporate Presentation June 2, 2015 SAFE HARBOR STATEMENT This presentation contains forward-looking statements. Although the Company believes its expectations are based on reasonable assumptions, these
Future strategies for myeloma: An overview of novel treatments In development Dr. Matthew Streetly Guys and St. Thomas NHS Trust How far have we come? Melphalan and prednisolone VAD Autologous SCT Thalidomide
Overview of Mesothelioma Raffit Hassan, M.D. Mesothelioma Is an aggressive tumor that arises from the serosal surfaces of body cavities In 1960, Wagner reported increased incidence of mesothelioma in asbestos
SAMO Interdisciplinary Workshop on Chest Tumors Lucerne, 13th and 14th January 2012 Surgical therapy of mesothelioma, who should be operated Walter Weder MD Professor of Surgery University Hospital Zurich
PARP Inhibitors in Lung Cancer Primo N. Lara, Jr., MD Professor of Medicine UC Davis Comprehensive Cancer Center Poly (ADP-ribose) Polymerase (PARP): Mechanism of Action PARPs: family of enzymes that repair
Evaluation of asbestos-exposure, clinical diagnosis and treatment of MPM Aija Knuuttila, MD, PhD Dept. of Pulmonary Medicine Helsinki University Central Hospital, Finland 15.11.2007 Malignant pleural mesothelioma
Tumori rari del rene: trattamento per stadio ed istologia Dr. Camillo Porta S.C. di Oncologia Medica, Fondazione I.R.C.C.S. Policlinico San Matteo, Pavia Non-Clear Cell Renal Cell Carcinoma (nccrcc) nccrcc
Latest developments in management Gianfilippo Bertelli Consultant Medical Oncologist Swansea Optimizing management of ovarian cancer in South Wales Diagnosis and referral pathways: Role of GPs, gynaecologists,
FAK INHIBITOR DEFACTINIB (VS-6063) TARGETS MESOTHELIOMA CANCER STEM CELLS Rationale for maintenance therapy after conventional therapy Jonathan Pachter, Ph.D. Vice President of Research, Verastem, Inc.