ESO-ESMO EASTERN EUROPE AND BALKAN REGION MASTERCLASS IN MEDICAL ONCOLOGY 15.June-19.June 2018 Belgrade, Serbia Systemic Management of Malignant Pleural Mesothelioma Dragana Jovanovic University Hospital of Pulmonology Clinical Center of Serbia Belgrade, Serbia
Malignant pleural mesothelioma (MPM) Highly aggressive tumor linked to asbestosis Median survival 6-8 months for patients treated with best supportive care and 12-16 months with pemetrexed-platinum therapy. Therapy is generally palliative, improving symptoms and modestly increasing survival. Carbone M et al. 2012, Lemen RA. 2016, Nicholson et al. 1982
Diagnosis delay! Advanced disease in most cases CT scan - diffuse or nodular pleural thickening suggestive of the disease.
Diagnosis of Mesothelioma Fine needle biopsies - low sensitivity (~30%) Surgical-type samples preferred for diagnosis Image-guided (US) needle core biopsies or Diagnosis in >90% of cases Complete visual examination and multiple large biopsies. intrapleural loculations Maskell et al. Lancet 2003; Metintas et al. Chest 2010; van Zandwijk et al. J Thorac Dis 2013, Scherpereel Eur Respir J 2010; Medford et al. Lung Cancer 2009; Zahid et al. Interact Cardiovasc Thorac Surg 2011;Greillier et al. Cancer 2007;ESMO GL 2015, NCCN GL 2016.
WHO Classification of Tumors of the Pleura 2015 Different treatment approach! TNM Staging: Pretreatment Chest/abdominal CT mandatory
Natural course of MPM Death is usually due to: Progressive dyspnea - respiratory Insuffiency with extensive weight loss & muscle wasting Acute abdomen Cardiac tamponade/ constriction Survival 6-12-18 months from Dagnosis
Prognostic factors Stage and histology - the strongest prognostic factors: sarcomatoid and biphasic histologic subtypes having worse outcomes compared with epithelioid mesothelioma. The pure epithelioid variant - the best prognosis especially if can be completely resected. Poor prognostic features include: poor PS, age >75 years, elevated lactate dehydrogenase (LDH), and hematologic abnormalities
Pleural mesothelioma survival based upon histology N2 disease or mixed histology at surgery Nonepitheloid subtype - poorer prognosis Rush et al JTO 2012
Treatment options depend on Stage and Histology!
Treatment principles Treatment decisions by multidisciplinary team with experience in MPM! Multimodality treatment for pts with stages I-III MPM who are medically operable. Chemotherapy alone for not operable patients, or clinical stage IV, or sarcomatoid or mixed histology. Radiotherapy for palliation, preventive, and as a part of multimodality treatment van Zandwijk et al. J Thorac Dis 2013, ESMO GL 2015, MPM NCCN v2017
Front-line Chemotherapy for Mesothelioma Cisplatin with pemetrexed standard of care Improves survival of patients with unresectable MPM Carboplatin is an acceptable alternative to cisplatin (elderly) van Meerbeeck et al. J Clin Oncol 2005; Santoro et al. J Thorac Oncol 2008; Ceresoli et al. Br J Cancer 2008;
Front-line Chemotherapy for Mesothelioma Cisplatin + Pemetrexed vs Cisplatin (ITT) Cisplatin 75 mg/m2 +/- Pemetrexed 500mg/m2 456 cases Event Cisplatin + Pemetrexed Cisplatin HR P Value Response rate, % 41.3 16.7 <.001 Median TTP, mos 5.7 3.9 0.68 <.001 Median OS, mos 12.1 9.3 0.77.028 Global QoL score 45 38.012 Improved symptom distress 51 44.009 Vogelzang NJ, et al. J Clin Oncol. 2003;21:2636-2644. Gralla RJ, et al. ASCO 2003. Abstract 2496.
Anti-angiogenic treatment in combination with cisplatin-pemetrexed 1st line treatment for MPM 445 pts Positive for both PFS (primary endpoint) & OS OS was significantly longer 18 8 mos vs 16 1 mos HR 0 77; p=0 0167, at the cost of expected manageable toxic effects. Zalcman et al, Lancet 2016
Chemotherapy of MPM Front-line Chemotherapy should be stopped in case of progressive disease, grade 3 4 toxicities or cumulative toxic doses or following up to six cycles in patients who respond or who are stable. Pretreatment After 4 cycles Cis/Pem Other acceptable 1 st line ChemoTh options Pemetrexed and Carboplatin Gemcitabine and Cisplatin Pemetrexed Vinorelbine Currently no second-line standard: Pem, Vb, Gem Low RRs 10-15%
Induction Chemotherapy Cis/Pem Resectable Clinical Stage I-III Medically operable
Radiotherapy in mesothelioma Palliation Preventive treatment Part of a multimodality treatment Palliative RT effective in temporarily relieving chest pain, bronchial or esophageal obstruction, infiltration of the chest wall or permeation nodules or other symptomatic sites. Debate whether a scar after thoracoscopy and/ or drainage procedures should be irradiated prophylactically in order to reduce the likelihood of seeding metastases. Price. Oncologist 2011, Macleod et al. Lung Cancer 2014, ESMO GL MPM 2015
Pleurodesis Active control of pleural effusion is the mainstay of treatment in most patients with MPM. Early and successful pleurodesis - symptom control and a trapped lung less likely to occur (before effusions have become loculated and/or the lung has become fixed and unable to expand fully). Pleurodesis should be performed at first relapse of effusion. Symptom control (pain, dyspnea ) Every patient should receive at least BSC
Malignant Pleural Mesothelioma: 2018 Majority of patients present with advanced disease and are not candidates for surgery 1 st line approved regimen is pemetrexed plus cisplatin with/without Bev New Anti-angiogenic treatment options? Several ongoing studies using different immune based therapies to treat mesothelioma
Clinical studies Non-Immunotherapy - related Study Patients Intervention RR, % Stable disease, % PFS (OS), mo Phase Status Clinical Trial Identifier Antiangiogenesis therapy LUME- Meso 93 87 Nintedanib C/P 56.8 NR 3.7 II/III A NCT01907100 Mesothelin-targeted therapy Mesothelin 95 248 Anetumab ravtansine 8.4 NR 4.3 (10.1) II A NCT02610140 Arginine deprivation therapy ADAM 96 68 ADI-PEG20 NR 52 3.2 II A NCT01279967 TRAP 97 9 ADI-PEG20 78 100 7.7 I R NCT02029690
LUME-Meso Phase II Study
Clinical Studies on MPM Immunotherapy
Clinical Studies on MPM Immunotherapy Study Patients Drug RR, % Stable disease, % DCR, % PFS, mo Target Phase Status Clinical Trial Identifier Combination immunotherapy NIBIT- Meso-1 109 40 Durvalumab Tremelimumab 20 37.5 62.5 NR PD-L1 CTLA4 II R NCT02588131 25 Nivolumab 20 4 72 NR PD-1 II R NCT03048474 INITIATE 110 Ipilimumab CTLA4 MAPS-2 108 54 Nivolumab Ipilimumab 27 26 52 5.6 PD-1 CTLA4
MAPS-2 (IFCT-1501)
MAPS-2 (IFCT-1501) Estimated Study Completion December 2018 Scherpereel et al. ASCO 2017.
Summary of new systemic therapies Predictive biomarkers unmet need!
Clinical trials yet to be published
Conclusion Malignant pleural mesothelioma (MPM) is a highly aggressive tumor, almost always a fatal disease. Early diagnosis of crucial importance, made based on histological and immunohystochemical examination. Active control of pleural effusion is the mainstay of treatment in most patients.