Systemic Management of Malignant Pleural Mesothelioma

Dragana JovanovicUniversity Hospital of Pulmonology

Clinical Center of SerbiaBelgrade, Serbia

ESO-ESMO EASTERN EUROPE ANDBALKAN REGION MASTERCLASS IN

MEDICAL ONCOLOGY15.June-19.June 2018

Belgrade, Serbia

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.

Malignant pleural mesothelioma (MPM)

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

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.

Complete visual examination and multiple large biopsies.

Diagnosis in >90% of cases

intrapleural loculations

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 epithelioidmesothelioma.

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…

Rush et al JTO 2012

Pleural mesothelioma survival based upon histology

N2 disease or mixed histology at surgery Nonepitheloid subtype - poorer prognosis

Treatment options depend on Stage and Histology!

Treatment principles

• 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

Treatment decisions by multidisciplinary team with experience in MPM!

• 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

Front-line Chemotherapy for MesotheliomaCisplatin + Pemetrexed vs Cisplatin (ITT)

Event Cisplatin +Pemetrexed

Cisplatin HR P Value

Response rate, % 41.3 16.7 < .001Median TTP, mos 5.7 3.9 0.68 < .001Median OS, mos 12.1 9.3 0.77 .028Global QoL score 45 38 .012Improved symptom distress 51 44 .009

Vogelzang NJ, et al. J Clin Oncol. 2003;21:2636-2644.Gralla RJ, et al. ASCO 2003. Abstract 2496.

• Cisplatin 75 mg/m2 +/-• Pemetrexed 500mg/m2

456 cases

Zalcman et al, Lancet 2016

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.

Positive for both PFS (primary endpoint) & OS

445 pts

Anti-angiogenic treatment in combination with cisplatin-pemetrexed 1st line treatment for MPM

Pretreatment After 4 cycles Cis/Pem

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.

Chemotherapy of MPM

Other acceptable 1st line ChemoTh options• Pemetrexed and Carboplatin• Gemcitabine and Cisplatin• Pemetrexed• Vinorelbine

Currently no second-line standard: Pem, Vb, GemLow RRs 10-15%

Clinical Stage I-III Medically operable

InductionChemotherapyCis/PemResectable

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

• 1st line approved regimen is pemetrexed plus cisplatinwith/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-Meso93

87 Nintedanib C/P

56.8 NR 3.7 II/III A NCT01907100

Mesothelin-targeted therapy Mesothelin95

248 Anetumab ravtansine

8.4 NR 4.3 (10.1)

II A NCT02610140

Arginine deprivation therapy ADAM96 68 ADI-PEG20 NR 52 3.2 II A NCT01279967

TRAP97 9 ADI-PEG20 78 100 7.7 I R NCT02029690

LUME-MesoPhase II Study

Clinical Studies on MPM Immunotherapy

Study Patients Drug RR, %

Stable disease, %

DCR, %

PFS, mo Target Phase Status

Clinical Trial Identifier

Combination immunotherapy

NIBIT-Meso-1109

40 Durvalumab Tremelimumab

20 37.5 62.5 NR PD-L1 CTLA4

II R NCT02588131

INITIATE110

25 Nivolumab Ipilimumab

20 4 72 NR PD-1 CTLA4

II R NCT03048474

MAPS-2108 54 Nivolumab Ipilimumab

27 26 52 5.6 PD-1 CTLA4

Clinical Studies on MPM Immunotherapy

MAPS-2 (IFCT-1501)

Estimated Study Completion December 2018

Scherpereel et al. ASCO 2017.

MAPS-2 (IFCT-1501)

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.