Giorgio V. Scagliotti IASLC President University of Torino Department of Oncology

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1 Giorgio V. Scagliotti IASLC President University of Torino Department of Oncology

Rare disease ( 3 cases/100.000), however.. In Italy more than 1.

2 Rare disease ( 3 cases/ ), however.. In Italy more than new cases/year Almost 40-50% arising from non-occupational exposure Mostly diagnosed in advanced disease stage If so, systemic chemotherapy ± talc pleurodesis is the standard of care. Recent data indicate a role for anti-angiogenetic agents added to chemotherapy No approved targeted therapy or second line agents Stage I patients may benefit from a multidisciplinary approach

Pemetrexed/cisplatin is the only approved regimen (since 2003), with a median OS of approximately 1 year The MAPS study showed that bevacizumab (anti-vegf

Lancet 2016) Patients with unresectable MPM Epithelioid and biphasic histology Measurable disease according to mrecist criteria ECOG PS 0 1 No prior chemotherapy

maintenance Placebo maintenance PD PD Selected endpoints Primary endpoint:pfs Secondary endpoints: OS and ORR Further endpoint: FVC Stratification for: histology

3 Pemetrexed/cisplatin is the only approved regimen (since 2003), with a median OS of approximately 1 year The MAPS study showed that bevacizumab (anti-vegf monoclonal antibody) combined with standard chemotherapy improved both median PFS and OS (Zalcman et al. Lancet 2016) Patients with unresectable MPM Epithelioid and biphasic histology Measurable disease according to mrecist criteria ECOG PS 0 1 No prior chemotherapy R 1:1 N=87 Nintedanib: 200 mg bid* + pemetrexed/cisplatin n=44 Placebo: 200 mg bid* + pemetrexed/cisplatin N=43 Non-PD patients Non-PD patients Nintedanib maintenance Placebo maintenance PD PD Selected endpoints Primary endpoint:pfs Secondary endpoints: OS and ORR Further endpoint: FVC Stratification for: histology (epithelioid vs biphasic) *On Days 2 21; 500 mg/m 2 /75 mg/m 2 i.v., every 21 days. Maximum treatment duration: 6 cycles. By investigator assessment according to mrecist. Grosso F., Scagliotti G. et al. J Clin Oncol. 2017;35:

PFS (%) 100 90 80 70 60 50 40 30 20 10 Intention-to-treat population Nintedanib Placebo PFS events 37 35 Median PFS (95% CI); months HR (95% CI); p- value 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Patients

4 PFS (%) Intention-to-treat population Nintedanib Placebo PFS events Median PFS (95% CI); months HR (95% CI); p- value Patients at risk Time from randomization (months) 9.4 ( ) 5.7 ( ) 0.54 ( ); p= Nintedanib Placebo Small phase II study Data quite compelling Compare well with MAPS Not unexpected toxicities Phase III finished Median PFS gain: 3.7 months (HR=0.54; p=0.010) Greatest benefit observed in patients with epithelioid histology Median PFS gain: 4.0 months (HR=0.49; p=0.006) Comparable gain in terms of OS (Median survival of 20.6 months in epithelioid pts, increased ORR Grosso F., Scagliotti G. et al. J Clin Oncol. 2017;35:

5 Pleural mesothelioma Completed #4-6 first line platinum-pemetrexed Non-progressive disease PS 0-2 <60 days of last chemo Pleurectomy / PORT OK Maintenance nintedanib (200mg bid), q28 R Maintenance placebo, q28 Primary: PFS: H0: 4 months ; H1 6.5 months (HR=0.62) N= 116 patients PI: Dr Sanjay Popat

6 Yap TA et al. Nat. Rev. Cancer 2017; 17:475

7 Tumors may have deficiency in ASS leading to dependency on arginine

8 214 patients Screen for ASS1 status Chemo-naive or prior platinum doublet 68 patients ASS1 negative or low ( 50% ASS1 low cells) R A N D O M I Z E Best supportive care Primary endpoint: PFS ADI-PEG20 IM Q week RR 4 mo PFS PFS OS BSC 0% 22% 1.9 mo 12.8 mo ADI-PEG20 0% 52% 3.2 mo 14.5 mo Szlosarek PW et al. JAMA Oncology 2017; 3:58-66

9 Szlosarek PW et al. JAMA Oncology 2017; 3:58-66

10 A phase I trial that assessed the combination of ADI-PEG20 with pemetrexed and cisplatin chemotherapy has been completed (Beddowes, E. et al. J. Clin. Oncol.35, ). A randomized phase II/III trial, ATOMIC, is now enrolling ( On the basis of the very high prevalence of ASS1 negativity in sarcomatoid and biphasic mesothelioma, enrolment is to be based on these histological subgroups, making a unique subpopulation for trial selection in mesothelioma.

A tumor differentiation antigen Normally expressed on

biphasic MM Precursor protein (71 kda) RR GPI MPF (31 kda)

Agents targeting mesothelin in current clinical trials:

11 A tumor differentiation antigen Normally expressed on mesothelial cells Highly expressed in epithelial and biphasic MM Precursor protein (71 kda) RR GPI MPF (31 kda) Mesothelin (40 kda) GPI Mesothelin processing Membrane Agents targeting mesothelin in current clinical trials: MORAb009 (pending for results), SS1P, CRS-207 (negative), BAY (negative)

12 Yap TA et al. Nat. Rev. Cancer 2017; 17:475

Inflammatory phenotype (T cells) and tumor expression of PD-L1 by MPM cells (and stroma): at least 20-40% of cases (Sarcomatoïd>Biph>Epithelioïd) 1 PD-L1 expression associated with bad prognosis in

13 Inflammatory phenotype (T cells) and tumor expression of PD-L1 by MPM cells (and stroma): at least 20-40% of cases (Sarcomatoïd>Biph>Epithelioïd) 1 PD-L1 expression associated with bad prognosis in MPM 2 : mos: 5.0 months if PD-L1+ tumor vs 14.5 months if PD-L1 negative PD-L1+ expression is an independent risk factor for OS: RR = 1.71 Conversely, patients with highest level of intra-tumor cytotoxic CD8+ T cells in resected MPM had a better prognosis 3 Thapa, JTO , Tremelimumab alone did not improve mos vs. placebo in a Phase 2b randomized trial (Determine) in II/III line MPM 6 1. Thapa, JTO 2017; Lanteajoul, JTO 2017; Mansfield, JTO 2014; 2. Khanna, JTO 2016; 3. Cedrés, PLoS One 2015; 4.Combaz-Lair C, Hum Pathol. 2016;5. Lievense, AJRCCM 2017; 6 Maio M. et al. Lancet Oncol 2017

Randomized, non-comparative phase 2 trial - One-step Fleming design (each arm independently) Histological diagnosis of MPM Unresectable cancer with documented progression after maximum 1 or 2

14 Randomized, non-comparative phase 2 trial - One-step Fleming design (each arm independently) Histological diagnosis of MPM Unresectable cancer with documented progression after maximum 1 or 2 previous lines of chemotherapy including a pemetrexed/platinum doublet Measurable disease (mrecist) ECOG PS 0-1 Weight loss <10% Age : > 18 years Life expectancy > 12 weeks Available tumor tissue Anti-PD-1 Nivolumab 3 mg/kg IV / 2 weeks (n=57) Anti-PD-1 Nivolumab 3 mg/kg IV / 2 weeks + Anti-CTLA4 Ipilimumab 1mg/kg IV / 6 weeks (n=57) Until Progression or unacceptable toxicity (or 2 years max) CT-scan reassessment at Week 12 Until progression or unacceptable toxicity (or 2 years max) MPM, malignant pleural mesothelioma Zalcman G, et al. ESMO Abstract LBA58_PR.

15 IFCT-1501 MAPS2: Second or 3rd line Nivo versus Nivo plus Ipi in MPM patients Updated results Conclusions Both arms achieved primary endpoint in 2L/3L MPM patients with meaningful increase in DCR compared to historical trials Toxicity was globally manageable, despite 3 potentially toxic deaths in combo arm QoL at 12 weeks favours (though NS) monotherapy arm for global, pain, anorexia, interference items, and combo arm for symptoms distress scales, but long-term data pending OS data still immature, with median OS beyond 15 months for combo and 13.6 in nivo arm PD-L1 tumor expression could favour response and longer OS in nivo arm but not combo Results support NCCN decision to recommend monotherapy or combo therapy as options for 2L/3L therapy in relapsing MPM patients AE Nivo arm Nivo + Ipi arm All grade 56 (88.9%) 57 (93.4%) Grade 3 8 (12.7%) 14 (22.9%) Grade (3.3%) Grade (4.9%)* *1 fulminant hepatitis, 1 encephalitis and acute kidney failure Mesothelioma is a major unmet need for new therapy Response rate highlights activity in biphasic mesothelioma Despite activity, PROs are discordant from efficacy data Debatable whether these results support NCCN recommendations Zalcman G, et al. ESMO Abstract LBA58_PR.

Key Eligibility Criteria Unresectable, untreated pleural mesothelioma Available tumor sample ECOG PS

vs sarcomatoid or mixed histology subtypes) Gender N=600 R Ipilimumab 1 mg/kg q6w [2] + Nivolumab 3

500 mg/m 2 q3w, 6 cycles [2] Study Start Date: October 2016 Estimated Completion Date: September 2021

Measures: OS, PFS Secondary Outcome Measures: ORR, DCR, association between PD-L1 expression and

16 Key Eligibility Criteria Unresectable, untreated pleural mesothelioma Available tumor sample ECOG PS 0 1 No prior chemotherapy for pleural mesothelioma Stratification Factors [2] Histology (epithelioid vs sarcomatoid or mixed histology subtypes) Gender N=600 R Ipilimumab 1 mg/kg q6w [2] + Nivolumab 3 mg/kg q2w [2] (up to progression/toxicity*) Cisplatin 75 mg/m 2 or carboplatin AUC 5 [2] + Pemetrexed 500 mg/m 2 q3w, 6 cycles [2] Study Start Date: October 2016 Estimated Completion Date: September 2021 Estimated Primary Completion Date: October 2020 Status: Recruiting Sponsor: Bristol-Myers Squibb Measures: OS, PFS Secondary Outcome Measures: ORR, DCR, association between PD-L1 expression and efficacy measures!. Clinicaltrials.gov. NCT Accessed February 24, BMS DOF CA Study design.

17 Lo Iacono M et al. J. Thorac. Oncol. 2015; 10: 452-9

Patil N, Righi L. et al. J. Thorac. Oncol. 2017 (accepted) 800 gene panel (Nanostring), MPMs were classified into three groups.

18 Patil N, Righi L. et al. J. Thorac. Oncol (accepted) 800 gene panel (Nanostring), MPMs were classified into three groups. Group 1 : Most immunologically ignorant or desert like phenotype with poor immune cell gene expression Group 2 : Moderate expression of T cell effector genes and high expression of B cell genes. Group 2-like molecular signature may be candidates for a combination of B and T cell activation therapeutic strategies. Group 3 : Associated with higher PD-L1 expression levels and a high expression of T effector cells suggesting to be the most responsive to PD-1 blockade

19 Pharmacogenomics Integration with targeted therapies Molecular landscape Genome-wide association studies BAP1 NF2 Germline BAP1 mutation and familiar MPM MESOLINE Pharmacological screening studies Immuno-enviroment

mechanisms to survive without BAP1; identifying these mechanisms may provide new

20 Loss of the deubiquitylase BAP1 alters class I histone deacetylase expression and sensitivity of mesothelioma cells to HDAC inhibitors Cancer cells develop compensatory mechanisms to survive without BAP1; identifying these mechanisms may provide new opportunities for synthetic lethal strategies. Sacco J.J. et al., Oncotarget, Vol. 6, No. 15; 2015

21 Mesothelioma cells that lack BAP1 (H226 and H2452, that have BAP1 mutations) are sensitive to EZH2 inhibition Studies are under construction with Tazemetostat BAP1 mut BAP1 wt La Fave LM et al., Nat Med. 2015;21:1344-9

22 1) Analysis of CSCs and link with chemoresistance 2) Analysis of the immune infiltrate and immune checkpoints expression 3) Effects of epigenetic drugs on tumor growth, immunogenic cell death/immuno-checkpoints 4) mirnas targeting BRDs members 5) Analysis of resistance to ER stress, chemotherapy and immunotherapy 6) In vivo models

23 Bromodomain (BRD) members are amplified or up-regulated in the MPM series analyzed in the TCGA. BRD inhibitors (BBI) show a strong efficacy in several hematological and solid tumors, where they reduce cell proliferation and increase apoptosis. BBI OTX105 lowers MPM cell proliferation by decreasing c-myc expression and delays the growth of MPM xenograft with efficacy equal to standard chemotherapy The broad spectrum of BRD-target genes, BBI may not only affect the expression of oncogenes, TSGs and regulators of apoptosis, but also the expression of genes involved in inflammatory response and immune system activity.

24 P< 0.05 NS P< 0.01 P <0.001 Riganti C. et al. Oncoimmunology 2018

25 Riganti C. et al. Oncoimmunology 2018

26 Abeegbe DO et al. Cancer Discovery 2017: 7:

27 Better classification/monitoring of the disease status with biologic markers discovered by genomics/ proteomics. More uniform selection of patients for multimodality therapy based on pre-treatment gene expression/clinical demographics. Platinum+Pemetrexed remains the standard of care. Consideration should be given to the addition of bevacizumab. PD-1 inhibitor +/-CTLA4 inhibitor have shown promising activity. Metabolic pathway inhibitors and drugs targeting mesothelin are also being evaluated Molecular characterization of MM may provide an opportunity to use targeted therapy.

Systemic Management of Malignant Pleural Mesothelioma

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