Maligant mesothelioma Which systemic therapy?

1 Maligant mesothelioma Which systemic therapy? Rolf Stahel Department of Oncology Universitiy Hospital Zürich, Switzerland Ermatingen, 8.3.2015

2 Malignant pleural mesothelioma Systemic therapy Platin combination with pemetrexed has evolved as preferred chemotherapy regimen, while not formally proven to be superior to other platin-based combinations Histone deacetylase inhibotors and bortuzemib are ineffective Bevacizumab added to platin pemetrexed leads to an increase in progression-free survival and overall survival Occasional responses to multitargeted TKIs, however inconsistent and accompanied by major toxicity PD-1 in second line effective

Pemetrexed + Cisplatin vs Cisplatin: Tumor response and survival Vogelzang, JCO 2003

4 Pemetrexed and carboplatin in MPM Phase II 102 pts, RR 19%, MST 12.7 months Ceresoli, JCO 2006 Phase II 76 pts, RR 25%, MST 14 months Castageneto, Ann Oncol 2008 Elderly patients: No significant difference in toxicity and outcome Ceresoli, BJC 2008 Pemetrexed with cisplatin or carboplatin in expanded access program: Reported responses: 28.3% for pem/cis and 21.7% for pem/carbo Manegold, JTO 2008

5 Important questions on local treatment modalities of pleural mesothelioma EPP or no surgery? Impossible to answer in context of a randomized study. MARS feasibility trial failed Treasure, Lancet Oncol 2011 PORT to hemithorax after neoadjuvant chemo and EPP: SAKK 17/04 Part 1 Part 2 Registration after staging Chemotherapy Restaging Surgery Follow-up if not operable Reassessment R0 or R1 R2 Follow-up Randomisation Arm A: No Radiotherapy Arm B: Hemithoracic Radiotherapy

6 SAKK 17/04

7 SAKK 17/04: Survival from registration All patients: RR 30% Median OS 15 (12.1-19.3) months

8 SAKK 17/04: locoregional relapse free survival from registration Stahel, Lancet Onol in press

9 Does Surgery Improve Survival of Patients with Malignant Pleural Mesothelioma?: A Multicenter Retrospective Analysis of 1365 Consecutive Patients. Survival curves according to the treatment (nonsurgical treatment versus EPP versus P/D) considering only patients with favorable prognostic factors. EPP, extrapleural pneumonectomy; P/D, pleurectomy/decortications. Bovolato, JTO 2014

10 Angiogenesis as target previously not proven effective Randomized phase II study o bevacizumab in combination with cis/gem Kindler ASCO 2007; JTO 2012 Randomized phase III trial of thalidomide maintenace after first line chemotherapy Buikhuisen, Lancet Oncol 2013

Bevacizumab 15mg/kg plus cisplatin-pemetrexed (CP) triplet versus CP doublet in Malignant Pleural Mesothelioma (MPM): Results of the IFCT-GFPC 0701 MAPS randomized phase 3 trial EUDRACT N : 2007-002574-63 N ClinicalTrials.gov : NCT00651456 Gérard ZALCMAN, Julien MAZIERES, Jacques MARGERY, Laurent GREILLER, Clarisse AUDIGIER-VALETTE, Denis MORO-SIBILOT, Olivier MOLINIER, Romain CORRE, Isabelle MONNET, Valérie GOUNANT, Henri JANICOT, Radj GERVAIS, Chrystèle LOCHER, Bernard MILLERON, Quan TRAN, Marie-Paule LEBITASY, Franck MORIN, Christian CREVEUIL, Jean-Jacques PARIENTI & Arnaud SCHERPEREEL, on behalf of the French Cooperative Thoracic Intergroup (IFCT).

n=108 Bevacizumab & MPM: the first randomized trial Although presented as negative Statistical objective reached: Median PFS = 6.9 months! PFS Bevacizumab Placebo Median PFS : 6.9 m Median : 6.0 m Bevacizumab Placebo Median OS : 15.6 m Median OS : 14.7 m SG 2 nd line? : Pemetrexed! H. Kindler et al. J. Clin. Oncol. 2012

IFCT-GFPC-0701 trial: MAPS Mesothelioma Avastin cisplatin Pemetrexed Study IFCT-sponsored, open-label, multi-centre randomized phase II-III trial Roche supplied bevacizumab Malignant Pleural Mesothelioma (MPM) Histologically proven PS= 0-2 No cardiovascular comorbidity Chemonaive R 1:1 A B Pemetrexed 500 mg/m 2 D1 Cisplatin 75mg/m 2 D1 6 cycles, Q21D Pemetrexed 500 mg/m 2 D1 Cisplatin 75mg/m 2 D1 Bevacizumab 15 mg/kg D1 6 cycles, Q21D Surveillance No cross-over allowed Maintenance Bevacizumab 15 mg/kg D1, Q21D until progression CT-scan Q 3 cycles in both arms. Response assessed with modified RECIST criteria for mesothelioma Stratification: center, histology (epithelioid vs. sarcomatoid/mixed), PS (0-1 vs. 2), smoking status (ever smoker vs. never-smoker)

Patient Eligibility Pleural Mesothelioma histologically proved pleural biopsies: - thoracoscopy with or without pleurodesis (pleurodesis with talc poudrage not recommended to avoid interference with tumor evaluation) - trans-parietal CT-guided biopsy only if thoracoscopy judged as not possible: tumoral solid mass without liquid Not amenable to curative intent surgery according to a Multidisciplinary Tumor Board including a Mesothelioma-experienced surgeon (IMIG T2N0/ stage II or greater). Written informed consent Prophylactic radiation therapy of all tracts (3 x 7 Gray) before chemo, within 28 days following pleural biopsy. At least one evaluable or measurable CT-lesion Age 18 years and < 75 years WHO Performance Status 2 Weight loss < 10% of usual weight within 3 months prior to enrollment Adequate hematological and liver functions Adequate renal function: creatinine clearance > 60 ml/mn International Normalised Ratio (INR) < 1.5, Prothrombin time (PTT) < 1.5 x ULN within 7 days prior to enrollment

IFCT-GFPC-0701: MAPS Mesothelioma Avastin cisplatin Pemetrexed Study Phase 2-3 Statistics (I) Phase 2: Exact single-step Plan Disease control rate at 6 months (H0: p<40%, H1: p>60%): if < 25 / 50 non progressive patients : stop! if > 25 / 50 non progressive patients : proceed to phase 3 Power = 90%, a = 10%: 110 patients (assuming 10% of ineligibility) Phase 2 objective reached in Jan. 2010 (ASCO mee ng 2010 Abstr. 7020, Poster Discussion) Phase 3: Increase of median Overall Survival from 13 to 17.3 months HR= 0.75 3 years-survival = 14.7% vs. 23.6% (+8,9%) Power = 80% ; two-sided a = 5% 445 patients during 48 months with 24 months of follow-up Intent to treat final analysis planned after 385 deaths

IFCT-GFPC-0701: MAPS Mesothelioma Avastin cisplatin Pemetrexed Study Phase 3 Statistics (II) An interim analysis was planned after 193 deaths with a p-value for H0 < 0.003, according to O Brien-Fleming sequential plan (Dec. 2014). The Independent Data Monitoring Committe (IDMC): Prof. Aimery de Gramont (medical oncologist, AP-HP, University Paris 5, France), Prof. Dominique Valeyre (pulmonologist, AP-HP, University Paris 13, France), Dr. Thierry Berghmans (medical oncologist, Institut Jules Bordet, Brussels, Belgium), Dr. Ariane Dunant (statistician, Institut Gustave Roussy, University Paris 11 France) recommended a second, unplanned, interim analysis after 85% of expected events, with a p-value for H0 <0.03, to denote statistical significance (O Brien-Fleming adaptative design). An amendment to the initial protocol was then made to follow this recommendation. The 2 nd interim analysis was available for IDMC meeting, on 2 nd Feb. 2015. The IDMC recommended the results to be publicly released, since mature enough, although 385 events (deaths) were not observed yet.

Ineligible (n=4) No Consent (n=1) Previous cancer < 5 years (n=1) Final diagnosis = NSCLC, NOS (n=1) Previous ADK > 5 years (n=1) A Patient Disposition Allocated Pemetrexed plus Cisplatin n = 225 Randomized n = 448 From Feb. 2008 to Jan. 2014 B Allocated Pemetrexed plus Cisplatin plus Bevacizumab n = 223 Ineligible (n=3) Previous cancer < 5 years (n=1) Final diagnosis= NSCLC, NOS (n=1) Prévious ADK> 5 years (n=1) Did not received allocated treatment Consent withdrawal (n=1) Study withdrawn (n=217) Disease Progression (n=188) Toxicity (n=13) Death (n=6) Other (n=10) Data cut-off: Jan 15, 2015 Received treatment n = 224 Including n=155 under surveillance Ongoing n = 7 Received treatment n = 222 Including n=146 received maintenance Bevacizumab Ongoing n = 4 Did not received allocated treatment internal jugular veins Thrombosis (n=1) Study withdrawn (n=218) Disease Progression (n=137) Toxicity (n=47) Death (n=5) Patient s choice (n=1) Protocol violation (n=1) Other (n=27)

Gender Arm A (n=225) Arm B (n=223) Total (n=448) Male 170 (75.6%) 168 (75.3%) 338 (75.4%) Female 55 (24.4%) 55 (24.7%) 110 (24.6%) Age Patients baseline characteristics (1) Mean +/- SD 64.7 +/- 7.7 65.2 +/- 6.6 65.0 +/- 7.2 Median 65.6 65.7 65.7 Range [34.7-75.9] [38.5-75.8] [34.7-75.9] Histology Epithelioid 182 (80.9 %) 179 (80.3 %) 361 (80.6 %) Sarcomatoid-Mixed 43 (19.1 %) 44 (19.7 %) 87 (19.4 %) Performance Status 0-1 217 (96.4) 216 (96.9) 433 (96.7) 2 8 (3.6) 7 (3.1) 15 (3.3) Smoking status Smoker 127 (56.4) 124 (55.6) 251 (56.0) Never Smoker 98 (43,6) 99 (44,4) 197 (44.0) blue: stratification variables

Efficacy: ITT Progression-free Survival (PFS) 1 0.9 median follow-up= 39.4 mo [11.0-83.05] Progression-Free Survival Probability 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Median PFS: 7.48 mo, 95%CI: [6.79-8.13] Median PFS: 9.59 mo, 95%CI: [8.49-10.59] Stratified HR=0.61; 95%CI [0.50-0.75] p<0.0001 0 0 10 20 30 40 50 60 Time (months) No. At risk CT(PEM+CIS) 225 67 17 4 1 1 1 223 105 37 16 10 3 3 IFCT 0701 MAPS randomized phase 3 trial CT(PEM+CIS)+Beva

Efficacy: ITT Overall Survival (OS) Survival Probability 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 median follow-up= 39.4 mo [11.0-83.05] Median Overall Survival: 16.07 mo, 95%CI: [14.00-17.93] Median Overall Survival: 18.82 mo, 95%CI: [15.90-22.62] Stratified HR=0.76; 95%CI [0.61-0.94] p=0.0127 0.1 CT(PEM+CIS) CT(PEM+CIS)+Beva 0 0 10 20 30 40 50 60 No. At risk Time (months) 225 166 77 36 16 10 7 223 171 91 45 20 8 8 IFCT 0701 MAPS randomized phase 3 trial

Systemic post-discontinuation therapy Second-line systemic therapy Arm A N=210 Arm B N=208 p-value 152 (72.4%) 129 (62.0%) 0.02 pemetrexed 79 65 gemcitabine 44 33 Carboplatine/Oxali 66 40 cisplatine 15 21 bevacizumab 0 11* Other treatments (phase I) IFCT 0701 MAPS randomized phase 3 trial 24 21 * off-label, off protocol

MAPS trial conclusions Adding bevacizumab 15 mg/kg to Pemetrexed cispla n doublet significantly increased both PFS (by 2 months) and OS (by 2.75 months) at the cost of a slight, manageable increase of toxicity; QOL was preserved in both arms and beva did not show a detrimental effect on QOL, despite the higher toxicity. In this study, standard arm patients had a longer OS than historical series, or patients in previous trials, possibly because of eligibility criteria for bevacizumab The triplet Pemetrexed, cisplatin and bevacizumab is a new treatment paradigm for pleural mesothelioma patients eligible for bevacizumab, not amenable to curative surgery

23 Considerations after first line therapy In case of response or SD: discuss continuation maintenance with pemetrexed? In case of disease progression: Carboplatin/gemcitabine Carboplatin/vinorelbine Single agent gemcitabine or vinorelbine In case of progression after long response (>3 months?): Resume carboplatin/pemetrexed

24 Sunitinib in second line for mesothelioma 53 patients, median of 2 6-weeks cycles 6 (12%) PRs Median time to progression 3.5 months 40% required dose reduction, fatigue most common side effect Nowak, JTO 2012

25 Histone deacetylase inhibitors and bortezomib are inactive Vorinostat: Negative phase III in second line vs BSC (621 pts) Krug, ECCO-ESMO 2011 and Lancer Oncol 2015 Bortezomib: 1 PR o 21 patients treated in second line, deemed inactive Fennell, JTO 2012

NF2 is a gatekeeper during tissue repair normal tissue repair hedgehog signaling Cell-cell contact stimulation of repair in NF2-deficient cancer cells hedgehog signaling NF2 NF2 Mst WW45 Mob Lats P P Hippo pathway Mst WW45 Mob Lats P P YAP YAP Ser127P YAP Gli YAP X NF2 Survivin Gli YAP X Survivin

27 Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship Shapiro, Sci Transl Med 2014

Randomized Phase II Study of VS6063 (Defactinib) Maintenance Unresectable MPM PR/SD after 4 cycles of chemo 4-6 weeks after last chemo Primary Objectives: PFS and OS Secondary Objective: QoL Stratify: Merlin status R A N D O M I Z E VS-6063 400mg orally twice daily Placebo twice daily Data will be analyzed based on Merlin status CT scans every 6 weeks Primary endpoint: Overall survival N=372 patients (186 per arm) Fennell ASCO 2014 #TPS7611

29 Loss of NF2 correlates with activation of mtorc1 signalling and sensitivity to rapamycin GF R AKT PIP3 PDK-1 P P PIP2 T K PI3K NF2 PTEN mtorc2 mtorc1 Translation Cell-size regulation RNA processing DNA replication Lopez-Lago et al. MCB 2009

30 Response to GDC-0980, an oral PI3K/mTOR inhibitor, in mesothelioma + + Median time on study 3.9 months [0.5-22.6] 31% pts on study > 6 months 8% pts on study > 12 months + Pts still on study at data cut-off Dolly, ECCO ESMO 2013

31 Exploring new therapeutic approaches with mesothelin antibodies Amatuximab and chemortherapy: RR responses in 40% and SD in 42 (51%). Six-month PFS rate was 51% Hassan, CCR 2014 Immunotoxin SS1P: Recombinant antibody FV and pseudomonas exotoxin: Phase I single agent 4/33 minor responses. Neutralizing antibodies and dose-limiting capillary leak. Combined with chemotherapy, no results available Reviewed by Kelly, Mol Cancer Therapeutics 2012 Redesign with superior activity in preclinical models Weldon, Mol Cancer Therapeutics 2013

32 Tremelimumab (CTLA4 antibody) in mesothelioma 29 patients with chemotherapy resistant disease 2 patients with durable partial responses lasting 6 and 18 months Disease control in 31% Median PFS and OS 6.2 and 10.7 months Calabro, Lancet Oncol 2013

40 BAP-1 mutation in mesothelioma BAP1 was initially identified in lung cancer cell lines as a protein that binds to BRCA1 Jensen, Oncogene 1989 Genetic alterations in BAP1 gene have been identified in 23% of MPM specimens Bott, Nature Genetics 2011 3p21 9p21 22q12

41 BAP-1 mutation in mesothelioma Germline BAP1 mutations have been detected in families with a high incidence of MPM Testa, Nature Genetics 2011 Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers Abdel-Rahman, Nature Genetics 2011 The Prevalence of BRCA-1 associated protein 1 germline mutation in sporadic malignant pleural mesothelioma is estimated around 1-2% Rusch, Lung Cancer 2014 Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival Baumann, Carcinogenesis 2015