Unresectable Malignant Pleural Mesothelioma Research Articles

Chemotherapy treatment in malignant pleural mesothelioma: a difficult history.

Malignant pleural mesothelioma (MPM) is a rare neoplasm that typically arises from mesothelial surfaces of the pleural cavity. Despite treatment improvements, it carries a dismal prognosis. The majority of patients either have unresectable disease or are not candidates for surgery due to medical comorbidities or old age. For such patients, chemotherapy (CT) represents the gold-standard treatment. To date, combination CT with cisplatin plus pemetrexed represents the most widely used regimen in first-line setting for patients with unresectable MPM. Other first-line options are currently available, including the use of raltitrexed instead of pemetrexed combined with platinum. In this review, we discuss the role of CT in MPM mainly focusing on the results of the trials conducted in first-line setting.

SPS-7 - Nintedanib plus pemetrexed/cisplatin in patients with MPM: Phase II findings from the placebo-controlled LUME-Meso trial

Standard 1st-line treatment for patients (pts) with unresectable malignant pleural mesothelioma (MPM) is pemetrexed/cisplatin (PEM/CIS); median overall survival (OS) is approximately 1 year. Nintedanib (N) is an oral inhibitor of VEGFR, PDGFR and FGFR, and Src and Abl kinases. VEGF and PDGF overexpression are associated with poor prognosis in MPM, and N has shown efficacy in preclinical models. This study evaluated the efficacy and safety of N+PEM/CIS vs placebo (P)+PEM/CIS in pts with MPM. Pts with unresectable MPM (chemo-naive, ECOG PS 0-1) were stratified by histology (epithelioid/biphasic) and randomised 1:1 to receive up to 6 cycles of PEM (500 mg/m2)/CIS (75 mg/m2) on Day 1 plus N or P (200 mg bid) on Days 2-21. Pts without disease progression received maintenance N or P. The primary endpoint was progression-free survival (PFS). 87 pts were randomised to N+PEM/CIS (n = 44) or P+PEM/CIS (n = 43). Pt characteristics were comparable between the groups; 89% had epithelioid MPM. PFS was significantly improved with N vs P (HR = 0.56 [95% CI 0.34-0.91]; p = 0.0174; median PFS 9.4 vs 5.7 months). PFS benefit was also seen in the epithelioid subgroup (HR = 0.51 [95% CI 0.30-0.86]; p = 0.0101). Preliminary OS data favoured N; objective tumour response was observed in 59% of the N arm vs 44% of the P arm (all partial responses). All pts experienced at least one adverse event (AE; any grade), with 7% of the N arm discontinuing due to AEs vs 15% with P. Serious AEs occurred in 36% vs 42% of pts in the N and P arms, respectively. The most common Grade ≥3 AEs (N vs P) were neutropenia (34% vs 10%), alanine aminotransferase increase (14% vs 2%) and gamma glutamyltransferase increase (14% vs 0%). N+PEM/CIS demonstrated clinical efficacy with improved PFS and a tolerable safety profile in pts with unresectable MPM. Based on these promising findings, the study was extended and the Phase III part is recruiting (NCT01907100).

Prognostic and predictive role of [18 F]fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with unresectable malignant pleural mesothelioma (MPM) treated with up-front pemetrexed-based chemotherapy.

The aim of this study was to evaluate the role of metabolic parameters analyzed at baseline and at interim FDG‐PET in predicting disease outcome in unresectable MPM patients receiving pemetrexed‐based chemotherapy. A consecutive series of MPM patients treated between February 2004 and July 2013 with first‐line pemetrexed‐based chemotherapy, and evaluated by FDG‐PET and CT scan at baseline and after two cycles of chemotherapy, was reviewed. Best CT scan response was assessed according to modified RECIST criteria. Progression‐free survival (PFS) and overall survival (OS) were correlated with FDG‐PET parameters, such as maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), and percentage changes in SUVmax (∆SUV) and TLG (∆TLG). Overall, 142 patients were enrolled; 77 (54%) received talc pleurodesis before chemotherapy. Baseline SUVmax and TLG showed a statistically significant correlation with PFS and OS (P < 0.05) in both group of patients (treated and untreated with pleurodesis). In 65 patients not receiving pleurodesis, SUVmax reduction ≥25% (∆SUV ≥ 25%) and TLG reduction ≥30% (∆TLG ≥ 30%) were significantly associated with longer PFS (P < 0.05). Patients showing both ∆SUV ≥ 25% and ∆TLG ≥ 30% responses had a significant reduction in the risk of disease progression (HR:0.31, P < 0.001) and death (HR:0.52, P = 0.044). Neither ∆SUV nor ∆TLG showed similar association with survival outcomes in patients treated with pleurodesis. Our study confirmed the prognostic role of baseline FDG‐PET in a large series of MPM patients treated with first‐line pemetrexed‐based chemotherapy. Moreover, use of ∆SUV ≥ 25% and ∆TLG ≥ 30% as cut‐off values to define early metabolic response supported the role of FDG‐PET in predicting disease outcome and treatment response in patients not receiving pleurodesis.

1616O - Multicenter, nonrandomized, open-label Phase 1b study of FP-1039/GSK3052230 with chemotherapy: results in malignant pleural mesothelioma (MPM)

Background: Fibroblast growth factor (FGF) signaling has a fundamental role in cancer development and tumor maintenance. FP-1039/GSK3052230 is a soluble decoy receptor that sequesters FGFs, including FGF2, blocking their ability to bind to and activate FGFRs, particularly FGFR1. This unique mechanism of action should avoid the on-target toxicities associated with small molecule pan FGFR kinase inhibitors, such as hyperphosphatemia and retinal, nail, and skin changes. MPM remains a disease with poor prognosis and few effective therapies, and preclinical models of MPM are particularly sensitive to inhibition of FGF/FGFR signaling by FP-1039/GSK3052230. Methods: Herein, the analysis of patients with untreated, unresectable MPM is reported. The MPM arm of the study evaluated the safety and efficacy of FP-1039/GSK3052230 (IV weekly) in combination with standard pemetrexed+cisplatin. The study design involved dose escalation until MTD followed by a cohort expansion phase. Endpoints included safety, overall response rate by modified RECIST 1.1, disease control rate (DCR), PFS, and exploratory translational objectives. Results: As of the cutoff date of 17 Mar 2017, 36 patients were dosed at 10, 15 and 20 mg/kg doses of FP-1039/GSK3052230. Three DLTs were observed at 20 mg/kg but none occurred at 15 mg/kg; therefore, MTD was declared at this dose. Most common related adverse events (all grades) were: nausea (56%) decreased appetite (36%), fatigue (33%), and infusion reaction (33%). The confirmed objective response rate (ORR) of all evaluable patients at or below the MTD was 48% (13/27 PRs), with disease control rate (DCR) of 100%. The median PFS was 7.4 months. As of 8 May 2017, six patients stayed on the study for over 1 year, of which 3 were still ongoing. Results of exploratory biomarker analyses will also be presented. Conclusions: The MTD of FP-1039/GSK3052230 (15 mg/kg) in combination with pemetrexed+cisplatin in MPM was well tolerated, and durable responses were observed. Importantly, AEs associated with small-molecule pan FGFR kinase inhibitors were not observed, as predicted by the unique mechanism of action of this drug. Study sponsored by GSK; clinical trial information: NCT01868022. Clinical trial identification: NCT01868022 Legal entity responsible for the study: GlaxoSmithKline Funding: GlaxoSmithKline Disclosure: D.A. Fennell: Advisory Board/consultant – Astra Zeneca, BMS, Bayer, Boehringer Ingelheim, Clovis, Roche, Eli Lilly, MSD H.L. Kindler: Advisor: Aduro; AZ; Bayer; Celgene; Genentech/Roche; Gilead; GSK; MedImmune; Merck; Plexxikon; Verastem. Grants: AB Science; Aduro; Astellas Pharma; AZ; Bayer; Celgene; GSK; Incyte; MedImmune; Merck; Verastem. Expert Testimony: Aduro S. Viteri: Grants: AbbVie, ARIAD, Astex, AZ, BI, Clovis, CytRx, Daiichi Sankyo, GSK, Hanmi, Incyte, Merck KGaA, Novartis, Pfizer, Puma, Roche, Servier, Vaxon. Advisor: BI, Clovis, Idea Pharma, Novartis, Promega Biotech Ibérica, Roche, Targovax S. Gadgeel: Advisor/Board member: Genentech/Roche, Pfizer, Ariad, Astra-Zeneca Speakers bureau: Genetech/Roche, Astra-Zeneca Travel Compensation: Genentech/Roche P. Garrido Lopez: Advisor/Board member: MSD, Pfizer, BMS, Novartis, Roche, BI, Guardant Speakers bureau: MSD, Pfizer, BMS, Novartis, Roche Honorarium recipient: BI D. Morgensztern: Advisor/Board member: Abbvie, Celgene, Bristo-Myers Squibb J.F. Vansteenkiste: Grants/research support recipient: AZ Honorarium/consulting: AZ, Novartis, MSD, BI, Eli-Lilly, Roche X. Wang: Full-time employee with GlaxoSmithkline A. Sharabidze: Consultant at GSK M.P. Deyoung: Full time employee and stock owner of GSK K.P. Baker: Full time employee of Five Prime Therapeutics L. Yan, I. Mitrica: Full time employee of GSK and stock owner All other authors have declared no conflicts of interest.

Phase I Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemonaive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905)

IntroductionIn malignant pleural mesothelioma, targeting angiogenesis with cediranib, a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, may have therapeutic potential. MethodsS0905 phase I combined cediranib (two dose cohorts [30 mg and 20 mg daily]) with cisplatin-pemetrexed for six cycles followed by maintenance cediranib in unresectable chemonaive patients with malignant pleural mesothelioma of any histologic subtype. The primary end point established the maximum tolerated dose in combination with cisplatin-pemetrexed in a dose deescalation scheme. ResultsA total of 20 patients were enrolled (seven to the 30-mg cohort and 13 to the 20-mag cohort). In the cediranib 30-mg cohort, two of the initial six patients reported dose-limiting toxicities and the dose was deemed too toxic to continue. In the next cohort, two patients experienced dose-limiting toxicities, and thus, the maximum tolerated dose of cediranib was established as 20 mg. During the six cycles of cisplatin-pemetrexed-cediranib, 20 mg, there were grade 3 toxicities (neutropenia and gastrointestinal) and grade 4 thrombocytopenia. No patients had any significant episodes of bleeding. According to the Response Evaluation Criteria in Solid Tumors (n = 17 evaluable patients), the median progression-free survival was 12.8 months (95% confidence interval [CI]: 6.9–17.2); according to the Modified Response Evaluation Criteria in Solid Tumors (n = 19 evaluable patients), the median progression-free survival was 8.6 months (95% CI: 6.1–10.9). For all patients, the disease control rate at 6 weeks was 90% and median overall survival time was 16.2 months (95% CI: 10.5–28.7). ConclusionsCediranib combined with cisplatin-pemetrexed has a reasonable toxicity profile and preliminary promising efficacy. The phase II S0905 trial will evaluate the efficacy of the triplet regimen compared with the current standard of care, cisplatin-pemetrexed.

Checkmate 743: A phase 3, randomized, open-label trial of nivolumab (nivo) plus ipilimumab (ipi) vs pemetrexed plus cisplatin or carboplatin as first-line therapy in unresectable pleural mesothelioma.

TPS8581 Background: Malignant pleural mesothelioma (MPM) is an aggressive cancer with a 5-year overall survival (OS) rate of &lt; 10%. At diagnosis, most patients (pts) have unresectable disease. Combination chemotherapy of cisplatin (or carboplatin as an alternative) + pemetrexed is the approved first-line standard of care. Phase 1 and 2 data suggest that targeting immune checkpoint pathways (eg, programmed death [PD]-1/PD-ligand 1 [PD-L1] and/or cytotoxic T-lymphocyte antigen-4 [CTLA-4]) may provide benefit with acceptable safety in MPM. In pts with previously treated, malignant mesothelioma, single-agent tremelimumab (a CTLA-4 inhibitor antibody) was active but did not improve OS vs placebo. In a phase 2 study of nivo (a fully human PD-1 immune checkpoint inhibitor antibody) in 34 pts with MPM that progressed after first-line platinum-based chemotherapy, 12-week disease control rate (DCR) was 50%, 5 pts had partial response, and 12 pts had stable disease. Given the data with single-agent CTLA-4 and PD-1 inhibitors and that CTLA-4 inhibition can induce PD-L1 expression, there is reason to anticipate synergy when combining CTLA-4 and PD-1 inhibitors in MPM. A phase 2 study assessing nivo alone and nivo + ipi (a CTLA-4 inhibitor antibody) in MPM is ongoing. CheckMate 743 (NCT02899299) is a phase 3 study that will evaluate the efficacy and safety of first-line nivo + ipi vs chemotherapy for MPM. Methods: Approximately 600 adult pts with unresectable MPM and ECOG performance status 0–1 will be randomized. Pts are ineligible if they have primary peritoneal, pericardial, or tunica vaginalis testis mesotheliomas; have active, untreated CNS metastases; or had received prior systemic therapy for pleural mesothelioma or a prior PD-1/PD-L1 or CTLA-4 checkpoint inhibitor antibody. Pts are randomized 1:1 to receive nivo + ipi or pemetrexed + cisplatin/carboplatin. Primary endpoints are OS and progression-free survival (PFS), assessed by blinded independent central review. Secondary endpoints are objective response rate (ORR), DCR, and correlation of PD-L1 expression level and efficacy (ORR, PFS, and OS). Clinical trial information: NCT02899299.

Mature overall survival (OS) results from the LUME-Meso study of nintedanib (N) + pemetrexed/cisplatin (PEM/CIS) vs placebo (P) + PEM/CIS in chemo-naïve patients (pts) with malignant pleural mesothelioma (MPM).

8506 Background: LUME-Meso is a Phase (Ph) II/III, double-blind, randomized study. N targets MPM by inhibiting VEGFR 1–3, PDGFR α/β, FGFR 1–3, Src and Abl kinases. Primary analysis of the Ph II data demonstrated improved progression-free survival (PFS; hazard ratio [HR]=0.56; 95% confidence interval [CI] 0.34–0.91; p=0.017). Mature Ph 2 OS and updated PFS results are reported here. Methods: Pts with unresectable MPM (ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomized 1:1 to receive ≤6 cycles PEM (500 mg/m2)/CIS (75 mg/m2) Day 1 + N or P (200 mg bid, Days 2–21), followed by N or P monotherapy until progression or toxicity. The primary endpoint was PFS. The primary OS analysis and updated PFS analysis were performed as predefined. Results: 87 pts were randomly assigned (N=44, P=43). OS benefit favored N over P treatment (HR=0.77; 95% CI 0.46–1.29; p=0.319; 62 [71%] OS events) and was greatest in epithelioid pts (HR=0.70; 95% CI 0.40–1.21; p=0.197) with a median (m) OS gain of 5.4 months (mOS [95% CI]: 20.6 [16.2–28.8] N vs 15.2 [12.2–23.6] P). Updated PFS results (HR=0.54; 95% CI 0.33–0.87; p=0.010) also showed greatest benefit for epithelioid pts (HR=0.49; 95% CI 0.30–0.82; p=0.006) with a mPFS gain of 4.0 months (mPFS [95% CI]: 9.7 [7.2–12.4] N vs 5.7 [5.5–7.0] P). Improved forced vital capacity, objective response rates and duration of response were also observed with N treatment. Drug-related adverse events (AEs) in N- vs P-treated pts were 97.7% vs 97.6%. Grade ≥3 AEs of note included neutropenia (27.3% vs 4.9%), ALT (11.4% vs 0) and GGT (6.8% vs 0) elevations, and diarrhea (6.8% vs 0). AEs led to trial discontinuation in only 3 (6.8%) N vs 7 (17.1%) P pts. Conclusions: Mature Ph II OS data show that adding N to standard 1st-line treatment gives a strong signal towards improved OS. Updated PFS confirmed the primary analysis; AEs were manageable. The greatest clinical benefit was observed in pts with epithelioid histology. Median survival of 20.6 months in epithelioid pts treated with N is unprecedented in advanced MPM trials. Ph III is actively recruiting in this pt population. Clinical trial information: NCT01907100.

Spotlight on bevacizumab and its potential in the treatment of malignant pleural mesothelioma: the evidence to date.

Malignant pleural mesothelioma (MPM) is a rare, but aggressive cancer. Surgery and radiation offer limited benefit, and systemic chemotherapy remains the primary treatment modality for the majority of patients. Vascular endothelial growth factor (VEGF) and its receptor have been recognized as important players in the biology of this disease. Bevacizumab is a monoclonal antibody that binds VEGF and blocks its interaction with the VEGF receptor. Recent studies have shown benefit with the addition of bevacizumab to the combination of cisplatin and pemetrexed in MPM. This combination is now included in the National Comprehensive Cancer Network guidelines (with a category 2A recommendation) as a possible first-line treatment for unresectable MPM in appropriately selected patients. This review discusses the rationale behind the use of bevacizumab in MPM, as well as summarizes the pharmacology, efficacy, safety, and toxicity of bevacizumab across multiple trials. The use of small-molecule inhibitors of angiogenesis in the treatment of MPM is also discussed.

LUME-Meso: Design and Rationale of the Phase III Part of a Placebo-Controlled Study of Nintedanib and Pemetrexed/Cisplatin Followed by Maintenance Nintedanib in Patients With Unresectable Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is a rare but aggressive disease: median survival is 6 to 9 months if untreated. Standard first-line treatment for patients with unresectable MPM is cisplatin/pemetrexed, with a median overall survival (OS) of approximately 1 year. Improvements in first-line treatment options are needed. With the benefit of combining bevacizumab with standard therapy shown in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS), vascular endothelial growth factor (VEGF) pathway inhibition has gained renewed interest as a treatment approach. Nintedanib is an oral angiokinase inhibitor targeting multiple signaling pathways implicated in the pathogenesis of MPM, including the VEGF receptor. The phase III part of the international, phase II/III LUME-Meso study is evaluating the efficacy and safety of nintedanib plus pemetrexed/cisplatin in patients with unresectable epithelioid MPM. Originally, this was a double-blind, randomized, phase II exploratory study and was amended to include a confirmatory phase III part following the recommendation of an internal Data Monitoring Committee and review of phase II data. The phase III part plans to enroll 450 chemotherapy-naive patients, who will be randomized to receive pemetrexed/cisplatin on day 1 and nintedanib or placebo on days 2 to 21, for a maximum of 6 cycles. Patients without disease progression who are eligible to continue study treatment will receive maintenance treatment with nintedanib or placebo until disease progression or undue toxicity. The primary end point is progression-free survival; OS is the key secondary end point. The study will use an adaptive design, including an interim analysis to reassess the number of OS events required to ensure sufficient power for OS analysis. The study is currently enrolling patients.

OA22.02 Nintedanib plus Pemetrexed/Cisplatin in Patients with MPM: Phase II Findings from the Placebo-Controlled LUME-Meso Trial

Standard first-line treatment for patients with unresectable malignant pleural mesothelioma (MPM) is pemetrexed/cisplatin, yielding a median overall survival (OS) of only ∼1 year, thus new approaches are required. As demonstrated by the bevacizumab MAPS study, inhibition of the VEGF pathway is of interest as a treatment approach for MPM. Nintedanib is an oral, triple angiokinase inhibitor of VEGFR, PDGFR and FGFR. This study will evaluate the efficacy and safety of nintedanib plus pemetrexed/cisplatin in patients with advanced MPM. Patients with unresectable MPM (chemo-naïve, ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomized (1:1) to receive up to 6 cycles of pemetrexed (500 mg/m2)/cisplatin (75 mg/m2) on Day 1 plus nintedanib (200 mg bid)/placebo on Days 2–21. Patients without disease progression received maintenance treatment with nintedanib/placebo. The primary endpoint was progression-free survival (PFS). 87 patients were randomized to receive pemetrexed/cisplatin, plus nintedanib/placebo. Patient characteristics were comparable between the groups. PFS was longer in the nintedanib vs the placebo arm, in both the overall study population and in epithelioid patients (Table 1). Preliminary OS data also favor nintedanib. All patients experienced at least one adverse event (AE, any grade), with 7% of patients in the nintedanib arm discontinuing due to AEs, vs 15% with placebo. Serious AEs occurred in 36% vs 42% of patients in the nintedanib and placebo arms, respectively. The most common ≥grade 3 AEs occurring in nintedanib vs placebo patients were neutropenia (34% vs 10%), ALT increase (14% vs 2%) and gamma glutamyltransferase increase (14% vs 0%). Nintedanib plus pemetrexed/cisplatin demonstrated clinical efficacy with improved PFS and a tolerable safety profile in patients with unresectable MPM. Based on these promising findings, this Phase II study was extended to a confirmatory Phase III trial, which is currently enrolling patients. Clinical trial identifier: NCT01907100.

SC06.04 Immunotherapy of Malignant Pleural Mesothelioma and Thymic Malignancies: The End of the Beginning?

SC06.04 Immunotherapy of Malignant Pleural Mesothelioma and Thymic Malignancies: The End of the Beginning?

ED13.05 Systemic Therapy of Inoperable Malignant Pleural Mesothelioma

ED13.05 Systemic Therapy of Inoperable Malignant Pleural Mesothelioma

Management of malignant pleural mesothelioma-part2: therapeutic approaches : Consensus of the Austrian Mesothelioma Interest Group (AMIG).

SummaryTreatment of malignant pleural mesothelioma (MPM) depends on performance status of the patient, tumor stage, and histological differentiation. Chemotherapy (CHT) can be administered as first- and second-line treatment in unresectable MPM or as neoadjuvant or adjuvant treatment before or after surgery. A combination of an antifolate and platinum-based CHT is the only approved standard of care. Several targeted and immunotherapies are in evaluation and further studies are warranted to determine the therapeutic value of these new treatment options. Radiotherapy (RT) can be considered either as adjuvant treatment after surgery or for palliation of pain-related tumor growth. Recent data support the use of RT in a neoadjuvant setting. Macroscopic complete resection by pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP) is indicated in selected patients with good performance status. Surgery should only be applied as part of a multimodality treatment (MMT) in combination with chemo- and/or radiotherapy. In a large number of cases, palliative attempts are needed to improve quality of life and to achieve symptom control.

Lume-meso: A double-blind, randomized, phase II/III study of nintedanib (N) + pemetrexed (P)/cisplatin (C) followed by maintenance N versus placebo + P/C followed by maintenance placebo for patients with unresectable malignant pleural mesothelioma (MPM).

TPS8574Background: Median overall survival (OS) is ~1 year with P/C, the standard front-line treatment for patients (pts) with unresectable MPM; additional improvement is needed. Nintedanib (N) is ...

Population pharmacokinetics and exposure-response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection.

To characterize amatuximab pharmacokinetics (PK) and the relationship of amatuximab exposure with response in patients with unresectable malignant pleural mesothelioma (MPM) receiving amatuximab with pemetrexed and cisplatin. A nonlinear mixed effects PK model was built using data from all of the amatuximab studies conducted to date. Patients received amatuximab alone or in combination with chemotherapy. The influence of demographic, laboratory and disease characteristics on PK parameters was assessed. Exposure-response analyses explored relationships between amatuximab exposure and overall survival (OS), progression-free survival (PFS) and safety. Alternative amatuximab dosing regimens were explored with simulations using population PK and parametric survival models. Amatuximab PK was best described by a two-compartment model with parallel linear and nonlinear elimination pathways. Body weight and an antidrug antibodies reaction with the titer >64 affected volume of distribution and clearance, respectively. Exposure-response analyses demonstrated that the amatuximab exposure (C min) showed a significant effect on OS (log-rank test, P=0.0202). For patients with amatuximab C min above the median (38.2μg/mL), the median OS was 583days (90% CI 418 -NE). For patients with C min≤38.2μg/mL, the median OS was 375days (90% CI 325-486). The amatuximab exposure showed similar significant effect on PFS. Exposure-response analysis for adverse events did not reveal any relationship. In patients with MPM, higher amatuximab exposure in combination with chemotherapy was shown to be associated with longer OS, supporting evaluation of more frequent dosing in future trials to achieve higher exposure and subsequently longer OS.

Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial

Malignant pleural mesothelioma is an aggressive cancer with poor prognosis, linked to occupational asbestos exposure. Vascular endothelial growth factor is a key mitogen for malignant pleural mesothelioma cells, therefore targeting of vascular endothelial growth factor might prove effective. We aimed to assess the effect on survival of bevacizumab when added to the present standard of care, cisplatin plus pemetrexed, as first-line treatment of advanced malignant pleural mesothelioma. In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged 18-75 years with unresectable malignant pleural mesothelioma who had not received previous chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0-2, had no substantial cardiovascular comorbidity, were not amenable to curative surgery, had at least one evaluable (pleural effusion) or measurable (pleural tumour solid thickening) lesion with CT, and a life expectancy of >12 weeks from 73 hospitals in France. Exclusion criteria were presence of central nervous system metastases, use of antiaggregant treatments (aspirin ≥325 mg per day, clopidogrel, ticlopidine, or dipyridamole), anti-vitamin K drugs at a curative dose, treatment with low-molecular-weight heparin at a curative dose, and treatment with non-steroidal anti-inflammatory drugs. We randomly allocated patients (1:1; minimisation method used [random factor of 0·8]; patients stratified by histology [epithelioid vs sarcomatoid or mixed histology subtypes], performance status score [0-1 vs 2], study centre, or smoking status [never smokers vs smokers]) to receive intravenously 500 mg/m(2) pemetrexed plus 75 mg/m(2) cisplatin with (PCB) or without (PC) 15 mg/kg bevacizumab in 21 day cycles for up to six cycles, until progression or toxic effects. The primary outcome was overall survival (OS) in the intention-to treat population. Treatment was open label. This IFCT-GFPC-0701 trial is registered with ClinicalTrials.gov, number NCT00651456. From Feb 13, 2008, to Jan 5, 2014, we randomly assigned 448 patients to treatment (223 [50%] to PCB and 225 [50%] to PC). OS was significantly longer with PCB (median 18·8 months [95% CI 15·9-22·6]) than with PC (16·1 months [14·0-17·9]; hazard ratio 0·77 [0·62-0·95]; p=0·0167). Overall, 158 (71%) of 222 patients given PCB and 139 (62%) of 224 patients given PC had grade 3-4 adverse events. We noted more grade 3 or higher hypertension (51 [23%] of 222 vs 0) and thrombotic events (13 [6%] of 222 vs 2 [1%] of 224) with PCB than with PC. Addition of bevacizumab to pemetrexed plus cisplatin significantly improved OS in malignant pleural mesothelioma at the cost of expected manageable toxic effects, therefore it should be considered as a suitable treatment for the disease. Intergroupe Francophone de Cancérologie Thoracique (IFCT).

Contemporary Analysis of Prognostic Factors in Patients with Unresectable Malignant Pleural Mesothelioma

IntroductionPrevious prognostic scoring systems for malignant pleural mesothelioma (MPM) included patients managed surgically and predated the use of pemetrexed. We analyzed prognostic factors in a contemporary cohort of patients with unresectable MPM who received pemetrexed-based chemotherapy. MethodsThis single-institution analysis included patients with MPM who were managed nonsurgically from 2000 to 2013. Variables correlated with overall survival (OS) included sex, performance status (PS), asbestos exposure, tumor laterality, histology, clinical stage, initial positron emission tomography maximum standardized uptake value, hemoglobin level, platelet count, lymphocyte count, white cell and neutrophil counts, treatment type, and clinical benefit from treatment. OS was analyzed by the Kaplan-Meier method, and significance (p < 0.05) of prognostic factors was analyzed by the log-rank test and Cox regression. ResultsA total of 191 patients met the study criteria: median age 71 years (range 46–90), 147 men (77%), 128 epithelioid tumors (67%), and 157 cases of stage III or IV MPM (82%). Median OS for all patients was 13.4 months. According to a univariate analysis, histology (p < 0.001), platelet count (≤450,000 versus >450,000, p < 0.001), initial PS (0–1 versus ≥2), maximum standardized uptake value (≤8.1 versus >8.1, p = 0.037), and lymphocyte counts (p = 0.019) were associated with OS. According to a multivariable analysis, only histology, platelet count, and PS were independent prognostic factors. Epithelioid histology, PS, and elevated lymphocyte count at diagnosis were significantly associated with clinical benefit from first-line chemotherapy. ConclusionsOur results confirm the significance of elements of the Cancer and Leukemia Group B and European Organisation for Research and Treatment of Cancer prognostic scoring systems, identify factors associated with clinical benefit from chemotherapy, and emphasize the impact of histology and clinical benefit of chemotherapy on outcomes.

Tomotherapy PET-guided dose escalation: A dosimetric feasibility study for patients with malignant pleural mesothelioma.

The aim of this study was to investigate whether a safe escalation of the dose to the pleural cavity and PET/CT-positive areas in patients with unresectable malignant pleural mesothelioma (MPM) is possible using helical tomotherapy (HT). We selected 12 patients with MPM. Three planning strategies were investigated. In the first strategy (standard treatment), treated comprised a prescribed median dose to the planning target volume (PTV) boost (PTV1) of 64.5 Gy (range: 56 Gy/28 fractions to 66 Gy/30 fractions) and 51 Gy (range: 50.4 Gy/28 fractions to 54 Gy/30 fractions) to the pleura PTV (PTV2). Thereafter, for each patient, two dose escalation plans were generated prescribing 62.5 and 70 Gy (2.5 and 2.8 Gy/fraction, respectively) to the PTV1 and 56 Gy (2.24 Gy/fraction) to the PTV2, in 25 fractions. Dose-volume histogram (DVH) constraints and normal tissue complication probability (NTCP) calculations were used to evaluate the differences between the plans. For all plans, the 95 % PTVs received at least 95 % of the prescribed dose. For all patients, it was possible to perform the dose escalation in accordance with the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) constraints for organs at risk (OARs). The average contralateral lung dose was < 8 Gy. NTCP values for OARs did not increase significantly compared with the standard treatment (p > 0.05), except for the ipsilateral lung. For all plans, the lung volume ratio was strongly correlated with the V20, V30, and V40 DVHs of the lung (p < 0.0003) and with the lung mean dose (p < 0.0001). The results of this study suggest that by using HT it is possible to safely escalate the dose delivery to at least 62.5 Gy in PET-positive areas while treating the pleural cavity to 56 Gy in 25 fractions without significantly increasing the dose to the surrounding normal organs.

Abstract B56: An immuno-gene therapy clinical trial evaluating in situ vaccination of malignant pleural mesothelioma with intrapleural delivery of adenovirus-interferon-alpha-2b in combination with chemotherapy

Abstract Background: “In situ vaccination” immune-gene therapy has the ability to induce broad, polyclonal anti-tumor responses directed by the patient's own immune system using standard “off the shelf” agents. In this trial, we activated endogenous tumor immunity by injection of an adenovirus expressing a Type I interferon into the pleural space of patients with malignant pleural mesothelioma (MM). Based on preclinical data showing synergy with chemotherapy, all patients then received standard systemic cytotoxic therapy. Methods: Two doses of intrapleural administration of a replication-defective recombinant adenoviral vector containing the human interferon-alpha (hIFN-α2b) gene at a dose of 3x1011 viral particles were given concomitant with a 14-day course of high-dose cyclo-oxygenase-2 (COX-2) inhibitor (Celecoxib) to reduce side effects and to modify the tumor microenvironment by decreasing PGE- 2 levels. This was followed by standard first-line or second-line chemotherapy agents. Primary outcome measures were safety, overall best response rate, and survival. Bio-correlates were measured. Results: Forty patients were treated in this study: 18 patients received first-line Pemetrexed-based chemotherapy; 7 patients who had previously received front-line Pemetrexed-based chemotherapy &amp;gt;6 months prior to enrollment received Pemetrexed-based second-line chemotherapy. Additionally, in the second-line chemotherapy arm, fifteen patients (n=15) received gemcitabine-based chemotherapy. Treatment was well tolerated and adverse events were comparable to historical controls. Follow-up chest CT scans demonstrated an overall response rate of 20% by Modified RECIST criteria and disease control rate (DCR) of 85% (partial and complete responses plus stable disease) at initial follow-up scan after the first two cycles of chemotherapy. Encouragingly, median survival for all patients with epithelial histology (including both first and second line) was 26 months (95% CI: 15-ND); median overall survival (MOS) for patients with non-epithelial histology (both first and second line) was 6.5 months (95% CI: 5.50 – ND). [See figure] Historical MOS with first line chemotherapy alone is 13.3 months. No clear predictors for response were identified including: baseline immunologic parameters (i.e. activated T cells or number of regulatory T cells); the presence of the immune-gene signature in their biopsies; peak levels of interferon in blood or pleural fluid; or induction of anti-tumor antibodies, activated T cells, or natural killer cells in peripheral blood. Conclusions: The combination of intrapleural Ad.IFN-α2b vector, Celecoxib, and systemic chemotherapy proved safe in patients with unresectable malignant pleural mesothelioma. Overall survival rates were significantly higher than historical controls, particularly in the second-line groups. The results of this study support proceeding with a multi-center randomized clinical trial of chemo-immunogene therapy versus standard chemotherapy alone. Citation Format: D. H. Sterman, E. Alley, J. Friedberg, S. Metzger, J. Stevenson, E. Moon, A. R. Haas, A. Vachani, S. I. Katz, G. Cheng, J. Sun, D. F. Heitjan, L. Litzky, K. Cengel, C. B. Simone, II, M. Culligan, M. Culligan, S. M. Albelda. An immuno-gene therapy clinical trial evaluating in situ vaccination of malignant pleural mesothelioma with intrapleural delivery of adenovirus-interferon-alpha-2b in combination with chemotherapy. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B56.

Single-dose dexamethasone for the prevention of pemetrexed associated cutaneous adverse reactions.

Pemetrexed (Alimta®) is a novel anti-folate antimetabolite agent that is used in combination with cisplatin for the treatment of patients with unresectable malignant pleural mesothelioma and as a single agent or in combination with cisplatin for patients with locally advanced or metastatic non-small-cell-lung-cancer. Cutaneous adverse reactions are common side effects of pemetrexed for which the manufacturer recommends 3-day premedication with dexamethasone 4 mg by mouth twice daily-(the day before, the day of, and the day after treatment). Patients' adherence to this premedication regimen is of concern. We report 14 cases of metastatic non-small-cell-lung-cancer patients who were premedicated with a single dose of dexamethasone 20 mg prior to pemetrexed or pemetrexed-based chemotherapy. None of these patients reported a grade 3 or above skin reactions over the course of their treatments. These findings suggest that a single dose of dexamethasone 20 mg may be an alternative premedication regimen in patients with metastatic non small cell lung cancer receiving pemetrexed or pemetrexed-based chemotherapy.