Advanced Mesothelioma Research Articles

Ipilimumab and nivolumab plus UV1, an anticancer vaccination against telomerase, in advanced melanoma.

LBA9519 Background: The combination of ipilimumab (IPI) and nivolumab (NIVO) remains a standard of care for patients with advanced melanoma, especially those with poor prognostic factors, albeit with a significant risk of toxicity. Therapeutic cancer vaccines are ideally positioned to improve outcomes without significantly increasing toxicity. UV1 is a therapeutic cancer vaccine generating T-cell responses against the universal cancer antigen telomerase. In a Phase I trial in melanoma (N = 30), UV1 plus pembrolizumab demonstrated a tolerable safety profile, a complete response rate of 33%, median PFS of 18.9 months, and 2-year OS rate of 73.3%. Recently, results from a randomized Phase II trial indicated a longer overall survival and a higher response rate for previously treated patients with advanced mesothelioma receiving UV1 in combination with IPI-NIVO (1). Methods: In this Phase II, open-label, multicenter study, we randomly assigned treatment-naïve patients with unresectable or metastatic melanoma (stage IIIb-IIId or IV) to IPI 3mg/kg + NIVO 1mg/kg for 4 cycles, followed by NIVO 480 mg as maintenance, with or without 8 intradermal injections of 300 µg UV1 (+GM-CSF). The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR) according to RECIST 1.1. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response, and safety. Results: A total of 156 patients underwent randomization; 78 patients were assigned to the IPI-NIVO-UV1 arm and 78 patients to the IPI-NIVO arm. The median age was 60, 48% had M1C or D disease, 38% had LDH >upper limit of normal, and 42% had a positive BRAF mutation status. With a minimum follow-up of 18 months, the 12-month PFS rate was 57% in both arms (HR 0.95, 95% CI 0.59-1.55, p value 0.845). The ORR was similar with IPI-NIVO-UV1 compared to IPI-NIVO, at 60% vs 59%, respectively (Odds ratio 1.12, 95% CI 0.58-2.16, p value 0.867). The 12-month OS rate was 87% and 88%, respectively (HR 1.15, 95% CI 0.60-2.20, p value 0.674). The occurrence of grade >3 adverse events was similar in both treatment arms. Conclusion: UV1 did not improve on outcomes of IPI-NIVO, in terms of PFS. Longer follow-up is required for the accurate assessment of OS. No significant toxicity increases were observed with the addition of UV1. Data from a biomarker driven cohort are awaited. 1. Helland et al, Eur J Cancer 2024. Clinical trial information: NCT04382664 .

Phase 2 study to evaluate the novel mitochondrial PRX3 inhibitor, RSO-021, as an intrapleural monotherapy and in combination with IV paclitaxel in patients with malignant pleural effusion due to mesothelioma or another advanced solid tumor.

TPS8124 Background: Tumor cells generate elevated levels of reactive oxygen species (ROS), leading to increased expression and activity of critical ROS scavenging pathways. Peroxiredoxin 3 (PRX3) is the principal peroxide scavenging enzyme in mitochondria. RSO–021 is a novel small molecule PRX3 inhibitor that inactivates PRX3 through direct covalent adduction of active site cysteine residues, in turn inducing oxidative stress that is incompatible with tumor cell survival. Preclinical studies of RSO-021 show that it selectively inhibits mitochondrial PRX3 in vitro and is highly effective in a variety of tumor models, including mesothelioma and many solid tumors. RSO-021 has completed phase 1 evaluation in patients with advanced mesothelioma or solid tumors with predominant pleural disease and malignant pleural effusions. The phase 1 data supported weekly intrapleural dosing of RSO-021 at the 90 mg dose level, with acceptable safety and early signals of efficacy. Some patients were able to receive >30 weeks of treatment. Pre- and post-dose primary prophylaxis for local inflammatory reactions to intrapleural injection was instituted during dose escalation, using corticosteroids, NSAIDS and paracetamol. It also became clear that RSO-021 should not be administered to patients with a dry pleural tap, due to risk of extravasation. Methods: The objectives of this open-label, multi-center, 4-arm phase 2 study (MITOPE) are to confirm the efficacy, safety, tolerability, and pharmacology of weekly intrapleural RSO-021 administration. Exploratory endpoints include target engagement as well as biomarkers of response and inflammation. The study explores 2 different RSO-021 doses (90 mg/wk and 45 mg/wk) per FDA Project Optimus, both as monotherapy and in combination with IV paclitaxel 175 mg/m2 every 3 weeks at until progression or limiting toxicity. Each arm at each dose has a 2-stage Simon design (12-21 patients) requiring 1 response to trigger stage 2 (null/target response rate 3%/20% and type I/type II error 0.05/0.8) for a maximum of 168 patients in the trial. Three of the 4 study arms are investigating the antitumor activity of RSO-021 monotherapy (arms 1-3) and the fourth is assessing the paclitaxel combination. Eligibility (by arm) requires: newly diagnosed treatment-naïve mesothelioma with pleural effusion; mesothelioma with pleural effusion that progressed on ≥1 standard of care (SoC) regimen; solid tumor with predominant pleural/lung disease and effusion that progressed on ≥1 SoC regimen; and breast, epithelial ovarian or non-small cell lung cancer with predominant pleural/lung disease and effusion that progressed on ≥1 SoC regimen. The first patient was treated in 4Q2023 and the trial is actively recruiting to all 4 arms at 9 UK sites. Additional sites are planned. Clinical trial information: NCT05278975 .

P2.19-01 First-in-Human Phase 1 Trial of VT3989, a First-in-Class YAP/TEAD Inhibitor in Patients with Advanced Mesothelioma

P2.19-01 First-in-Human Phase 1 Trial of VT3989, a First-in-Class YAP/TEAD Inhibitor in Patients with Advanced Mesothelioma

PD-1-expressing macrophages and CD8 T cells are independent predictors of clinical benefit from PD-1 inhibition in advanced mesothelioma

BackgroundFew tissue biomarkers exist to date that could enrich patient with cancer populations to benefit from immune checkpoint blockade by programmed cell death protein 1/ligand-1 (PD-/L-1) inhibitors. PD-L1 expression has...

Inhibition of Mitochondrial Antioxidant Defense and CDK4/6 in Mesothelioma.

Advanced mesothelioma is considered an incurable disease and new treatment strategies are needed. Previous studies have demonstrated that mitochondrial antioxidant defense proteins and the cell cycle may contribute to mesothelioma growth, and that the inhibition of these pathways may be effective against this cancer. We demonstrated that the antioxidant defense inhibitor auranofin and the cyclin-dependent kinase 4/6 inhibitor palbociclib could decrease mesothelioma cell proliferation alone or in combination. In addition, we determined the effects of these compounds on colony growth, cell cycle progression, and the expression of key antioxidant defense and cell cycle proteins. Auranofin and palbociclib were effective in decreasing cell growth and inhibiting the above-described activity across all assays. Further study of this drug combination will elucidate the contribution of these pathways to mesothelioma activity and may reveal a new treatment strategy.

P034 Checkpoint inhibitor-induced coexisting myositis and myasthenia gravis in a malignant mesothelioma patient: a case report

Abstract Background/Aims Nivolumab & ipilimumab are immune checkpoint inhibitors (ICIs) and combination therapy has shown efficacy in patients with malignant pleural mesothelioma. Nivolumab is a fully human IgG4 monoclonal antibody known as a programmed cell death 1 (PD-1) immune checkpoint inhibitor. The combination therapy nivolumab & ipilimumab features a potentially synergistic mechanism of action that targets 2 different checkpoints (PD-1 and CTLA-4) respectively. Myositis, an immune-related adverse event, has been reported in the literature. Ipilimumab and nivolumab have also been associated with the development/exacerbation of myasthenia gravis (MG). Methods A 75-year-old woman with right sarcomatoid malignant mesothelioma presented to the hospital with muscle cramps and a raised creatinine kinase, a few weeks after initiation of nivolumab & ipilimumab. In addition to myalgia and proximal limb weakness, her symptoms progressed to involve new right eye ptosis, double vision, and dysphagia. She was diagnosed with ICI-related myositis after an EMG was suggestive of myositis, but antibody screens for myositis and myasthenia gravis were negative. Treatment was started with intravenous methylprednisolone and subsequently was treated with IVIG and mycophenolate mofetil 1g twice daily alongside the tapering oral steroids for maintenance, leading to resolution of proximal muscle weakness caused by immunotherapy-induced myositis. Following the initial improvement of muscle weakness, reassessment revealed worsening bulbar symptoms including ptosis, dysphagia, and diplopia. She was therefore readmitted. As her creatinine kinase, muscle weakness and CRP had now normalized, the impression at this stage was of symptoms predominantly related to myasthenia gravis rather than of myositis flare-up. Pyridostigmine was commenced as a trial, which demonstrated improvement with regards to the ptosis. Results ICIs have led to the development of new approaches for cancer treatment with positive outcomes. However, checkpoint blockade is associated with a unique spectrum of immune-related adverse events, which may cause irreversible neurological deficits and even death. This is a rare reported case of a patient developing nivolumab & ipilimumab-induced myositis concomitant with new-onset MG after treatment for advanced mesothelioma. Additional studies are needed to explore the association between myositis, MG, and ICI therapy. This woman is having ongoing multidisciplinary management involving oncologists, rheumatologists, and neurologists. She continues to be treated with mycophenolate mofetil and pyridostigmine. Ipilimumab and nivolumab were permanently discontinued. Conclusion This case demonstrates that rheumatologists must be alert to the possibility of myositis overlapping with MG in patients treated with checkpoint inhibitors who develop weakness. Early recognition complete evaluation and a team approach are essential in such a complex case. Disclosure F. Javaid: None. S. Byravan: None. S. Makan: None. M. Kadicheeni: None. R. Neame: None. M. Durrani: None.

Systemic treatment in patients with malignant pleural mesothelioma \u2013 real life experience

BackgroundMalignant pleural mesothelioma (MPM) is a rare, aggressive malignancy of the pleural cavity linked to asbestos exposure. The combination of pemetrexed and platinum is a standard first-line therapy for malignant pleural mesothelioma. Despite some progress, almost all MPM patients experience progression after first-line therapy. The second-line treatment is still being under discussion and there are very limited data available on the second-line and subsequent treatments.MethodsThe retrospective analysis included 57 patients (16 females and 41 males) from two Polish oncological institutions treated for advanced mesothelioma between 2013 and 2019. We analysed the efficacy of first-line and second-line therapy: progression-free survival (PFS), overall survival (OS), overall response rate (ORR).ResultsIn the first-line treatment, 55 patients received pemetrexed-based chemotherapy (PBC) and two cisplatin in monotherapy. Patients’ characteristics at baseline: median age was 64.2 years, ECOG PS ≤ 1 (86.2%), epithelial histology (85.7%). Median PFS and OS were 7.6 months and 14 months, respectively. Patients with ECOG PS ≤ 1 vs > 1 had a longer median OS (14.8 months vs 9.7 months, p = 0.057). One-year OS and PFS were 60.9% and 32.0%, respectively. Disease control rate (DCR) was 82.5%. Response to first-line therapy: PFS ≥ 6 months and PFS ≥ 12 months had a significant impact on median OS. Twelve patients received second-line therapy (seven PBC and five other cytotoxic single agents: navelbine, gemcitabine, or adriamycin/vincristine/methotrexate triplet). Median PFS and OS were 3.7 months and 7.2 months, respectively. DCR was 83%. One-year OS and PFS were 37% and 16.7%, respectively.In the group receiving PBC, OS was prolonged by 4.5 months compared to the non-PBC group (6.0 months vs 10.5 months, p = 0.47).ConclusionPatients who benefited from first-line therapy and had prolonged PFS at first-line and achieve PFS longer than 6 months at first-line should be offered second-line treatment. Consideration of retreatment with the same cytotoxic agent could to be a viable option when no other treatment are available.

Abstract P032: Expression of an IL-15 receptor fusion protein enhances the persistence of TRuC-T cells

Abstract Adoptive cell therapies have shown great promise in hematological malignancies. To realize the potential of T cell therapies in solid tumors, we have developed T cell receptor fusion construct (TRuC®) T cells, which are equipped with an engineered T cell receptor that utilizes all TCR signaling subunits and recognizes tumor-associated antigens independent of HLA. In clinical trials, mesothelin-targeting TRuC-T cells (aka TC-210 or gavo-cel) have shown unprecedented results in patients suffering from advanced mesothelioma and ovarian cancer. To potentially increase the effector function and persistence of TRuC-T cells in the hostile tumor microenvironment, we generated TC-210 T cells that express a membrane-tethered IL15Rα-IL15 fusion protein. IL-15 is a common γ chain cytokine that promotes the differentiation, maintenance, and effector function of memory CD8+ T cell subsets and confers resistance to IL-2-mediated activation induced cell death (AICD). In vitro, the co-expression of the IL-15 fusion protein enhances T cell proliferation and persistence upon repeated stimulation with MSLN+ cancer cell lines, while exhaustion marker expression is decreased. Furthermore, IL-15 enhanced TC-210 T cells sustain a significantly higher TCF-1+ population. When tested in a mesothelioma xenograft mouse model, the presence of the IL-15 fusion protein increased tumor infiltration and persistence of TC-210 T cells. Altogether, the presented data support clinical studies that explore the impact of IL-15 enhancement on the persistence of TC-210 T cells and depth of response in patients with MSLN+ malignancies. Citation Format: Michelle Fleury, Courtney Anderson, Amy Watt, Holly Horton, Adam Zieba, Jian Ding, Robert Tighe, Robert Hofmeister, Derrick McCarthy, Dario Gutierrez. Expression of an IL-15 receptor fusion protein enhances the persistence of TRuC-T cells [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P032.

Preclinical Evaluation of Podoplanin-Targeted Alpha-Radioimmunotherapy with the Novel Antibody NZ-16 for Malignant Mesothelioma.

The prognosis of advanced mesothelioma is poor. Podoplanin (PDPN) is highly expressed in most malignant mesothelioma. This study aimed to evaluate the potential alpha-radioimmunotherapy (RIT) with a newly developed anti-PDPN antibody, NZ-16, compared with a previous antibody, NZ-12. Methods: The in vitro properties of radiolabeled antibodies were evaluated by cell binding and competitive inhibition assays using PDPN-expressing H226 mesothelioma cells. The biodistribution of 111In-labeled antibodies was studied in tumor-bearing mice. The absorbed doses were estimated based on biodistribution data. Tumor volumes and body weights of mice treated with 90Y- and 225Ac-labeled NZ-16 were measured for 56 days. Histologic analysis was conducted. Results: The radiolabeled NZ-16 specifically bound to H226 cells with higher affinity than NZ-12. The biodistribution studies showed higher tumor uptake of radiolabeled NZ-16 compared with NZ-12, providing higher absorbed doses to tumors. RIT with 225Ac- and 90Y-labeled NZ-16 had a significantly higher antitumor effect than RIT with 90Y-labeled NZ-12. 225Ac-labeled NZ-16 induced a larger amount of necrotic change and showed a tendency to suppress tumor volumes and prolonged survival than 90Y-labeled NZ-16. There is no obvious adverse effect. Conclusions: Alpha-RIT with the newly developed NZ-16 is a promising therapeutic option for malignant mesothelioma.

1732MO Pembrolizumab and nintedanib for patients with advanced mesothelioma

We report the results from the advanced malignant mesothelioma (aMM) expansion cohort of the PEMBIB phase Ib trial (NCT02856425) evaluating the safety, efficacy & biomarkers of an antiangiogenic TKI (nintedanib = [N]) with an anti-PD1 immunotherapy (pembrolizumab = [P]).

Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study

Malignant pleural mesothelioma (MPM) has few treatment options. Pembrolizumab showed preliminary clinical benefit in programmed death ligand 1 (PD-L1)-positive MPM. We evaluated the efficacy and safety of pembrolizumab monotherapy in patients with previously treated MPM irrespective of PD-L1 status in the KEYNOTE-158 study. The ongoing open-label, multicohort, single-arm, phase 2 KEYNOTE-158 study enrolled eligible adults (≥18 years) with MPM who had progression on or intolerance to standard therapy, Eastern Cooperative Oncology Group performance status 0-1, and biomarker-evaluable tumour samples. Individuals were enrolled from 35 academic facilities and community-based institutions across 14 countries in Australia, North America, Europe, and Asia. Participants received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. The primary efficacy endpoint was objective response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, based on radiological imaging every 9 weeks for the first year of the study and every 12 weeks thereafter and assessed by independent central review. Efficacy and safety were analysed in all patients who received at least one dose of pembrolizumab. This trial is registered with ClinicalTrials.gov, NCT02628067. Patients were enrolled in the MPM cohort between Feb 9, 2016, and Aug 16, 2016. As of June 27, 2019, 118 patients had been enrolled and received at least one dose of pembrolizumab. Ten (8% [95% CI 4-15]) patients had an objective response. Median duration of objective response was 14·3 months (range 4·0 to 33·9+), and 60% of objective responses were ongoing at 12 months. Objective responses were observed in six (8%) of 77 patients with PD-L1-positive MPM (median response duration 17·7 months [range 5·8 to 33·9+]) and four (13%) of 31 patients with PD-L1-negative MPM (10·2 months [4·0-16·6]). Median overall survival was 10·0 months (95% CI 7·6-13·4) and median progression-free survival was 2·1 months (2·1-3·9). Treatment-related adverse events occurred in 82 (69%) of 118 patients and serious adverse events that were considered to be treatment-related occurred in 14 (12%) of 118 patients. 19 (16%) patients had grade 3-4 treatment-related events, and most common of these were colitis (three patients), hyponatraemia (three), and pneumonitis (two). One patient died from treatment-related apnoea. By the end of the trial, 113 (96%) patients had discontinued pembrolizumab and progressive disease was the most common reason for discontinuation. Pembrolizumab showed durable antitumour activity and manageable toxicity in patients with advanced MPM, regardless of PD-L1 status. Our data support the programmed death 1 (PD-1) and PD-L1 pathway as a potential therapeutic target in some patients with previously treated mesothelioma but biomarkers that can effectively identify such patients are yet to be elucidated. Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.

Phase 1 cohort expansion study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced mesothelioma

SummaryBACKGROUND LY3023414 is a selective, ATP competitive inhibitor of class I PI3K isoforms, mTORC1/2 and DNA-PK. A Phase 1 dose escalation, 200 mg twice daily (BID) of LY3023414 was the determined recommended phase 2 dose (RP2D). We report the antitumor activity and safety of LY3023414 monotherapy in patients with advanced mesothelioma.METHODS Patients enrolled had advanced malignant pleural or peritoneal mesothelioma with measurable disease, ECOG PS 0–1, were refractory or ineligible to receive standard therapies. Patients received LY3023414 200 mg BID. This dose expansion cohort is intended to evaluate preliminary antitumor activity of LY3023414 by overall response rate. Safety, tolerability and pharmacokinetics were assessed. Biomarkers associated with treatment response was an exploratory endpoint. RESULTS Forty-two patients received LY3023414 for a median duration of 11.2 weeks (range: 1.1–53.0). One patient had a confirmed partial response (PR) (ORR 2.4%). Three patients had an unconfirmed PR. Seventeen patients had stable disease (SD) (DCR 43%). Most common adverse events (AEs) included fatigue (43%), nausea (43%), decreased appetite (38%), vomiting (33%), and diarrhea (29%). AEs were mostly mild or moderate. Grade ≥ 3 AEs were reported for 21% of patients with fatigue as the most frequent event (10%). Alterations of BAP1 were identified in 11/19 patients as the most common molecular aberration, followed by SETD2 and NF2 alterations. No obvious pattern of genetic changes/mutations in single genes or pathways was associated with anti-tumor activity. CONCLUSION LY3023414 monotherapy (200 mg BID) demonstrated an acceptable and manageable safety profile with limited single-agent activity in patients with advanced mesothelioma. ClinicalTrials.gov identifier: NCT01655225; Date of registration: 19 July 2012.

Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors

BackgroundCD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with...

Abstract CT159: A phase 1 study of intraperitoneal MCY-M11 therapy for women with platinum resistant high grade serous adenocarcinoma of the ovary, primary peritoneum, or fallopian tube, or subjects with peritoneal mesothelioma with recurrence after prior chemotherapy

Abstract Background: Chimeric antigen receptor CAR T cell therapy for solid tumors has not yet achieved the success seen in hematologic malignancies. Many challenges remain, including the type of antigen being targeted, the risk for on-target off-tumor toxicity, a frequent high degree of immune tolerance within an immune suppressive environment, together with autologous product manufacturing hurdles, which hinder timely delivery of treatment to the patient. Also, most current CAR T therapies are viral based, limiting the ability to administer repeated, longer-term treatments. MaxCyte has developed its first CAR product, MCY-M11, applying the CARMA™ non-viral, mRNA-based platform for rapid (less than 1 day) manufacturing with efficient transfection of a human scFv targeting mesothelin, using fresh non-expanded peripheral blood mononuclear cells for autologous cell therapy. Mesothelin is an attractive and relevant therapeutic target because of its high differential expression in many solid tumors with only low levels of expression in mesothelial cells of mostly non-critical normal tissues. The transient expression of the CAR transgene may be important in limiting potential excessive or unwanted toxicity, while allowing for multiple therapeutic infusions needed to trigger a potent and more effective host immune response. In an in vivo murine model, MCY-M11 cells were shown to have the ability to traffic to and inhibit growth of mesothelin-expressing ovarian cancer and improve survival, both in a dose-dependent manner and with multicycle administration. The first in human phase 1 study of MCY-M11 in patients with advanced ovarian cancer and peritoneal mesothelioma (NCT03608618) is described here. Methods: A standard 3+3 design phase 1 study exploring 4 ascending cell dose levels, in patients with relapsed/refractory adenocarcinoma of the ovary, fallopian tube, primary peritoneum, or peritoneal mesothelioma. A minimum of 15 patients will be enrolled to receive one cycle of 3 weekly doses (D1, D8, D15) of MCY-M11 administered intraperitoneally. The primary objective is to characterize safety (Incidence and severity of adverse events assessed per NCI CTCAE v5.0), tolerability, and feasibility of infusion of MCY-M11. Secondary objectives include assessment of antitumor activity (RECIST, irRECIST, and serum biomarkers), and correlates of CAR performance and immune activation. The study is being conducted at two centers, and the first patient was dosed in October 2018. Recruitment in dose level 1 cohort continues. Citation Format: Armin Ghobadi, Premal Thaker, David Weng, Julie Vanas, Irene Ekwede, Mira Pavlova, Robert Keefe, Michael Kuo, Claudio Dansky Ullmann, Raffit Hassan, Christina Annunziata. A phase 1 study of intraperitoneal MCY-M11 therapy for women with platinum resistant high grade serous adenocarcinoma of the ovary, primary peritoneum, or fallopian tube, or subjects with peritoneal mesothelioma with recurrence after prior chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT159.

Association of BAP1 alterations with malignant pleural mesothelioma treated with trimodality therapy.

8552 Background: Trimodality therapy with pleurectomy/decortication, cytotoxic chemotherapy, and adjuvant pleural intensity modulated radiation therapy (IMPRINT) is an emerging standard of care for locally advanced epithelioid mesothelioma (Rimner, Zauderer et al. JCO 2016). Some patients, however, progress rapidly and we therefore sought to identify potential predictive markers of response to this treatment. Given the putative role of BAP1 in DNA damage repair, we hypothesized that alteration in BAP1 would be associated with improved local control after radiation therapy. Methods: We identified patients previously treated at our institution with IMPRINT to a median dose of 4680cGy in 26 fractions. Targeted next generation sequencing was performed with MSK-IMPACT on archival tissue samples. Chart review was undertaken for clinicopathologic features and outcome data. Results: MSK-IMPACT testing was successfully performed on 58 patients who completed IMPRINT. The majority were male with a median age of 70 years. Ninety-seven percent had epithelioid subtype while 3% were biphasic with predominantly epithelioid histology. Median overall survival was 30.2 months with a median follow-up of 45.3 months, consistent with prior reports. Somatic BAP1 mutations were identified in 34% of the specimens. Those with BAP1 mutant tumors had a median time to local failure of 22.4 months (IQR 10.9 – 36.9 months) while those with BAP1 wild type tumors only had a median of 12.1 months (IQR 8.7-15.85 months) to local failure (p = 0.057). We identified a trend towards improved overall survival among those with BAP1 altered tumors compared to those with BAP1 wild type (HR = 0.61, p = 0.14). Conclusions: BAP1 alteration may be associated with improved duration of local control and improved overall survival after IMPRINT therapy. Further analysis and validation in a large data set is needed and a platform for identifying and validating predictive biomarkers should be included in the planned NRG randomized trial of IMPRINT.

Liver scalloping – An unusual presentation of a benign disease

Introduction: Abdominal tuberculosis frequently mimics other conditions such as inflammatory bowel disease, sarcoidosis, advanced ovarian tumour, lymphoma, mesothelioma or carcinomatosis. Case Report: The authors report the case of a 19-year-old woman with fever, abdominal pain and history of right pleural empyema. Laboratory findings showed anaemia, lymphopenia and positive interferon-gamma release assay. Computed tomography findings included apical lung nodules, pleural thickening, right pleural effusion and ascites. Treatment for suspected tuberculosis was started. Two months later, computed tomography showed peritoneal thickening causing liver scalloping. Fluid collection from a peritoneal fluid-filled nodule confirmed the diagnosis. Conclusion: Visceral scalloping is a common finding of carcinomatosis and pseudomyxoma peritonei; only seven cases are reported in peritoneal tuberculosis. We emphasize the need for a high suspicion level and early sample collection.

Abstract CT020: Safety and tolerability of the dual PI3K/mTOR inhibitor LY3023414 in treatment of patients with advanced mesothelioma

Abstract Background: The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is aberrantly activated in malignant mesothelioma. LY3023414 (LY) is a potent oral ATP- competitive inhibitor that selectively and potently inhibits class I PI3K isoforms, mTOR, and DNA-PK. The recommended phase 2 dose (RP2D) of LY monotherapy was previously established to be 200 mg twice daily (BID). Here we report safety and clinical activity of LY monotherapy in advanced mesothelioma patients (pts) as part of a multi-cohort Phase 1 study (NCT01655225). Methods: In this cohort, 42 pts with malignant pleural or peritoneal mesothelioma with measurable disease as per RECIST v1.1, ECOG PS 0-1 and refractory or ineligible to standard therapies were enrolled to receive LY 200 mg BID. Primary objective was to explore single agent activity of LY. Other objectives included assessment of pharmacokinetics (PK), antitumor activity, and biomarker analysis. Results: 41 pts received treatment. Common treatment-related adverse events (TRAEs) included fatigue (44%), nausea (37%), vomiting (34%), decreased appetite (29%), diarrhea (22%) and maculo-papular rash (15%). Grade(G) 3/4 TRAEs reported were G3 fatigue (10%), G3 maculo-papular rash (7%), G3 pruritus (5%), G3 constipation (2%), G3 hyperglycemia (2%), G3 hyponatraemia (2%), G3 dyspnoea exertional (2%), G3 hypoxia (2%) and G4 hyperglycemia (2%). Serious adverse events related to study treatment were reported in 7(17%) pts. There were no deaths related to study treatment. Median duration of treatment was 12 weeks (range 3-48). In the 41 pts evaluable for tumor response, 2 pts (5%) had durable partial response (PR) and 17 pts (42%) had stable disease (SD) according to RECIST for an ORR of 5% and DCR of 46%. Overall, 29% of pts had a decrease in tumor lesions from baseline. The median progression-free survival for this cohort is 2.8 months (90% CI 2.5, 3.9). Alterations in the BAP1 gene, a potent tumor suppressor implicated in PI3K signaling pathway and in the pathogenesis of malignant mesothelioma, was identified in one pt with PR and in 4 of 17 pts (24%) with SD. Further biomarker analysis is ongoing. Conclusions: LY monotherapy at the RP2D of 200 mg BID demonstrated an acceptable and manageable safety profile. Single agent LY activity is limited in pts with advanced mesothelioma and more work is needed to identify the characteristics of benefitting patients. Citation Format: Marjorie G. Zauderer, David M. Hyman, Evan W. Alley, Johanna C. Bendell, Silvia Novello, Todd M. Bauer, Axel-Rainer Hanauske, Anna M. Szpurka, Suhyun Kang, Anindya Chatterjee, Volker Wacheck, Patrick Brueck, Anna M. Varghese. Safety and tolerability of the dual PI3K/mTOR inhibitor LY3023414 in treatment of patients with advanced mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT020.

A systematic review and meta-analysis of second-line therapies for treatment of mesothelioma.

Advanced malignant pleural mesothelioma (MPM) is generally treated with platinum/pemetrexed-based first-line therapy. Once the disease progresses, evidence for the efficacy of palliative treatments is lacking, and platinum re-challenge or single-agent chemotherapy are commonly used. To assess the effects of cytostatic or targeted therapy for treating MPM, we performed a systematic review and meta-analysis. PubMed, the Cochrane Library, and Embase databases were searched to identify published articles on second-line treatments for recurrent or advanced mesothelioma. Inclusion criteria were publication in the English language, describing clinical trials with 20 or more patients, and evaluability for efficacy and for receiving second-line systemic therapies. Data were pooled using number of events/number of evaluable patients, median overall survival (OS) and progression-free survival (PFS), according to a fixed or random effect model. Pooled median OS was the primary endpoint. A total of 49 eligible studies (n = 3938 patients; range, 12-400) were identified. Median progression-free survival (PFS) was 3.4 months (95%CI 2.87-3.93). Median pooled OS was 7.86 (95%CI 7.01-8.72). The pooled overall response rate (ORR) was 8.63% (95%CI 6-11.26), and the pooled disease control rate (DCR) was 54.8% (95%CI 48.9-60.6). Median pooled OS with platinum- and pemetrexed-based chemotherapy were 7.93 and 7.78 months, respectively. There remains uncertainty about the ideal second-line agent for MPM. Based on this meta-analysis, palliative chemotherapy or other experimental agents can be considered for patients with MPM who desire further treatment after their disease has progressed, during or after first-line therapy.

P3.09-001 The Dosimetric Advantages of Intensity Modulated Proton Therapy (IMPT) for Mesothelioma after Pleurectomy/Decortication

Radiotherapy (RT) after surgery for locoregionally advanced mesothelioma is particularly challenging. Recent surgical advances with pleurectomy and decortication techniques are clinically promising, however, applying comprehensive ipsilateral pleural irradiation is technically difficult with two RT-sensitive, intact lungs. With state-of-the-art IMPT, we have successfully treated a 77-year-old woman who has now been disease-free and alive for 7 months after RT (and 18 months since diagnosis), with minimal therapy-related toxicities so far.

Abstract 68: Methotrexate prevents primary immune responses against recombinant immunotoxin in murine models

Abstract Recombinant immunotoxins (rITs) are composed of a tumor antigen-targeting antibody fragment fused to a portion of Pseudomonas exotoxin A. rITs have been effective in clinical trials for patients with hematologic malignancies. The CD22 targeting rIT Moxetumomab Pasudotox has achieved overall response rates of 86% and complete remission rates of 46% in patients with relapsed-refractory Hairy Cell Leukemia. However, the therapeutic efficacy of rITs against solid tumors is limited by their immunogenicity in immune-competent patients. In clinical trials to treat mesothelioma patients with SS1P, a rIT targeting mesothelin, 90% of patients developed neutralizing antibodies against SS1P after one cycle of treatment. When immunosuppressive chemotherapy and SS1P were combined, more cycles of rIT could be given and several patients with advanced chemo-refractory mesothelioma had striking tumor regressions. This implicates high therapeutic potential for rITs against solid tumors once immunogenicity is surmounted. Methotrexate (MTX) is a folate antagonist which interferes with purine biosynthesis, and is used to treat osteosarcomas and other cancers. MTX also interferes with T cell responses and is used to treat autoimmune diseases. Based on its immunosuppressive properties, Joly et al. demonstrated that low-dose MTX prevented the formation of ADAs against recombinant human alglucosidase alfa in mice in an antigen-specific manner. We hypothesized that MTX would similarly prevent the formation of ADAs against rITs in an antigen-specific manner. To test our hypotheses, mice were treated with the mesothelin-targeting rIT RG7787 with or without MTX given 0, 24, and 48 hours after RG7787 treatment. Serum was collected and anti-RG7787 ADAs were measured by direct ELISA. We found that six doses of RG7787 combined with low dose MTX (1 mg/kg) inhibited the formation of ADAs against RG7787. This inhibition was sustained through six challenges with RG7787 without additional MTX. Further, we found that immunization with RG7787 plus MTX induced RG7787-specific tolerance, and had no effect on the ADA response against a second protein, ovalbumin. We conclude that combination of MTX and RG7787 is effective at preventing primary immune responses in a durable, antigen-specific manner. We propose to combine this agent in immune-competent cancer patients receiving rIT therapy to prevent rIT immunogenicity. Citation Format: Emily M. King, Ronit Mazor, Ira Pastan. Methotrexate prevents primary immune responses against recombinant immunotoxin in murine models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 68. doi:10.1158/1538-7445.AM2017-68