Anti-mesothelin Antibody Research Articles

99mTc-A1 as a Novel Imaging Agent Targeting Mesothelin-Expressing Pancreatic Ductal Adenocarcinoma.

Mesothelin is a membrane-associated protein overexpressed in pancreatic ductal adenocarcinoma (PDAC). Some mesothelin-targeted therapies are in clinical development but the identification of patients eligible for such therapies is still challenging. The objective of this study was to perform the imaging of mesothelin in mice models of PDAC with a technetium-labeled anti-mesothelin single-domain antibody (99mTc-A1). Methods: The Cancer Genomic Atlas (TCGA) database was used to determine the prognostic role of mesothelin in PDAC. 99mTc-A1 was evaluated both in vitro in PDAC cells (SW1990 and AsPC-1) and in vivo in an experimental model of mesothelin-expressing PDAC (AsPC-1) in mice. Results: TCGA analysis showed that PDAC patients with high mesothelin expression had a shorter overall survival (P = 0.00066). The binding of 99mTc-A1 was 2.1-fold greater in high-mesothelin-expressing AsPC-1 cells when compared to moderate-mesothelin-expressing SW1990 cells (p < 0.05). In vivo, the 99mTc-A1 uptake was 3.5-fold higher in AsPC-1-derived tumors as compared to a technetium-labeled irrelevant antibody (99mTc-Ctl) (p < 0.01). Conclusions: 99mTc-A1 accurately allows imaging of mesothelin-expressing experimental PDAC tumors. Our experiments paved the way for the development of a companion test for mesothelin-targeted therapies.

Uncialamycin as a novel payload for antibody drug conjugate (ADC) based targeted cancer therapy

Uncialamycin analogs were evaluated as potential cytotoxic agents in an antibody-drug conjugate (ADC) approach to treating human cancer. These analogs were synthesized using Hauser annulations of substituted phthalides as a key step. A highly potent uncialamycin analog 3c with a valine-citrulline dipeptide linker was conjugated to an anti-mesothelin monoclonal antibody (mAb) through lysines to generate a meso-13 conjugate. This conjugate demonstrated subnanomolar potency (IC50 = 0.88 nM, H226 cell line) in in vitro cytotoxicity experiments with good immunological specificity to mesothelin-positive lung cancer cell lines. The potency and mechanism of action of this uncialamycin class of enediyne antitumor antibiotics make them attractive payloads in ADC-based cancer therapy.

Gold-coated nanoporous polycarbonate track–etched solid platform for the rapid detection of mesothelin

Gold nanolayer—coated polycarbonate track–etched membrane (PCTE)–based microfluidic electrochemical biosensor grown on a highly interactive sandwich-like nanolayer has been designed. The gold nanolayer behaves like a sandwich further underwent thiol modification, EDC/NHS chemistry endowed excellent interaction with the immobilized biomolecule. The gold-coated surface of the biosensor has been functionalized with the anti-mesothelin antibody for the selective detection of the corresponding antigen. Specific antigen-antibody interaction has been recorded via ionic current vs. applied voltage (keeping the value in the range of 0.1–1.5 V). The biosensor exhibit adequate changes in ionic current upon the application of different concentrations (100 ng mL−1 to 10 ag mL−1) of mesothelin antigen and present excellent sensitivity, such as 0.011 ag mL−1 cm−1 (for 50-nm pore), 0.027 ag mL−1 cm−1 (for 80-nm pore), and 0.017 ag mL−1 cm−1 (for 100-nm pore). The antigen concentration was kept variable (six concentrations) against fixed antibody concentration.

The anti-mesothelin monoclonal antibody amatuximab enhances the anti-tumor effect of gemcitabine against mesothelin-high expressing pancreatic cancer cells in a peritoneal metastasis mouse model.

Pancreatic cancer often has a very poor prognosis, even after complete resection. The recurrence of hepatic and peritoneal metastases is an important prognostic factor; therefore, the development of improved adjuvant therapy is urgently required. Mesothelin is a cell surface glycoprotein whose expression is restricted to a variety of cancer types, including pancreatic cancer. This expression pattern makes mesothelin an attractive target for cancer therapy, and several agents targeting mesothelin are currently in clinical trials. Here, we used the chimerized high-affinity anti-mesothelin monoclonal antibody amatuximab to investigate its effect on peritoneal metastasis. We used the AsPC-1 pancreatic cancer cell line engineered to express Gaussia luciferase (Gluc), (AsPC-1-Gluc) for in vivo experiments. Results showed that while amatuximab was not directly cytotoxic on an AsPC-1-Gluc tumor cells in a peritoneal metastasis model, it prevented the formation of tumor growth. In combination therapy with gemcitabine, amatuximab exhibited synergistic killing. Our results suggest that blockade of mesothelin by amatuximab may be a useful strategy for preventing the peritoneal dissemination of pancreatic cancer under an adjuvant setting.

Phase Ib study of anti-mesothelin antibody drug conjugate anetumab ravtansine in combination with pegylated liposomal doxorubicin in platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer.

5571Background: Anetumab ravtansine (AR) comprises a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4. A phase Ib dose escalation was conducted i...

Preclinical Evaluation of Mesothelin-Specific Ligands for SPECT Imaging of Triple-Negative Breast Cancer.

Mesothelin is a cell-surface glycoprotein restricted to mesothelial cells overexpressed in several types of cancer, including triple-negative breast cancer not responding to trastuzumab or hormone-based therapies. Mesothelin-targeting therapies are currently being developed. However, the identification of patients potentially eligible for such a therapeutic strategy remains challenging. The objective of this study was to perform the radiolabeling and preclinical evaluation of 99mTc-A1 and 99mTc-C6, two antimesothelin single-domain antibody (sdAb)-derived imaging agents. Methods: A1 and C6 were radiolabeled with 99mTc and evaluated in vitro on recombinant protein and cells, as well as in vivo in xenograft mouse models of the triple-negative breast cancer cell lines HCC70 (mesothelin-positive) and MDA-MB-231 (mesothelin-negative). Results: Both 99mTc-A1 and 99mTc-C6 bound mesothelin with high affinity in vitro, with 99mTc-A1 affinity being 2.4-fold higher than that of 99mTc-C6 (dissociation constant, 43.9 ± 4.0 vs. 107 ± 16 nM, P < 0.05). 99mTc-A1 and 99mTc-C6 remained stable in vivo in murine blood (>80% at 2 h) and ex vivo in human blood (>90% at 6 h). In vivo 99mTc-A1 uptake (percentage injected dose) in HCC70 tumors was 5-fold higher than in MDA-MB-231 tumors and 1.5-fold higher than that of 99mTc-C6 (2.34% ± 0.36% vs. 0.48% ± 0.18% and 1.56% ± 0.43%, respectively, P < 0.01) and resulted in elevated tumor-to-background ratios. In vivo competition experiments demonstrated the specificity of 99mTc-A1 uptake in HCC70 tumors. Conclusion: Mesothelin-positive tumors were successfully identified by SPECT using 99mTc-A1 and 99mTc-C6. Considering its superior characteristics, 99mTc-A1 was selected as the most suitable tool for further clinical translation.

An open-label, phase II study of intravenous anetumab ravtansine, an anti-mesothelin antibody drug conjugate, in pretreated mesothelin-expressing advanced pancreatic cancer.

TPS540 Background: Advanced pancreatic cancer remains one of the deadliest malignancies with median OS of 11 months with the most aggressive therapy regimen. Hence, a need exists for more effective, durable, and targeted therapies. Mesothelin is a membrane associated antigen overexpressed in most pancreatic adenocarcinomas. The biological function of mesothelin remains unknown but it is an internalizing antigen. Given its limited expression in normal tissue and high expression in malignant cells, mesothelin is an excellent target for antibody directed cytotoxic drug delivery. Anetumab ravtansine (AR) is an ADC consisting of a fully human IgG1 antibody directed at mesothelin and conjugated to tubulin-binding toxophore, DM4 (maytansine derivative). Preclinical efforts have shown antiproliferative activity in mesothelin positive cancer cell lines and 75% tumor regression in pancreatic xenograft models (Golfier S, et al. Mol Cancer Ther 13(6):1537-48, 2014). Methods: This is a multicenter, non-randomized, Phase II study evaluating the efficacy of AR in pretreated mesothelin-expressing advanced pancreatic cancer. The study utilizes minimax, Simon 2-stage design testing 5% null hypothesis versus 21% alternative. If no response among the first 20, trial will terminate early. If at least one response among the first 20, trial will accrue additional 10 patients for maximum of 30. Four or more responses out of 30 will reject the null hypothesis. Significance level (alpha) is 0.1 and power is 90%. Probability of stopping early is 36% if the response rate is 5% or lower. Patients will receive AR infusion at 6.5 mg/kg on Day 1 of 21-day cycle. Primary objective: response rate per RECIST 1.1. Secondary objectives: time to progression; toxicity. Eligibility: measurable disease per RECIST 1.1; no more than two prior chemotherapy regimens; 30% of cells with 2+/3+ mesothelin staining per IHC; no history of keratitis or corneal disease. Correlative studies: serum soluble mesothelin levels and apoptotic factors (CK18, caspase-cleaved fragments) at baseline and throughout the study to predict treatment response/outcome. Enrollment is on-going. Clinical trial information: NCT03023722.

Capture of mesothelioma cells with 'universal' CTC-chip.

Malignant mesothelioma (MM) is a highly aggressive malignant tumor, predominantly associated with job-related exposure to asbestos. Development of effective and non-invasive modalities for diagnosis is an important issue in occupational medicine. Circulating tumor cells (CTCs), which are tumor cells that are shed from primary tumors and circulate in the peripheral blood, may be detected at an earlier stage than malignant tumors, and detection of CTCs may provide a novel insight into the diagnosis of MM. In a previous study evaluating clinical utility of CTCs, detected with a widely used system 'CellSearch', the authors indicated a significant however insufficient capability in the diagnosis of MM, suggesting need for a more sensitive system. Accordingly, the authors developed a novel microfluidic system to capture CTCs (CTC-chip), and demonstrated that the CTC-chip effectively captured MM cells (ACC-MESO-4) spiked in the blood by conjugating an anti-podoplanin antibody. The results of the present study demonstrated that the CTC-chip coated with the anti-podoplanin antibody captured another MM cell (ACC-MESO-1). However, the capture efficiencies were lower than those for ACC-MESO-4. In addition, an anti-mesothelin antibody was used to capture CTCs, however the CTC-chip coated with the anti-mesothelin antibody failed to effectively capture MM cells, possibly due to low mesothelin expression. Overall, the CTC-chip may capture specific types of CTCs by conjugating any antibody against an antigen expressed on CTCs, and may be a useful system for the diagnosis of malignant tumors, including MM.

Targeted Delivery of Auristatin-Modified Toxins to Pancreatic Cancer Using Aptamers.

Pancreatic cancer is one of the most lethal malignancies. Treatment with the first-line agent, gemcitabine, is often unsuccessful because it, like other traditional chemotherapeutic agents, is non-specific, resulting in off-target effects that necessitate administration of subcurative doses. Alternatively, monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) are highly toxic small molecules that require ligand-targeted delivery. MMAE has already received FDA approval as a component of an anti-CD30 antibody-drug conjugate, brentuximab vedotin. However, in contrast to antibodies, aptamers have distinct advantages. They are chemicals, which allows them to be produced synthetically and facilitates the rapid development of diagnostics and therapeutics with clinical applicability. In addition, their small size allows for enhanced tissue distribution and rapid systemic clearance. Here, we assayed the toxicity of MMAE and MMAF conjugated to an anti-transferrin receptor aptamer, Waz, and an anti-epidermal growth factor receptor aptamer, E07, on the pancreatic cancer cell lines Panc-1, MIA PaCa-2, and BxPC3. In vitro, our results indicate that these aptamers are a viable option for the targeted delivery of toxic payloads to pancreatic cancer cells.

P1.04-013 Phase 1b Multi-Indication Study of the Antibody Drug Conjugate Anetumab Ravtansine in Patients with Mesothelin-Expressing Advanced or Recurrent Malignancies

Mesothelin is expressed in a wide variety of tumors, including mesothelioma, ovarian, pancreatic, gastric/GEJ, NSCLC, triple-negative breast cancer, cholangiocarcinoma, and thymic carcinomas. Anetumab ravtansine (BAY 94-9343), is a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4 and has shown encouraging anti-tumor activity in mesothelioma and ovarian cancer patients in a phase I study. We will therefore conduct a signal generating study with anetumab ravtansine in six additional high unmet medical need malignancies with mesothelin expression (NCT03102320).

MS 08.04 Immunotherapy in MPM

MS 08.04 Immunotherapy in MPM

OA 02.01 Randomized Phase II Study of Anetumab Ravtansine or Vinorelbine in Patients with Metastatic Pleural Mesothelioma

Anetumab ravtansine (BAY 94-9343) is a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4. We report the results of a randomized phase II trial of anetumab ravtansine compared to vinorelbine in patients with advanced malignant pleural mesothelioma (MPM) who have high mesothelin expression and have progressed on platinum/pemetrexed-based first-line chemotherapy (NCT02610140).

Abstract LB-135: New cancer prevention model using imaging for early detection of mesothelin-expressing cancers

Abstract A major challenge to the discovery and development of novel cancer prevention strategies is the availability of reliable animal models. Key elements for chemoprevention testing in animal include relevance to human cancers, with tumors of similar pathology and genetic abnormalities, the presence of intermediate lesions that resemble human cancer development both histologically and molecularly; and consistent tumor incidence of &amp;gt;60% within less than 6 months. To our knowledge no established animal model responds to these requirements for ovarian cancer prevention. We sought to adapt the Dicerflox/flox-Ptenflox/flox double knockout (DKO) ovarian cancer mouse model (Kim, Matzuk PNAS 2012) for cancer prevention studies, by synchronized induction of the disease with intra-ovary injection of an adenovirus encoding CRE protein (Ad-mCherry-Cre). Premalignant lesions in DKO AdCRE mice were visible by H&amp;E staining after 12 weeks, and evolved into typical serous ovarian cancer by 24 weeks. Histology demonstrated that tumors overexpressed cytokeratin 8, cyclin D, CA125, and mesothelin. In addition, CA125, the main biomarker for ovarian cancer in woman, was consistently elevated in the serum of DKO AdCRE mice 15 weeks after CRE induction, but not in age-matched DKO mice. To assess whether mesothelin-targeted imaging could help monitor cancer development in DKO AdCRE mice, we used an anti-mesothelin recombinant antibody derived from llama (G3a nanobody) that we previously identified and in vitro characterized (Prantner, Scholler, JBN 2015). G3a nanobody is conveniently secreted by yeast with an N-terminal biotinylation (Scholler, JIM 2006) for streptavidin coupling. We addressed here whether G3a nanobody could detect mesothelin-expressing tumors using in vivo imaging (IVIS). Ni-purified G3a nanobody was incubated with fluorescently-labelled streptavidin (IRB680W) for 30 min and injected retro orbitally just before imaging. We found that G3a nanobody generated a robust and mesothelin-specific signal that peeked 4 hours after injection, and detected DKO AdCRE tumors as early as 8 weeks after CRE induction. G3a nanobody specific detection of mesothelin was confirmed in other mouse models of cancer, including in syngeneic models of ovarian cancer induced by orthotopic or intraperitoneal injection of mesothelin+ Luc-ID8 cells, and in xenograft models of human lung cancer obtained by IV injection of mesothelin high EKVX, mesothelin int H460, and mesothelin lo A549 cells. In summary, our results indicate that G3a nanobody is a valuable reagent for early detection of mesothelin-expressing cancer, and that DKO mice induced for Pten and Dicer double knockout by intra ovarian injection of CRE adenovirus develop serous ovarian cancer that express CA125 and mesothelin. We propose this model for in vivo monitoring of cancer development, as a novel system model for ovarian cancer prevention studies. Citation Format: Khushboo Sharma, Catherine Yin, Kalika Kamat, Claire Repellin, Lidia C. Sambucetti, Nathalie Scholler. New cancer prevention model using imaging for early detection of mesothelin-expressing cancers [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 LB-135. doi:10.1158/1538-7445.AM2017-LB-135

Abstract 58: Local intratumoral treatment with anti-mesothelin Immunotoxins overcomes resistance to anti-CTLA-4 therapy

Abstract Background: SS1P and RG7787 are immunotoxins composed of anti-mesothelin antibody fused to a fragment from pseudomonas exotoxin A. We previously observed delayed tumor responses in patients treated with SS1P leading us to hypothesis that immunotoxins can provoke anti-tumor immunity. We hypothesize that intra-tumoral injection of SS1P or RG7787 will produce immunologic death and convert living tumors to a source of antigens and boost the therapeutic effect of immune check point blockade. Method: A BALB/c breast cancer cell line was transfected with human mesothelin (66C14-M) and grown in BALB/c mice transgenic for human mesothelin. SS1P or RG7787 was injected directly into established tumors (80-100 mm3) and anti-CTLA-4 administered IP. Results: We observed total tumor regressions in 23 out of 38 mice (60%) treated with anti-CTLA-4 and either RG7787 or SS1P. No cure was achieved when the drugs were given as a monotherapy supporting the case for synergic anti-tumor activity. Pathologic evaluation of regressing tumors showed a massive inflammation of admixed eosinophils and mononuclear cells located in a collar surrounding the tumors. Tumor regression was associated with increased number of CD8+ cells and was blocked when CD8+ cells were depleted by an antibody. In addition, cured mice were resistant to re-implantation of 66C14 cells not expressing mesothelin indicating that a long-term anti-tumor immunity was formed. To determine if pathogen associated molecular patterns contributed to the response, we combined anti-CTLA-4 with an inactive RG7787 and observed a major reduction in anti-tumor activity (P&amp;lt;0.01) indicating that the effect is not mediated by recognition of a foreign bacterial protein. Conclusions: We suggest that injecting immunotoxins into tumors is a useful approach to boost the activity of anti-CTLA-4. Based on the synergistic anti-tumor effect demonstrated in this study we believe that there is a strong rational to explore such combination therapies in patients. Citation Format: Yasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Jay A. Berzofsky, Birgit Bossenmaier, Gerhard Niederfellner, James O'Brien, Yoram Reiter, Ira Pastan. Local intratumoral treatment with anti-mesothelin Immunotoxins overcomes resistance to anti-CTLA-4 therapy [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 58. doi:10.1158/1538-7445.AM2017-58

Preclinical Efficacy of an Antibody-Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET.

Antibody-drug conjugates (ADC) use monoclonal antibodies (mAb) as vehicles to deliver potent cytotoxic drugs selectively to tumor cells expressing the target. Molecular imaging with zirconium-89 (89Zr)-labeled mAbs recapitulates similar targeting biology and might help predict the efficacy of these ADCs. An anti-mesothelin antibody (AMA, MMOT0530A) was used to make comparisons between its efficacy as an ADC and its tumor uptake as measured by 89Zr immunoPET imaging. Mesothelin-targeted tumor growth inhibition by monomethyl auristatin E (MMAE), ADC AMA-MMAE (DMOT4039A), was measured in mice bearing xenografts of ovarian cancer OVCAR-3×2.1, pancreatic cancers Capan-2, HPAC, AsPC-1, and HPAF-II, or mesothelioma MSTO-211H. Ex vivo analysis of mesothelin expression was performed using immunohistochemistry. AMA-MMAE showed the greatest growth inhibition in OVCAR-3×2.1, Capan-2, and HPAC tumors, which showed target-specific tumor uptake of 89Zr-AMA. The less responsive xenografts (AsPC-1, HPAF-II, and MSTO-211H) did not show 89Zr-AMA uptake despite confirmed mesothelin expression. ImmunoPET can demonstrate the necessary delivery, binding, and internalization of an ADC antibody in vivo and this correlates with the efficacy of mesothelin-targeted ADC in tumors vulnerable to the cytotoxic drug delivered. Mol Cancer Ther; 16(1); 134-42. ©2016 AACR.

ED13.05 Systemic Therapy of Inoperable Malignant Pleural Mesothelioma

ED13.05 Systemic Therapy of Inoperable Malignant Pleural Mesothelioma

AB027. PS01.09. In-progress: phase 1b study of anetumab ravtansine in patients with mesothelin-expressing malignancies

Background: Mesothelin is expressed in a wide variety of tumors, including mesothelioma, ovarian, pancreatic, gastric/GEJ, non-small cell lung cancer (NSCLC), triple-negative breast cancer, cholangiocarcinoma, and thymic carcinomas. Indeed, in tissue samples from 34 patients with thymic carcinomas assessed for mesothelin expression, approximately three quarters were positive and of those approximately half had high expression (Thomas et al. Lung Cancer 2016;101:104). Anetumab ravtansine (BAY 94-9343), is a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4 and has shown encouraging anti-tumor activity in mesothelioma and ovarian cancer patients in a phase I study. We will therefore conduct a signal generating study with anetumab ravtansine in six additional high unmet medical need malignancies with mesothelin expression (NCT03102320).

P2.06-027 Randomized Phase II Study of Anetumab Ravtansine or Vinorelbine in Patients with Metastatic Pleural Mesothelioma: Topic: Mesothelioma and SCLC

Mesothelioma is a rare but aggressive cancer with a poor prognosis. Mesothelin is a cell surface protein that is highly expressed in mesothelioma and other epithelial cancers. Anetumab ravtansine (BAY 94-9343), a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4, has shown encouraging efficacy in mesothelioma patients in a phase I study. To further explore the possible benefit of antibody-drug conjugate therapy for mesothelioma, we initiated a randomized, open-label, active-controlled, phase II trial to evaluate the efficacy and safety of anetumab ravtansine in patients with metastatic pleural mesothelioma (MPM) overexpressing mesothelin and who have previously progressed on platinum/pemetrexed-based first-line chemotherapy (NCT02610140). Patients (≥18 years) with unresectable locally advanced or metastatic MPM are eligible. Patients should have recurrent or relapsing disease after having previously receiving first-line treatment with pemetrexed-based chemotherapy, with or without bevacizumab. Obligatory biomarker sampling will be performed on all patients at pre-screening and mesothelin-positivity as determined by Ventana MSLN (SP74) companion diagnostic assay as a requirement for entry. The primary objective is to test the superiority of anetumab ravtansine monotherapy over vinorelbine in progression-free survival (PFS) per modified RECIST criteria for MPM per central review. The secondary objectives of this study include overall survival, patient-reported outcomes (PRO), tumor response, and safety. Exploratory objectives include immunogenicity of anetumab ravtansine, pharmacokinetics, and biomarkers of response. Approximately 210 patients will be randomized in a 2:1 ratio to receive anetumab ravtansine 6.5 mg/kg Q3W or vinorelbine 30 mg/m2 QW. Novel study methods include a grading system for AEs of special interest and the PRO instruments. This trial is open and currently accruing patients globally. Section not applicable.

Mesothelin Immunotherapy for Cancer: Ready for Prime Time?

Mesothelin is a tumor antigen that is highly expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. It is an attractive target for cancer immunotherapy because its normal expression is limited to mesothelial cells, which are dispensable. Several antibody-based therapeutic agents as well as vaccine and T-cell therapies directed at mesothelin are undergoing clinical evaluation. These include antimesothelin immunotoxins (SS1P, RG7787/LMB-100), chimeric antimesothelin antibody (amatuximab), mesothelin-directed antibody drug conjugates (anetumab ravtansine, DMOT4039A, BMS-986148), live attenuated Listeria monocytogenes-expressing mesothelin (CRS-207, JNJ-64041757), and chimeric antigen receptor T-cell therapies. Two antimesothelin agents are currently in multicenter clinical registration trials for malignant mesothelioma: amatuximab in the first-line setting and anetumab ravtansine as second-line therapy. Phase II randomized clinical trials of CRS-207 as a boosting agent and in combination with immune checkpoint inhibition for pancreatic cancer are nearing completion. These ongoing studies will define the utility of mesothelin immunotherapy for treating cancer.

Abstract CT083: A pivotal randomized phase II study of anetumab ravtansine or vinorelbine in patients with advanced or metastatic pleural mesothelioma after progression on platinum/pemetrexed-based chemotherapy (NCT02610140)

Abstract Background: Mesothelioma is a rare but aggressive cancer with a 5-year survival rate less than 10%. Mesothelin is a protein normally present on mesothelial cells and overexpressed in the majority of mesotheliomas. Anetumab ravtansine (BAY 94-9343) is a novel fully human anti-mesothelin IgG1 antibody conjugated to ravtansine, an antitubulin cytotoxic agent. In a phase I study, anetumab ravtansine at 6.5 mg/kg on a q3w IV schedule was well tolerated and showed encouraging durable tumor responses in patients with previously treated mesothelioma. Design: A randomized, open-label, active-controlled, 2-arm, multicenter, phase II trial to evaluate the efficacy and safety of anetumab ravtansine at 6.5 mg Q3W versus vinorelbine 30 mg/m2 QW in patients with advanced or metastatic malignant pleural mesothelioma overexpressing mesothelin and who have progressed on first-line platinum/pemetrexed-based chemotherapy. Objectives: The primary objective is to test the superiority of anetumab ravtansine monotherapy over vinorelbine in progression-free survival (PFS). The secondary objectives of this study include overall survival, patient-reported outcomes (PRO), tumor response, and safety. Exploratory objectives include immunogenicity of anetumab ravtansine, pharmacokinetics, and biomarkers of response. Methods: Biomarker sampling will be performed on all patients to measure tumor mesothelin expression levels at prescreening. Biomarker-positive patients with moderate (2+) and/or strong (3+) level in at least 30% of tumor cells will be randomized and start study treatment following progression after 1st line treatment of platinum/pemetrexed (with or without bevacizumab). Approximately 183 patients meeting eligibility criteria will berandomized in a 2:1 ratio to receive anetumab ravtansine or vinorelbine. Randomization will be stratified by geographic region (Rest of World v. Asia) and time to progression on 1st line treatment (? 6 months vs &amp;lt; 6 months). The primary endpoint, PFS per modified RECIST criteria for metastatic pleural mesothelioma per central review, will be tested using a log-rank test stratified by randomization strata, with 1-sided significance level 0.0125. The primary analysis will occur after approximately 117 PFS events. Assuming true median PFS of 3.6 months under vinorelbine treatment, the primary hypothesis test is designed to detect a 100% prolongation of true PFS (median 7.2 months) with 90% power. Novel study methods include a grading system for AEs of special interest and the PRO instrument. Results: This trial is open and currently accruing patients. Citation Format: Raffit Hassan, John J. Nemunaitis, Jan P. van Meerbeeck, Ross Jennens, George R. Blumenschein, Jr, Dean A. Fennell, Hedy L. Kindler, Silvia Novello, Cem Elbi, Annette Walter, Danila Serpico, Emma Fountain, Sandra Vingerhoedt, Christine Brown, Jonathan Siegel, Barrett H. Childs. A pivotal randomized phase II study of anetumab ravtansine or vinorelbine in patients with advanced or metastatic pleural mesothelioma after progression on platinum/pemetrexed-based chemotherapy (NCT02610140). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT083.