anetumab ravtansine (BAY 94-9343) / Bayer, AbbVie, Novartis - LARVOL DELTA

Randomized phase II study of bevacizumab with weekly anetumab ravtansine or weekly paclitaxel in platinum-resistant/refractory high grade ovarian cancer (NCI trial). (PubMed, Clin Cancer Res) - "Our study stopped at interim analysis highlighting the benefit of PB in prrHGOC as standard of care."

Journal • P2 data • Hematological Disorders • Neutropenia • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • IL6 • MSLN

Final results and preliminary correlative analysis of a phase I study of anetumab ravtansine in combination with checkpoint inhibitors and gemcitabine in mesothelin-positive advanced pancreatic adenocarcinoma (NCI10208). (ASCO 2026) - P1 | "Here, we present the final analysis of a phase I study evaluating AR in combination with nivolumab, ipilimumab, or gemcitabine in patients (pts) with metastatic pancreatic adenocarcinoma (PDAC). AR had an acceptable safety profile in PDAC and the 6.5 mg/kg was identified as the R2PD. Evidence of clinical benefit was observed with some pts with prolonged disease stabilization and one complete response in a setting of limited therapeutical options. Correlative analysis to identify predictive biomarkers for treatment benefit is ongoing."

Checkpoint inhibition • Clinical • Combination therapy • Metastases • P1 data • Hematological Disorders • Keratitis • Ocular Inflammation • Oncology • Ophthalmology • Pancreatic Adenocarcinoma • Pneumonia • Thrombocytopenia • MSLN

DB-1323, a next-generation mesothelin targeting antibody-drug conjugate, demonstrated anti-tumor activity and favorable safety profile in pre-clinical models (AACR 2026) - "Anti-tumor activity was tested in MSLN-positive pancreatic and ovarian cancer xenograft models compared to that of anetumab ravtansine and other MSLN ADCs. DB-1323 overcomes historical MSLN-targeting liabilities through unique rapid-on/off binding, efficient internalization, and potent topoisomerase I inhibition, delivering superior tumor eradication versus at well-tolerated doses. These data support clinical evaluation of DB-1323 for patients with MSLN expressing tumors."

ADC • Preclinical • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • MSLN

Pembrolizumab With or Without Anetumab Ravtansine in Treating Patients With Mesothelin-Positive Pleural Mesothelioma (clinicaltrials.gov) - P1/2 | N=49 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2026 ➔ Feb 2027

Trial completion date • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • MSLN • PD-L1

NCI10208: Testing the Combination of Anetumab Ravtansine With Either Nivolumab, Nivolumab and Ipilimumab, or Gemcitabine and Nivolumab in Advanced Pancreatic Cancer (clinicaltrials.gov) - P1 | N=74 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jan 2026 ➔ Jan 2027 | Trial primary completion date: Jan 2026 ➔ Jan 2027

IO biomarker • Trial completion date • Trial primary completion date • Tumor mutational burden • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • MSLN

Therapeutic Applications and Target Strategies of Antibody-Drug Conjugates in Ovarian Cancer. (PubMed, Iran J Pharm Res) - "This review summarizes a range of ADCs targeting tumor-associated antigens in ovarian cancer, including mirvetuximab soravtansine (MIRV), trastuzumab deruxtecan (T-DXd), datopotamab deruxtecan (Dato-DXd), sacituzumab tirumotecan (SKB-264), PF-06664178, anetumab ravtansine (BAY 94-9343), BMS-986148, DMOT4039A, RC88, lifastuzumab vedotin (DNIB0600A), upifitamab rilsodotin (ABBV-181), ZW220, DMUC4064A, and sofituzumab vedotin (DMUC5754A). The ADCs hold significant potential to reshape the treatment landscape for ovarian cancer by providing targeted therapeutic options. Further research is required to optimize patient selection, address resistance mechanisms, and improve safety profiles."

Journal • Review • Oncology • Ovarian Cancer • Solid Tumor • MUC4

Development of recombinant Mesozumab-CPTin that dual-targets mesothelin and CP2c for anticancer therapy. (PubMed, Biomed Pharmacother) - "It efficiently promoted pancreatic cancer cell death without causing non-cancerous cytotoxicity from the early phase, showing anti-cancer properties than the commercial therapies including Cisplatin, Abraxane, Gemcitabine, and their combination treatment. In xenograft mice models for pancreatic cancer, Mesozumab-CPTin displayed lower average values in tumor volume and well-tolerated without significant side effects in a single high-dose acute toxicity assessment, compared to the anti-MSLN ADC Anetumab ravtansine. Mesozumab-CPTin is a genetically engineered peptide-based biomaterial to overcome limitations of traditional ADCs, which is a novel therapeutic candidate with stability and safety for pancreatic cancer."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • MSLN

Pembrolizumab With or Without Anetumab Ravtansine in Treating Patients With Mesothelin-Positive Pleural Mesothelioma (clinicaltrials.gov) - P1/2 | N=49 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2025 ➔ Sep 2026

Trial completion date • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • MSLN • PD-L1

NCI-2018-01503: Bevacizumab and Anetumab Ravtansine or Paclitaxel in Treating Patients With Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (clinicaltrials.gov) - P2 | N=96 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2025 ➔ Oct 2026 | Trial primary completion date: Oct 2025 ➔ Oct 2026

Platinum resistant • Trial completion date • Trial primary completion date • Fallopian Tube Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Refractory Ovarian Cancer • Solid Tumor • MSLN

Pharmacologic and pharmacometric studies of factors affecting the pharmacokinetics and pharmacodynamics of antibody drug conjugate anetumab ravtansine in patients with solid tumors. (ASCO 2025) - "Thus, we evaluated the effects of patient characteristics, including novel biomarkers of the innate immune system (IIS), on the PK/PD of AR Studies were performed in patients in three clinical trials of different cancers with AR as part of treatment: 1) platinum-resistant or refractory high-grade ovarian cancer treated with AR at 2.2mg/kg IV weekly plus bevacizumab(N = 19); 2) pleural mesothelioma treated with AR at 6.5 mg/kg IV every 3 weeks plus pembrolizumab(N = 28); and 3) mesothelin-positive advanced pancreatic adenocarcinoma treated with AR at 5.5-6.5 mg/kg IV every 3 weeks plus nivolumab (and ipilimumab or gemcitabine, N = 27). These results suggest that TBW-based dosing of AR ADC is not optimal, whereas precision dosing of antibodies and ADCs based on the use of novel metrics of body habitus, IIS biomarkers, and sex may be more appropriate to reduce PK variability and improve response."

Clinical • PK/PD data • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Ovarian Cancer • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pleural Mesothelioma • Refractory Ovarian Cancer • Solid Tumor • FCGR2A • FCGR2B • MSLN

Evaluating therapeutic plasma exchange and protease inhibitors as mechanisms to reduce soluble mesothelin. (PubMed, Sci Rep) - "We investigated the effects of sMSLN on anetumab, an antibody-based therapy against MSLN, anetumab ravtansine, an antibody drug conjugate, and mechanisms to decrease sMSLN...Overall, sMSLN could represent a predictive biomarker for MSLN directed therapies. TPE may be more reliable than PIs to reduce sMSLN and ultimately restore sensitivity to these therapies in patients with high sMSLN."

Journal • Mesothelioma • Oncology • Solid Tumor • MSLN

Evaluation of Innate Immune System, Body Habitus, and Sex on the Pharmacokinetics and Pharmacodynamics of Anetumab Ravtansine in Patients With Cancer. (PubMed, Clin Transl Sci) - "In both studies, patients with stable disease (SD) and partial response (PR) had higher anetumab ravtansine AUC0-inf compared to patients with progressive disease (PD). Individualizing the dose of anetumab ravtansine and potentially other ADCs based only on TBW is not optimal, whereas precision dosing of an ADC based on the inclusion of novel metrics of IIS biomarkers, body habitus, and sex may be more appropriate to reduce variability in PK exposure, reduce toxicity, and improve response."

Journal • PK/PD data • Mesothelioma • Oncology • Ovarian Cancer • Solid Tumor

NCI10208: Testing the Combination of Anetumab Ravtansine With Either Nivolumab, Nivolumab and Ipilimumab, or Gemcitabine and Nivolumab in Advanced Pancreatic Cancer (clinicaltrials.gov) - P1 | N=74 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jan 2025 ➔ Jan 2026 | Trial primary completion date: Jan 2025 ➔ Jan 2026

Trial completion date • Trial primary completion date • Tumor mutational burden • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • MSLN

NCI-2018-01503: Bevacizumab and Anetumab Ravtansine or Paclitaxel in Treating Patients With Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (clinicaltrials.gov) - P2 | N=96 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2024 ➔ Oct 2025 | Trial primary completion date: Oct 2024 ➔ Oct 2025

Trial completion date • Trial primary completion date • Fallopian Tube Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Refractory Ovarian Cancer • Solid Tumor • MSLN

Pembrolizumab With or Without Anetumab Ravtansine in Treating Patients With Mesothelin-Positive Pleural Mesothelioma (clinicaltrials.gov) - P1/2 | N=49 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2024 ➔ Sep 2025

Trial completion date • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • MSLN • PD-L1

Randomized trial of anetumab ravtansine and pembrolizumab compared to pembrolizumab for mesothelioma. (PubMed, Lung Cancer) - "The numeric difference in PFS between treatment groups was not statistically significant, likely related to a smaller than planned sample size. High levels of soluble mesothelin should potentially be considered to select against the use of mesothelin-targeting therapies in development that are neutralized by soluble mesothelin."

IO biomarker • Journal • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • MSLN

Randomized trial of anetumab ravtansine and pembrolizumab compared to pembrolizumab for mesothelioma (Lung Cancer) - P1/2 | N=46 | NCT03126630 | "In phase 1 (n = 12) only one dose limiting toxicity was observed and the rules for dose reduction were not met. In phase 2, there was no difference in the confirmed response rates between the combination group (n = 18, 2 partial responses [PR], 11 %) and the pembrolizumab group (n = 17, 1 PR, 6 %; z = -0.5523, p = 0.29116). The median PFS was 12.2 months (95 % CI 5.1–not evaluable [NE]) for the combination, and 3.9 months for pembrolizumab (95 % CI 2.1-NE)(HR=0.55, p = 0.20). Patients with high baseline levels of soluble mesothelin who received anetumab ravtansine had a median PFS of 5 months."

P1/2 data • Mesothelioma

Soluble mesothelin neutralizes mesothelin antibody-based therapies. (ASCO 2024) - P1/2 | "We found that high sMSLN levels are associated with shorter PFS for anetumab ravtansine, but not pembrolizumab. Additionally, anetumab binds to sMSLN in the plasma, which suggests that sMSLN can sequester anti-MSLN antibodies and may limit the efficacy of MSLN-targeted therapies. High levels of sMSLN could potentially be used as a biomarker to select which patients should not receive MSLN-targeting therapies."

IO biomarker • Hematological Disorders • Immunology • Mesothelioma • Oncology • Solid Tumor • MSLN

NCI10208: Testing the Combination of Anetumab Ravtansine With Either Nivolumab, Nivolumab and Ipilimumab, or Gemcitabine and Nivolumab in Advanced Pancreatic Cancer (clinicaltrials.gov) - P1 | N=74 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jan 2024 ➔ Jan 2025 | Trial primary completion date: Jan 2024 ➔ Jan 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Tumor mutational burden • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • MSLN

NCI-2018-01503: Bevacizumab and Anetumab Ravtansine or Paclitaxel in Treating Patients With Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (clinicaltrials.gov) - P2 | N=96 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2023 ➔ Oct 2024 | Trial primary completion date: Oct 2023 ➔ Oct 2024

Trial completion date • Trial primary completion date • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Refractory Ovarian Cancer • Solid Tumor • MSLN

NCI10208: Testing the Combination of Anetumab Ravtansine With Either Nivolumab, Nivolumab and Ipilimumab, or Gemcitabine and Nivolumab in Advanced Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=74 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Phase classification: P1 ➔ P1/2

Combination therapy • IO biomarker • Metastases • Phase classification • Tumor mutational burden • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD8 • MSLN

Phase 1/2 Randomized Trial of Anetumab Ravtansine and Pembrolizumab Compared to Pembrolizumab for Pleural Mesothelioma - NCT03126630 (IASLC-WCLC 2023) - P1/2 | "Accrual was closed prior to meeting accrual goals following approval of frontline ipilimumab and nivolumab. The addition of anetumab ravtansine to pembrolizumab did not result in significant dose limiting toxicities. There were no differences in confirmed response rates between patients treated with the combination of anetumab ravtansine and pembrolizumab, or pembrolizumab alone. The confirmed response rates were lower than reported previously reported for pembrolizumab in pleural mesothelioma."

Clinical • IO biomarker • P1/2 data • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Respiratory Diseases • Solid Tumor • MSLN

Protocol # 10107: Phase 1 Safety Run-In and Phase 2 Randomized Clinical Trial of Anetumab Ravtansine and Pembrolizumab (MK-3475) Compared to Pembrolizumab Alone for Mesothelin-Positive Malignant Pleural Mesothelioma (National Cancer Institute)

CME

A Clinical Study of Anetumab Ravtansine in Adults With Solid Tumors Who Have Been Treated in Previous Bayer-sponsored Anetumab Ravtansine Studies (clinicaltrials.gov) - P2 | N=9 | Terminated | Sponsor: Bayer | Completed ➔ Terminated; Due to strategic company decisions, the development of anetumab ravtansine was stopped.

Trial termination • Oncology • Solid Tumor

Pembrolizumab With or Without Anetumab Ravtansine in Treating Patients With Mesothelin-Positive Pleural Mesothelioma (clinicaltrials.gov) - P1/2 | N=46 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=110 ➔ 46 | Trial completion date: Mar 2023 ➔ Jul 2024 | Trial primary completion date: Mar 2023 ➔ Jul 2023

Enrollment change • Trial completion date • Trial primary completion date • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • CCL2 • MSLN • PD-L1